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Zhaochang Jiang,1 Haohao Lu,2 Beibei Gao,3 Jinyu Huang,3 Yu Ding4 1Department of Pathology, Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang, 310009, People’s Republic of China; 2Zhejiang Center of Laboratory Animals, Hangzhou Medical College, Hangzhou, Zhejiang, 310063, People’s Republic of China; 3Department of Cardiology, Hangzhou First People’s Hospital, Hangzhou, Zhejiang, 310006, People’s Republic of China; 4Department of Clinical Laboratory, Hangzhou First People’s Hospital, Hangzhou, Zhejiang, 310006, People’s Republic of ChinaCorrespondence: Yu Ding, Department of Clinical Laboratory, Hangzhou First People’s Hospital, Hangzhou, Zhejiang, 310006, People’s Republic of China, Email dingyu_zj@126.comPurpose: Coronary microembolization (CME) can result in cardiac dysfunction, severe arrhythmias, and a reduced coronary flow reserve. Impairment of mitochondrial energy metabolism has been implicated in the progression and pathogenesis of CME; however, its role remains largely undetermined. This study aimed to explore alterations in mitochondria-related genes in CME.Methods: A rat model of CME was successfully established by injecting plastic microspheres into the left ventricle. The cardiac tissues of the two groups were sequenced and mitochondrial functions were assessed.Results: Using RNA-Seq, together with GO and KEGG enrichment analyses, we identified 3822 differentially expressed genes (DEGs) in CME rats compared to control rats, and 101 DEGs were mitochondria-related genes. Notably, 36 DEGs were up-regulated and 65 DEGs were down-regulated (CME vs control). In particular, the oxidative phosphorylation (OXPHOS) and mitochondrial electron transport were obviously down-regulated in the CME group. Functional analysis revealed that CME mice exhibited marked reductions in ATP and mitochondrial membrane potential (MMP), by contrast, the production of reactive oxygen species (ROS) was much higher in CME mice than in controls. Protein–protein interaction (PPI) and quantitative PCR (qPCR) validation suggested that eight hub genes including Cmpk2, Isg15, Acsl1, Etfb, Ndufa8, Adhfe1, Gabarapl1 and Acot13 were down-regulated in CME, whereas Aldh18a1 and Hspa5 were up-regulated.Conclusion: Our findings suggest that dysfunctions in mitochondrial activity and metabolism are important mechanisms for CME, and mitochondria-related DEGs may be potential therapeutic targets for CME.Keywords: CME, rat model, RNA-Sequence, DEGs, OXPHOS, energy metabolism

Fengyi Yang,1,2,* Qiaoyan Dong,3,* Zhuo Chen,1,2,* Benjian Gao,1,2,* Dongning Zheng,1,2 Rui Wang,1,2 Shu Qin,1,2 Fangyi Peng,1,2 Ming Luo,1,2 Jin Yang,1,2 Mengmei Nie,4 Bo Li,1,2 Xiaoli Yang1,2 1Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 2Academician (Expert) Workstation of Sichuan Province, Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 3Luzhou Senior High School, Luzhou, 646000, People’s Republic of China; 4Department of Urological Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bo Li; Xiaoli Yang, Email liboer2002@126.com; 344920646@qq.comPurpose: The efficacy of systemic therapy for hepatocellular carcinoma (HCC) is limited mainly by the complex tumor defense mechanism and the severe toxic side-effects of drugs. The efficacy of apatinib (Apa), a key liver cancer treatment, is unsatisfactory due to inadequate targeting and is accompanied by notable side-effects. Leveraging nanomaterials to enhance its targeting represents a crucial strategy for improving the effectiveness of liver cancer therapy.Patients and Methods: A metal polyphenol network-coated apatinib-loaded metal-organic framework-based multifunctional drug-delivery system (MIL-100@Apa@MPN) was prepared by using metal-organic frameworks (MOFs) as carriers. The nanoparticles (NPs) were subsequently characterized using techniques such as X-ray diffraction (XRD), transmission electron microscopy (TEM), zeta potential measurements, and particle size analysis. In vitro experiments were conducted to observe the drug release kinetics and cytotoxic effects of MIL-100@Apa@MPN on HepG2 cells. The in vivo anti-tumor efficacy of MIL-100@Apa@MPN was evaluated using the H22 tumor-bearing mouse model.Results: The formulated MIL-100@Apa@MPN demonstrates remarkable thermal stability and possesses a uniform structure, with measured drug-loading (DL) and encapsulation efficiency (EE) rates of 28.33% and 85.01%, respectively. In vitro studies demonstrated that HepG2 cells efficiently uptake coumarin-6-loaded NPs, and a significant increase in cumulative drug release was observed under lower pH conditions (pH 5.0), leading to the release of approximately 73.72% of Apa. In HepG2 cells, MIL-100@Apa@MPN exhibited more significant antiproliferative activity compared to free Apa. In vivo, MIL-100@Apa@MPN significantly inhibited tumor growth, attenuated side-effects, and enhanced therapeutic effects in H22 tumor-bearing mice compared to other groups.Conclusion: We have successfully constructed a MOF delivery system with excellent safety, sustained-release capability, pH-targeting, and improved anti-tumor efficacy, highlighting its potential as a therapeutic approach for the treatment of HCC.Keywords: metal-organic frameworks nanoparticles, apatinib, drug-targeting delivery, ferroptosis therapy, hepatocellular carcinoma

Weitang Sun,1 Jingbin Zhong,1 Buyun Gao,2 Jieling Feng,1 Zijie Ye,1 Yueling Lin,3 Kelan Zhang,3 Wenqi Su,3 Shibo Zhu,1 Yinghua Li,4 Wei Jia1 1Department of Pediatric Urology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, People’s Republic of China; 2School of Pharmacy, Fudan University, Shanghai, People’s Republic of China; 3Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, People’s Republic of China; 4Center Laboratory, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, People’s Republic of ChinaCorrespondence: Wei Jia, Email jiawei198044@hotmail.comPurpose: Hydroxyapatite-based nanoparticles have found diverse applications in drug delivery, gene carriers, diagnostics, bioimaging and tissue engineering, owing to their ability to easily enter the bloodstream and target specific sites. However, there is limited understanding of the potential adverse effects and molecular mechanisms of these nanoparticles with varying geometries upon their entry into the bloodstream. Here, we used two commercially available hydroxyapatite nanoparticles (HANPs) with different geometries (less than 100 nm in size each) to investigate this issue.Methods: First, the particle size, Zeta potential, and surface morphology of nano-hydroxyapatite were characterized. Subsequently, the effects of 2~2000 μM nano-hydroxyapatite on the proliferation, migration, cell cycle distribution, and apoptosis levels of umbilical vein endothelial cells were evaluated. Additionally, the impact of nanoparticles of various shapes on the differential expression of genes was investigated using transcriptome sequencing. Additionally, we investigated the in vivo biocompatibility of HANPs through gavage administration of nanohydroxyapatite in mice.Results: Our results demonstrate that while rod-shaped HANPs promote proliferation in Human Umbilical Vein Endothelial Cell (HUVEC) monolayers at 200 μM, sphere-shaped HANPs exhibit significant toxicity to these monolayers at the same concentration, inducing apoptosis/necrosis and S-phase cell cycle arrest through inflammation. Additionally, sphere-shaped HANPs enhance SULT1A3 levels relative to rod-shaped HANPs, facilitating chemical carcinogenesis-DNA adduct signaling pathways in HUVEC monolayers. In vivo experiments have shown that while HANPs can influence the number of blood cells and comprehensive metabolic indicators in blood, they do not exhibit significant toxicity.Conclusion: In conclusion, this study has demonstrated that the geometry and surface area of HANPs significantly affect VEC survival status and proliferation. These findings hold significant implications for the optimization of biomaterials in cell engineering applications.Keywords: hydroxyapatite nanoparticle, circulatory system, biocompatibility, survival, proliferation

Siyuan Wang,1,* Beiyao Gao,1,* Minghui Shi,2– 6 Shiwei Qumu,2– 5 Fen Dong,2– 5,7 Peijian Wang,1 Ting Yang,2– 5 Shan Jiang1 1Department of Rehabilitation Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 2National Center for Respiratory Medicine, Beijing, People’s Republic of China; 3National Clinical Research Center for Respiratory Diseases, Beijing, People’s Republic of China; 4Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 5Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 6Capital Medical University, Beijing, People’s Republic of China; 7Department of Clinical Research and Data management, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shan Jiang; Ting Yang, China-Japan Friendship Hospital, 2 Yinghuayuan East St. Hepingli, Chaoyang District, Beijing, 100029, People’s Republic of China, Email landjiang@126.com; dryangting@qq.comObjective: Given the established impact of exercise in reducing arterial stiffness and the potential for intermittent hypoxia to induce its elevation, this study aims to understand how oxygen desaturation during exercise affects arterial stiffness in individuals with COPD.Methods: We enrolled patients with stable COPD from China-Japan Friendship Hospital from November 2022 to June 2023. The 6-minute walk test (6-MWT) was performed with continuous blood oxygen saturation (SpO2) monitoring in these patients. The patients were classified into three groups: non-exercise induced desaturation (EID), mild-EID and severe-EID, according to the changes in SpO2 during the 6-MWT. The Cardio-Ankle Vascular Index (CAVI) and the change in CAVI (ΔCAVI, calculated as CAVI before 6MWT minus CAVI after the 6MWT) were measured before and immediately after the 6MWT to assess the acute effects of exercise on arterial stiffness. GOLD Stage, pulmonary function, and other functional outcomes were also measured in this study.Results: A total of 37 patients with stable COPD underwent evaluation for changes in CAVI (ΔCAVI) before and after the 6-MWT. Stratification based on revealed three subgroups: non-EID (n=12), mild-EID (n=15), and severe-EID (n=10). The ΔCAVI values was − 0.53 (− 0.95 to − 0.31) in non-EID group, − 0.20 (− 1.45 to 0.50) in mild-EID group, 0.6 (0.08 to 0.73) in severe-EID group. Parametric tests indicated significant differences in ΔCAVI among EID groups (p = 0.005). Pairwise comparisons demonstrated significant distinctions between mild-EID and severe-EID groups, as well as between non-EID and severe-EID groups (p = 0.048 and p = 0.003, respectively). Multivariable analysis, adjusting for age, sex, GOLD stage, diffusion capacity, and blood pressure, identified severe-EID as an independent factor associated with ΔCAVI (B = 1.118, p = 0.038).Conclusion: Patients with COPD and severe-EID may experience worsening arterial stiffness even during short periods of exercise.Keywords: COPD, arterial stiffness, exercise-induced oxygen desaturation, rehabilitation

