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Jiyong Ge,1 Yuan Ji,1 Fangfang Wang,1 Xuejun Zhou,1 Jiazhan Wei,1 Chunjian Qi2 1Department of Cardiology, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu, 213003, People’s Republic of China; 2Oncology Institute, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu, 213003, People’s Republic of ChinaCorrespondence: Chunjian Qi, Oncology Institute, The Affiliated Changzhou Second People’s Hospital, Nanjing Medical University, Xinglong Alley 29, Changzhou, Jiangsu, 213003, People’s Republic of China, Tel +86 519 88119730, Fax +86 519 88115560, Email qichunjianedu@outlook.comIntroduction: To investigate the relationship between cystatin C and cardiac dysfunction severity in patients with systolic heart failure.Methods: We recruited 100 hospitalized patients with systolic heart failure and 100 age-gender-matched controls. The clinical information of each patient was collected. Blood pressure, heart rate, height, and weight were measured, as were serum concentrations of cholesterol, renal function indices, cystatin C, and B-type natriuretic peptide (BNP). Transthoracic echocardiography was performed on each patient.Results: Cystatin C and other indices of renal function, such as urea nitrogen, creatinine, and uric acid, were significantly elevated in the serum of patients with heart failure and those with more severe cardiac dysfunction. The stepwise regression analyses showed that cystatin C was positively associated with BNP (β = 0.18, P = 0.04, 95% CI: 21.1 ~ 1420.4) and left atrial diameter (LAD) (β = 0.19, P = 0.04, 95% CI: 0.03 ~ 9.21) and was negatively associated with ejection fraction (β = − 0.22, P = 0.023, 95% CI: − 12.4 ~ − 0.93), while creatinine was only positively correlated with BNP (β = 0.23, P = 0.03, 95% CI: 1.11 ~ 20.7). The Receiver Operating Characteristic (ROC) curves demonstrated significantly more severe cardiac dysfunction (NYHA III/IV) in patients with cystatin C ≥ 0.895mg/L (sensitivity was 83.0%, specificity was 80.9%, AUC = 0.893) and creatinine ≥ 91.5μmol/L (sensitivity was 71.7%, specificity was 70.2%, AUC = 0.764).Conclusion: Cystatin C was significantly correlated with cardiac structure and function in patients with systolic heart failure, and it was more valuable than creatinine to evaluate the severity of heart failure.Keywords: cystatin C, renal function, systolic heart failure

Yazhuo Wang,1,2 Cong Qi,1,2 Fang Feng,3 Xueqing Hu,3 Ning Zhao,1,2 Jingxia Zhao,1 Tingting Di,1 Yujiao Meng,1 Danyang Yang,1,2 Haoyue Zhu,1,2 Xiawei Zhang,1,2 Ping Li,1 Yan Wang1 1Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, Beijing Key Laboratory of Clinic and Basic Research with Traditional Chinese Medicine on Psoriasis, Beijing, People’s Republic of China; 2Capital Medical University, Beijing, 100069, People’s Republic of China; 3Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of ChinaCorrespondence: Ping Li; Yan Wang, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, Beijing Key Laboratory of Clinic and Basic Research with Traditional Chinese Medicine on Psoriasis, Beijing, 100010, People’s Republic of China, Email liping61871@sina.com; wangyan11339@bjzhongyi.comPurpose: Resveratrol (Res) is a natural polyphenol with anti-inflammatory and immunomodulatory effects. Alterations in metabolic pathways have been studied in psoriasis. This study is aimed to further explore the potential molecular mechanism of psoriasis improvement by Res.Patients and Methods: Imiquimod (IMQ)-induced psoriasis-like mouse model was established to observe the effects of Res. NanoString nCounter Metabolic Pathways Panel was used to analyze the changed mRNA and qRT-PCR was used for validation. Flow cytometry was used to analyze immune cell subsets in skin lesions. In vitro, we observed the effects of Res on R848-stimulated macrophages glycolysis and inflammation.Results: Res reduced the proliferation of keratinocytes and the secretion of inflammatory cytokines in IMQ-induced psoriasis-like mouse model. Psoriasis model skin lesions were in a state of hypoxia, with upregulated glycolysis and downregulated AMPK activity. Res inhibited the levels of hypoxia-related genes (hif1α, hif3α) and glycolysis-related genes (hk1, ldha), meanwhile increased the levels of AMPK genes (prkaa1, prkaa2). Flow cytometry analysis revealed that Res decreased the infiltration of macrophages in psoriasis-like lesions. In addition, Res decreased the secretion of macrophage-associated pro-inflammatory cytokines (IL-23, TNF-α, IL-1β). In vitro, Res diminished the secretion of IL-23, TNF-α, IL-1β, and lactate by R848-stimulated macrophages and activated AMPK.Conclusion: This study suggested that Res diminished psoriasis symptoms by inhibiting macrophages infiltration and inhibiting glycolysis, which providing novel insights into the underlying mechanisms of therapeutic action of Res in the treatment of psoriasis.Keywords: resveratrol, psoriasis, macrophage, AMPK, glycolysis

