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Mengjie Xie,1,* Fansu Meng,2,* Panpan Wang,3,* Alicia Marcelina Díaz-García,4 Marina Parkhats,5 Ralph Santos-Oliveira,6 Mulazim Hussain Asim,7 Nazish Bostan,8 Honghui Gu,9 Lina Yang,9 Qi Li,9 Zhenjiang Yang,9 Haibiao Lai,2 Yu Cai1 1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China / Guangdong Key Laboratory of Traditional Chinese Medicine Informatization / International Science and Technology Cooperation Base of Guangdong Province/School of Pharmacy, Jinan University, Guangzhou, Guangdong, 510632, People’s Republic of China; 2Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Zhongshan, Guangdong, 528400, People’s Republic of China; 3The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, 510632, People’s Republic of China; 4Bioinorganic Laboratory, Faculty of Chemistry, University of Havana, Havana, 1400, Cuba; 5B. I. Stepanov Institute of Physics, National Academy of Sciences of Belarus, Minsk, 220072, Belarus; 6Brazilian Nuclear Energy Commission, Nuclear Engineering Institute, Laboratory of Nanoradiopharmacy and Synthesis of New Radiopharmaceuticals, Rio de Janeiro, RJ, 21941906, Brazil; 7College of Pharmacy, University of Sargodha, Punjab, 40100, Pakistan; 8Department of Pharmaceutics, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur, 63100, Pakistan; 9Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, 518033, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yu Cai; Haibiao Lai, Email caiyu8@sohu.com; lhb8829@163.comAbstract: Data published in 2020 by the International Agency for Research on Cancer (IARC) of the World Health Organization show that breast cancer (BC) has become the most common cancer globally, affecting more than 2 million women each year. The complex tumor microenvironment, drug resistance, metastasis, and poor prognosis constitute the primary challenges in the current diagnosis and treatment of BC. Magnetic iron oxide nanoparticles (MIONPs) have emerged as a promising nanoplatform for diagnostic tumor imaging as well as therapeutic drug-targeted delivery due to their unique physicochemical properties. The extensive surface engineering has given rise to multifunctionalized MIONPs. In this review, the latest advancements in surface modification strategies of MIONPs over the past five years are summarized and categorized as constrast agents and drug delivery platforms. Additionally, the remaining challenges and future prospects of MIONPs-based targeted delivery are discussed. Keywords: Nanopreparations, Organic Nanomaterials, Inorganic Nanomaterials, Surface Engineering, Targeted Delivery

Lingjia Li,1 Yulan Wang,2 Hua Gu2 1Department of Dermatology, Jiangnan University Medical Center, Jiangnan University, Wuxi, People’s Republic of China; 2Department of Dermatology, The First Affiliated Hospital of Kunming Medical University Kunming, Kunming, People’s Republic of ChinaCorrespondence: Hua Gu, Department of Dermatology, The first Affiliated Hospital of Kunming Medical University Kunming, Kunming, People’s Republic of China, Tel +86-18762675765, Email guhua1978@sina.comAbstract: We report a case of rash in a 35-year-old female presenting with erythematous papules and infiltrative plaques on the nose and upper jaw resembling rosacea. The patient had been experiencing these symptoms for one year. A pathological biopsy revealed an inflammatory infiltrate consisting of dense perivascular lymphocytes surrounding hair follicles and sweat glands in the dermis. Immunohistochemistry demonstrated a predominance of CD4+ T cells compared to CD8+ T cells. Based on the clinical manifestations, histopathology, and immunohistochemistry, the patient was diagnosed with Jessner’s Lymphocytic infiltration of the skin (JLIS). The patient was treated with oral Minocycline, 100mg twice daily. After 4 weeks, the dosage was reduced by half and the treatment continued for 2 months, resulting in complete resolution of the rash. The clinical presentation resembled rosacea, and this particular manifestation of JLIS has not been previously reported. Treatment with minocycline yielded satisfactory efficacy, and no recurrence has been observed for 5 year.Keywords: lymphocytic infiltration, skin, rosacea, minocycline

Pingyang Ke,1,* Jing Liu,1,2,* Chengzhi Chen,3,* Sen Luo,3,* Huiwen Gu,3,* Juan Gu,4 Yan Liu,1 Yuanlin Ma,1 Yuan Meng,1 Liqin Hu,1 Xin Tian,1 Fei Xiao1 1Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, People’s Republic of China; 2Department of Neurology, Chongqing University Three Gorges Hospital, Chongqing, People’s Republic of China; 3Department of Occupational and Environmental Health, School of Public Health and Management, Chongqing Medical University, Chongqing, People’s Republic of China; 4Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fei Xiao; Xin Tian, Email feixiao81@126.com; xintian@cqmu.edu.cnBackground: Zinc oxide nanoparticles (ZnO NPs) has been widely used in various fields and has had an important impact on human public health. In addition, it inevitably damages human health, including neurological diseases. Therefore, this study explored the effect of ZnO NPs on epilepsy.Methods: The effect of ZnO NPs on epilepsy was observed by behavioral analysis. TLR4 expression and autophagy related pathways were detected by RNA-seq and Western blot. In addition, the cell types of autophagy were detected by immunofluorescence. Further, the electrophysiological changes of ZnO NPs induced autophagy were detected by whole-cell patch-clamp. Finally, the recovery experiment was carried out by TLR4 inhibitor (TAK-242).Results: We found that ZnO NPs enhanced epilepsy susceptibility and severity. Through RNA-seq analysis and Western blot, it was found that ZnO NPs affected the changes of TLR4 and autophagy related pathways. In addition, we found that ZnO NPs mainly affects autophagy of inhibitory neurons, resulting in excitation/inhibition imbalance. The autophagy and epileptic phenotypes were reversed with TAK-242. In general, ZnO NPs exacerbate epileptic seizures by modulating the TLR4-autophagy axis.Conclusion: ZnO NPs enhanced the susceptibility and severity of epilepsy. Mechanistically, ZnO NPs affected autophagy by changing the expression of TLR4. In particular, the ZnO NPs mainly affected the synaptic function of inhibitory neuron, leading to excitation/inhibition imbalances.Keywords: zinc oxide nanoparticles, epilepsy, excitation/inhibition balance, autophage

Xin Su,1,&ast; Hengqiong Gu,1,&ast; Fajun Li,2 Donglei Shi,3 Zhaojun Wang3 1Department of Respiratory, Hainan Hospital of PLA General Hospital, Sanya, People’s Republic of China; 2Department of Critical Care Medicine, The First People’s Hospital of Kunshan, Kunshan, People’s Republic of China; 3Department of Thoracic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Donglei Shi; Zhaojun Wang, Department of Thoracic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, 628 Zhenyuan Road, Shenzhen, 518107, People’s Republic of China, Tel/Fax +86-755-81206874, Email shidlei@mail.sysu.edu.cn; wangzhj55@mail.sysu.edu.cnBackground: A study aimed to estimate the burden of Chronic obstructive pulmonary disease (COPD) caused by occupational exposure to particulate matter, gases, and fumes in 204 countries from 1990 to 2019.Methods: Data on the deaths number, age-standardized mortality rates (ASMR), and age-standardized disability-adjusted life years (DALYs) rates (ASDR) of COPD attributable to occupational particulate matter, gases, and fumes were collected from the GBD study 2019. We also investigated the association between the ASDR and SDI.Results: There were 517.7 thousand deaths [95% UI: 413.9 to 634.5] in 2019. The number of deaths increased from 1990 to 2019. The ASMR and ASDR were 6.61 (5.24 to 8.17) and 143.02 (118.56 to 168.69) in 2019, respectively, representing a 46% and 44.5% decrease since 1990. China had the highest number of deaths [200,748.4 (151,897.6 to 260,703.9)], while Nepal had the highest ASMR [39 (27.7 to 50)] and ASDR [724.5 (549 to 894.2)]. Males and females 75– 79 and 80– 84 years old had the highest number of COPD deaths. A negative correlation was observed when SDI > 0.4, whereas a positive correlation was found when SDI < 0.4.Conclusion: From 1990 to 2019, there was an increase in the number of deaths, but a decline in ASMR and ASDR globally. Besides, there was a heterogeneous burden of COPD attributable to occupational particulate matter, gases, and fumes across regions and countries. It is important to develop and implement strategies to prevent and reduce the burden of COPD attributable to occupational particulate matter, gases, and fumes.Keywords: chronic obstructive pulmonary disease, occupational particulate matter, gases, fumes, global burden of disease, deaths number, age-standardized rates

Yang Zhou, Yongxiang Ge, Jian Liu, Weijian Shen, Hailiang Gu, Guochang Cheng Department of Hernia and Pediatric Surgery, Taizhou People’s Hospital, Taizhou Clinical Medical School of Nanjing Medical University, Taizhou City, Jiangsu Province, 225300, People’s Republic of ChinaCorrespondence: Guochang Cheng, Email chengguochang@hotmail.comBackground: Postoperative seroma is the most common minor complication after inguinal hernia repair surgery and can have negative consequences. The objective of this study was to identify potential risk factors for postoperative seroma.Methods: This study consecutively included 354 elderly patients with inguinal hernia who underwent laparoscopic Transabdominal preperitoneal Patch Plasty (TAPP). Seroma diagnosis was conducted by the same experienced surgeon based on the physical examinations combined with ultrasound. Risk factors for seroma were identified through univariate analysis and subsequently included in the binary multivariate logistic regression model.Results: A total of 40 patients experienced postoperative complications of seroma, with an incidence rate of 11.3% (40/354). The binary logistic regression analysis revealed that obesity (OR: 2.98, 95% CI: 1.20– 7.41, P = 0.018), disease duration ≥ 4.5 years (OR: 4.88, 95% CI: 2.14– 11.18, P < 0.001), albumin-fibrinogen ratio (AFR) level < 9.25 (OR: 6.13, 95% CI: 2.00– 18.76, P = 0.001), and modified frailty index (mFI) score ≥ 0.225 (OR: 6.38, 95% CI: 2.69– 15.10, P < 0.001) were four independent risk factors for postoperative seroma.Conclusion: Obesity, prolonged disease duration, decreased AFR level, and increased mFI score independently predict postoperative seroma after laparoscopic TAPP.Keywords: inguinal hernia, Transabdominal preperitoneal Patch Plasty, modified frailty index, albumin-fibrinogen ratio, risk factor

Lijuan Wang,1,&ast; Huoliang Liu,2,&ast; Yi Wang,1 XiaoFan Hong,1 Xiaoyan Huang,1,3,4 Miaoru Han,1 Dan Wang,1 Wenjun Shan,1 Ping Li,1,3 Haowen Gu,1 Bo Liu,3,5 Kun Bao1,3,4,6 1Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2The Affiliated TCM Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 3State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, People’s Republic of China; 4Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, Guangzhou, People’s Republic of China; 5Guangzhou Key Laboratory of Chirality Research on Active Components of Traditional Chinese Medicine, Guangzhou, People’s Republic of China; 6Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Disease, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bo Liu; Kun Bao, Email doctliu@gzucm.edu.cn; baokun@aliyun.comBackground: Nephrotic syndrome (NS) and its numerous complications remain the leading causes of morbidity and mortality globally. Sanqi Qushi granule (SQG) is clinically effective in NS. However, its potential mechanisms have yet to be elucidated.Methods: A network pharmacology approach was employed in this study. Based on oral bioavailability and drug-likeness, potential active ingredients were picked out. After acquiring overlapping targets for drug genes and disease-related genes, a component-target-disease network and protein–protein interaction analysis (PPI) were constructed using Cytoscape, followed by GO and KEGG enrichment analyses. Adriamycin was injected into adult male Sprague-Dawley (SD) rats via the tail vein to establish NS model. Kidney histology, 24-hr urinary protein level, creatinine (Cr), blood urea nitrogen (BUN), triglyceride (TG), total cholesterol (TC), and low-density lipoprotein (LDL-C) level were assessed. Western blotting, immunohistochemistry, and TUNEL staining were applied.Results: In total, 144 latent targets in SQG acting on NS were screened by a network pharmacology study, containing AKT, Bax, and Bcl-2. KEGG enrichment analysis suggested that PI3K/AKT pathway was enriched primarily. In vivo validation results revealed that SQG intervention ameliorated urine protein level and podocyte lesions in the NS model. Moreover, SQG therapy significantly inhibited renal cells apoptosis and decreased the ratio of Bax/Bcl-2 protein expression. Moreover, we found that Caspase-3 regulated the PI3K/AKT pathway in NS rats, which mediated the anti-apoptosis effect.Conclusion: By combining network pharmacology with experimental verification in vivo, this work confirmed the treatment efficacy of SQG for NS. SQG protected podocyte from injury and inhibited kidney apoptosis in NS rats via the PI3K/AKT pathway at least partially.Keywords: Sanqi Qushi granule, nephrotic syndrome, podocyte injury, kidney apoptosis, network pharmacology, PI3K/AKT pathway