Wenjie Qu,1,2,* Xinyu Wang,1,* Yufei Liu,3 Jinfeng Mao,2 Mengchi Liu,4 Yaqin Zhong,1,2 Bella Gao,5 Miaomiao Zhao,1 Yuexia Gao1,2 1Department of Health Management, School of Public Health, Nantong University, Nantong, People’s Republic of China; 2Institute for Health Development, Nantong University, Nantong, People’s Republic of China; 3Faculty of Health Sciences, University of Macau, Macau, People’s Republic of China; 4National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People’s Republic of China; 5Ulink College of Suzhou Industrial Park, Suzhou, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Miaomiao Zhao; Yuexia Gao, Department of Health Management, School of Public Health, Nantong University, 9 Seyuan Road, Jiangsu, 226019, People’s Republic of China, Tel +86150 0450 1812 ; +86139 6296 8819, Email zhaomiaomiao@ntu.edu.cn; yxgao@ntu.edu.cnBackground: Self-medication with antibiotics (SMA) among children is a common practice in low-income and middle-income countries, which has accelerated antibacterial abuse.Objective: This study aimed to estimate the prevalence and associated factors of SMA among children in China, including parents’ knowledge, attitudes, and practices towards antibiotic use.Methods: A cross-sectional study based on a structured questionnaire survey of parents was conducted in Nantong between July and September 2020. A total of 1699 respondents participated. Information on participants’ demographic and family characteristics, knowledge, attitudes, and practices towards antibiotics use was collected. Hierarchical binary logistic regression was used to examine the predictors of SMA among children.Results: Among 1699 participants, 23.31% practiced SMA to their children in the past year. Cough (59.6%) was the most common symptom leading to self-medication and penicillins (85.4%) were the most commonly used drugs. Hierarchical regression indicated that parents with higher level of antibiotic knowledge scores (OR=1.163, 95% CI: 1.067– 1.268) and buying antibiotics without a prescription from pharmacy (OR=1.475, 95% CI: 1.097– 1.983) were more likely to practice SMA to their children both in urban and in rural areas. Storing antibiotics at home resulted in an increased likelihood of self-medication in urban areas but not in rural areas. In addition, there was also a higher probability of non-prescribed antibiotics in children without chronic diseases (OR=1.959, 95% CI:1.072– 3.578).Conclusion: The prevalence of SMA in children is high in China. Higher knowledge scores and practices of buying and storing non-prescribed antibiotics behaviors increased parents’ antibiotic self-medication in their children. Practical and effective education intervention for children’s rational use of antibiotics is urgently strengthened.Keywords: antibiotic, self-medication, children, China, antibiotic knowledge, attitude

Benjian Gao,1,2,* Fengyi Yang,1,2,* Dongning Zheng,1,2 Shuai Hu,1,2 Jie Liu,1,2 Hong Liu,1,2 Yongfa Liu,1,2 LinXin Liu,1,2 Rui Wang,1,2 Yi Zhao,1,2 Cheng Cui,1,2 Cheng Fang,1,2 Jin Yang,1,2 Song Su,1,2 Yunwei Han,3 Xiaoli Yang,1,2 Bo Li1,2 1Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 2Academician (Expert) Workstation of Sichuan Province, Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, The Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 3Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoli Yang; Bo Li, Email 344920646@qq.com; liboer2002@126.comPurpose: This study aimed to explore the clinical efficacy of transarterial chemoembolization (TACE) in combination with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs) (triple therapy) compared to TACE alone (monotherapy) for advanced hepatocellular carcinoma (HCC).Material and Methods: Data of consecutive advanced HCC patients receiving triple therapy or monotherapy at our center between January 2019 and December 2022 were collected and retrospectively analyzed. Propensity score matching (PSM) and subgroup analyses were performed to reduce the bias between the two groups. The primary outcomes of the study were the overall survival (OS) and progression-free survival (PFS). The secondary outcomes were the objective response rate (ORR) and disease control rate (DCR).Results: A total of 104 patients were enrolled in this study: 41 in the triple therapy group and 63 in the monotherapy group. After PSM analysis, each group included 37 patients. The median OS and PFS were significantly longer in the triple therapy group than in the monotherapy group in the whole cohort (median OS, 18.8 vs 11.7 months, P = 0.022; median PFS, 10.5 vs 6.4 months, P = 0.012) and after PSM (median OS, 19.6 vs 12.5 months, P = 0.030; median PFS, 10.5 vs 6.7 months, P = 0.008). Furthermore, the treatment modality was an independent prognostic factor for OS (hazard ratio [HR]: 0.449, 95% confidence interval [CI]: 0.240– 0.840, P = 0.012) and PFS (HR: 0.406, 95% CI: 0.231– 0.713, P = 0.002) according to the multivariate cox regression analysis. A greater ORR was also observed in the triple therapy group (ORR: 56.7% vs 32.4%, P = 0.035). No significant difference was observed in DCR between the two groups (83.7% vs 72.9%, P = 0.259).Conclusion: The triple therapy was superior to the monotherapy regarding OS, PFS, and ORR of advanced HCC patients.Keywords: hepatocellular carcinoma, transarterial chemoembolization, tyrosine kinase inhibitors, immune checkpoint inhibitors, efficacy

Jinling Yu,1 Haofeng Wang,1 Weida Shen,1 Yingzi Zhou,2 Jing Cui,1 Haichuan Li,3 Beimin Gao1 1Department of Breast Surgery, Shanghai Changning Maternity and Infant Health Hospital, East China Normal University, Shanghai, 200050, People’s Republic of China; 2Department of Pathology, Shanghai Changning Maternity and Infant Health Hospital, East China Normal University, Shanghai, 200050, People’s Republic of China; 3Department of Laboratory, Shanghai Changning Maternity and Infant Health Hospital, East China Normal University, Shanghai, 200050, People’s Republic of ChinaCorrespondence: Beimin Gao; Haichuan Li, Shanghai Changning Maternity and Infant Health Hospital, East China Normal University, No. 786, Yuyuan Road, Changning District, Shanghai, 200050, People’s Republic of China, Tel +86-21-62288686-2401, Email gbgaobeimin@163.com; lihaichuancfy@163.comBackground: This study aimed to analyze the specific expression of hsa_circ_0007823 in triple-negative breast cancer (TNBC) and explore the roles and related molecular mechanisms of hsa_circ_0007823 in TNBC.Materials and Methods: Relative hsa_circ_0007823 levels in TNBC tissues and cell lines were examined by reverse transcription-quantitative polymerase chain reaction. The value of hsa_circ_0007823 levels was evaluated in patients’ clinicopathological characteristics and prognostic prediction. A dual-luciferase reporter assay was used to determine the relationship between hsa_circ_0007823, miR-182-5p, and FOXO1. The effect of circ_0007823 overexpression on the growth of TNBC cells was investigated in vitro and in vivo.Results: Lower levels of hsa_circ_0007823 were found in TNBC tissues and cell lines and were closely associated with lymph node metastasis, poorer overall and disease-free survival rates. MiR-182-5p was significantly up-regulated, whereas FOXO1 was down-regulated in TNBC cell lines. The miR-182-5p inhibition up-regulated FOXO1 in TNBC cells. Dual-luciferase reporter assays showed that hsa_circ_0007823, miR-182-5p, and FOXO1 interacted with each other. Overexpression of circ_0007823 significantly inhibited the viability, migration, and invasion of TNBC cell lines, but promoted apoptosis. In vivo experiments showed that circ_0007823 overexpression inhibited tumor growth and down-regulated miR-182-5p and up-regulated FOXO1.Conclusion: Hsa_circ_0007823 overexpression could suppress the growth, invasion, and migration of TNBC cells, and inhibit tumor growth by regulating miR-182-5p/FOXO1.Keywords: triple-negative breast cancer, hsa_circ_0007823, miR-182, FOXO1, biological functional analysis

Wenfang He,1,* Siqiang Zheng,1,* Hua Zhang,2 Bowen Gao,3 Juan Jin,1 Mingzhen Zhang,3,4 Qiang He1 1Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, Zhejiang, 310000, People’s Republic of China; 2Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China; 3School of Basic Medical Sciences, Xi’an Key Laboratory of Immune Related Diseases, Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, People’s Republic of China; 4Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Ministry of Education, Xi’an, Shaanxi, 710061, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qiang He; Mingzhen Zhang, Email qianghe1973@126.com; mzhang21@xjtu.edu.cnAbstract: The utilization of plant-derived vesicle-like nanoparticles (PDVLNs) has shown effectiveness in the prevention/treatment of inflammatory-mediated diseases, malignancies, and immune-related diseases, such as acute liver injury, allergic asthma, gastric cancer and so on. This highlights the promising potential of PDVLNs as biotherapeutics. Furthermore, it should be noted that PDVLNs possess the ability to function as both natural and engineered drug carriers, making them an appealing option. This review aims to present the appropriate extraction methods of PDVLNs, summarize the applications of PDVLNs in different diseases, and provide an outlook on the prospects of PDVLNs. At the same time, the authors also express their discussion on the current limitations of PDVLNs.Keywords: plant-derived vesicle-like nanoparticles, extraction methods, anti-inflammatory, immune regulation, antitumor

Bin Gao,1,2,* Yuanyuan Liu,3,* Quanwei Shen,4 Changqing Fu,3 Weiyi Li,5 Xu Li4 1Research Institute for International and Comparative Education, Shanghai Normal University, Shanghai, 200234, People’s Republic of China; 2Lab for Educational Big Data and Policymaking, Shanghai Normal University, Shanghai, 200234, People’s Republic of China; 3Mental Health Center, Hubei University of Medicine, Shiyan, 442000, People’s Republic of China; 4School of Education, Shanghai Normal University, Shanghai, 200234, People’s Republic of China; 5School of Business Administration, Jimei University, Xiamen, 361021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Quanwei Shen, School of Education, Shanghai Normal University, 100 Guilin Road, Xuhui District, Shanghai, 200234, People’s Republic of China, Tel +86 13429962432, Email psywe@qq.comBackground: With the popularity of smartphone and their increasingly rich functions, people’s attachment to their phones is increasing. While people enjoy the convenience that smartphone bring (eg, accessing information and socializing), it also leads to problematic smartphone use (eg, phubbing). Previous research has shown that boredom proneness can trigger phubbing. However, the underlying psychological mechanisms are not yet clear.Methods: To address this research gap, we surveyed 556 Chinese college students (Mage = 18.89 years, SD = 1.18) during the COVID-19 pandemic and all participants completed a self-report questionnaire. Drawing the Interaction of Person-Affect-Cognition-Execution model (I-PACE) for addictive behaviors, this study developed and examined a multiple mediation model incorporating boredom proneness, loneliness, fear of missing out (FoMO), and phubbing.Results: (1) Boredom proneness could positively predict phubbing; (2) loneliness and FoMO mediated the relationship between boredom proneness and phubbing, respectively; and (3) loneliness and FoMO sequentially mediated the relationship between boredom proneness and phubbing.Conclusion: These findings are not only valuable for understanding the underlying mechanisms linking boredom proneness and phubbing, but also suggest that three types of interventions could be effectively used to decrease the risk of phubbing among college students, namely, reducing boredom proneness, relieving loneliness, and decreasing FoMO.Keywords: boredom proneness, loneliness, FoMO, phubbing, multiple mediation model, college students