Chang Qi1 *, Sheng-Wen Sun2 *, Xian-Zhi Xiong1 1Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 2Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xian-Zhi Xiong, Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People’s Republic of China, Tel/Fax +86 27-85726705, Email xxz0508@hust.edu.cnAbstract: Many studies have proved that the pathogenesis of the chronic obstructive pulmonary disease (COPD) and lung cancer is related, and may cause and affect each other to a certain extent. In fact, the change of chronic airway obstruction will continue to have an impact on the screening, treatment, and prognosis of lung cancer.In this comprehensive review, we outlined the links and heterogeneity between COPD and lung cancer and finds that factors such as gene expression and genetic susceptibility, epigenetics, smoking, epithelial mesenchymal transformation (EMT), chronic inflammation, and oxidative stress injury may all play a role in the process. Although the relationship between these two diseases have been largely determined, the methods to prevent lung cancer in COPD patients are still limited. Early diagnosis is still the key to a better prognosis. Thus, it is necessary to establish more intuitive screening evaluation criteria and find suitable biomarkers for lung cancer screening in high-risk populations with COPD. Some studies have indicated that COPD may change the efficacy of anti-tumor therapy by affecting the response of lung cancer patients to immune checkpoint inhibitors (ICIs). And for lung cancer patients with COPD, the standardized management of COPD can improve the prognosis. The treatment of lung cancer patients with COPD is an individualized, comprehensive, and precise process. The development of new targets and new strategies of molecular targeted therapy may be the breakthrough for disease treatment in the future.Graphical Abstract: Keywords: COPD, lung cancer, endo-phenotyping of COPD, early diagnosis, biomarkers, immunotherapy

Dan-Yang Li,1,* Long Chen,1,* Shuai-Ying Miao,1,2 Mei Zhou,1 Jiang-Hua Wu,1 Sheng-Wen Sun,1 Lan-Lan Liu,1 Chang Qi,1 Xian-Zhi Xiong1 1Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of National Health Commission of the People’s Republic of China, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 2Department of Critical Care Medicine, General Hospital of Pingmei Shenma Medical Group, Pingdingshan, 467000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xian-Zhi Xiong, Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of National Health Commission of the People’s Republic of China, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China, Email xxz0508@hust.edu.cnBackground: The role of inducible costimulator (ICOS) signaling in chronic obstructive pulmonary disease (COPD) has not been fully elucidated.Methods: We compared the percentages of ICOS+ T cells and ICOS+ regulatory T (Treg) cells in CD4+ T cells and CD4+CD25+FOXP3+ Tregs, respectively, in the peripheral blood of smokers with or without COPD to those in healthy controls. We further characterized their phenotypes using flow cytometry. To investigate the influence of ICOS signaling on C-X-C motif chemokine receptor 3 (CXCR3) expression in COPD, we evaluated the expression levels of ICOS and CXCR3 in vivo and in vitro.Results: ICOS expression was elevated on peripheral CD4+ T cells and CD4+ Tregs of COPD patients, which positively correlated with the severity of lung function impairment in patients with stable COPD (SCOPD), but not in patients with acute exacerbation of COPD (AECOPD). ICOS+CD4+ Tregs in patients with SCOPD expressed higher levels of coinhibitors, programmed cell death protein 1 (PD-1) and T-cell immunoreceptor with Ig and ITIM domains (TIGIT), than ICOS−CD4+ Tregs, whereas ICOS+CD4+ T cells mostly exhibited a central memory (CD45RA−CCR7+) or effector memory (CD45RA−CCR7−) phenotype, ensuring their superior potential to respond potently and quickly to pathogen invasion. Furthermore, increased percentages of CXCR3+CD4+ T cells and CXCR3+CD4+ Tregs were observed in the peripheral blood of patients with SCOPD, and the expression level of CXCR3 was higher in ICOS+CD4+ T cells than in ICOS−CD4+ T cells. The percentage of CXCR3+CD4+ T cells was even higher in the bronchoalveolar lavage fluid than in matched peripheral blood in SCOPD group. Lastly, in vitro experiments showed that ICOS induced CXCR3 expression on CD4+ T cells.Conclusions: ICOS signaling is upregulated in COPD, which induces CXCR3 expression. This may contribute to increased numbers of CXCR3+ Th1 cells in the lungs of patients with COPD, causing inflammation and tissue damage.Keywords: chronic obstructive pulmonary disease, T cell, Treg, ICOS, CXCR3