Xi Luo,1,&ast; Sudan Wu,2,&ast; Meng Xiao,1 Huan Gu,1 Huan Zhang,1 Jianping Chen,3 Yang Liu,4 Chen Zhang,1 Jinming Zhang1 1State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China; 2Blood Purification Center, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 3Lika Shing Faculty of Medicine, School of Chinese Medicine, the University of Hong KOng, Hong Kong, People’s Republic of China; 4Department of Vascular Surgery, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yang Liu, Hospital of Chengdu University of Traditional Chinese Medicine, No. 37, Shierqiao Road, Jinniu District, Chengdu, Sichuan, People’s Republic of China, Email zjobliu@163.com Jinming Zhang, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, No.1166, Liutai Avenue, Wenjiang District, Chengdu, Sichuan, People’s Republic of China, Email cdutcmzjm@126.comAbstract: Zein is a type of prolamine protein that is derived from corn, and it has been recognized by the US FDA as one of the safest biological materials available. Zein possesses valuable characteristics that have made it a popular choice for the preparation of drug carriers, which can be administered through various routes to improve the therapeutic effect of antitumor drugs. Additionally, zein contains free hydroxyl and amino groups that offer numerous modification sites, enabling it to be hybridized with other materials to create functionalized drug delivery systems. However, despite its potential, the clinical translation of drug-loaded zein-based carriers remains challenging due to insufficient basic research and relatively strong hydrophobicity. In this paper, we aim to systematically introduce the main interactions between loaded drugs and zein, administration routes, and the functionalization of zein-based antitumor drug delivery systems, in order to demonstrate its development potential and promote their further application. We also provide perspectives and future directions for this promising area of research.Graphical Abstract: Keywords: zein, nanomedicine, drug delivery, antitumor

Hanqing Yu,&ast; Wen Xue,&ast; Hanjie Yu, Hongchen Gu, Ling Qin, Ai Peng Center for Nephrology and Clinical Metabolomics, Division of Nephrology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ai Peng; Ling Qin, Center for Nephrology and Clinical Metabolomics, Division of Nephrology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, People’s Republic of China, Email pengai@tongji.edu.cn; qinling@tongji.edu.cnPurpose: This study aimed to explore the accuracy for joint application of inflammatory cytokines in diagnosis of gout flare by comparison with peripheral blood cells.Methods: We collected the clinical data of 96 acute gout patients and 144 remission gout patients, and compared the levels of peripheral blood cells, inflammatory cytokines and blood biochemistry indexes between acute and remission gout. We respectively assessed the area under curves (AUCs) for single and multiple inflammatory cytokines including C-reactive protein (CRP), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), and single and multiple peripheral blood cells including platelet (PLT), white blood cell (WBC), percentages of neutrophils (N%), lymphocytes (L%), eosinophils (E%), basophils (B%) in diagnosis of acute gout by receiver operating characteristic (ROC) curve analysis.Results: By contrast with remission gout, the levels of PLT, WBC, N%, CRP, IL-1β, IL-6 and TNF-α increased, and the levels of L%, E% and B% decreased in acute gout. The AUCs of PLT, WBC, N%, L%, E% and B% in diagnosis of acute gout were respectively 0.591, 0.601, 0.581, 0.567, 0.608 and 0.635, while the AUC for joint application of these peripheral blood cells was 0.674. Moreover, the AUCs of CRP, IL-1β, IL-6 and TNF-α in diagnosis of acute gout were respectively 0.814, 0.683, 0.622 and 0.746, while the AUC for joint application of these inflammatory cytokines was 0.883, reflecting significantly higher levels than peripheral blood cells.Conclusion: The joint application of multiple inflammatory cytokines can better distinguish acute gout from remission gout compared with peripheral blood cells.Keywords: acute gout, diagnosis, multiple inflammatory cytokines

Shuang Guan,1,&ast; Ya-Nan Yu,1,&ast; Bing Li,2 Hao Gu,1 Lin Chen,1 Nian Wang,1 Bo Wang,1 Xi Liu,1 Jun Liu,1 Zhong Wang1 1Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 2Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhong Wang; Jun Liu, Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, No. 16 Nanxiaojie, Dongzhimennei, Beijing, People’s Republic of China, Email zhonw@vip.sina.com; franlj1104@aliyun.comBackground: The Xueyu Zheng (XYZ) phenome is central to coronary heart disease (CHD), but efforts to detect genetic associations in the XYZ phenome have been disappointing.Methods: The phenomic alteration-related genes (PARGs) for the XYZ phenome were screened using |ρ| > 0.4 and p < 0.05 after treatment with Danhong injection at day 14 and day 30. Then, the driver genes for the Protein-Protein Interaction (PPI) networks of the PARGs established using STRING 11.0 were detected using a personalized network control algorithm (PNC). Finally, the molecular correlations of the driver genes with the XYZ phenome were analyzed with the Gene Ontology (GO) biological processes and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways from a holistic viewpoint.Results: A total of 525 and 309 PARGs in the XYZ phenome at day 14 and day 30 were identified. These genes were separately enriched in 48 and 35 pathways. Furthermore, five driver genes were detected. These genes were mainly correlated with endoplasmic reticulum stress-mediated apoptosis and autophagy regulation, which could suppress atherosclerosis progression.Conclusion: Our study detected the drug-responsive PARGs of the XYZ phenome in CHD and provides an exemplary strategy to investigate the genetic associations among this common phenome and its component symptoms in patients with CHD.Trial Registration: ClinicalTrials.gov, NCT01681316; registered on September 7, 2012.Graphical Abstract: Keywords: coronary heart disease, Xueyu Zheng phenome, phenomics strategy, driver gene

Dandan Wang,1,2 Zhentang Cao,3 Zixiao Li,1,2,4 Hongqiu Gu,2 Qi Zhou,2 Xingquan Zhao,1,2,4 Yongjun Wang1,2,4 1Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2China National Clinical Research Center for Neurological Diseases, Beijing, People’s Republic of China; 3Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 4Research Unit of Artificial Intelligence in Cerebrovascular Disease, Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Xingquan Zhao; Yongjun Wang, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing, 100070, People’s Republic of China, Tel +86-010-59978891 ; +86-010-59978330, Email zxq@vip.163.com; yongjunwang@ncrcnd.org.cnObjective: Elevated homocysteine (Hcy) levels play a detrimental role in ischemic stroke. Acute spontaneous intracerebral hemorrhage (ICH) accounts for nearly 25% of all stroke cases. However, the influence of Hcy levels and ICH severity on clinical outcomes is unclear.Participants and Study Location: Data were obtained from 85,705 ICH patients enrolled in the China Stroke Center Alliance (CSCA) study, a national, hospital-based, multicenter, voluntary, quality assessment and improvement initiative performed in China. Patients were divided into high and normal Hcy groups according to their Hcy levels observed at admission.Outcome Measures: The outcome indices included severe ICH, in-hospital mortality, and a poor functional outcome at discharge. Multivariable logistic regression was used to analyze the association of different Hcy levels with outcomes.Results: The final analysis included 55,793 ICH patients. High homocysteine (HHcy) levels had higher adjusted odds ratios for severe ICH (OR 1.09, 95% CI 1.01– 1.10, P< 0.0001) and a poor functional outcome at discharge (OR 1.06, 95% CI 1.01– 1.10, P=0.0100) compared with normal Hcy levels. There was no significant difference between HHcy and in-hospital mortality. In the subgroup analysis, stratified by sex and history of hypertension, significant interactions were observed between HHcy and severe ICH (P for interactions was 0.0138 and 0.0120, respectively). HHcy levels exhibited greater associations for severe ICH in female patients (OR 1.07, 95% CI 1.02– 1.12) and patients without hypertension (OR 1.20, 95% CI 1.09– 1.33).Conclusion: An elevated Hcy level exhibited significant association with severe ICH on admission and a poor functional outcome at discharge. The relationship between HHcy and ICH severity on admission was more robust in female patients and patients without hypertension. Hcy might be a valuable biomarker for ICH patients to predict severity at onset and functional outcome at discharge.Keywords: intracerebral hemorrhage, homocysteine, stroke severity, outcome

Junfeng Chen,&ast; Wei Lin,&ast; Haiting Gu, Kangtai Ying, Tingjian Li, Haiyan Shao Department of Respiration, The First People’s Hospital of Wenling, Wenling, Zhejiang, 317500, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haiyan Shao, Department of Respiration, The First People’s Hospital of Wenling, 333 Chuanan Nan Road, Chengxi Street, Wenling, Zhejiang, 317500, People’s Republic of China, Tel +86 057689668688, Email shaohy_101043@tzc.edu.cnObjective: This study aimed to compare lung function and airway inflammation among cough variant asthma (CVA), chronic cough and classical asthma (CA) and investigate the relationship between these indicators and their possible mechanisms of action in the progression of CVA to CA.Methods: 36 patients with chronic cough, 39 patients with CA, and 57 patients with CVA were included in this study. Pulmonary function tests, bronchial provocation tests and FeNO tests were performed. The patients’ bronchoalveolar lavage fluid (BALF) was collected, the cells in BALF were counted, and the levels of Th1 and Th2 cytokines were detected.Results: The neutrophils, lymphocytes, and eosinophils in BALF in the CA and CVA groups were significantly higher than those in the chronic cough group. Also, they were negatively correlated with FEV1, FVC, and FEV1/FVC and positively correlated with IgE and FeNO. The expression of Th2-related cytokines was increased in CVA and CA patients, and it was positively correlated with FEV1, FVC and FEV1/FVC and negatively correlated with IgE and FeNO, while the results of Th1-related cytokines were the opposite of those for Th2-related cytokines.Conclusion: CVA differs from asthma and chronic cough in terms of Th1/Th2 cytokines and lung function and provides a reference for understanding the disease mechanism of early clinical progression of CVA to CA.Keywords: cough variant asthma, cytokines, pulmonary function, Th1/Th2 balance, cell classified count

Jia-qi Chen,&ast; Jie-ru Chen,&ast; Sheng Wang, Wei Gao, Hai Gu, Xin-lu Yang, Ji-cheng Hu, Xiao-qing Chai, Di Wang Pain Clinic, Department of Anesthesiology, The First Affiliated Hospital of USTC (Anhui Provincial Hospital), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Di Wang; Xiao-qing Chai, Department of Anesthesiology, The First Affiliated Hospital of USTC (Anhui Provincial Hospital), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People’s Republic of China, Tel/Fax +86-551-62283963 ; +86-551-62283912, Email di.wang@ustc.edu.cn; xiaoqingchai@ustc.edu.cnPurpose: The goal of this study was to evaluate the analgesic efficiency of dexamethasone with ropivacaine in continuous serratus anterior plane block (cSAPB) after video-assisted thoracoscopic surgery (VATS).Patients and Methods: Sixty-six patients who underwent VATS were randomized into two groups. All patients received cSAPB postoperatively, and patients in Group RD received 20 mL of 0.375% ropivacaine plus 0.1 mg/kg dexamethasone followed by an infusion of 0.2% ropivacaine plus 0.02 mg/kg/hour dexamethasone at a rate of 5 mL/h in patient-controlled analgesia (PCA) pump. Patients in Group R received 20 mL of 0.375% ropivacaine with normal saline followed by an infusion of 5 mL/h of 0.2% ropivacaine in PCA pump. Fifty milligrams of tramadol was given as rescue medication when the visual analog scale (VAS) score was ≥ 4 at rest. The primary outcomes were the sum of pressing number within 48 hours postoperatively and the time to the first patient-controlled bolus. The secondary outcomes were VAS scores, the incidence of rescue analgesia, wound infection and nausea/vomiting.Results: Within 48 hours postoperatively, the sum of pressing number was more in Group R (18.33 ± 3.149 vs 16.09 ± 3.292, P = 0.006), and the Log Rank Test showed a significant difference in time to the first patient-controlled bolus (P = 0.006). After the PCA infusion finished, there were significantly lower VAS scores in Group RD at 60 and 72 hours postoperatively (P < 0.001). Additionally, the incidence of rescue analgesia in Group R was significantly more than that in Group RD (P < 0.001). No incision infection was observed in any patient.Conclusion: The cSAPB with ropivacaine plus dexamethasone prolonged the duration of analgesia and motor blockade, reduced pain intensity and rescued analgesia requirements after the end of PCA infusion for patients undergoing VATS, which provide further improvement to continuous perineural block.Keywords: continuous serratus anterior plane block, video-assisted thoracoscopic surgery, dexamethasone, levobupivacaine