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

Lihua Han,1 Bo Gao,2 En-Hua Wang,3 Liang Wang3 1The Central Laboratory of Morphology, Shenyang Medical College, Shenyang, People’s Republic of China; 2Department of Pathology, Cancer Hospital of China Medical University, Shenyang, People’s Republic of China; 3Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, People’s Republic of ChinaCorrespondence: Lihua Han, The Central Laboratory of Morphology, Shenyang Medical College, Shenyang, People’s Republic of China, Email hanlihualn@163.comAbstract: The metaplastic thymoma with giant multilocular-cyst formation had not been documented. The metaplastic thymoma is an extremely rare primary thymic epithelial tumor with an indolent clinical course. It is characterized by a histologic biphasic appearance, which is consisted of solid epithelial areas and spindle cells as the background. This specific pattern can be easily mistaken as the type A thymoma or the type A components of type AB thymoma. When cystic change occurs in metaplastic thymoma, it will bring more challenges for both imaging and pathological diagnosis. Herein, we reported an extremely rare case of a 14.9-cm giant tumor located in the anterior mediastinum of an elderly female. The tumor is consisted of both multilocular cysts and solid components, with the largest cyst measuring 6 cm in diameter. The multilocular cyst contained hemorrhage, calcification, and cholesterol crystal cracks without cell lining. In the solid area, the epithelial cell nests were surrounded by spindle cells with scattered lymphocytes. With immunostains, neither type of cells was CD20 positive. The epithelial cells were positive for CK and P63, while the spindle cells expressed vimentin and EMA. Fluorescence in situ hybridization analysis revealed that the tumor harbored YAP1-MAML2 gene fusions. Accordingly, although the multilocular cystic pattern set a diagnostic challenge, the diagnosis of metaplastic thymoma was rendered due to the immunohistochemistry staining and YAP1-MAML2 gene rearrangement detection.Keywords: metaplastic thymoma, thymoma, thymic cyst, FISH, YAP1-MAML2

Bo Gao,1,* Rui Li,2,* Xiaojia Song,3 Shan Hu,4 Fengmei Yang4 1Departments of Laboratory Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People’s Republic of China; 2Departments of Medical office, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People’s Republic of China; 3Shiyan Prefecture Center for Disease Control and Prevention, Shiyan, Hubei, 442000, People’s Republic of China; 4Departments of Obstetrics and Gynecology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fengmei Yang, Email 29256175@qq.comBackground: Lung squamous cell carcinoma (LUSC) is a type of lung cancer that originates from segmental or subsegmental bronchial mucosa. There is evidence that miRNA plays an important role in the occurrence and progression of tumors.Methods: In this study, plasma samples of patients with early LUSC and healthy volunteers were subjected to miRNA sequencing, and the levels of differentially expressed miRNAs (DEMs) in LUSC tissues were analyzed using R language. Cox regression and Kaplan–Meier (K-M) survival curve analyses were performed to determine the relationship between DEMs and prognosis in LUSC, and PCR method was verified for the plasma expression level of DEMs in patients with LUSC. The levels of CYFRA21-1 and SCC-Ag in plasma were measured, and area under curve (AUC) was used to evaluate the diagnostic value of the DEMs.Results: A total of 21 DEMs were screened out by sequencing. The expression levels of DEMs in tissue samples in the TCGA database were analyzed, and four DEMs with consistent expression levels were further screened from plasma and tissue samples. Regression analysis and K-M curve were performed to select two DEMs (miR-139-5p, miR-451a) that were correlated with the prognosis. PCR verification results showed that the levels of miR-451a and miR-139-5p were low in patients, and the level of miR-139-5p in late stages III & IV with the patients of LUSC was higher than that in stages I & II. The AUC values of the four indicators (SCC-Ag, CYFRA21-1, miR-451a and miR-139-5p) in the diagnosis of LUSC, early and late cases were 0.884, 0.935 and 0.778, respectively.Conclusion: The detection of miR-139-5p and miR-451a levels in plasma has a certain potential in the non-invasive diagnosis, especially in patients with early stages of LUSC.Keywords: miR-139-5p, LUSC, miR-451a, diagnosis, prognosis

Zhaolin Li,1,&ast; Qiaojun Zeng,1,&ast; Shuwan Xu,2,&ast; Yuewei Li,1 Tiantian Tang,1 Jianting Shi,1 Xueming Song,1 Wenman He,1 Liang Chen,1 Guirong Liu,1 Boying Gao,3 Jianming Zheng,4 Linjie Huang,1 Ming Chen,1 Shanping Jiang1 1Department of Pulmonary and Critical Care Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 2Department of Cardiology, the Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, People’s Republic of China; 3Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 4Cardiovascular Medicine Department, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shanping Jiang; Ming Chen, Department of Pulmonary and Critical Care Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Yan-jiang Xi Road 107, Guangzhou, 510120, People’s Republic of China, Tel +86-20-81332441, Email jiangshp@mail.sysu.edu.cn; chenm69@mail.sysu.edu.cnBackground: Although tigecycline is an effective drug against drug-resistant bacteria, it demonstrated a higher all-cause mortality than comparator antibiotics and a high incidence of coagulation disorders which can be accompanied by severe bleeding. At present, a predictive model for tigecycline-related coagulopathy is not readily available, and the prognostic value of coagulopathy in tigecycline-administered patients has not been elucidated. In this paper, we investigate the association between tigecycline-related coagulopathy and in-hospital mortality to develop a nomogram for the prediction of tigecycline-related coagulopathy.Methods: This retrospective cohort study includes 311 adults prescribed with tigecycline from 2018 to 2020. The primary cohort and validation cohort were constructed by dividing the participants in a ratio of 7:3. The endpoint is tigecycline-related coagulopathy, defined as a condition with no abnormality in coagulation prior to tigecycline application but developed the following symptoms upon prescription: activated partial thromboplastin time (APTT) extended by > 10 s than the upper limit of normal (ULN), prothrombin time (PT) prolonged for > 3 s than the ULN or reduced serum level of fibrinogen to < 2.0 g/L. A predictive nomogram based on logistic regression was subsequently constructed.Results: Tigecycline intake for over 7 days, combined other antibiotics, initial PT, initial fibrinogen and estimated glomerular filtration rate (eGFR), are independent prognostic factors of tigecycline-related coagulopathy. The primary and validation cohort each has an area under the receiver operating characteristic curve (AUC) of 0.792 (0.732– 0.851) and 0.730 (0.629– 0.832) for nomogram, respectively. Furthermore, the fitted calibration curve illustrated adequate fit of the model, while the decision curve analysis demonstrated good clinical value. Survival curves showed a high mortality rate among patients with tigecycline-related coagulopathy.Conclusion: This nomogram exhibited helpful clinical value in predicting tigecycline-related coagulopathy that could reduce the high mortality rate of patients prescribed with tigecycline.Keywords: tigecycline, drug-resistant bacteria, coagulopathy, nomogram

Jie Zhou,1,2 Hongjin Xiang,1,2 Jianbo Huang,1,2 Yi Zhong,3 Xiaoxia Zhu,1,2 Jinshun Xu,1,2 Qiang Lu,1,2 Binyang Gao,1,2 Huan Zhang,1,2 Rui Yang,1,2 Yan Luo,1,2 Feng Yan1,2 1Ultrasound Department, West China Hospital of Sichuan University, Chengdu, People’s Republic of China; 2Laboratory of Ultrasound Imaging, West China Hospital of Sichuan University, Chengdu, People’s Republic of China; 3Laboratory of Mitochondria and Metabolism, West China Hospital of Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Feng Yan, Laboratory of Ultrasound Imaging, West China Hospital of Sichuan University, Chengdu, People’s Republic of China, Tel/Fax +86 028 8516 4146, Email yan_feng@scu.edu.cn Yan Luo, Ultrasound Department, West China Hospital of Sichuan University, Chengdu, People’s Republic of China, Tel/Fax +86 028 8542 3192, Email yanluo@scu.edu.cnPurpose: To prepare nanoscale ultrasound contrast agents (Nano-UCAs) and examine the role of their surface charge in complement activation and phagocytosis.Materials and Methods: We analyzed serum proteins present in the corona formed on Nano-UCAs and evaluated two important protein markers of complement activation (C3 and SC5b-9). The effect of surface charge on phagocytosis was further assessed using THP-1 macrophages.Results: When Nano-UCAs were incubated with human serum, they were opsonized by various blood proteins, especially C3. Highly charged Nano-UCAs, whether positive or negative, were favorably opsonized by complement proteins and phagocytized by macrophages.Conclusion: Charged Nano-UCAs show a higher tendency to activated complement system, and are efficiently engulfed by macrophages. The present results provide meaningful insights into the role of the surface charge of nanoparticles in the activation of the innate immune system, which is important not only for the design of targeted Nano-UCAs, but also for the effectiveness and safety of other theranostic agents.Graphical Abstract: Keywords: nanoscale ultrasound contrast agents, surface charge, protein corona, complement activation, opsonization, phagocytosis

Rui Yang,1 Jiayan Huang,1 Min Liao,1 Jianbo Huang,1 Binyang Gao,1 Huan Zhang,1 Jie Zhou,1 Jinshun Xu,2 Qiang Lu1 1Department of Ultrasound, Laboratory of Ultrasound Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China; 2Ultrasound Medical Center, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Cancer Hospital Affiliated to School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610041, People’s Republic of ChinaCorrespondence: Qiang Lu, Department of Ultrasound, Laboratory of Ultrasound Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China, Tel/Fax +86 13882175090, Email luqiang@scu.edu.cn Jinshun Xu, Ultrasound Medical Center, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Cancer Hospital Affiliated to School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610041, People’s Republic of China, Tel/Fax +86 18708491127, Email jsxu86@163.comBackground: Microwave dynamic therapy (MDT) as a novel reactive oxygen species (ROS)-based therapeutic modality has been explored as a promising modality for cancer treatment. However, the intrinsic hypoxic tumor microenvironment (TME) restricted the effectiveness of the MDT. The aim of this study is to develop an oxygen-sufficient nanoplatform with multi-modal imaging capability for enhanced MDT against hypoxic tumors.Methods and Materials: The liquid perfluorocarbon-based nanoplatform PFP@IR780@O2 was constructed by the phospholipid hydration and sonication method. Then, the characteristics, intracellular uptake process, and subcellular localization of PFP@IR780@O2 were verified. Additionally, the abilities of ROS generation, the anti-hypoxia capability, multi-mode imaging capabilities, and MDT efficacy of the nanoplatform were evaluated via in vitro and in vivo experiments. Finally, the in vivo biocompatibility and toxicity were also evaluated.Results: The prepared nanoparticles PFP@IR780@O2 exhibited suitable size, improved stability, elevated dissolved oxygen level, enhanced cellular uptake, and mitochondria targeting capacity. Additionally, PFP@IR780@O2 demonstrated in vitro and in vivo multimodal imaging capabilities involving ultrasound, fluorescence, and photoacoustic imaging. In vivo studies also indicated that nanoparticles were safe and capable of accumulating in the tumor site after intravenous injection. Furthermore, the PFP@IR780@O2 nanoplatform mediated MDT could effectively alleviate the hypoxic TME, and elevate ROS concentration, thereby resulting in significant tumor growth inhibition.Conclusion: Overall, the oxygen-sufficient nanoplatform with multi-bimodal imaging capability demonstrated improved MDT efficiency, indicating a promising strategy for treating hypoxic tumors.Keywords: nanomedicine, perfluorocarbon, reactive oxygen species, tumor hypoxia relief