Zelin Li,1,2 Cuijuan Qi,1 Zhuoya Jia,1,2 Ruoxi Zhen,1,2 Lin Ren,1,3 Yujiao Jia,1,2 Shuchun Chen1,2,4 1Graduate School of Hebei Medical University, People’s Republic of China; 2Department of Endocrinology, Hebei General Hospital, People’s Republic of China; 3North China University of Science and Technology, People’s Republic of China; 4Hebei Key Laboratory of Metabolic Diseases, People’s Republic of ChinaCorrespondence: Shuchun Chen, Department of Endocrinology, Hebei General Hospital, 348 Heping West Road, 050051, People’s Republic of China, Tel +86 031185988406, Fax +86 031185988406, Email chenshuc2014@163.comPurpose: To study the correlation between estimated glucose disposition rate (eGDR) and coagulation parameters in type 2 diabetes patients (T2DM).Materials and Methods: A total of 948 patients suffering from T2DM were enrolled for this research. Various blood coagulation parameters including prothrombin time (PT), activated partial thromboplastin time (APTT), and fibrinogen (FIB) were assessed. Body mass index (BMI), hypertension, and the levels of glycated hemoglobin (HbA1c) were used to calculate the patients’ eGDRs. All patients were sorted into two groups: those with high eGDRs (eGDR≥ 7.5) and those with low eGDRs (eGDR< 7.5). The patients were then separated into groups of men and women. The connection between eGDR and coagulation indexes was examined using Spearman correlation, Pearson correlation, and multiple linear regression analysis.Results: In comparison to the high-eGDR group, reduced PT and APTT levels with increased FIB levels were observed in the low-eGDR group (P =0.006, P < 0.001, and P = 0.035, respectively). The eGDR showed a positive relation with APTT (r = 0.142, P < 0.001), a negative relation with FIB (r = − 0.082, P = 0.012), and no correlation with PT (r =0.064, P =0.050) in the all patients. As well as, the eGDR demonstrated a positive relation with APTT (r = 0.173, P < 0.001), a negative relation with FIB (r = − 0.093, P = 0.03), and no relation with PT (r = 0.045, P = 0.300) in the male subgroups. Additionally, this correlation persisted following the adjustment of other factors in multilinear regression analysis. However, the female subgroup demonstrated no correlation among eGDR and PT, APTT or FIB (r = 0.086, P = 0.083, r = 0.097, P = 0.05;r = − 0.058, P = 0.240, respectively).Conclusion: Our study is the first to prove that eGDR demonstrates a correlation with coagulation indexes in T2DM patients. And, this correlation is gender-specific.Keywords: estimated glucose disposal rate, coagulation indexes, type 2 diabetes mellitus