Hong Gu,1,&ast; Yiwen Ru,1,&ast; Wei Wang,1,2 Guanhui Cai,1 Lanxin Gu,1 Junjie Ye,1 Wei-Bing Zhang,3,4 Lin Wang1,2 1Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, People′s Republic of China; 2Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, People′s Republic of China; 3Department of Stomatology, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, People′s Republic of China; 4Department of Stomatology, Medical Center of Soochow University, Suzhou, People′s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei-Bing Zhang, Department of Stomatology, Dushu Lake Hospital Affiliated to Soochow University, 9 Chongwen Road, Suzhou, 215000, People′s Republic of China, Tel +86-512-67505200, Email wbzhang@suda.edu.cn Lin Wang, Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029, People′s Republic of China, Tel +86-025-69593060, Email lw603@njmu.edu.cnBackground: Recent studies suggest that there is a potential connection between obstructive sleep apnea (OSA) and osteoporosis through dysregulation of bone metabolism. Orexin-A, a neuroprotective peptide secreted by the hypothalamus, is at a lower level in the plasma of OSA patients, which regulates appetite, energy expenditure and sleep-wake states. However, the protective effect of orexin-A on bone metabolism in OSA is unclear.Purpose: To investigate whether the activation of OX1R by orexin-A can reverse bone mass loss induced by chronic intermittent hypoxia (CIH).Methods: Mice were randomly divided into the normoxia group and CIH group. Within the CIH or normoxia groups, treatment groups were given a subcutaneous injection of either orexin-A or saline vehicle once every day for 4 weeks and then femurs were removed for micro-CT scans. Histology and immunohistochemical staining were performed to observe and calculate the changes in femurs as a result of hypoxia. Cell immunofluorescence and immunohistochemical staining were used to detect the expression of orexin receptors in MC3T3-E1 cells or in bones. CCK-8 assay, ALP assay kit and alizarin red staining were used to detect the viability, alkaline phosphatase (ALP) activity, and capacity of mineralization, respectively. The effect of orexin-A on osteogenic differentiation of MC3T3-E1 cells was evaluated using qRT-PCR, Western blot and cell staining.Results: CIH led to a decrease in the amount and density of trabecular bone, downregulated OCN expression while increasing osteoclast numbers in femurs and inhibited the expression of RUNX2, OSX, OPN and Nrf2 in MC3T3-E1 cells. Orexin-A treatment alleviated these CIH-induced effects by combining to OX1R. The level of HIF-1α was elevated both in CIH and orexin-A treatment groups.Conclusion: CIH environment inhibits osteogenesis and orexin-A can reverse bone mass loss induced by CIH through OX1R-Nrf2/HIF-1α pathway.Keywords: obstructive sleep apnea, dysregulation, bone metabolism, osteogenesis

Liya Xu,1 Hongyi Gu,1 Yimin Zhang2 1Faculty of Sports and Human Sciences, Beijing Sports University, Beijing, People’s Republic of China; 2China Institute of sports and Health, Key Laboratory of sports and Physical Health Ministry of Education, Beijing Sports University, Beijing, People’s Republic of ChinaCorrespondence: Yimin Zhang, China Institute of sports and health, Key Laboratory of sports and physical health Ministry of Education, Beijing Sports University, Beijing, 100084, People’s Republic of China, Tel +86 13641108252, Email ymzhangno1@163.comObjective: Surface electromyography (sEMG) has been widely applied to rehabilitation medicine. However, the bibliometric analysis of the rehabilitation medicine use of sEMG is vastly unknown. Therefore, this research aimed to investigate the current trends of the rehabilitation medicine use of sEMG in the recent 12 years by using CiteSpace (5.8).Methods: Literature relating to rehabilitation medicine use of sEMG from 2010 to 2021 was retrieved from the Web of Science. CiteSpace analyzed country, institution, cited journals, authors, cited references and keywords. An analysis of counts and centrality was used to reveal publication outputs, countries, institutions, core journals, active authors, foundation references, hot topics and frontiers.Results: A total of 1949 publications were retrieved from 2010 to 2021. The total number of publications continually increased over the past 12 years, and the most active countries, institutions, journals and authors in rehabilitation medicine use of sEMG were identified. The most productive country and institution in this field were America (484) and the University of Sao Paulo (36). Andersen LL (28) was the most prolific author, and Dario Farina ranked first among the cited authors. Besides, there were three main frontiers in keywords for sEMG research, including “activation”, “exercise”, and “strength”.Conclusion: The findings from this bibliometric study provide the current status and trends in clinical research of rehabilitation medicine use of sEMG over the past ten years, which may help researchers identify hot topics and explore new directions for future research in this field.Keywords: surface electromyography, rehabilitation medicine, bibliometric analysis, CiteSpace

Song Zhang, Xin Wang, Hao Gu, Jun-Qi Liu Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of ChinaCorrespondence: Jun-Qi Liu, Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jian-She East Road, Zhengzhou, Henan, 450052, People’s Republic of China, Tel +86 13938550770, Email fccliujq@zzu.edu.cnObjective: This study was to investigate the feasibility and safety of anlotinib monotherapy for patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) retrospectively.Methods: This study was designed as a real-world study. A total of 83 patients with advanced or metastatic ESCC who received anlotinib monotherapy were included. Demographic characteristics of the patients, efficacy data of the treatment and adverse reactions during the treatment were documented and analyzed through the electronic medical record system in the hospital. All the patients were followed up regularly. The primary endpoint of this study was progression-free survival (PFS), secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), safety profile and PFS analysis according to adverse reactions.Results: A total of 83 patients with ESCC who received anlotinib monotherapy were included. Partial response was observed in 7 patients, stable disease was noted in 51 patients and progressive disease was found in 25 patients, which yielded an ORR of 8.4% (95% CI: 3.5– 16.6%), and a DCR of 69.9% (95% CI: 58.8– 79.5%). Furthermore, the median PFS of the 83 patients with advanced ESCC was 3.3 months (95% CI: 2.20– 4.40) and the median OS was 7.8 months (95% CI: 5.40– 10.20). Common adverse reactions among the 83 patients were hypertension (51.8%), fatigue (48.2%), weight loss (41.0%), diarrhea (34.9) and hand-foot syndrome (30.1%). Correlation analysis between hypertension status and PFS suggested that PFS of the patients with hypertension was longer than that of those with non-hypertension (median PFS: 4.5 vs 3.0 months, P = 0.019).Conclusion: Anlotinib monotherapy demonstrated promising efficacy and tolerable toxicity for patients with previously treated advanced or metastatic ESCC. Hypertension that occurs during anlotinib administration might be used as a potential biomarker to predict PFS of patients with ESCC. The conclusion should be confirmed in prospective clinical trials subsequently.Keywords: esophageal squamous cell carcinoma, anlotinib, efficacy, safety, hypertension, biomarker

Huali Gu,1 Yizhuo Wang,1 Dongsheng Huang,1 Xunda Ji,2 Yi Zhang,1 Jianmin Ma,3 Mei Li,4 Weiling Zhang,1 Huimin Hu,1 Jing Li,1 Pinwei Zhang1 1Department of Pediatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Ophthalmology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Ophthalmic Oncology, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Department of Nuclear Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Dongsheng Huang, Department of Pediatrics, Beijing Tongren Hospital, Capital Medical University, West South Road 2, Yizhuang Economic and Technological Development Zone, Daxing District, Beijing, 100176, People’s Republic of China, Tel +86 01058266032, Email hds5180@sina.com Xunda Ji, Department of Ophthalmology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Kong Jiang Road 1665, Shanghai, 200092, People’s Republic of China, Tel +86 15921670980, Email jixunda@xinhuamed.com.cnPurpose: Retinoblastoma (RB) is the most common intraocular malignancy in infancy and childhood. This study evaluated the clinical and imaging features, treatment, and prognosis of patients with recurrent RB with limb bone metastases and without central nervous system involvement.Patients and Methods: The clinical data of five patients with RB with limb bone metastases who were diagnosed at the Department of Pediatrics in Beijing Tongren Hospital between January 2015 and January 2021 were analyzed retrospectively.Results: Three males and two females were included (seven eyes: four group E and one each of group D, C, and B). The most common symptom was pain. Three patients had bone marrow and lymph node metastases. Three patients had single and two had multiple skeletal lesions. The main bones that were involved were the femur, humerus, talus, and ulna. The simultaneous involvement of the bone marrow and cortex was also observed. Serum neuron-specific enolase (NSE) levels were significantly elevated in four cases and slightly elevated in one case; primary intravenous chemotherapy resulted in a decrease in NSE levels and the gradual resolution of the bone lesions. Two patients died at the time of follow-up and three were in complete remission. The results of the statistical analysis showed that anterior chamber invasion was correlated with prognosis, and there was significant difference in the decrease in the serum NSE levels after intravenous chemotherapy.Conclusion: Regular lifelong follow-up of patients with RB is warranted to identify bone metastases earlier. Anterior chamber invasion may be a risk factor. The simultaneous involvement of the bone marrow and cortex is characteristic manifestations in images of RB with bone metastases. Multidisciplinary treatment especially intravenous chemotherapy is useful, at least at the beginning.Keywords: recurrent, NSE, SRE, pathological fracture, pamidronate, osteoclast inhibitors

Ning Wang,1 Meifang Song,2 Haike Gu,2 Yiyuan Gao,1 Ge Yu,3 Fang Lv,4 Cuige Shi,5 Shangming Wang,5 Liwen Sun,1 Yang Xiao,6 Shucheng Zhang1 1Department of Health Quality Center, National Research Institute for Family Planning, Beijing, People’s Republic of China; 2Beijing Radiation Center, Beijing Academy of Science and Technology, Beijing, People’s Republic of China; 3Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China; 4Reproductive Medicine Center, Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Soochow University, Soochow, People’s Republic of China; 5Department of Cell Biology, National Research Institute for Family Planning, Beijing, People’s Republic of China; 6Graduate School of Chinese Academy of Agricultural Sciences, Beijing, People’s Republic of ChinaCorrespondence: Shucheng Zhang; Yang Xiao, Tel/Fax +86 10 62197760 ; +86 10 82109683, Email shuchengzz87@email.cn; xiao_y87sd@163.comObjective: The objective of this study is to reduce the dimension of several indicators with a strong correlation when conducting semen quality analysis in a small number of comprehensive variables that could retain most of the information in the original variables.Methods: A total of 1132 subjects were recruited from the Maternal and Child Health Institutions of seven provinces in mainland China. They completed the questionnaire and provided semen samples. Visualization of the correlation between variables was realized by using a function chart and correlation in the PerformanceAnalytics package of the R programming language (version 3.6.3 [2020-02-29]). Factor analysis was conducted using the principal function in the psych package of R. Principal component analysis, combined with varimax rotation, was used in the operation of the model, and two common factors were selected and measured to provide values for the common factor. The score coefficient was estimated using the regression method.Results: The contribution rates of the two common factors to variable X were 43.7% and 33.98%, respectively. When the two common factors were selected, approximately 78% of the information of the original variables could be explained. The correlation coefficients between the first common factor (the quantitative factor) and sperm density, total sperm count, and semen volume were 0.824, 0.984, and 0.544, respectively. The correlation coefficients between the second common factor (the quality factor) and sperm motility and the percentage of forward-moving (progressive spermatozoa) sperm were 0.978 and 0.976, respectively.Conclusion: The correlation between the original variables of a semen quality analysis was strong and suitable for dimensionality reduction by factor analysis. Factor analysis and dimensionality reduction provide a fast and accurate assessment of semen quality. Patients with low fertility or infertility can be identified and provided with corresponding treatments.Keywords: semen quality analysis, factor analysis, score coefficient, dimensionality reduction