Shucheng Liu,1 Yilin Wang,2 Bin Gao,2 Jun Peng2 1Department of Urology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang City, Hunan Province, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang City, Hunan Province, People’s Republic of ChinaCorrespondence: Jun PengDepartment of Neurology, The First Affiliated Hospital, Hengyang Medical School, University of South China, No. 69 Chuanshan Road, Hengyang City, Hunan Province, People’s Republic of China, Tel +86 19958919270, Fax +86 734-8578774, Email pengjun278@163.comPurpose: To establish and validate a nomogram model for predicting stress-related gastrointestinal bleeding in critically ill patients with primary intracerebral hemorrhage.Patients and Methods: From January 2018 to March 2021, we conducted a hospital-based study by screening eligible patients with acute intracerebral hemorrhage. Univariate and multivariate logistic regression analyses were performed to determine the predictors for stress-related gastrointestinal bleeding in patients with primary intracerebral hemorrhage. The nomogram was constructed on the basis of multivariate logistic model and was internally validated by bootstrap resampling. The discriminative performance of the nomogram was evaluated using the calibration and concordance index (C-index), which was equal to the area under the curve of receiver-operating characteristics. Hosmer-Lemeshow test was performed to check the model’s goodness of fit. A decision curve analysis was used to assess its clinical utility.Results: A total of 410 patients were enrolled in this study. Stress-related gastrointestinal bleeding occurred in 115 patients (28.0%). Multivariate analysis demonstrated that gastric pH at admission [odds ratio (OR): 0.52, 95% confidence interval (CI): 0.41– 0.66, P < 0.001], ICH volume (OR: 1.03, 95% CI: 1.02– 1.05, P < 0.001) and sepsis (OR: 2.56, 95% CI: 1.54– 4.25, P < 0.001) were independent predictors for stress-related gastrointestinal bleeding in critically ill patients with ICH. The nomogram including gastric pH at admission, ICH volume and sepsis presented good discrimination with C-index of 0.770 (95% CI: 0.716 to 0.822), which was confirmed to be 0.764 through bootstrapping validation. The calibration plot showed good agreement between the predicted and observed outcomes. The Hosmer–Lemeshow test showed a goodness-of-fit (Chi-Square = 8.085, DF = 8, P = 0.425). Decision curve analysis demonstrated that the nomogram was clinically beneficial.Conclusion: The proposed nomogram based on gastric pH at admission, ICH volume and sepsis can accurately predict the risk of stress-related gastrointestinal bleeding in critically ill patients with primary intracerebral hemorrhage.Keywords: nomogram, stress-related gastrointestinal bleeding, intracerebral hemorrhage, prediction, decision curve analysis

Bin Liu,1 Faping Li,1 Mingdi Liu,2 Zhixiang Xu,2 Baoshan Gao,1 Yishu Wang,2 Honglan Zhou1 1Department of Urology, the First Hospital of Jilin University, Changchun, 130021, Jilin, People’s Republic of China; 2Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, Jilin, People’s Republic of ChinaCorrespondence: Yishu WangKey Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, Jilin, People’s Republic of China, Tel +86-18686686698Email wangys@jlu.edu.cnHonglan ZhouDepartment of Urology, the First Hospital of Jilin University, Changchun, 130021, Jilin, People’s Republic of ChinaTel +86 0431-81875821Email hlzhou@jlu.edu.cnBackground: Abnormal expression of phosphofructokinase platelet (PFKP) has been reported in various cancer types. However, the role of PFKP in clear cell renal cell carcinoma (ccRCC) remains unclear.Methods: In this study, the PFKP expression levels in various cancers were systemically described by integrating multiple kinds of publicly available databases. The relationship between PFKP expression and clinical prognosis of ccRCC patients was analyzed based on the TCGA database. Furthermore, PFKP-related genes and the top 10 hub genes were identified. The enrichment analysis, PPI network, and the relationship between PFKP and tumor-infiltrating immune cells were conducted to explore why PFKP was associated with clinical outcomes in ccRCC patients.Results: PFKP was significantly highly expressed in kidney cancer, especially in ccRCC. Moreover, patients with low expression of PFKP were correlated with poor 5-year and 10-year overall survival (OS) (P < 0.05). Low PFKP expression was a risk factor associated with decreased OS in subgroups including males, females, grade 3– 4, and stage III–IV (all P < 0.05). GO and KEGG enrichment analyses showed that 10 hub genes were mainly enriched in the tumor immune response. Finally, PFKP expression level was highly correlated with the infiltration of B cell, CD8+ T cell, CD4+ T cell, macrophage, neutrophil, and dendritic cell.Conclusion: In short, our findings suggested that PFKP is highly expressed in ccRCC significantly and facilitated tumor immune response which in turn associated with a good prognosis.Keywords: phosphofructokinase platelet, clear cell renal cell carcinoma, prognosis, biological function enrichment analyses, tumor immune infiltrating cells

Haiyan Ge,1,&ast; Xuanqi Liu,1,&ast; Wenchao Gu,2 Xiumin Feng,3,4 Fengying Zhang,5 Fengfeng Han,6 Yechang Qian,7 Xiaoyan Jin,8 Beilan Gao,9 Li Yu,10 Hong Bao,11 Min Zhou,12 Shengqing Li,13 Zhijun Jie,14 Jian Wang,15 Zhihong Chen,16 Jingqing Hang,5 Jingxi Zhang,3 Huili Zhu1 1Department of Respiratory and Critical Care Medicine, Huadong Hospital, Fudan University, Shanghai, People’s Republic of China; 2Department of Respiratory Medicine, Pudong New District People’s Hospital, Shanghai, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Changhai Hospital Affiliated to Navy Military Medical University, Shanghai, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, Changji Branch of First Affiliated Hospital of Xinjiang Medical University, Xinjiang, People’s Republic of China; 5Department of Respiratory Medicine, Putuo District People’s Hospital, Shanghai, People’s Republic of China; 6Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 7Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, People’s Republic of China; 8Department of Respiratory Medicine, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 9Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University, Shanghai, People’s Republic of China; 10Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 11Department of Respiratory Medicine Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China; 12Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 13Department of Respiratory and Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 14Department of Respiratory Medicine, Shanghai Fifth’s Hospital, Fudan University, Shanghai, People’s Republic of China; 15Department of Respiratory Medicine, Shanghai Ninth’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 16Department of Respiratory and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huili Zhu Email zhuhuili001@126.comJingxi Zhang Email jingxizhang2000@126.comBackground: Chronic obstructive pulmonary disease (COPD) often coexists with multiple comorbidities which may have a significant impact on acute exacerbations of patients. At present, what kind of comorbidities affects acute exacerbations and how comorbidities lead to poor prognosis are still controversial. The purpose of our study is to determine the impact of comorbidities on COPD exacerbation and establish an acute exacerbation risk assessment system related to comorbidities.Methods: A total of 742 COPD patients participated in the Shanghai COPD Investigation on Comorbidity Program (SCICP, ChiCTR2000030911). Finally, the baseline information of 415 participants and one-year follow-up data were involved in the analysis. We collected hemogram indices, pulmonary function tests and acute exacerbation of COPD with regular medical follow-up. Q-type cluster analysis was used to determine the clusters of participants. Receiver operating characteristic (ROC) analysis was constructed to assess the ability of indicators in predicting acute exacerbations.Results: Almost 65% of the population we investigated had at least one comorbidity. The distribution and incidence of comorbidities differed between exacerbation group and non-exacerbation group. Three comorbidity clusters were identified: (1) respiratory, metabolic, immune and psychologic disease (non-severe cases); (2) cardiovascular and neoplastic disease (severe cases); (3) less comorbidity. Different sub-phenotypes of COPD patients showed significant distinction in health status. Anxiety (OR=5.936, P=0.001), angina (OR=10.155, P=0.025) and hypertension (OR=3.142, P=0.001) were found to be independent risk factors of exacerbation in a year. The novel risk score containing BODEx and four diseases showed great prognostic value of COPD exacerbation in developing sample.Conclusion: Our study detailed the major interaction between comorbidities and exacerbation in COPD. Noteworthily, a novel risk score using comprehensive index – BODEx – and comorbidity parameters can identify patients at high risk of acute exacerbation.Keywords: chronic obstructive pulmonary disease, exacerbation, comorbidity, risk score

Benjian Gao,1– 3,* Jia Luo,4,* Ying Liu,1– 3,* Song Su,1– 3 Shaozhi Fu,4 Xiaoli Yang,1– 3 Bo Li1– 3 1Department of General Surgery (Hepatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, People’s Republic of China; 2Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan Province, People’s Republic of China; 3Academician (Expert) Workstation of Sichuan Province, Luzhou, Sichuan Province, People’s Republic of China; 4Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoli Yang; Bo LiDepartment of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, No. 25 Taiping Road, Luzhou, Sichuan, 646000, People’s Republic of ChinaTel +86-15086878251; +86-13518371998Email 344920646@qq.com; liboer2002@126.comBackground: The efficacy of systemic chemotherapy for hepatocellular carcinoma (HCC) is predominantly hampered by low accumulation in tumor tissue and the high systemic toxicity of anticancer drugs. In this study, we designed an in situ drug-loaded injectable thermosensitive hydrogel system for the simultaneous delivery of norcantharidin-loaded nanoparticles (NCTD-NPs) and doxorubicin (Dox) via intratumoral administration to HCC tumors.Methods: NCTD-NPs were prepared by the thin film dispersion method using PCEC polymers as the carrier. Then, NCTD-NPs and Dox were co-encapsulated in a thermosensitive hydrogel based on Pluronic F127 (PF127) to construct a dual drug-loaded hydrogel system. The rheological properties of the drug-loaded hydrogel were studied using a rheometer. Drug release of the drug-loaded hydrogel and cytotoxicity in HepG2 cells were evaluated in vitro. An H22 tumor-bearing mice model was used to assess the in vivo antitumor activity of the drug-loaded hydrogel via intratumoral administration.Results: The prepared drug-loaded hydrogel exhibited good thermal-sensitive properties, which remained liquid at room temperature and rapidly transformed into a non-flowing gel at body temperature, and released the drugs in a sustained manner. In vitro studies revealed that the drug-loaded hydrogel exhibited remarkable antiproliferative activity in HepG2 cells compared to free drugs. In vivo antitumor efficacy experiments showed that the drug-loaded hydrogel significantly suppressed tumor growth, alleviated side effects, and prolonged the survival time of mice bearing H22 tumors compared to the other groups. Moreover, immunohistochemical staining revealed that the expression of Ki-67 and CD31 in the drug-loaded hydrogel group was significantly lower than that in the other groups (P < 0.05), indicating that the drug-loaded hydrogel effectively inhibited tumor proliferation and angiogenesis.Conclusion: The formulated hybrid thermosensitive hydrogel system with sustained drug release and enhanced therapeutic efficacy was demonstrated to be a promising strategy for the local-regional treatment of HCC via intratumoral administration.Keywords: Norcantharidin, Doxorubicin, Nanoparticles, Thermosensitive hydrogel, Hepatocellular carcinoma, Intratumoral injection