Hongxia Ma,1 Qian Zhang,1 Yanwen Zhao,1 Yaohui Zhang,1 Jingjing Zhang,1 Guoqing Chen,1 Yuan Tan,2– 4 Qin Zhang,2– 4 Qianqian Duan,2– 4 Tingting Sun,2– 4 Chuang Qi,2– 4 Fengsen Li1 1Pneumology Department, The Fourth Affiliated Hospital of Xinjiang Medical University, Urumqi, The Xinjiang Uygur Autonomous Region, People’s Republic of China; 2The Medical Department, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, Jiangsu Province, People’s Republic of China; 3Nanjing Simcere Medical Laboratory Science Co., Ltd, Nanjing, Jiangsu Province, People’s Republic of China; 4The State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, Jiangsu Province, People’s Republic of ChinaCorrespondence: Fengsen Li, Pneumology department, The Fourth Affiliated Hospital of Xinjiang Medical University, Urumqi, The Xinjiang Uygur Autonomous Region, People’s Republic of China, Email drmahongxia@163.comIntroduction: Chronic obstructive pulmonary disease (COPD) and lung cancer often coexist, but its pathophysiology and genomics features are still unclear.Methods: In this study, we retrospectively collected lung cancer concomitant COPD (COPD-LC) and non-COPD lung cancer (non-COPD-LC) patients, who performed next generation sequencing (NGS) and had clinicopathological information simultaneously. The COPD-LC data from the TCGA cohort were collected to conduct further analysis.Results: A total of 51 COPD-LC patients and 88 non-COPD-LC patients were included in the study. Clinicopathological analysis showed that proportion of male gender, older age, and smoking patients were all substantially higher in COPD-LC group than in non-COPD-LC group (all P< 0.01). Comparing the genomic data of the two groups in our cohort, COPD-LC had higher mutation frequency of LRP1B (43% vs 9%, P = 0.001), EPHA5 (24% vs 1%, P = 0.002), PRKDC (14% vs 1%, P = 0.039), PREX2 (14% vs 0%, P = 0.012), and FAT1 (14% vs 0%, P = 0.012), which had a relationship with improved tumor immunity. Immunotherapy biomarker of PD-L1 positive expression (62.5% vs 52.0%, P = 0.397) and tumor mutation burden (TMB, median TMB: 7.09 vs 2.94, P = 0.004) also were higher in COPD-LC. In addition, RNA data from TCGA further indicated tumor immunity increased in COPD-LC. Whereas, COPD-LC had lower frequency of EGFR mutation (19% vs 50%, P = 0.013) and EGFR mutant COPD-LC treated with EGFR-TKI had worse progression-free survival (PFS) (HR = 3.52, 95% CI: 1.27– 9.80, P = 0.01).Conclusion: In this retrospective study, we first explored molecular features of COPD-LC in a Chinese population. Although COPD-LC had lower EGFR mutant frequency and worse PFS with target treatment, high PD-L1 expression and TMB indicated these patients may benefit from immunotherapy.Keywords: lung cancer, COPD, mutation landscape, Chinese population, molecular markers

Amina Nazir,1– 3 Chunling Qi,4 Na Shi,4 Xue Gao,4 Qiang Feng,4 Hong Qing,2 Fei Li,3,4 Yigang Tong3 1Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, Shandong Province, People’s Republic of China; 2Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Sciences, Beijing Institute of Technology, Beijing, People’s Republic of China; 3College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, People’s Republic of China; 4Clinical Laboratory Center, The Affiliated Taian City Central Hospital of Qingdao University, Taian, 271000, People’s Republic of ChinaCorrespondence: Fei Li; Yigang Tong, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, People’s Republic of China, Email lf-314@163.com; tong.yigang@gmail.comIntroduction: Klebsiella pneumoniae, a multidrug resistant bacterium, that causes nosocomial infections including septicemia, pneumonia etc. Bacteriophages are potential antimicrobial agents for the treatment of antibiotic resistant bacteria.Methods and Results: In this study, a novel bacteriophage IME268 was isolated from hospital sewage against clinical multi-drug resistant Klebsiella pneumoniae. Transmission electron microscopy and genomic characterization of this phage exhibited it belongs to the Webervirus genus, Drexlerviridae family. Phage IME268 possessed a double-stranded DNA genome composed of 49,552bp with a GC content of 50.5%. The phage genome encodes 77 open reading frames, out of 44 are hypothetical proteins while 33 had assigned putative functions. No tRNA, virulence related or antibiotic resistance genes were found in phage genome. Comparative genomic analysis showed that phage IME268 has 95% identity with 87% query cover with other phages in NCBI database. Multiplicity of infection, one step growth curve and host range of phage were also measured.Conclusion: According to findings, Phage IME268 is a promising biological agent that infects Klebsiella pneumoniae and can be used in future phage therapies.Keywords: Klebsiella pneumoniae, bacteriophage, therapy, lytic, drug resistant