Guitao Zhang,1 Zixiao Li,1– 3 Hongqiu Gu,1– 3 Runhua Zhang,1,2 Xia Meng,1,2 Hao Li,1,2 Yilong Wang,1,2 Xingquan Zhao,1,2 Yongjun Wang,1– 6 Gaifen Liu1,2 On behalf of Chinese Stroke Center Alliance investigators1Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 3National Center for Healthcare Quality Management in Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, People’s Republic of China; 5Research Unit of Artificial Intelligence in Cerebrovascular Disease, Chinese Academy of Medical Sciences, Beijing, 2019RU018, People’s Republic of China; 6Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, People’s Republic of ChinaCorrespondence: Yongjun Wang; Gaifen Liu, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, People’s Republic of China, Tel +86 10-59978350 ; +86 10-59976746, Email yongjunwang@ncrcnd.org.cn; liugaifen@ncrcnd.org.cnPurpose: To investigate the effectiveness of dysphagia screening and subsequent swallowing rehabilitation in elderly stroke patients with malnutrition risk.Patients and Methods: Based on the Chinese Stroke Center Alliance (CSCA) from August 1, 2015 to July 21, 2019, we compared the in-hospital adverse outcomes among stroke patients (including ischemic stroke, intracranial hemorrhage, and subarachnoid hemorrhage) over 70 years old with and without dysphagia screening. The primary outcome was in-hospital all-cause mortality. Secondary outcomes were the composite endpoint of discharge against medical advice (DAMA) or in-hospital death.Results: Among 365,530 stroke patients ≥ 70 years old with malnutrition risk in the CSCA, documented dysphagia screening was performed for 288,764 (79.0%) participants. Of these, 41,482 (14.37%) patients had dysphagia, and 33,548 (80.87%) patients received swallowing rehabilitation. A total of 1,694 (0.46%) patients experienced in-hospital death. After adjustment for traditional risk factors, dysphagia screening was associated with a low risk of all-cause mortality in stroke patients [adjusted odds ratio (aOR): 0.75, 95% confidence interval (CI):0.65– 0.87]. Compared to patients with dysphagia who did not receive swallowing rehabilitation, patients reveiving swallowing rehabilitation had a reduced risk of in-hospital death (aOR:0.39, 95% CI: 0.33– 0.46). Additionally, dysphagia screening had a lower risk for the composite endpoint of DAMA or in-hospital death (aOR:0.83,95% CI: 0.80– 0.87), as did subsequent swallowing rehabilitation (aOR:0.43,95% CI: 0.40– 0.47). Similar results were observed in the sensitivity analysis through inverse probability of treatment weighting, propensity score matching, and excluding patients without National Institutes of Health Stroke Scale scores. A similar association was observed between dysphagia management and adverse clinical outcomes in ischemic stroke and intracranial hemorrhage patients.Conclusion: Dysphagia screening and swallowing rehabilitation were associated with a reduced risk of in-hospital death and composite outcome of DAMA or in-hospital death for stroke patients with malnutrition risk. Future research should concentrate on improving the quality of medical care for dysphagia management to improve patients’ outcomes.Keywords: stroke, malnutrition risk, dysphagia screening, in-hospital death, discharge against medical advice

Jing Li,* Weiling Zhang,* Huimin Hu, Yi Zhang, Yizhuo Wang, Huali Gu, Dongsheng Huang Department of Pediatrics, Beijing Tongren Hospital of China Capital Medical University, Beijing, 100176, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dongsheng HuangDepartment of Pediatrics, Beijing Tongren Hospital of China Capital Medical University, No. 1 Dongjiao Lane, Dongcheng District, Beijing, 100730, People’s Republic of ChinaTel +86 10 5826 6032Email huamgdomgshemg@163.comObjective: This study aims to summarize the clinical features and prognoses of the malignant rhabdoid tumor of the kidney (MRTK) in children. It further aims to analyze the high-risk factors affecting MRTK prognosis.Methods: Clinical data from 14 children with MRTK treated in Paediatrics of Beijing Tongren Hospital from January 2010 to December 2019, along with the high-risk factors affecting prognosis, were retrospectively analyzed.Results: There were 14 children with MRTK included in the study, with a median onset age of 13 (3– 46) months. Thirteen patients had distant metastases, the most common site for metastases being inside the lung. A comprehensive treatment protocol combined with chemotherapy was mainly applied during the surgery. A surgical resection of primary tumors was performed on 13 (13/14) patients, and all 14 children received chemotherapy with ifosfamide + carboplatin + etoposide, ifosfamide + etoposide, and vincristine + pirarubicin + cyclophosphamide regimens, alternately. Three patients received radiotherapy and two received oral targeted drugs after partial response. The median follow-up was after 16.5 months (3– 53 months) and the four-year overall survival (OS) was 41.8%. In children aged ≤ 24 months and children aged > 24 months, the two-year OS was 67.2% and 100% (χ2 = 108.998, P< 0.05), respectively. In children with Ki 67 > 70% and children with Ki 67 < 70%, the two-year OS was 52.6% and 86.9% (χ2 = 8.544, P = 0.003), respectively. In children with distant metastases and children without distant metastasis, the two-year OS was 70% and 100% (χ2 = 14.239, P< 0.05), respectively.Conclusion: The most common MRTK distant metastasis site is the lung. Risk factors for poor MRTK prognoses include an age of < 24 months, Ki 67 > 70%, and distant metastases.Keywords: children, malignant rhabdoid tumor of the kidney, MRTK, treatment, prognosis

Jiayu Yao,1 Xiaotong Liu,1 Yingxu Sun,1 Xin Dong,1 Li Liu,1 Hailun Gu2 1Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, Shenyang, 110122, People’s Republic of China; 2Department of Orthopedics, Shengjing Hospital, China Medical University, Shenyang, 110004, People’s Republic of ChinaCorrespondence: Hailun GuDepartment of Orthopedics, Shengjing Hospital, China Medical University, Shenyang, 110004, People’s Republic of ChinaTel +86-18940257206Email guhailun_@163.comPurpose: The mechanism underlying curcumin’s protective effect on osteoarthritis (OA) has not been clarified. This study aimed to determine whether curcumin exerts a chondroprotective effect by inhibiting apoptosis via upregulation of E2F1/PITX1 and activation of autophagy via the Akt/mTOR pathway by targeting microRNA-34a (miR-34a).Methods: Male Sprague–Dawley rats were fed a normal diet (ND) or high-fat diet (HFD) for 28 weeks. Five rats from each diet group were selected randomly for histological analysis of OA characteristics. Rats fed a HFD were given a single intra-stifle joint injection of the miR-34a mimic agomir-34a or negative control agomir (NC), followed by weekly low-dose (200 μg/kg body weight) or high-dose (400 μg/kg body weight) curcumin intra-joint injections from weeks 29 to 32. The rats’ stifle joints were submitted to histological analysis and to an apoptotic assay. Expression of miR-34a was detected using a real-time RT-PCR. E2F1 and PITX1 protein levels were determined by Western blot analysis, and the expressions of Beclin1, LC3B, p62, phosphorylated (p)-Akt, and p-mTOR were measured using immunofluorescence analysis.Results: We found that rats fed a HFD had OA-like lesions in their articular cartilage and had increased apoptosis of chondrocytes and decreased autophagy compared to rats fed a ND. Curcumin treatment alleviated OA changes, inhibited apoptosis, and upregulated autophagy. Agomir-34a treatment reduced E2F1, PITX1, Beclin1, and LC3B expression and increased p62, p-Akt, and p-mTOR expression in HFD-fed rats given low- or high-dose curcumin. Greater numbers of apoptotic cells, lesser expression of p62, p-Akt, and p-mTOR, and greater expression of E2F1, PITX1, and LC3B were observed in the agomir-34a and high-dose curcumin-treated group than in agomir-34a and low-dose curcumin-treated group.Conclusion: Curcumin’s chondroprotective effect was mediated by its suppression of miR-34a, apparently by reducing apoptosis, via upregulation of E2F1/PITX1, and by augmenting autophagy, likely via the Akt/mTOR pathway.Keywords: curcumin, osteoarthritis, apoptosis, autophagy, microRNA-34a, high-fat diet

Jiangnan Zhang,1 Wenwei Mao,2 Zhe Chen,2 Haiting Gu,2 Chan Lian2 1Orthopedics, The First People’s Hospital of Wenling, Wenling, Zhejiang, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, The First People’s Hospital of Wenling, Wenling, Zhejiang, People’s Republic of ChinaCorrespondence: Chan LianDepartment of Respiratory and Critical Care Medicine, The First People’s Hospital of Wenling, Wenling 317500 Zhejiang, People’s Republic of ChinaTel +86-15868658983Email lianchan8983@163.comBackground: Bone metastasis can induce multiple types of bone diseases which reduce the non-small-cell lung cancer (NSCLC) patient’s quality-of-life. Due to the difficulty of finding bone metastases and lack of effective early diagnosis, it is easy to miss the best treatment. Therefore, the study of serum tumor biomarkers is of great significance in the diagnosis of NSCLC bone metastasis.Methods: The qRT-PCR assay was performed to assess has_circ_0060937 expression in 100 NSCLC patients. Furthermore, the small interfering RNAs si-has_circ_0060937 or si-NC were transfected into NSCLC bone metastasis cells. CCK8 assay was exercised to detect cell proliferation, and cell invasion assays were used to detect cell invasion in NSCLC bone metastasis cells.Results: In this study, we firstly found that the expression of has_circ_0060937 in boneless metastasis NSCLC tissues and bone metastasis NSCLC tissues was significantly increased compared to normal tissues, and the expression of has_circ_0060937 was highest in bone metastasis. Expression of serum has_circ_0060937 in bone metastasis group from Grade I to Grade III NSCLC was drastically higher than boneless metastasis group or healthy group. In the Grade I to Grade III bone metastasis group, the expression of serum has_circ_0060937 gradually boosted with the increase of bone metastasis grades. Additionally, knockdown of has_circ_0060937 inhibited cell proliferation and cell invasion in NSCLC bone metastasis cell line.Conclusion: The results suggestthat has_circ_0060937 is closely associated with bone metastasis in NSCLC, and the circRNAs we inspected may be a potential biomarker of bone metastasis in NSCLC.Keywords: circRNA, has_circ_0060937, bone metastasis, NSCLC

Xin-lu Yang,1,* Hai Gu,1,* Ji-cheng Hu,1 Sheng Wang,1 Xin Wei,1 Shu-hua Shu,1 Wei-de Zhou,1 Chun-rong Tao,2 Di Wang,1 Xiao-qing Chai1 1Department of Anesthesiology, Pain Clinic, First Affiliated Hospital, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China; 2Department of Neurology, First Affiliated Hospital, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China*These authors contributed equally to this workCorrespondence: Di Wang; Xiao-qing ChaiDepartment of Anesthesiology, First Affiliated Hospital, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, People’s Republic of ChinaTel/Fax +86-551-62283963; +86-551-62283912Email di.wang@ustc.edu.cn; xiaoqingchai@ustc.edu.cnPurpose: This randomized, double-blind study evaluated the effectiveness and limitations of continuous serratus anterior plane block (cSAPB) by comparing the effect of cSAPB to patient-controlled intravenous analgesia (PCIA) on postoperative acute pain after thoracoscopic surgery in adults.Patients and Methods: Sixty-six patients who underwent elective video-assisted thoracoscopic surgery (VATS) were randomly allocated to cSAPB or PCIA groups (n=33 per group) after surgery. For the cSAPB group, patients were treated by an initial does of 20 mL ropivacaine (0.375%), followed by continuous infusion at a rate of 5 mL/h of ropivacaine (0.2%) and a patient-controlled bolus of 5 mL ropivacaine (0.2%). PCIA started with an initial does of 0.03 μg/kg sufentanil, followed by a basal infusion of 0.03 μg/kg/h sufentanil and a patient-controlled bolus of 0.03 μg/kg sufentanil. Visual analog scale (VAS) and other items were examined postoperatively. The area under the curve of VAS-time (AUCVAS-time) at rest and on coughing in the first 24 hours postoperatively were primary outcomes.Results: At the first 24 hours postoperatively, patients in the cSAPB group exhibited a smaller AUCVAS-time at rest (44.0± 17.1 vs 68.9± 11.8 cm·h, P< 0.001) and AUCVAS-time on coughing (67.1± 8.8 vs 78.0± 12.5 cm·h, P< 0.001) compared with those in the PCIA group. The differences in means of VAS score at rest were more than 1.0 cm between the two groups, however, on coughing they were less than 1.0 cm at each observation point. Additionally, patients in the cSAPB group had a longer time to first patient-controlled bolus (15.8± 7.6 vs 10.6± 8.6 hours, P=0.011). Furthermore, a higher rank of satisfaction was recorded with patients in the cSAPB group.Conclusion: cSAPB using PCA devices might be superior to traditional intravenous continuous analgesia, particularly with an advantage of pain relief at rest following VATS operation. Meanwhile, cSAPB lacks a satisfactory analgesic effect on cough.Keywords: patient-controlled regional analgesia, continuous regional analgesia, continuous peripheral nerve blocks, postoperative acute pain, video-assisted thoracoscopic surgery