Yong-Ren Wang, Zhao-Sheng Li, Wei Huang, Hui-Qiang Yang, Bo Gao, Yu-Ting Chen Department of Radiology, Chinese Medical Hospital of Yiwu, Yiwu, 322000, People’s Republic of ChinaCorrespondence: Yong-Ren WangDepartment of Radiology, Chinese Medical Hospital of Yiwu, No. 266 Xuefeng West Road, Yiwu, 322000, People’s Republic of ChinaTel +86 579 85439171Fax +86 579 85527330Email wangry65398@163.comBackground: The aim of this study was to discuss the value of susceptibility-weighted imaging (SWI) in evaluating the ischemic penumbra of patients with acute cerebral ischemic stroke.Methods: Data were collected from 52 patients with acute cerebral ischemic stroke upon clinical diagnosis and routine examinations of magnetic resonance imaging (MRI), including SWI, diffusion-weighted imaging (DWI), and perfusion-weighted imaging (PWI) within 72 hours after onset in this retrospective study. The methods also included fusing the DWI and SWI images and calculating the volume of anomaly extension of DWI and PWI-MTT (mean transit time) using semi-automatic analysis software. The SWI-DWI and PWI-DWI mismatches were interpreted, and the statistical analysis was completed.Results: The two physicians found that the ischemic penumbra consistency is high throughout the SWI-DWI and PWI-DWI mismatches, without a significant difference (P > 0.05).Conclusion: SWI-DWI mismatch can prevent the injection of contrast agents and make an accurate diagnosis of acute stroke ischemic penumbra, which helps guide the selection of the clinical therapeutic plan.Keywords: ischemic penumbra, diffusion-weighted imaging, susceptibility-weighted imaging, perfusion-weighted imaging

Yueping Chen,1,* Junli Ren,2,3,* Naiping Yang,2,3,* Honghao Huang,2,3 Xueting Hu,2,3 Fangyue Sun,2,3 Tian Zeng,2,3 Xinbo Zhou,2,3 Wenjing Pan,2,3 Jingyu Hu,2,3 Beibei Gao,4 Shunkai Zhang,2 Guangyong Chen2 1Clinical Laboratory, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 2Department of Neurology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 3School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, People’s Republic of China; 4Department of Internal Medicine, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China*These authors contributed equally to this work.Correspondence: Shunkai Zhang; Guangyong ChenDepartment of Neurology, The Third Affiliated Hospital of Wenzhou Medical University, No. 108 Wansong Road, Wenzhou, 325000, Zhejiang, People’s Republic of ChinaEmail shunkaizhang@126.com; gychen6@126.comBackground: Eosinophil and monocyte have been demonstrated separately to be independent predictors of acute ischemic stroke (AIS). This study aimed to evaluate the association between eosinophil-to-monocyte ratio (EMR) and 3-month clinical outcome after treatment with recombinant tissue plasminogen activator (rt-PA) for AIS patients. Simultaneously, we made a simple comparison with other prognostic indicators, such as 24h neutrophil-to-lymphocyte ratio (NLR) and 24h platelet-to-lymphocyte ratio (PLR) to investigate the prognostic value of EMR.Methods and Results: A total of 280 AIS patients receiving intravenous thrombolysis were retrospectively recruited for this study. Complete blood count evaluations for EMR were conducted on 24 hours admission. The poor outcome at 3-month was defined as the modified Rankin Scale (mRS) of 3– 6 and the mRS score for death was 6. The EMR levels in patients with AIS were lower than those in the healthy controls and showed a negative correlation with the NIHSS score. At the 3-month follow-up, multivariate logistic regression analysis indicated an association among EMR, poor outcome and mortality. In addition, EMR had a higher predictive ability than popular biomarkers like NLR and PLR for 3-month mortality.Conclusion: The lower levels of EMR were independently associated with poor outcome and dead status in AIS patients.Keywords: acute ischemic stroke, eosinophil-to-monocyte ratio, intravenous thrombolysis, treatment outcome, modified rankin scale

Yiyun Weng,1,* Tian Zeng,2,3,* Honghao Huang,2,3,* Junli Ren,2,3 Jianing Wang,2,3 Chenguang Yang,2,3 Wenjing Pan,2,3 Jingyu Hu,2,3 Fangyue Sun,2,3 Xinbo Zhou,2,3 Haojie Qiu,2,3 Yufan Gao,2,3 Beibei Gao,4 Lifen Chi,3 Guangyong Chen3 1Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 2School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, People’s Republic of China; 3Department of Neurology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 4Department of Internal Medicine, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guangyong ChenDepartment of Neurology, The Third Affiliated Hospital of Wenzhou Medical University, No. 108 Wansong Road, Wenzhou, 325000, Zhejiang, People’s Republic of ChinaTel +86-13777770788Fax +86-577-65623263Email gychen6@126.comLifen ChiDepartment of Neurology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of ChinaEmail chilifenry@126.comBackground and Purpose: Systemic immune-inflammation index (SII), a novel inflammation index derived from counts of circulating platelets, neutrophils and lymphocytes, has been studied in developing incident cancer. However, the clinical value of SII in acute ischemic stroke (AIS) patients had not been further investigated. Therefore, we aimed to explore the association between SII and severity of stroke as well as 3-month outcome of AIS patients.Methods: A total of 216 AIS patients receiving intravenous thrombolysis (IVT) and 875 healthy controls (HCs) were retrospectively recruited. Blood samples were collected within 24h after admission. Severity of stroke was assessed by the National Institute of Health stroke scale (NIHSS) scores on admission and poor 3-month functional outcome was defined as Modified Rankin Scale (mRS) > 2.Results: SII levels in AIS patients were higher than in HCs. The cut-off value of SII is 545.14× 109/L. Patients with SII > 545.14× 109/L had higher NIHSS scores (median: 5 vs 9, p < 0.001), a positive correlation between SII and NIHSS was observed (rs = 0.305, p < 0.001). Multivariate logistic regression analyses showed that high SII was one of the independent risk factors for poor prognosis at 3 months of AIS patients (OR = 3.953, 95% CI = 1.702– 9.179, p = 0.001). The addition of SII to the conventional prognostic model improved the reclassification (but not discrimination) of the functional outcome (net reclassification index 39.3%, p = 0.007).Conclusion: SII is correlated with stroke severity at admission and can be a novel prognostic biomarker for AIS patients treated with IVT.Keywords: systemic immune-inflammation index, ischemic stroke, inflammation, prognosis

Rui Yang,1,2 Qiang Lu,1 Jinshun Xu,1,2 Jiayan Huang,1 Binyang Gao,1,2 Huan Zhang,1,2 Jie Zhou,1,2 Lanxin Du,1 Feng Yan2 1Ultrasound Department, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Laboratory of Ultrasound Imaging, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Feng YanLaboratory of Ultrasound Imaging, West China Hospital of Sichuan University, No. 88 Keyuan Road South, Chengdu, Sichuan, 610041, People’s Republic of ChinaTel +86 18980606323Email yan_feng@scu.edu.cnPurpose: To identify and validate contrast-enhanced ultrasound (CEUS) features for differentiating malignant from benign splenic lesions.Patients and Methods: Splenic lesions in 123 patients who underwent conventional ultrasound (B-mode US) and CEUS were included in this study. Two radiologists evaluated the sonograms of B-mode and CEUS. Statistical analysis was performed to identify significant imaging predictors for splenic malignant lesions. Two other radiologists independently reviewed B-mode and CEUS sonograms and diagnosed the lesions based on proposed criteria as 1) benign, 2) probably benign, 3) probably malignant or 4) malignant. The diagnostic efficiency between B-mode US and CEUS was compared.Results: Common imaging findings of malignant lesions included hypoechoic, ill-defined margin, absence of cystic/necrotic portion, presence of splenomegaly on B-mode US, and hypoenhancement, rapid washout and presence of intralesional vessels on CEUS (P < 0.05). Among them, three independent features were identified using multivariate logistic regression analysis: hypoechoic pattern, hypoenhancement pattern and intralesional vessels. When three of these findings were combined as a predictor for splenic malignant lesions, 22 (55.0%) of 40 malignant splenic lesions were identified with a specificity of 100%. The diagnostic performance of two readers using receiver operating characteristic curve analysis was 0.622 and 0.533, respectively, for B-mode US, which was significantly improved to 0.908 and 0.906 for CEUS (P < 0.001). The degree of other diagnostic efficiency and inter-reader agreement also increased with CEUS compared to B-mode US.Conclusion: CEUS may provide more useful information than B-mode US and improve the diagnosis efficiency for distinguishing malignant from benign splenic lesions.Keywords: spleen, splenic diseases, contrast-enhanced ultrasound, conventional ultrasound

Na Su,* Chenyang Zhao,* Bo Zhang, Zhenhong Qi, Bin Gao, Zhenzhen Liu, Meng Yang, Yuxin Jiang, Qing Dai Department of Ultrasound, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qing Dai; Yuxin JiangDepartment of Ultrasound, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shuaifuyuan No. 1, Dongcheng District, Beijing 100730, People’s Republic of ChinaTel +86 10-69155491; +86 10-69155494Email daiqing_pumch@163.com; yuxinjiangxh@163.comObjective: We aimed to compare the imaging features of gestational trophoblastic neoplasias (GTNs) and benign pregnancy-related uterine diseases on contrast-enhanced ultrasound (CEUS) to explore the clinical value of CEUS in differentiating these two types of uterine lesions.Materials and Methods: In this prospective study, patients with GTNs before and after chemotherapy and benign pregnancy-related uterine lesions received conventional US and CEUS. The imaging features and parameters of CEUS of the lesions were assessed.Results: A total of 73 patients were enrolled in this study, including 48 with GTNs and 25 with benign lesions. The enhancement pattern of newly diagnosed GTNs was mainly diffuse enhancement (70.8%), with a non-enhanced area of less than 1/3 of the entire lesion. For the benign group, the enhancement pattern was mainly ring-shaped enhancement (72.0%), and the non-enhanced area was more than 1/2 (68.0%), significantly different from that of GTNs (P = 0.000 and 0.002, respectively). Forty-one lesions demonstrated unclear boundaries on greyscale US but clearly displayed on CEUS. In both the benign and malignant groups, the measurements of lesion size on CEUS were larger than those on greyscale US (P = 0.000). The measurement differences (ΔD: D2-D1) of the malignant cases were higher than those of the benign cases (P = 0.001).Conclusion: GTNs and benign pregnancy-related uterine diseases have different imaging characteristics on CEUS. The boundary and involved range of the lesion can be clearly demonstrated on CEUS. CEUS possesses clinical value in diagnosing and evaluating GTNs and benign pregnancy-related diseases.Keywords: ultrasound, contrast-enhanced ultrasound, gestational trophoblastic neoplasia