Fangqing Wang, 1,* Yanying Li, 1,* Hong Jiang, 1,* Chenglei Li, 2 Zhaohuan Li, 2 Cuiping Qi, 3 Zhipeng Li, 1 Zhiqin Gao, 1 Bo Zhang, 2 Jingliang Wu 1 1School of Bioscience and Technology, Weifang Medical University, Weifang, 261053, People’s Republic of China; 2School of Pharmacy, Weifang Medical University, Weifang, 261053, People’s Republic of China; 3School of Nursing, Weifang Medical University, Weifang, 261053, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bo Zhang; Jingliang Wu Email zhangbo@wfmc.edu.cn ; jlwu2008@163.comBackground: Tumor angiogenesis has been proven to potentiate tumor growth and metastasis; therefore, the strategies targeting tumor-related angiogenesis have great potentials in antitumor therapy.Methods: Here, the GA&Gal dual-ligand-modified liposomes co-loaded with curcumin and combretastatin A-4 phosphate (CUCA/GA&Gal-Lip) were prepared and characterized. A novel “BEL-7402+HUVEC” co-cultured cell model was established to mimic tumor microenvironment. The cytotoxicity and migration assays were performed against the novel co-cultured model. Angiogenesis ability was evaluated by tube formation test, and in vivo metastatic ability was evaluated by lung metastasis test.Results: The result demonstrated that dual-ligand-modified liposomes showed greater inhibition of tumor angiogenesis and metastasis in comparison with other combined groups. Significantly, the mechanism analysis revealed that curcumin and combretastatin A-4 phosphate could inhibit tumor angiogenesis and metastasis via down-regulation of VEGF and VEGFR2 expression, respectively, and that GA&Gal-Lip could improve antitumor effect by GA/Gal-mediated active-targeting delivery.Conclusion: CUCA/GA&Gal-Lip hold great potentials in hepatoma-targeting delivery of antitumor drugs and can achieve anti-angiogenic and anti-metastatic effects by simultaneously blocking VEGF/VEGFR2 signal pathway, therefore exhibiting superior anti-hepatoma efficacy.Keywords: dual-ligand-modified, liposomes, anti-angiogenesis, VEGF, co-delivery

To recycle vanadium from V-bearing steelmaking slag and V-bearing black shale, both were jointly roasted to generate vanadium-rich phase, and then vanadium was separated by magnetic separation in this study. The compositions of samples were determined by X-ray fluorescence meter and the phases in the samples were characterized using X-ray diffractometer. The experimental results showed that with increasing the ratio of CaO content to SiO2 content in the samples the vanadium separation efficiency first decreased, increased, and then decreased again. With increasing roasting temperature from 1423 to 1623 K, the vanadium separation efficiency increased. With increasing roasting time from one hour to four hours, the vanadium separation efficiency increased. The optimum conditions for vanadium recycling are the basicity of 1.2, roasting temperature of 1623 K, and roasting time of 4 hours. Under this condition, the separation efficiency of vanadium reaches 71.6%, and the concentrate contains 3.67% V2O5 and 46.9% Fe2O3. A flow for joint processing of V-bearing steelmaking slag and V-bearing black shale was proposed, which involves vanadium separating, and tailings utilizing.