Heyang Zhang,1 Lijun Zhang,1 Yan Li,1 Hongcang Gu,2 Xiaoxue Wang1 1Department of Hematology, The First Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China; 2Broad Institute of MIT and Harvard, Cambridge, MA, USACorrespondence: Xiaoxue Wang; Hongcang Gu Email liang195691@163.com; gu_hongcang@hotmail.comObjective: To investigate the characteristics of hematological malignancies in patients with the SET-CAN fusion gene and provide a literature review.Methods: We retrospectively analyzed the clinical data of three cases of acute leukemia and myeloid neoplasms harboring the SET-CAN fusion gene who were treated at our hospital. Their clinical manifestations, pathological results and treatment strategies were investigated.Results: The three cases were diagnosed with T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia (AML) and myeloid sarcoma (MS), respectively. Karyotype analyses identified a normal result in all three patients. Subsequently, we confirmed del(9q34) utilizing FISH analysis. Mutation of the BRAF gene was detected in case 1, while mutations in PHF6 and BCOR were detected in case 2, which have not been officially reported in patients with SET-CAN fusions. Finally, relevant literature focusing on adult patients with hematological malignancies harboring the SET-CAN fusion gene were summarized.Conclusion: Adult patients with the SET-CAN fusion gene were rare among cases of hematological malignancies. There was a large degree of heterogeneity between different patients. Notably, some patients remained sensitive to chemotherapy. Overall prognosis may be related to the type of disease and other cytogenetic abnormalities. Systemic cytogenetic and molecular studies are needed to make accurate diagnoses. Additional cases need to be accumulated and summarized to better understand these diseases.Keywords: T-lymphoblastic lymphoma/leukemia, acute myeloid leukemia, myeloid sarcoma, SET-CAN, ASCT, prognosis

Lei Huang,1 Kun Xie,1 Hongwen Li,1 Ruiqin Wang,1 Xiaoqing Xu,1 Kaiming Chen,1 Hua Gu,1 Jianmin Fang1– 3 1Laboratory of Molecular Medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, People’s Republic of China; 2Department of Neurology, Tongji Hospital, Tongji University, Shanghai, People’s Republic of China; 3Biomedical Research Center, Tongji University Suzhou Institute, Suzhou, Jiangsu, People’s Republic of ChinaCorrespondence: Hua Gu Tel +86-21-6598-2867Correspondence Email gu_hua@tongji.edu.cnJianmin Fang Tel +86-21-6598-2878Email jfang@tongji.edu.cnIntroduction: Overexpression of c-Met, or hepatocyte growth factor (HGF) receptor, is commonly observed in tumor biopsies and often associated with poor patient survival, which makes HGF/c-Met pathway an attractive molecular target for cancer therapy. A number of antibody-based therapeutic strategies have been explored to block c-Met or HGF in cancers; however, clinical efficacy has been very limited, indicating that blockade of c-Met signal alone is not sufficient. Thus, an alternative approach is to develop an immunotherapy strategy for c-Met-overexpressing cancers. c-Met/CD3 bispecific antibody (BsAb) could bridge CD3-positive T lymphocytes and tumor cells to result in potent tumor cell killing.Materials and Methods: A bispecific antibody, BS001, which binds both c-Met and CD3, was generated using a novel BsAb platform. Western blotting and T cells-mediated killing assays were utilized to evaluate the BsAb’s effects on cell proliferation, survival and signal transduction in tumor cells. Subcutaneous tumor mouse models were used to analyze the in vivo anti-tumor effects of the bispecific antibody and its combination therapy with PD-L1 antibody.Results: BS001 showed potent T-cell mediated tumor cells killing in vitro. Furthermore, BS001 inhibited phosphorylation of c-Met and downstream signal transduction in tumor cells. In A549 lung cancer xenograft model, BS001 inhibited tumor growth and increased the proportion of activated CD56+ tumor infiltrating lymphocytes. In vivo combination therapy of BS001 with Atezolizumab (an anti-programmed cell death protein1-ligand (PD-L1) antibody) showed more potent tumor inhibition than monotherapies. Similarly, in SKOV3 xenograft model, BS001 showed a significant efficacy in tumor growth inhibition and tumor recurrence was not observed in more than half of mice treated with a combination of BS001 and Pembrolizumab.Conclusion: c-Met/CD3 bispecific antibody BS001 exhibited potent anti-tumor activities in vitro and in vivo, which was achieved through two distinguished mechanisms: through antibody-mediated tumor cell killing by T cells and through inhibition of c-Met signal transduction.Keywords: c-Met, bispecific antibody, lung cancer, ovarian cancer, checkpoint antibody

Xiaolei Xu,1,2,* Xudan Liu,1,* Yingchun Yang,1 Jianyi He,1 Mengqi Jiang,1 Yue Huang,1 Xiaotong Liu,1 Li Liu,1 Hailun Gu3 1Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, Shenyang, People’s Republic of China; 2Department of Nutrition and Food Hygiene, School of Public Health, Beihua University, Jilin, People’s Republic of China; 3Department of Orthopedics, Shengjing Hospital, China Medical University, Shenyang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hailun GuDepartment of Orthopedics, Shengjing Hospital, China Medical University, Shenyang 110004, Liaoning Province, People’s Republic of ChinaTel +86-18940257206Email guhailun_@163.comLi LiuDepartment of Nutrition and Food Hygiene, School of Public Health, China Medical University, Shenyang 110122, Liaoning Province, People’s Republic of ChinaTel +86-18900910766Email lliu@cmu.edu.cnPurpose: Osteoarthritis (OA) is associated with chronic low-grade inflammation. Resveratrol exerts protective effects on OA through its anti-inflammatory property; however, the mechanism of resveratrol on anti-inflammatory signaling pathways has not been fully elucidated yet. The aim of the present study was to investigate whether resveratrol-mediated PI3K/Akt expression is linked to TLR4/NF-κB pathway and the role of TLR4/Akt/FoxO1 axis in the anti-osteoarthritic effect of resveratrol.Methods: SW1353 cells stimulated by IL-1β (10 ng/mL) were cultured in the presence or absence of resveratrol (50 μM) and then treated with TLR4 siRNA, PI3K inhibitor LY294002 or FoxO1 siRNA, respectively. The associated proteins of TLR4 signaling pathways and TLR4/Akt/FoxO1 axis were evaluated by Western blot. The level of IL-6 in the supernatant was detected by ELISA.Results: IL-1β treatment increased the expression of TLR4/NF-κB and phosphorylation of PI3K/Akt and FoxO1, while additional resveratrol further upregulated the expression of PI3K/Akt and FoxO1 phosphorylation but downregulated TLR4 signals in SW1353 cells. Further analyses by the inhibition of TLR4, PI3K/Akt and FoxO1 signaling pathways, respectively, showed that the activation of TLR4 can induce PI3K/Akt phosphorylation, which increases the phosphorylation of FoxO1 and inactivates it. Next, inactivated-FoxO1 can reduce the expression of TLR4, which forms a self-limiting mechanism of inflammation. Resveratrol treatment can upregulate PI3K/Akt phosphorylation and inactivate FoxO1, thereby reducing TLR4 and inflammation.Conclusion: This study reveals that TLR4/Akt/FoxO1 inflammatory self-limiting mechanism may exist in IL-1β-stimulated SW1353 cells. This study reveals a novel cross-talk mechanism which is between integrated PI3K/Akt/FoxO1 signaling network and TLR4-driven innate responses in IL-1β-stimulated SW1353 cells. Resveratrol may exert anti-OA effect by enhancing the self-limiting mechanism of inflammation through TLR4/Akt/FoxO1 axis.Keywords: resveratrol, toll-like receptor 4, osteoarthritis, interleukin-1β, forkhead box O1, phosphoinositide-3-kinase/protein kinase B

Nan Cui,1 Jing Cui,2 Jianping Sun,2 Xinping Xu,1 Bilal Aslam,3,4 Lan Bai,1 Decheng Li,1 Di Wu,1 Zhongren Ma,3 Hai Gu,1 Zulqarnain Baloch3 1Research Center for Health Policy and Management, Nanjing University, Nanjing, People’s Republic of China; 2Qingdao Centers for Disease Control and Prevention, Qingdao Institute for Preventive Medicine, Qingdao, People’s Republic of China; 3Biomedical Research Center, Northwest Minzu University, Lanzhou 730030, People’s Republic of China; 4Department of Microbiology, Government College University Faisalabad, Faisalabad, Punjab, PakistanCorrespondence: Hai GuResearch Center for Health Policy and Management, Nanjing University, 101 Longmian Avenue, Jiangning District, Nanjing 210093, People’s Republic of ChinaTel/Fax +8613687616923Email njuhaigu@126.comZulqarnain BalochBiomedical Research Center, Northwest Minzu University, Minying Road, Lanzhou 730030, People’s Republic of ChinaTel +86-18344564625Email znbalooch@yahoo.comObjective: To assess the association between triglycerides (TG), total cholesterol (TC) and hyperuricemia (HUA) in the general Chinese population.Methods: A population-based cross-sectional survey included 9680 participants aged 35– 74 years in 2006 and 2009 in Qingdao, China. TG, TC and uric acid (UA) were measured. The logistic regression model was performed to estimate the association between TG, TC, and HUA with an odds ratio (OR) and 95% confidence intervals (CI). Meanwhile, age stratification analysis (< 55 years group and ≥ 55 years group) was performed to evaluate whether age potentially affects the association between TG, TC and HUA using multivariable logistic regression.Results: Higher TG and TC showed significantly increased HUA prevalence in both men and women (Ptrend all < 0.05). Multivariate logistic regression indicated that borderline high TG (OR: 1.68, 95% CI: 1.31, 2.15 and HTG (OR: 2.98, 95% CI: 2.39, 3.72) indicated increased risk for HUA in men, and borderline high TG (OR: 2.09; 95% CI: 1.68,2.62); HTG (OR: 3.62; 95% CI: 2.90,4.51), borderline high TC (OR: 2.09, 95% CI: 1.68, 2.62) and HTC (OR: 3.62, 95% CI: 2.90, 4.51) showed significant association with HUA in women after adjusted age, school years, marital status, geographic division, personal monthly income, BMI and HDL-C. Age stratification analyses demonstrated that the association between TG and HUA was stronger in males aged ≥ 55 years and female aged < 55 years, and the association between TC and HUA was stronger in both gender aged < 55 years.Conclusion: This large cross-sectional study focusing on the association between single indictor of blood lipid as exposure and HUA as outcome on the east coast of China for the first time. From a sample of Chinese adults, this study demonstrated that elevated TG in men and women and TC in women were associated with increased HUA prevalence.Keywords: triglycerides, total cholesterol, hyperuricemia, Qingdao, Chinese population