Di Wu,1 Lin Kang,2 Jingjing Tian,2 Yuanhao Wu,2 Jieying Liu,2 Zhengyao Li,1 Xiangdong Wu,1 Yue Huang,1 Bo Gao,3 Hai Wang,1 Zhihong Wu,2,4 Guixing Qiu1 1Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, People’s Republic of China; 2Medical Science Research Center (MRC), Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, People’s Republic of China; 3Umibio (Shanghai) Co. Ltd, Shanghai 201210, People’s Republic of China; 4Beijing Key Laboratory for Genetic Research of Bone and Joint Disease, Beijing 100730, People’s Republic of ChinaCorrespondence: Hai WangDepartment of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing 100730, People’s Republic of ChinaEmail wanghai907@hotmail.comZhihong WuMedical Science Research Center (MRC), Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing 100730, People’s Republic of ChinaEmail wuzh3000@126.comBackground: Both magnetic nanoparticles (MNPs) and exosomes derived from bone mesenchymal stem cells (BMSC-Exos) have been reported to improve wound healing. In this study, novel exosomes (mag-BMSC-Exos) would be fabricated from BMSCs with the stimulation of MNPs and a static magnetic field (SMF) to further enhance wound repair.Methods: Mag-BMSC-Exos, namely, exosomes derived from BMSCs preconditioned with Fe3O4 nanoparticles and a SMF, together with BMSC-Exos were both first isolated by ultracentrifugation, respectively. Afterwards, we conducted in vitro experiments, including scratch wound assays, transwell assays, and tube formation assays, and established an in vivo wound healing model. The miRNA expression profiles were compared between BMSC-Exos and mag-BMSC-Exos to detect the potential mechanism of improving wound healing. At last, the function of exosomal miR-21-5p during wound healing was confirmed by utilizing a series of gain- and loss-of-function experiments in vitro.Results: The optimal working magnetic condition was 50 μg/mL Fe3O4 nanoparticles combined with 100 mT SMF. In vitro, mag-BMSC-Exo administration promoted proliferation, migration and angiogenesis to a greater extent than BMSC-Exo administration. Local transplantation of mag-BMSC-Exos into rat skin wounds resulted in accelerated wound closure, narrower scar widths and enhanced angiogenesis compared with BMSC-Exo transplantation. Notably, miR-21-5p was found to be highly enriched in mag-BMSC-Exos and served as a critical mediator in mag-BMSC-Exo-induced regulatory effects through inhibition of SPRY2 and activation of the PI3K/AKT and ERK1/2 signaling pathways.Conclusion: Mag-BMSC-Exos can further enhance wound healing than BMSC-Exos by improving angiogenesis and fibroblast function, and miR-21-5p upregulation in mag-BMSC-Exos might be the potential mechanism. This work offers an effective and promising protocol to improve wound healing in clinic.Keywords: exosomes, wound healing, miR-21-5p, angiogenesis, fibroblast function

Xiao Lei Zhang,1– 5 Bo Gao,1– 3 Teng Han,1,2 Bo Yun Xiang,1,2 Xin Liu1,2 1Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 2National Clinical Research Center for Respiratory Diseases, Beijing, People’s Republic of China; 3Capital Medical University, Beijing, People’s Republic of China; 4The Graduate School of Peking Union Medical College, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China; 5Peking University Health Science Center, Beijing, People’s Republic of ChinaCorrespondence: Xiao Lei ZhangDepartment of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of ChinaFax +86-10-8420-6380Email yutian728@sina.comPurpose: Prior studies have indicated that patients with chronic obstructive pulmonary disease (COPD) exhibit significant cognitive defects on neuropsychological testing. Obstructive sleep apnea (OSA) is common in patients with COPD and is associated with reduced cognitive function; however, the combined impact of these two conditions on cognitive function is unknown. The aim of the study was to investigate the impact of OSA on cognitive impairment in patients with COPD.Methods: Sixty-five stable COPD patients aged over 60 years underwent overnight polysomnography (PSG). Global cognitive functions were evaluated using the Mini-Mental State Examination (MMSE).Results: Compared to patients with COPD alone, patients with both COPD and OSA performed worse on the MMSE (25.5± 2.9 vs 23.5± 3.2; p=0.01) and were more likely to be at risk for developing dementia based on the MMSE score (MMSE≤ 24) (31% vs 66%; p< 0.01), independent of key demographic, educational and medical variables known to affect cognitive function in COPD. COPD patients with an apnea hypopnea index (AHI) of ≥ 30 events/h had lower MMSE scores than those with an AHI of < 15 events/h. In addition to age and education level, the severity of nocturnal intermittent hypoxia is an independent predictor of the risk of dementia in patients with COPD (OR=1.24, 95% CI 1.04– 1.48, p = 0.02).Conclusion: The current findings indicate that patients with COPD with comorbid OSA may be at greater risk for global cognitive impairment relative to patients with COPD alone. The mechanisms underlying the exaggerated cognitive dysfunction seem to be related to intermittent hypoxia. Further work is needed to understand the impact of OSA on the specific domains of cognitive impairment and the therapeutic implications of OSA in COPD.Keywords: chronic obstructive pulmonary disease, obstructive sleep apnea, cognitive function

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

Jason D Lickliter, 1 Hui K Gan, 2–4 Mark Voskoboynik, 1, 5, 6 Surein Arulananda, 2–4 Bo Gao, 7 Adnan Nagrial, 7 Peter Grimison, 8 Michelle Harrison, 8 Jianjun Zou, 9 Lianshan Zhang, 9 Stacey Luo, 9 Michael Lahn, 10 Howard Kallender, 11 Andrea Mannucci, 10 Catello Somma, 10 Katherine Woods, 3 Andreas Behren, 3, 4 Pablo Fernandez-Penas, 12 Michael Millward, 13 Tarek Meniawy 13 1Nucleus Network, Melbourne, Victoria, Australia; 2Department of Medicine, University of Melbourne, Heidelberg, Victoria, Australia; 3Olivia Newton-John Cancer Wellness and Research Centre, Austin Hospital, Melbourne, Victoria, Australia; 4Department of Medical Oncology, La Trobe University School of Cancer Medicine, Bundoora, Victoria, Australia; 5Department of Medical Oncology, Alfred Hospital, Melbourne, Victoria, Australia; 6Department of Medical Oncology, Monash University, Central Clinical School, Alfred Campus, Melbourne, Victoria, Australia; 7Blacktown Cancer and Haematology Centre, Blacktown Hospital, University of Sydney, Sydney, New South Wales, Australia; 8Department of Medical Oncology, Chris O’Brien Life House, Camperdown, New South Wales, Australia; 9Jiangsu Hengrui Medicine Co. Ltd, Shanghai, People’s Republic of China; 10Incyte Biosciences International Sarl, Geneva, Switzerland; 11Incyte Corporation, Wilmington, Delaware, USA; 12Department of Dermatology, The University of Sydney, Westmead Hospital, Westmead, New South Wales, Australia; 13Linear Clinical Research, Nedlands, Western Australia, AustraliaCorrespondence: Jason D LickliterNucleus Network, Level 5, Burnet Tower, 89 Commercial Road, Melbourne, Victoria, AustraliaTel +61 3 9076 8900Fax +61 3 9076 8911Email j.lickliter@nucleusnetwork.com.auPurpose: Camrelizumab inhibits PD-1 in non-clinical models and showed typical non-clinical pharmacokinetic (PK) and safety profiles for an IgG4 monoclonal antibody. We report results from the First-in-Human Phase 1 trial of camrelizumab in Australian population.Methods: Camrelizumab was administered to patients with advanced solid tumors who had failed standard therapies. In the dose-escalation phase (n=23), camrelizumab was administered intravenously at 1 mg/kg, 3 mg/kg, 6 mg/kg, and 10 mg/kg every 2 weeks. In dose expansion (n=26), camrelizumab was given at 200 mg or 600 mg every 4 weeks.Results: Two dose-limiting toxicities were observed during dose escalation: transaminase elevation and diarrhea (both grade 3). Overall, treatment-related adverse events were consistent with the expected toxicity profile of immune checkpoint inhibition, with the striking exception of the dose-related development of angiomatous skin lesions characterized as reactive cutaneous capillary endothelial proliferation. The PK profile showed a dose-progressive increase in half-life from 3 days at 1 mg/kg to 7 days at 10 mg/kg. Moreover, receptor occupancy assays showed a PD-1 occupancy of > 50% in most patients out to 28 days post-dose. The objective response rate was 15.2% (95% CI 6.3– 28.9).Conclusion: Camrelizumab has manageable toxicity and encouraging preliminary antitumor activity in advanced solid tumors in Australia.Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02492789.Keywords: PD-1, monoclonal antibody, first-in-human dose study, cancer, reactive cutaneous capillary endothelial proliferation

Yongwei Gu,1,2,* Juanjuan Ma,2,* Zhiqin Fu,1,2,* Youfa Xu,1,2 Baoan Gao,1,2 Jianzhong Yao,3 Wei Xu,1 Kedan Chu,1 Jianming Chen1,2 1Department of Pharmacy, Fujian University of Traditional Chinese Medicine, Fujian 350108, People’s Republic of China; 2Shanghai Wei Er Biopharmaceutical Technology Co., Ltd., Shanghai 201707, People’s Republic of China; 3School of Pharmacy, Second Military Medical University, Shanghai 200433, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Xu; Jianming ChenDepartment of Pharmacy, Fujian University of Traditional Chinese Medicine, Fujian 350108, People’s Republic of ChinaTel/fax +86-591-22861693; +86-21-31198900-8949Email 2000017@fjtcm.edu.cn; chenjm0711@163.comPurpose: The objective of the present study was to develop a liposomal drug delivery system based on combretastatin A4 (CA4) prodrugs modified with varying alkyl chains and investigate the in vitro drug conversion from prodrug and in vivo antitumor effect.Methods: The prodrug of CA4 was synthesized with stearyl chloride (18-carbon chain), palmitoyl chloride (16-carbon chain), myristoyl chloride (14-carbon chain), decanoyl chloride (10-carbon chain), and hexanoyl chloride (6-carbon chain) at the 3′-position of the CA4. Subsequently, it was encapsulated with liposomes through the thin-film evaporation method. Furthermore, the characteristics of prodrug-liposome were evaluated using in vitro drug release, conversion, and cytotoxicity assays, as well as in vivo pharmacokinetic, antitumor, and biodistribution studies.Results: The liposome system with loaded CA4 derivatives was successfully developed with nano-size and electronegative particles. The rate of in vitro drug release and conversion was reduced as the fatty acid carbon chain lengthened. On the contrary, in vivo antitumor effects were improved with the enlargement of the fatty acid carbon chain. The results of the in vivo pharmacokinetic and tissue distribution studies indicated that the reduced rate of CA4 release with a long carbon chain could prolong the circulation time and increase the drug concentration in the tumor tissue.Conclusion: These results suggested that the release or hydrolysis of the parent drug from the prodrug was closely related with the in vitro and in vivo properties. The slow drug release of CA4 modified with longer acyl chain could prolong the circulation time and increase the concentration of the drug in the tumor tissue. These effects play a critical role in increasing the antitumor efficacy.Keywords: combretastatin A4, liposome, prodrug, drug release, anticancer