Xiaomin Liu,1 Yi Zhou,1 Yu-e Ning,1 Hui Gu,2 Yuxin Tong,3 Ning Wang1 1Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110000, People’s Republic of China; 2Key Laboratory of Health Ministry for Congenital Malformation, Shengjing Hospital, China Medical University, Shenyang 110004, People’s Republic of China; 3Medical Research Center, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, People’s Republic of ChinaCorrespondence: Ning WangDepartment of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110000, People’s Republic of ChinaEmail nonaware@sina.comPurpose: Our previous studies have shown that miR-195 is reduced in cervical cancer tissues, and that upregulation of miR-195 suppressed cervical cancer cell growth and induced a cell cycle block. In this study, we aimed to further elucidate the mechanism of action between miR-195-5p and Yes-associated protein 1 (YAP1) in the malignant progression of cervical cancer.Methods: MiR-195-5p and YAP1 were detected using qRT-PCR in cervical cancer cells transfected with miR-195-5p mimics or inhibitor. Cell proliferation, migration, and invasion ability were detected using MTT, wound healing, and transwell invasion assays. Dual luciferase reporter assay, qRT-PCR, and Western blot analysis were used to demonstrate that YAP1 was a target of miR-195-5p.Results: Our results showed that miR-195-5p is negatively correlated with YAP1 protein levels but not with mRNA expression. Moreover, upregulation of miR-195-5p by transient transfection with miR-195-5p mimics in HeLa and SiHa cells inhibited cell proliferation, migration ability, invasiveness, and the EMT. Conversely, miR-195-5p downregulation produced opposite results. In addition, multiple miRNA target prediction sites showed that YAP1 was a potential target gene; this was confirmed by dual luciferase assay. Rescue experiments further confirmed that YAP1 is involved in miR-195-5p-mediated inhibition of proliferation, migration ability, invasiveness, and the EMT of cervical cancer cells.Conclusion: Taken together, our data suggest that miR-195-5p may act as a tumor suppressor which could provide a theoretical basis for cervical cancer patient targeted therapy.Keywords: cervical cancer, miR-195-5p, YAP1, epithelial to mesenchymal transition

Jia-An Zhang,* Chao Luan,* Dan Huang, Mei Ju, Kun Chen, Heng Gu Institute of Dermatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Chinese Academy of Medical Science & Peking Union Medical College, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kun Chen; Heng GuInstitute of Dermatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Chinese Academy of Medical Science & Peking Union Medical College, 12 JiangWangMiao Street, Nanjing, Jiangsu 210029, People’s Republic of ChinaTel/Fax +86 25 85478030Email kunchen181@aliyun.com; doctor_guheng@hotmail.comBackground: Baicalin, a natural product isolated from Scutellaria radix, has been reported to exert anti-oxidant and anti-apoptotic effects on skin, but the underlying mechanism remains poorly understood. This study aimed to investigate the possible mechanism of anti-UVB effect of baicalin in human skin fibroblasts.Methods: Cell proliferation was estimated by CCK-8 Kit. Apoptotic incidence was detected by flow cytometry with Annexin V-PE/PI apoptosis detection kit. Autophagy was determined by the evaluation of fluorescent LC3 puncta and Western blotting. Cell signalling was analysed by Western blotting.Results: Baicalin exerted cytoprotective effects in UVB-induced HSFs. Moreover, baicalin increased autophagy and suppressed UVB-induced apoptosis of HSFs. Pretreatment with 3-MA, an autophagy inhibitor, attenuated baicalin-induced HSFs autophagy and promoted apoptosis. Baicalin activated AMPK, which leads to suppression of basal mTOR activity in cultured HSFs. Administration of compound C, an AMPK inhibitor, abrogated AMPK phosphorylation and increased mTOR phosphorylation and apoptosis compared with baicalin alone.Conclusion: Taken together, these results indicate the important role of mTOR inhibition in UVB protection by baicalin and provide a new target and strategy for better prevention of UV-induced skin disorders.Keywords: autophagy, baicalin, ultraviolet B, apoptosis, AMPK

Mengchun Chen,1,2 Ledan Wang,1 Fang Wang,1 Fan Li,3 Weiliang Xia,3 Hongchen Gu,3 Yijie Chen11Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325027, People’s Republic of China; 2Department of Pharmacy, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People’s Republic of China; 3State Key Laboratory of Oncogenes and Related Genes, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200032, People’s Republic of ChinaPurpose: Combining siRNA and other chemotherapeutic agents into one nanocarrier can overcome the multidrug resistance (MDR) phenomenon by synergistically MDR relative genes silencing and elevated chemotherapeutic activity. Most of these systems are typically fabricated through complicated procedures, which involves materials preparation, drug loading and modifications. Herein, the purpose of this study is to develop a new and fast co-delivery system of siRNA and doxorubicin for potentially synergistic cancer treatment.Methods: The co-delivery system is constructed conveniently by a stable complex consisting of doxorubicin bound to siRNA via intercalation firstly, followed by interacting with (3-Aminopropyl)triethoxysilane (APTES) electrostatically and Tetraethyl orthosilicate (TEOS) co-condensed, and the characterizations of the resultant nanocarrier are also investigated. Furthermore, this study evaluates the synergistic anti-cancer efficacy in MCF-7/MDR cells after treatment of siRNA and doxorubicin ‘two in one’ nanocarriers.Results: We establish a new and fast method to craft a co-delivery system of siRNA and doxorubicin with controllable and nearly uniform size, and the entire fabrication process only costs in about 10 minutes. The resultant co-delivery system presents high loading capacities of siRNA and doxorubicin, and the encapsulated doxorubicin plays a pH-responsive control release. Further, biological functionality tests of the synthesized co-delivery nanocarriers show high inhibition of P-gp protein encoded by MDR-1 gene in MCF-7/MDR cells (a variant of human breast cancer cell line with drug resistance) after transfection of these nanocarriers carrying MDR-1 siRNA and doxorubicin simultaneously, which sensitize the MCF-7/MDR cells to doxorubicin, overall leading to improved cell suppression.Conclusion: Collectively, this co-delivery system not only serves as potent therapeutics for synergistic cancer therapy, it also may facilitate the bench-to-bedside translation of combinatorial delivery system as a robust drug nanocarrier by allowing for fabricating a simply and fast nanocarrier for co-delivery of siRNA and doxorubicin with predictable high production rate.Keywords: siRNA, doxorubicin, codelivery system, multidrug resistance, cancer therapy

Jiyong Yang,1* Zhen Ye,1* Dan Mei,2 Honggang Gu,1 Jingzhe Zhang1 1Department of General Surgery, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai 210000, China; 2Department of General Surgery, Wuxi Hospital of Traditional Chinese Medicine, Wuxi 214000, China *These authors contributed equally to this work Background: Long noncoding RNAs (lncRNAs) are abnormally expressed in various human tumors and play an important role in multiple tumorigeneses, including pancreatic cancer (PC). Materials and methods: The present study was designed to evaluate the role of lncRNA DLX6-AS1 in tumorigenesis of PC. The expression of DLX6-AS1 and its effect on proliferation, apoptosis, migration, and invasion was investigated in vitro. Its effect on tumor growth and metastasis in vivo and its potential targets were also examined. Results: We observed that DLX6-AS1 was highly expressed in PC tissues and PC cell lines, and was negatively correlated with the survival of PC patients. We found that overexpression of DLX6-AS1 promoted proliferation, migration, and invasion of PC cells, inhibited apoptosis, increased Bcl-2, cyclin D1, and MMP-2 expression, and decreased cleaved caspase 3, p27, and E-cadherin expression in PC cells. In addition, overexpression of DLX6-AS1 promoted PC growth by increasing tumor volume and weight and increasing the number of liver and lung metastatic foci. Knockdown of DLX6-AS1 showed an opposite effect in all the experiments. miR-497-5p was demonstrated to be a direct target of DLX6-AS1 and was regulated by DLX6-AS1. We also demonstrated that miR-497-5p targeted FZD4 and FZD6 and decreased their expression. miR-497-5p mimics also decreased the expression of FZD4, FZD6, and β-catenin; the expression of FZD4 or FZD6 was reversed by the overexpression of vectors FZD4 or FZD6, respectively, while the expression of β-catenin was reversed by either vector. Finally, the effect of DLX6-AS1 on proliferation, cell cycle, migration, invasion, and apoptosis of cells and expression of FZD4, FZD6, and β-catenin was neutralized by overexpression of vectors of miR-497-5p, FZD4, or FZD6, totally or partially. Conclusion: Collectively, these findings suggested that DLX6-AS1/miR-497-5p/FZD4/FZD6/Wnt/β-catenin signaling pathway is involved in the pathogenesis of PC, and DLX6-AS1 could be a potential biomarker and target for PC treatment. Keywords: pancreatic cancer, DLX6-AS1, long noncoding RNAs, miR-497-5p, FZD4

Lu Sun,1,2 Zihui Dong,3 Hongli Gu,2 Zhixian Guo,2 Zujiang Yu2 1Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; 2Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; 3Department of Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China Background and purpose: Tubulointerstitial nephritis antigen-like 1 (TINAGL1) is an ­extracellular matrix protein that plays an important role in cell adhesion and therefore modulates cell proliferation, migration, and differentiation. In addition, it is frequently upregulated in highly metastatic tumors. The aim of our study was to determine the role of TINAGL1 in the progression and metastasis of hepatocellular carcinoma (HCC).Materials and methods: TINAGL1 mRNA levels were analyzed in HCC and adjacent nontumorous samples by reverse transcription polymerase chain reaction (RT-PCR). Human HCC cell lines were transfected with lentiviral plasmids expressing either si-TINAGL1 or TINAGL1 and subjected to CCK-8, colony forming, transwell migration, Annexin V/propidium iodide, and 5-ethynyl-2′-deoxyuridine uptake assays. Suitably transfected HCC cells were injected into athymic nude mice to establish xenograft tumors that were imaged and measured on a weekly basis. Mediators of the TGF-β signaling pathway were analyzed by Western blot.Results: TINAGL1 was upregulated in human HCC tissues and associated with poor prognosis. TINAGL1 knockdown suppressed HCC cell growth, proliferation, and migration and induced apoptosis in HCC cells, whereas TINAGL1 overexpression had opposite effects. In addition, inhibition of TINAGL1 retarded xenograft tumor growth in a nude mouse model. Mechanistically, TINAGL1 activated the TGF-β signaling pathway and increased VEGF secretion.Conclusion: TINAGL1 promotes hepatocellular carcinogenesis and metastasis via the TGF-β/Smad3/VEGF axis and is a potential new biomarker of HCC.Keywords: TINAGL1, LCN7, hepatocellular carcinoma, TGF-β, VEGF

Ling Yu,1 Lei Yang,2 Xiaoyu Zhang,2 Junliang Yuan,2 Yue Li,2 Shuna Yang,2 Hua Gu,2 Wenli Hu,2 Shan Gao1 1Department of Endocrinology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Neurology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China Background and purpose: White matter hyperintensities (WMH) is identified as a marker of cerebral small vessel diseases and is a major contributor to cognitive impairment, depression, gait disturbance, and urinary incontinence. However, the risk factors for WMH in patients with type 2 diabetes mellitus (T2DM) has not been well explored. Thus, in this study, we aimed to investigate the relationship between the severity of WMH and vascular risk factors in lacunar infarction patients with T2DM. Methods: Consecutive lacunar infarction patients with T2DM were recruited in this cross-sectional study. Paraventricular WMH (P-WMH) and deep WMH (D-WMH) were separately scored by the Fazekas scale, and classified into two categories by the severity. Vascular risk factors and clinical features were compared between the mild and severe WMH. Multiple logistic regression analysis was used to determine the relationship between severity of WMH and vascular risk factors. Results: A total of 327 participants aged 34–91 years were enrolled in this study. Compared with the patients with mild P-WMH, the patients with severe P-WMH had higher age (P=0.031), higher proportion of hypertension (P=0.042) and stroke (P

Min Zhang,1 Xiaohong Jiang,2 Meidi Qu,1 Hongliu Gu,1 Qi Sha,1 Fei Hua2 1Department of Clinical Nutrition, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; 2Department of Endocrinology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China Background: The prevalence of obesity is growing rapidly and has become a global problem that increases the risk for many diseases. It is influenced by many factors, including consumption of the Western-style diet, characterized as a high-fat diet. Within the central nervous system, the hypothalamus is a critical site in maintaining energy homeostasis and sensing nutrient status, including palmitate, the major component of high-fat-diet.Methods: In the present study, we conducted a variety of studies to investigate the specific role of salubrinal on palmitate-induced hypothalamic cell death, leptin signaling, and ER stress in an embryonic hypothalamic cell line. Experiments were also performed to identify the underlying mechanisms of the protective effect of salubrinal.Results: Our results indicate that salubrinal protects hypothalamic cells against PA-induced ER stress and improves hypothalamic leptin sensitivity. Conclusion: Taken together, our findings conclusively reveal that salubrinal abrogates palmitate-induced hypothalamic leptin resistance and ER stress via NF-κB pathway. Keywords: obesity, high-fat diet, palmitate, leptin resistance, ER stress, salubrinal

Huahua Gu,1,* Xianyu Deng,2,* Yizheng Lv,1 Qian Chen,1 Weifeng Yu3 1Department of Anesthesiology, Huashan Hospital, Fudan University, Shanghai, China; 2Department of Neurosurgery, Tenth People’s Hospital of Tongji University, Shanghai, China; 3Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China *These authors contributed equally to this work Purpose: This study aimed to investigate the relationship of preoperative chronic pain and postoperative cognitive dysfunction (POCD) in non-elderly patients who underwent arthroscopic surgery.Materials and methods: The pain intensity was estimated using visual analog scale, and the cognitive function was assessed by Syndrom Kurz Test. The effects of preoperative chronic pain on the cognitive scales were comparatively studied between the patients of observational group (OG, with chronic pain) and control group (CG, without chronic pain) pre- and postoperatively, and followed up for 3 months.Results: A total of 57 non-elderly patients completed the study. Twenty-five patients (44%) with preoperative chronic pain were assigned to OG and 32 patients (56%) without chronic pain were assigned to CG. Preoperation chronic pain impaired the attention ability before surgery and caused less recovery of attention and memory abilities from 24 hours to 3 months after the surgery. Surgery procedures improved the attention and memory abilities and impaired the ability of numerical ability in CG patients. A postoperative pain relief in OG patients caused more recovery of cognition in addition to surgery procedure-mediated cognitive recovery. The incidence of POCD was ~3.5% and temporary at 24 hours after surgery, and disappeared at 2 weeks, 6 weeks and 3 months after the surgery.Conclusion: The incidence of POCD in non-elderly population who underwent arthroscopic surgery was low. Surgery improved the abilities of attention and memory, and impaired the ability of counting. The preoperative chronic pain distracted the attention before surgery, and reduced the recovery of attention and memory abilities during the follow-up period after the surgery in non-elderly patients. Keywords: cognition dysfunction, chronic pain, non-elderly population

Laiyin Zhang,1 Shuangxing Hou,2 Bo Li,3 Jianjian Pan,4 Liping Jiang,5 Guiying Zhou,2 Hong Gu,6 Caixing Zhao,6 Huiping Lu,6 Fenfen Ma6 1Department of Pharmacy, Linyi People’s Hospital, Linyi, 2Department of Neurology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 3Department of Hand Surgery, Huashan Hospital, Fudan University, 4Department of General Medicine, Fudan University, 5Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, 6Department of Pharmacy, Pudong Hospital, Fudan University, Shanghai, China Background: Betulinic acid (BA) is a complex lupane triterpenoid with unique antineoplastic activity. However, its antiproliferative activity is far from satisfaction. In order to improve its anticancer efficacy, betulinic acid was conjugated with a nitric oxide (NO)-releasing moiety to get a novel hybrid, BA-78. Methods: The antiproliferative activity of BA-78 against 6 cell lines and the ability of releasing nitric oxide were determined. The pro-apoptosis mechanism of BA-78 was investigated as well. Results: BA-78 exhibited time-dependent release of NO, and it displayed higher antiproliferative potential than BA through increasing apoptosis and inducing cell cycle arrest at G1 phase. Western blotting results showed that BA-78 increased the expression of Bax, Bid, Bad and cytochrome C and reduced the level of anti-apoptosis proteins including Bcl-2 and Bcl-xl. Conclusion: Our study revealed that novel compound BA-78, possessing betulinic acid and nitric oxide (NO)-releasing moiety, could be developed as an antitumor agent. Keywords: lupane triterpenoid, nitric oxide, anticancer, apoptosis, NONOate, Bcl-2 family

Electromagnetic field is applied widely in metallurgy and other high temperature processes, and affects the behavior of melts. The lightweight alumina based carbon free refractory is of importance for energy-saving, consumption reduction and high quality steel production, and the slag corrosion resistance is significant concerning its service life. Does electromagnetic field control the slag corrosion behavior on the lightweight alumina refractory? In this paper, a multi-field coupled model was established to describe the slag corrosion process in an electromagnetic field. The mathematical modeling in combination of experiments was applied to clarify slag corrosion behavior of lightweight alumina refractory in static magnetic field. The simulation results agree with that of the experiments, which means the proposed model is promising for slag corrosion modeling. The results show that the combination of the slag properties change, and electromagnetic damping caused by MHD (magnetohydrodynamics) effect can enhance the slag corrosion resistance by inhibiting slag penetration and promoting formation of a directional isolation layer, and be beneficial to high-quality clean steel production.

Guangtao Xu,1,2 Huan Gu,1,3 Bo Hu,4 Fei Tong,2 Daojun Liu,1 Xiaojun Yu,1 Yongxia Zheng,1,2 Jiang Gu1 1Department of Pathology and Chemistry, Provincial Key Laboratory of Infectious Diseases and Immunopathology, Collaborative and Creative Center, Molecular Diagnosis and Personalized Medicine, Shantou University Medical College, Shantou, Guangdong, 2Department of Pathology, Provincial Key Discipline of Pharmacology, Jiaxing University Medical College, Jiaxing, Zhejiang, People’s Republic of China; 3Department of Physics, University of Maryland, College Park, Annapolis, MD, USA; 4Department of Chemical Pathology, Jiaxing Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Jiaxing, Zhejiang, People’s Republic of China Abstract: Brain ischemia/reperfusion (I/R) injury (BI/RI) is a leading cause of death and disability worldwide. However, the outcome of pharmacotherapy for BI/RI remains unsatisfactory. Innovative approaches for enhancing drug sensitivity and recovering neuronal activity in BI/RI treatment are urgently needed. The purpose of this study was to evaluate the protective effects of tumor necrosis factor (TNF)-α-loaded poly(ethylene glycol)-b-(poly(ethylenediamine l-glutamate)-g-poly(l-lysine)) (TNF-α/PEG-b-(PELG-g-PLL)) nanoparticles on BI/RI. The particle size of PEG-b-(PELG-g-PLL) and the loading and release rates of TNF-α were determined. The nanoparticle cytotoxicity was evaluated in vitro using rat cortical neurons. Sprague Dawley rats were preconditioned with free TNF-α or TNF-α/PEG-b-(PELG-g-PLL) polyplexes and then subjected to 2 hours ischemia and 22 hours reperfusion. Brain edema was assessed using the brain edema ratio, and the antioxidative activity was assessed by measuring the superoxide dismutase (SOD) activity and the malondialdehyde (MDA) content in the brain tissue. We further estimated the inflammatory activity and apoptosis level by determining the levels of interleukin-4 (IL-4), IL-6, IL-8, IL-10, and nitric oxide (NO), as well as the expression of glial fibrillary acidic protein (GFAP), intercellular adhesion molecule-1 (ICAM-1), and cysteine aspartase-3 (caspase-3), in the brain tissue. We provide evidence that TNF-α preconditioning attenuated the oxidative stress injury, the inflammatory activity, and the apoptosis level in I/R-induced cerebral injury, while the application of block copolymer PEG-b-(PELG-g-PLL) as a potential TNF-α nanocarrier with sustained release significantly enhanced the bioavailability of TNF-α. We propose that the block copolymer PEG-b-(PELG-g-PLL) may function as a potent nanocarrier for augmenting BI/RI pharmacotherapy, with unprecedented clinical benefits. Further studies are needed to better clarify the underlying mechanisms. Keywords: PEG-b-(PELG-g-PLL), TNF-α, ischemia/reperfusion, brain

Liwen Fan,1 Haitang Yang,1,2 Feng Yao,1 Yang Zhao,1 Haiyong Gu,1 Ke Han,1 Heng Zhao1 1Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Division of General Thoracic Surgery, Inselspital University Hospital Bern, Bern, Switzerland Purpose: The therapeutic efficacy of targeted therapy for adenosquamous carcinoma (ASC) of the lung remains unclear and the role of epidermal growth factor receptor (EGFR) testing in patients with ASC also remains controversial. We aimed to analyze the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in ASC. Methods: Clinical records of patients with ASC who received treatment with EGFR-TKIs between January 2006 and December 2014 at two institutions were retrospectively reviewed. Results: A total of 27 EGFR mutation-positive patients with ASC who received TKI therapy were enrolled in this study. EGFR mutations included a deletion in exon 19 in 15 cases and a point mutation at codon 858 (L858R) in exon 21 in 12 cases. Among the 27 ASC patients who received treatment with EGFR-TKIs, nine had a partial response and 11 achieved stable disease, accounting for a disease control rate of 74.1% (20/27). The median postoperative overall survival (OS) of the EGFR-mutant patients who received TKI therapy was 39 months (95% confidence interval [CI]: 25.6–52.4). The median progression-free survival for EGFR mutation-positive patients was 15 months (95% CI: 12.9–17.1), and the median relapse OS was 19 months (95% CI: 0.9–37.1). In addition, the 3- and 5-year postoperative survival rate was 51.9% and 15.3%, respectively. Conclusion: ASC patients harboring EGFR mutations had a good response to TKI therapy. Routine EGFR testing for ASCs was recommended. Further studies on TKI therapy versus chemotherapy alone for EGFR-mutant ASCs are required. Keywords: adenosquamous carcinoma of the lung, epidermal growth factor receptor tyrosine kinase inhibitors, mutation, survival

Xuchu Gong,1 Jinna Wu,1 Jian Wu,2 Jun Liu,2 Hailin Gu,1 Hao Shen3 1Department of Surgery, 2Department of Endocrinology, 3Department of Doppler Ultrasonic, Traditional Chinese Medicine Hospital of Nantong City, Nantong, Jiangsu, People’s Republic of China Objective: SASH1 is a member of the SH3/SAM adapter molecules family and has been identified as a new tumor suppressor and critical protein in signal transduction. An ectopic expression of SASH1 is associated with decreased cell viability of breast cancer. The aim of this study was to explore the association between SASH1 expression and the ultrasonographic features in breast cancer. Patients and methods: A total of 186 patients diagnosed with breast cancer were included in this study. The patients received preoperative ultrasound examination, and the expression of SASH1 was determined using immunohistochemistry methods. Spearman’s rank correlation analysis was used to analyze the correlation between SASH1-positive expression and the ultrasonographic features. Results: The positive expression of SASH1 was observed in 63 (33.9%) patients. The positive expression rate of SASH1 was significantly decreased in patients with breast cancer (63/186, 33.9%) compared with controls (P

Heng Zhao,1,* Haitang Yang,2–4,* Ke Han,5,* Jianlin Xu,6 Feng Yao,5 Yang Zhao,5 Liwen Fan,5 Haiyong Gu,5 Zhenya Shen1,* 1Department of Cardiovascular Surgery of First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Division of General Thoracic Surgery, Inselspital, Bern University Hospital, 3Graduate School for Cellular and Biomedical Sciences, 4Department of Clinical Research, University of Bern, Bern, Switzerland; 5Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 6Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: The incidence of adenocarcinomas as multiple primary lung cancers (MPLCs) is increasing. How to determine the treatment strategies of MPLCs, especially second primary lung adenocarcinomas (SPLACs), and the prognostic factors associated with it are unclear.Methods: The clinical records of patients undergoing surgery for second adenocarcinomas based on Martini–Melamed criteria between 2001 and 2014 were retrospectively reviewed. Survival rates were calculated by the Kaplan–Meier method and compared using the log-rank test. Multivariate analysis was conducted using the Cox proportional hazards model.Results: A total of 115 patients with SPLACs were identified based on Martini–Melamed criteria. With respect to the second resections, three subgroups with low- (adenocarcinoma in situ, n=6; minimally invasive adenocarcinoma, n=19), intermediate- (lepidic, n=9; acinar, n=40; papillary, n=23), and high-grades (solid, n=9; micropapillary, n=2; invasive mucinous, n=7) were assigned. The 5-year overall survival (OS) rates from the time of the first and the second resections were 86.5% and 69.5%, respectively. Cox multivariate analysis identified computed tomography (CT) morphology of SPLACs (ground glass opacity predominant versus solid predominant; hazard ratio [HR]=0.42; P=0.036), histologic classification (same/similar vs different; HR=0.06; P