Shujie Wang1,*, Erhei Dai2,*, Xiaoyuan Jiang3, Lijun Zeng3, Qiaoxiang Cheng2,3, Ying Jing3, Lingfei Hu3, Zhe Yin3, Bo Gao3, Jinglin Wang3, Guixin Duan4, Xuehui Cai1, Dongsheng Zhou3 1State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, People’s Republic of China; 2Department of Laboratory Medicine, The Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, Hebei 050021, People’s Republic of China; 3State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, People’s Republic of China; 4Animal Science and Technology College, Heilongjiang Bayi Agricultural University, Daqing 163000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dongsheng ZhouState Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, No. 20 Dongdajie Street, Fengtai District, Beijing 100071, People’s Republic of ChinaTel +86 106 694 8503Email dongshengzhou1977@gmail.comXuehui CaiState Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, No. 678 Haping Road, Xiangfang District, Harbin 150069, People’s Republic of ChinaTel +86 4 515 105 1766Email aci139@sina.comBackground: Multiple incompatibility (Inc) groups of plasmids have been identified in Enterobacteriaceae species, but there are still quite a few sequenced plasmids that could not be assigned to any known Inc groups.Methods: One IncFIIpKF727591β plasmid p205880-qnrS and two IncpKPHS1 plasmids p11219-CTXM and p205880-NR1 were fully sequenced in this work. Detailed genomic comparison was applied to all available sequenced plasmids of IncFIIpKF727591 or IncpKPHS1 group.Results: p205880-qnrS carried a novel transposon Tn6396, which was an ISKpn19-compsite transposon and represented a prototype transposable element carrying a minimum core qnrS1 module. p11219-CTXM harbored a novel transposon Tn6559, which was generated from integration of a truncated IS903D–blaCTX-M-14–ISEcp1 unit into the Tn3-family cryptic unit transposon Tn1722. Two Inc groups, IncFIIpKF727591 and IncpKPHS1, of plasmids from Enterobacteriaceae species were proposed, and IncFIIpKF727591 was further grouped into two subgroups IncFIIpKF727591α and IncFIIpKF727591β. Each of the 11 IncFIIpKF727591 plasmids carried multiple accessory modules including at least one resistance module, and the relatively small IncFIIpKF727591 backbones could acquire a wealth of foreign genetic contents. The modular structures of plasmid backbones were conserved within each of IncFIIpKF727591α and IncFIIpKF727591β subgroups but dramatically different, although with similar gene organizations, between these two subgroups. The IncpKPHS1 backbones were conserved with respect to modular structures, and only four of the 14 IncpKPHS1 plasmids carried accessory modules, two of which contained resistance genes.Conclusion: A genomic comparison of sequenced IncpKPHS1 or IncFIIpKF727591 plasmids provides insights into modular differences and genetic diversification of these plasmids, some of which carries antimicrobial resistance genes.Keywords: plasmids, IncFIIpKF727591, IncpKPHS1, Tn6396, Tn6559

Jingping Liao,1,2 Xiaofang Ma,1,3 Bin Gao,4 Mingfeng Zhang,5 Yuanfang Zhang,6 Maoqun Liu,7 Xiaolin Li11Department of Nursing, West China Hospital, West China School of Medicine, Sichuan University, Chengdu 610041, People’s Republic of China; 2School of Nursing, Peking University, Beijing 100191, People’s Republic of China; 3Department of Emergency, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China; 4Department of Nursing, Dujiangyan Medical Center, Dujiangyan 611830, People’s Republic of China; 5Department of Nursing, People’s Hospital of Mianzhu City, Deyang 618200, People’s Republic of China; 6Department of Nursing, Wenchuan People’s Hospital, Aba Tibetan and Qiang Autonomous Prefecture 623000, People’s Republic of China; 7Department of Nursing, Dujiangyan Second People’s Hospital, Dujiangyan 611830, People’s Republic of ChinaPurpose: Nursing survivors are often not only the victims but also the rescuers in a disaster. Severe natural disasters can cause them long-term psychological impact. This study aimed to investigate the psychological status of nursing survivors and its associated factors 6 years after the severe earthquake that occurred in Wenchuan, Sichuan, on May 12, 2008.Methods: The study used a cross-sectional design. A total of 597 nurses who survived the earthquake and took care of victims were recruited about 6 years after the disaster. They completed a self-report questionnaire assessing information about demographics, earthquake-related characteristics, psychological status, posttraumatic stress disorder, and posttraumatic growth and resilience.Results: The mean score on the Symptom Checklist-90-Revised (SCL-90-R) was (123.56±41.26). Of symptoms indicated by the SCL-90-R, obsessive-compulsive dimension had the highest score (1.62±0.62). The psychological status of nursing survivors differed with the title, monthly per capita household income, financial loss, health status, residential satisfaction, and satisfaction with leaders and colleagues. Severe financial loss and poor health status were significant factors of psychological distress. In addition, psychological status was negatively related to posttraumatic stress disorder and posttraumatic growth, and positively related to resilience.Conclusion: Nursing survivors had a relatively normal level of psychological status 6 years after the 2008 Sichuan earthquake. However, psychological symptoms such as obsessive-compulsive patterns still remained. Interventions focusing on the improvement of financial subsidies and physical health may be particularly useful in reducing psychological problems after the disaster.Keywords: natural disaster, posttraumatic growth, resilience, rescue, mental health, disaster response

Huijuan Fan,*,1 Shujiao Chen,*,1,2 Bizhen Gao,1 Shanshan Ding,1 Qiang Zhao,1 Candong Li,1 Tetsuya Asakawa1,31Research Base of Traditional Chinese Medicine Syndrome, Fujian University of Traditional Chinese Medicine, Fuzhou, Shangjie Minhou 350122, People’s Republic of China; 2Department of Internal Medicine, The Third People’s Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, Shangjie Minhou 350122, People’s Republic of China; 3Department of Neurosurgery, Hamamatsu University School of Medicine, Hamamatsu-city, Shizuoka 431-3192, Japan*These authors contributed equally to this workPurpose: We aimed to evaluate the clinical value of systemic levels of estrogen and adipokines as well as estrogen receptors from peripheral blood mononuclear cells (PBMCs) in childbearing and perimenopausal women with obesity.Subjects and methods: We observed 292 women, including 160 perimenopausal women (80 with obesity and 80 without obesity) and 132 women of childbearing age (67 with obesity and 65 without obesity). Body parameters, such as body mass index and waist circumference, were measured. Fat distribution was evaluated using a computerized tomography scanner. The levels of serum estrogen, leptin, visfatin, and adiponectin were measured using an enzyme-linked immunosorbent assay. The expression of circulating ERs was evaluated by Western blot analysis.Results: Perimenopausal women and childbearing women with obesity exhibited lower levels of estrogen and adiponectin, in addition to a distribution of visceral fat with higher levels of leptin and visfatin. These findings reflect the current data of menopausal women, which confirms the reliability of this experimental system. However, the expression of ERα in peripheral blood was significantly enhanced in women with obesity of both childbearing and perimenopausal age. This result is contrary to the common understanding of adipose tissue, namely that ERα is protective. The expression of ERβ in the women without obesity of both childbearing and perimenopausal age was higher than in women with obesity, which coincides with the results of a previous study on adipose tissue.Conclusion: Our data fundamentally contradicts the utility of circulating ERα and ERα/ERβ evaluations in obesity studies. Because estrogen exerts pleiotropic effects on multiple tissues in the body through differential regulation of ERs, although the expression of ERβ coincides with the results of a previous study on adipose tissue, the expression levels of ERs in blood cannot be used as a diagnostic of informative tool for obesity in women.Keywords: estrogen receptors, obesity, estrogen, fat distribution, adipokines, perimenopause

Wenjia Guo,1 Bo Gao,1 Li Li,1 Wei Gai,2 Jianghui Yang,3 Yan Zhang,2 Lijun Wang41Department of Pulmonary and Critical Care Medicine, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, People’s Republic of China; 2National Engineering Research Center for Beijing Biochip Technology, Beijing, People’s Republic of China; 3Department of Pathology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, People’s Republic of China; 4Clinical Research Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, People’s Republic of ChinaAbstract: A lung abscess is an infectious pulmonary disease characterized by pus-filled cavity formation and often an air-fluid level. In this article, we described an indolent community-acquired lung abscess suspected as a tumor previously. A 56-year-old male presented with cough and expectoration for 2 months and hemoptysis for 2 weeks. His physical examinations, whole blood count and C-reactive protein level were normal. The chest computed tomography (CT) scan showed a 40×38×39 mm high-density mass in the right upper pulmonary lobe, with irregular borders. The pathology of a CT-guided percutaneous needle aspiration biopsy showed numerous inflammatory cells and bacteria infiltration without tumor lesions. Bacteriological detection of lung tissue revealed the cause was odontogenic flora. A next-generation sequencing demonstrated the etiologic correlation between lung abscess and periodontitis. After a 2-month pathogen-directed oral antibiotics therapy combined with chlorhexidine gargle oral care, this patient showed a remarkable improvement. Periodontitis can be a cause of a lung abscess, which would be taken into account in the treatment regimes preventing infectious recurrence.Keywords: community-acquired lung abscess, periodontitis, odontogenic flora

Xiao-Bo Liu,1* Zi-Ye Gao,2* Qing-Hui Zhang,1* Shu Jin,1 Bo Gao,3 Gong-Li Yang,4 Sheng-Bao Li11Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, People’s Republic of China; 2Department of Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, People’s Republic of China; 3Department of Laboratory Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, People’s Republic of China; 4Department of Gastroenterology, Shenzhen University General Hospital, Shenzhen, Guangdong 518000, People’s Republic of China*These authors contributed equally to this work Background: Serum pepsinogen I (PGI) concentration and PGI/PGII ratio (PGR) are often used as serological markers for gastric fundus atrophy (AGA) and gastric carcinoma. However, their diagnostic value in esophageal carcinoma (EC) is inaccurate.Methods: This study evaluated the diagnostic value of PGI and PGR in EC by searching the PubMed, Web of Science, Embase, Cochrane Library and Cochrane Central Register of Controlled Trials databases for literature on the diagnosis of EC with PGI and PGR from January 1, 2000 to October 2, 2018. The included literature were systematically evaluated using QUSDAS-2 software. Meta-analysis was conducted using STATA 15.0 software. The summary receiver operating characteristic curve (SROC) accuracy was plotted, the area under the curve was calculated.Results: A total of 84 papers were selected, and after screening, nine papers on esophageal squamous cell carcinoma (ESCC) were finally included. Results showed low an ESCC-specific diagnostic sensitivity (0.27), high specificity (0.85), and 0.63 AUC of SROC when PGI≤70 ng/mL. When PGR≤3, the ESCC-specific diagnostic sensitivity was low (0.29), the specificity was high (0.83), and the AUC of SROC was 0.63.Conclusion: According to the current research results, PGI≤70 ng/mL or PGR≤3 diagnostic ESCC sensitivity is low, and specificity is high. These findings indicate that neither PGI≤70 ng/mL nor PGR≤3 can be used as an ESCC-screening index.Keywords: esophageal squamous cell carcinoma, PGI, PGR, diagnosis, meta-analysis