Jie Xu,1,2,* Yi Liu,3,* Yongli Tao,4 Xuewei Xie,1,2 Hongqiu Gu,1,2 Yuesong Pan,1,2 Xingquan Zhao,1,2 Yongjun Wang,1,2 Aoshuang Yan,3 Yilong Wang1,21Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, 2China National Clinical Research Center for Neurological Diseases, 3Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, 4Department of Neurology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China*These authors contributed equally to this workBackground: The relationship between poststroke blood pressure (BP) and clinical outcomes in ischemic stroke (IS) is still controversial. However, there is no large BP database for IS or transient ischemic attack (TIA) in China. This study aims to describe the rationale, study design, and baseline characteristics of a nationwide BP database in IS or TIA patients in China.Materials and methods: The BOSS (blood pressure and clinical outcome in TIA or ischemic stroke) study was a hospital-based, prospective cohort study aiming to assess BP parameters and clinical outcome in IS/TIA patients. BP parameters were based on office BP, ambulatory BP, and home BP. Clinical outcomes included stroke recurrence, combined vascular events, and disability. Electronic case-report forms were used to record baseline and follow-up data. The patients were followed up for clinical outcomes at 3 months through face-to-face interview and at 12 months by telephone.Results: Between October 2012 and February 2014, the BOSS registry recruited 2,608 patients from 61 hospitals, with a mean age of 62.5 years, 32.4% of whom were female, 88.9% with an entry diagnosis of IS, and 86% diagnosed with hypertension. The rates of patients lost-to-follow-up were 3.1% at 3 months and 5.1% at 1 year; 93% of patients completed ambulatory BP monitoring during hospitalization and 94.7% finished a 3-month BP diary.Conclusion: The BOSS registry will provide important evidence about BP management in the acute phase and secondary prevention for IS/TIA patients. Keywords: blood pressure, ischemic stroke, transient ischemic attack

Hao Qiu,1,* Chengguo Cheng,2,* Yafeng Wang,3 Mingqiang Kang,4 Weifeng Tang,4,5 Shuchen Chen,4 Haiyong Gu,6 Chao Liu,5 Yu Chen7,8 1Department of Immunology, School of Medicine, Jiangsu University, 2Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, 3Department of Cardiology, The People’s Hospital of Xishuangbanna Dai Autonomous Prefecture, Jinghong, 4Department of Thoracic Surgery, Affiliated Union Hospital, Fujian Medical University, Fuzhou, 5Department of Cardiothoracic Surgery, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, 6Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, 7Department of Medical Oncology, Fujian Provincial Cancer Hospital, Fujian Medical University Cancer Hospital, 8Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, People’s Republic of China *These authors contributed equally to this work Abstract: The relationship between cyclin D1 (CCND1) rs9344 G>A polymorphism and colorectal cancer (CRC) risk is still ambiguous. To obtain a precise estimation of the relationship, we performed an extensive meta-analysis based on the eligible studies. Crude odds ratios with their 95% confidence intervals were harnessed to determine the strength of correlation between CCND1 rs9344 G>A polymorphism and CRC risk under the allele, the homozygote, the dominant, and the recessive genetic models, respectively (28 studies with 5,784 CRC cases and 7,858 controls). Our results indicated evidence of the association between CCND1 rs9344 G>A polymorphism and the increased risk of CRC in four genetic models: A vs G, AA vs GG, AA+GA vs GG, and AA vs GA+GG. In a stratified analysis by cancer type of CRC, there was an increased risk of sporadic CRC found in three genetic models: A vs G, AA vs GG, and AA+GA vs GG. In a stratified analysis by ethnicity, there was an increased CRC risk found among Asians in allele comparison genetic models, as well as Caucasians in two genetic models: AA+GA vs GG and A vs T. In summary, this meta-analysis demonstrates that CCND1 rs9344 G>A polymorphism may be a risk factor for CRC. Keywords: polymorphism, CCND1, colorectal cancer, susceptibility, meta-analysis

Meng Xu, Yuli Jia, Zhikui Liu, Linglong Ding, Run Tian, Hua Gu, Yufeng Wang, Hongyong Zhang, Kangsheng Tu, Qingguang Liu Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China Abstract: Several studies have revealed that the abnormal expression of chromatin assembly factor 1, subunit A (P150) (CHAF1A) was involved in the development of some types of malignant tumors. However, CHAF1A expression and its role in hepatocellular carcinoma (HCC) remain poorly characterized. In this study, we first investigated CHAF1A expression in six cell lines and 116 pairs of HCC and matched normal tumor-adjacent tissues to evaluate the clinicopathological characteristics of CHAF1A in HCC. Then, we detected the proliferation and apoptosis in HCC cells. In addition, a subcutaneous tumor model in nude mice was performed to evaluate tumor growth in vivo. We found that the expression of CHAF1A was significantly higher in HCC tissues than that in adjacent nontumor tissues (P

Lu Zhang,1 Hao Gu,2 Yihang Gu,2 Xiaoning Zeng2 1Clinical Research Centre, 2Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China Background and objective: The association between TNF-α -308 G/A polymorphism and COPD remains controversial due to insufficiently strict study designs and small group sizes among different studies. In the present study, a meta-analysis update which followed a stricter procedure was performed to obtain a clearer understanding of this association.Methods: A comprehensive database search was conducted to identify the case–control studies published up to July 2015 which reported an association between the TNF-α -308 G/A polymorphism and COPD risk. Data were extracted to calculate pooled odds ratios with 95% confidence intervals under the most appropriate genetic and allelic models. Sensitivity was analyzed, and heterogeneity as well as publication bias was assessed.Results: Thirty-eight eligible studies, comprising 3,951 COPD cases and 5,110 controls, were included in this study, among which 22 studies comprising 2,067 COPD cases and 2,167 controls were performed in Asians, and 16 studies comprising 1,884 COPD cases and 2,943 controls were in non-Asians. The overall result showed that TNF-α -308 G/A polymorphisms were significantly associated with increased COPD risk in both the codominant genetic and allelic models. Individuals with the GA or AA genotype were more susceptible to COPD development than those with the GG genotype. In addition, individuals with the AA genotype were more susceptible to developing COPD than those with the GA genotype. The subgroup analysis stratified by ethnicity supported the results in Asians but not in non-Asians. However, no association was found between TNF-α -308 G/A polymorphisms and COPD susceptibility either in Asians or in non-Asians in the meta-analysis conducted with restriction to former/current smokers.Conclusion: The present meta-analysis suggested that the TNF-α -308 G/A polymorphism was associated with an increased risk of COPD among Asians but not in non-Asians. Furthermore, individuals with the AA genotype of TNF-α -308 were more susceptible to developing COPD. Keywords: cytokine, genotype, ethnicity, COPD, smokers

Yijie Chen,1,2,* Xinran Wang,3,4,* Ting Liu,3,4 Ding Sheng-zi Zhang,1,2 Yunfei Wang,3,4 Hongchen Gu,1,2 Wen Di3,4 1State Key Laboratory of Oncogenes and Related Genes, Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, 2School of Biomedical Engineering and Med-X Research Institute, 3Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 4Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Therapeutic antiangiogenesis strategies have demonstrated significant antitumor efficacy in ovarian cancer. Recently, RNA interference (RNAi) has come to be regarded as a promising technology for treatment of disease, especially cancer. In this study, vascular endothelial growth factor (VEGF)-small interfering RNA (siRNA) was encapsulated into a magnetic mesoporous silica nanoparticle (M-MSN)-based, polyethylenimine (PEI)-capped, polyethylene glycol (PEG)-grafted, fusogenic peptide (KALA)-functionalized siRNA delivery system, termed M-MSN_VEGF siRNA@PEI-PEG-KALA, which showed significant effectiveness with regard to VEGF gene silencing in vitro and in vivo. The prepared siRNA delivery system readily exhibited cellular internalization and ease of endosomal escape, resulting in excellent RNAi efficacy without associated cytotoxicity in SKOV3 cells. In in vivo experiments, notable retardation of tumor growth was observed in orthotopic ovarian tumor-bearing mice, which was attributed to significant inhibition of angiogenesis by systemic administration of this nanocarrier. No obvious toxic drug responses were detected in major organs. Further, the magnetic core of M-MSN_VEGF siRNA@PEI-PEG-KALA proved capable of probing the site and size of the ovarian cancer in mice on magnetic resonance imaging. Collectively, the results demonstrate that an M-MSN-based delivery system has potential to serve as a carrier of siRNA therapeutics in ovarian cancer. Keywords: antiangiogenesis, small interfering RNA, mesoporous silica nanoparticles, vascular endothelial growth factor, ovarian cancer

Sihan Xue,1 Yao Wang,1 Mengxing Wang,2 Lu Zhang,1 Xiaoxia Du,2 Hongchen Gu,1 Chunfu Zhang1,31School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, 2Shanghai Key Laboratory of Magnetic Resonance, Department of Physics, East China Normal University, 3State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, People’s Republic of ChinaAbstract: In this study, a novel magnetic resonance imaging (MRI)/computed tomography (CT)/fluorescence trifunctional probe was prepared by loading iodinated oil into fluorescent mesoporous silica-coated superparamagnetic iron oxide nanoparticles (i-fmSiO4@SPIONs). Fluorescent mesoporous silica-coated superparamagnetic iron oxide nanoparticles (fmSiO4@SPIONs) were prepared by growing fluorescent dye-doped silica onto superparamagnetic iron oxide nanoparticles (SPIONs) directed by a cetyltrimethylammonium bromide template. As prepared, fmSiO4@SPIONs had a uniform size, a large surface area, and a large pore volume, which demonstrated high efficiency for iodinated oil loading. Iodinated oil loading did not change the sizes of fmSiO4@SPIONs, but they reduced the MRI T2 relaxivity (r2) markedly. I-fmSiO4@SPIONs were stable in their physical condition and did not demonstrate cytotoxic effects under the conditions investigated. In vitro studies indicated that the contrast enhancement of MRI and CT, and the fluorescence signal intensity of i-fmSiO4@SPION aqueous suspensions and macrophages, were intensified with increased i-fmSiO4@SPION concentrations in suspension and cell culture media. Moreover, for the in vivo study, the accumulation of i-fmSiO4@SPIONs in the liver could also be detected by MRI, CT, and fluorescence imaging. Our study demonstrated that i-fmSiO4@SPIONs had great potential for MRI/C/fluorescence trimodal imaging.Keywords: multifunctional probe, SPIONs, mesoporous silica, iodinated oil

Qian Liu*, Jixi Zhang*, Wei Sun, Qian Reuben Xie, Weiliang Xia, Hongchen Gu School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, People's Republic of China*These authors contributed equally to this workAbstract: Using nanoparticles to deliver chemotherapeutics offers new opportunities for cancer therapy, but challenges still remain when they are used for the delivery of multiple drugs, especially for the synchronous delivery of hydrophilic and hydrophobic drugs in combination therapies. In this paper, we developed an approach to deliver hydrophilic–hydrophobic anticancer drug pairs by employing magnetic mesoporous silica nanoparticles (MMSNs). We prepared 50 nm-sized MMSNs with uniform pore size and evaluated their capability for the loading of two combinations of chemotherapeutics, namely doxorubicin–paclitaxel and doxorubicin– rapamycin, by means of sequential adsorption from the aqueous solution of doxorubicin and nonaqueous solutions of paclitaxel or rapamycin. Experimental results showed that the present strategy successfully realized the co-loading of hydrophilic and hydrophobic drugs with high-loading content and widely tunable ratio range. We elaborate on the theory behind the molecular interaction between the silica hydroxyl groups and drug molecules, which underlie the controllable loading, and the subsequent release of the drug pairs. Then we demonstrate that the multidrug-loaded MMSNs could be easily internalized by A549 human pulmonary adenocarcinoma cells, and produce enhanced tumor cell apoptosis and growth inhibition as compared to single-drug loaded MMSNs. Our study thus realized simultaneous and dose-tunable delivery of hydrophilic and hydrophobic drugs, which were endowed with improved anticancer efficacy. This strategy could be readily extended to other chemotherapeutic combinations and might have clinically translatable significance.Keywords: co-delivery, combination chemotherapy, doxorubicin, mesoporous nanoparticles