Daofeng Qu,1,2 Yang Shen,2 Lingfei Hu,1 Xiaoyuan Jiang,1 Zhe Yin,1 Bo Gao,1 Yuee Zhao,1 Wenhui Yang,1 Huiying Yang,1 Jianzhong Han,2 Dongsheng Zhou1 1State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China; 2School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, China Background: IncR, IncFII, IncpA1763-KPC, and IncN1 plasmids have been increasingly found among Enterobacteriaceae species, but plasmids with hybrid structures derived from the above-mentioned incompatibility groups have not yet been described.Methods: Plasmids p721005-KPC, p504051-KPC, and pA3295-KPC were fully sequenced and compared with previously sequenced related plasmids pHN84KPC (IncR), pKPHS2 (IncFIIK), pKOX_NDM1 (IncFIIY), pHN7A8 (IncFIIpHN7A8), and R46 (IncN1).Results: The backbone of p721005-KPC/p504051-KPC was a hybrid of the entire 10-kb IncR-type backbone from pHN84KPC, the entire 64.3-kb IncFIIK-type maintenance, and conjugal transfer regions from pKPHS2, a 15.5-kb IncFIIY-type maintenance region from pKOX_NDM1 and a 5.6-kb IncpA1763-KPC-type backbone region from pA1763-KPC, and it contained a primary IncR replicon and two auxiliary IncpA1763-KPC and IncN1 replicons. The backbone of pA3295-KPC was a hybrid of a 7.2-kb IncFIIpHN7A8-type backbone region from pHN7A8, the almost entire 33.3-kb IncN1-type maintenance and conjugal transfer regions highly similar to R46, a 26.2-kb IncFIIK-type maintenance regions from pKPHS2, the above 15.5-kb IncFIIY-type maintenance region, and the above 5.6-kb IncpA1763-KPC-type backbone region, and it contained a primary IncFIIpHN7A8 replicon and two auxiliary IncpA1763-KPC and IncN1 replicons. Each of p721005-KPC, p504051-KPC, and pA3295-KPC acquired a wealth of accessory modules, carrying a range of intact and residue mobile elements (such as insertion sequences, unit transposons, and integrons) and resistance markers (such as blaKPC, tetA, dfrA, and qnr).Conclusion: In each of p721005-KPC, p504051-KPC, and pA3295-KPC, multiple replicons in coordination with maintenance and conjugation regions of various origins would maintain a broad host range and a stable replication at a steady-state plasmid copy number. Keywords: multi-replicon plasmids, multi-drug resistance, blaKPC-2, mobile elements

Wuguo Tian, Shuai Hao, Bo Gao, Yan Jiang, Xiaohua Zhang, Shu Zhang, Lingji Guo, Jianjie Zhao, Gang Zhang, Yi Chen, Zhirong Li, Donglin Luo Department of Breast, Thyroid Surgery, Research Institute of Surgery, Daping Hospital, Army Military Medical University, Chongqing 400042, China Objective: Lobaplatin shows antitumor activity against a wide range of tumors, including metastatic breast cancer (BCa). The overexpression of metadherin (MTDH) is associated with poor prognosis of BCa patients. This study was designed to investigate the effect of lobaplatin on MCF-7 cell proliferation and its association with MTDH expression.Patients and methods: Clinical treatment for BCa using lobaplatin, in combination with other general chemotherapy drugs, was administered to 32 BCa patients. The safety, effectiveness, and prognosis in lobaplatin-treated BCa patients were compared with those in controls (n=32). In vitro experiments were performed in MCF-7 cells to investigate the effect of lobaplatin on cell proliferation, apoptosis, and MTDH expression.Results: We found the intraoperative local chemotherapy using lobaplatin was safe and effective for BCa treatment, in comparison with the patients administered general chemotherapy drugs. Treatment of MCF-7 cell cultures with lobaplatin significantly reduced cell proliferation and increased cell apoptotic percentage. The expression of MTDH and Bcl-2 was inhibited by lobaplatin and that of Bax was increased by lobaplatin. Moreover, we observed the inhibition of MTDH by shRNA reduced cell proliferation and enhanced cell apoptosis.Conclusion: Lobaplatin was a safe and effective adjuvant chemotherapy for BCa. The effect of lobaplatin on inhibiting MCF-7 cell proliferation and inducing cell apoptosis might be, as least in part, mediated by suppressing the expression of oncogene MTDH. Keywords: breast cancer, lobaplatin, proliferation, apoptosis, MTDH

Lining Shi,1,* Jiao Feng,2,* Zhe Zhan,2 Yuzong Zhao,2,3 Haijian Zhou,4 Haifeng Mao,5 Yingjie Gao,6 Ying Zhang,7 Zhe Yin,2 Bo Gao,2 Yigang Tong,2 Yanping Luo,7 Defu Zhang,2,3 Dongsheng Zhou2 1Institute of Medical Laboratory Sciences, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China; 2State Key Laboratory of Pathogen & Biosecurity, Beijing Institute of Microbiology & Epidemiology, Beijing 100071, China; 3College of Food Science & Project Engineering, Bohai University, Jinzhou 121013, China; 4National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China; 5Department of Laboratory Medicine, The First People’s Hospital of Lianyungang, Lianyungang 222002, China; 6College of Veterinary Medicine, Jilin University, Changchun 130062, China; 7Medical Laboratory Center, Chinese People’s Liberation Army General Hospital, Beijing 100085, China *These authors contributed equally to this work Background: We recently reported the complete sequence of a blaKPC-2- and rmtB-carrying IncFII-family plasmid p675920-1 with the pKPC-LK30/pHN7A8 hybrid structure. Comparative genomics of additional sequenced plasmids with similar hybrid structures and their prevalence in blaKPC-carrying Klebsiella pneumoniae strains from China were investigated in this follow-up study. Methods: A total of 51 blaKPC-carrying K. pneumoniae strains were isolated from 2012 to 2016 from five Chinese hospitals and genotyped by multilocus sequence typing. The blaKPC-carrying plasmids from four representative strains were sequenced and compared with p675920-1 and pCT-KPC. Plasmid transfer, carbapenemase activity determination, and bacterial antimicrobial susceptibility test were performed to characterize resistance phenotypes mediated by these plasmids. The prevalence of pCT-KPC-like plasmids in these blaKPC-carrying K. pneumoniae strains was screened by PCR. Result: The six KPC-encoding plasmids p1068-KPC, p20049-KPC, p12139-KPC and p64917-KPC (sequenced in this study) and p675920-1 and pCT-KPC slightly differed from one another due to deletion and acquisition of various backbone and accessory regions. Two major accessory resistance regions, which included the blaKPC-2 region harboring blaKPC-2 (carbapenem resistance) and blaSHV-12 (β-lactam resistance), and the MDR region carrying rmtB (aminoglycoside resistance), fosA3 (fosfomycin resistance), blaTEM-1B (β-lactam resistance) and blaCTX-M-65 (β-lactam resistance), were found in each of these six plasmids and exhibited several parallel evolution routes. The pCT-KPC-like plasmids were present in all the 51 K. pneumoniae isolates, all of which belonged to CG258. Conclusion: There was clonal dissemination of K. pneumoniae CG258 strains, harboring blaKPC-2- and rmtB-carrying IncFII-family pKPC-LK30/pHN7A8 hybrid plasmids, among multiple Chinese hospitals. Keywords: Klebsiella pneumoniae, multidrug resistance, carbapenemase, plasmids

Shicheng Li,1,* Yunpeng Xuan,1,* Bing Gao,2 Xiao Sun,1 Shuncheng Miao,1 Tong Lu,1 Yuanyong Wang,1 Wenjie Jiao1 1Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China; 2School of Basic Medicine, Qingdao University, Qingdao, China *These authors contributed equally to this work Background: Lung adenocarcinoma (LUAD) is the leading cause of cancer-related death worldwide. The main obstacle to early diagnosis or monitoring of patients at high risk of poor survival has been the lack of essential predictive biomarkers.Methods: RNA-sequencing was performed on LUAD affected tissue and paired adjacent to noncancerous tissue samples and Gene Expression Omnibus dataset GSE19188 and GSE33532 were used to obtain an intersection of differential expressed genes and construct a protein–protein interaction network to get hub genes. Then corresponding overall survival information of two cohorts of LUAD patients from our hospital and The Cancer Genome Atlas project-LUAD were included in the present study. An analysis of the Kyoto Encyclopedia of Genes and Genomes database and Gene Ontology were carried out to study the signature mechanism.Results: In our study, we identified eight candidate genes (DLGAP5, KIF11, RAD51AP1, CCNB1, AURKA, CDC6, OIP5 and NCAPG) closely related to survival in LUAD. A linear prognostic model of the eight genes was constructed and weighted by the regression coefficient (β) from the multivariate Cox regression analysis of The Cancer Genome Atlas-LUAD cohort to divide patients into low- and high-risk groups. The prognostic ability of the signature was validated in LUAD patients at our hospital. Patients assigned to the high-risk group exhibited poor overall survival compared to patients in the low-risk group. Finally, functional enrichment analysis showed that cell division played a vital role in the development of LUAD.Conclusion: The study identified an mRNA signature including eight genes, which may serve as a potential prognostic marker of LUAD. Keywords: RNA-seq, prognostic, signature, lung adenocarcinoma

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

Coal fly ash from coal power plants is a potential raw material for the production of alumina. An objective aluminothermic reduction method for the preparation of Al-Si master alloy and alumina from coal fly ash was investigated. The kinetic analysis using non-isothermal differential scanning calorimetry indicated that the reduction of Al6Si2O13, Fe2O3, and TiO2 by aluminum in coal fly ash occurs at 1618 K, 1681 K, and 1754 K, respectively. Moreover, the influence of reaction temperature on product composition was studied. The phases and morphologies of the products obtained by the aluminothermic reduction of coal fly ash at 1373-1773 K were analyzed by X-ray diffraction, scanning electron microscopy, and energy-dispersive spectroscopy, respectively. The results from X-ray diffraction show that no oxide reduction has taken place at 1373 K and 1473K, the compositions of the product obtained by aluminothermic reduction of fly ash at 1573K- 1673 K are Al2O3, mullite, Al and Si, while the compositions of the product at 1773 K are Al2O3, Al, and Si. In addition, the chemical compositions of Al-Si alloy obtained at 1773 K are 86.81 wt% Al and 13.19 wt% Si.