Chuang Qi,1,* Xianxiong Qin,2,* Zuozhi Zhou,1 Yan Wang,1 Qin Yang,1 Tianzhi Liao1 1Department of Oncology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi 445000, Hubei, People’s Republic of China; 2Department of Breast Surgery, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi 445000, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tianzhi LiaoDepartment of Oncology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, No. 158 Wuyang Street, Enshi 445000, Hubei, People’s Republic of ChinaTel +86-718-8233580Email kzj3dgk@163.comBackground: Circ_0072995 is a novel identified circRNA and has been identified to involve in the metastasis of breast cancer. However, the detailed function and mechanism of circ_0072995 in the biological property of breast cancer cell remain vague.Materials and Methods: The expression of circ_0072995, microRNA (miR)-149-5p and serine hydroxymethyltransferase 2 (SHMT2) mRNA was detected using quantitative real-time polymerase chain reaction. Western blot was used to detect the protein levels of SHMT2, hexokinase-2 (HK-2), lactate dehydrogenase a chain (LDHA), and glucose transporter 1 (GLUT1). Cell proliferation, apoptosis, migration, and invasion were analyzed using cell counting kit-8 assay, flow cytometry, caspase-3 activity analysis, cell adhesion assay and transwell assay, respectively. Glucose metabolism was calculated by measuring glucose uptake, lactate production, and adenosine triphosphate (ATP) levels. The interaction between miR-149-5p and circ_0072995 or SHMT2 was confirmed by dual-luciferase reporter assay. In vivo tumorigenesis was performed using the murine xenograft model.Results: Circ_0072995 and SHMT2 were up-regulated in breast cancer tissues and cell lines, and knockdown of circ_0072995 or SHMT2 suppressed cell malignant properties and anaerobic glycolysis; importantly, SHMT2 overexpression attenuated the anticancer action of circ_0072995 knockdown in breast cancer. Besides, we also found circ_0072995 directly targeted miR-149-5p, thereby regulating its downstream gene SHMT2 by competitively binding to miR-149-5p. Additionally, xenograft analysis showed circ_0072995 silencing suppressed tumor growth via regulating SHMT2 and miR-149-5p in vivo.Conclusion: This study demonstrated that circ_0072995 promoted cell malignant phenotypes and anaerobic glycolysis in breast cancer via up-regulating SHMT2 through sponging miR-149-5p, indicating a promising molecular target for breast cancer treatment.Keywords: circ_0072995, miR-149-5p, SHMT2, breast cancer

Chunhou Qi,1 Shankai Li,1 Lei Zhang2 1Department of Interventional Medicine, Linyi City Central Hospital, Yishui, Shandong, People’s Republic of China; 2Department of Interventional Radiology, Shandong Medical Imaging Research Institute, Affiliated to Shandong University, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Lei ZhangDepartment of Interventional Radiology, Shandong Medical Imaging Research Institute, Affiliated to Shandong University, 324 Jingwu Road, Jinan, Shandong, People’s Republic of ChinaTel +86-531-68776767Fax +86-531-87938550Email zhanglei0422@yeah.netAim: To develop and validate a nomogram for predicting the overall survival (OS) in patients with recurrent hepatocellular carcinoma (HCC) after hepatectomy who underwent microwave ablation (MWA).Methods: The training cohort included 299 patients with recurrent HCCs after hepatectomy who met the Milan criteria and received MWA from April 2007 to December 2017. Baseline characteristics were collected to identify risk factors for the determination of death after MWA. A multivariate Cox proportional hazards model based on significant risk factors was used to develop the nomogram, which was then assessed for its predictive accuracy using Harrell’s C-index and the area under the curve (AUC). The nomogram was validated by internal (n = 240) and external cohorts (n = 205) from another hospital.Results: After a median follow-up of 32.3 months, 38.8% (116/299) of patients had died. Multivariate Cox proportional hazards analyses showed that comorbid disease, early recurrence, and albumin-bilirubin (ALBI) grades 2– 3 were independent prognostic factors for poor OS. This nomogram accurately stratified patients into subgroups with low or high risk. The 1-, 3- and 5-year OS rates in the low-risk subgroup were 99.4%, 97.2%, and 86.1%, respectively, and they were 92.8%, 70.3%, and 45.8% in the high-risk subgroup (P < 0.001). The nomogram predicted OS in the training cohort with a C-index score of 0.801 (95% CI 0.761– 0.841). The nomogram was validated by internal and external cohorts, with C-index scores of 0.792 (95% CI 0.738– 0.846) and 0.744 (95% CI 0.703– 0.785), respectively.Conclusion: The nomogram provides individualized risk estimates for long-term OS for patients with recurrent HCC after hepatectomy who underwent MWA.Keywords: recurrent hepatocellular carcinoma, microwave ablation, overall survival, nomogram, hepatectomy

Hang Zhao,1 Cuijuan Qi,1 Chong Zheng,2 Kexin Gan,1 Luping Ren,1,* Guangyao Song1,* 1Endocrinology Department, Hebei General Hospital, Hebei 050051, People’s Republic of China; 2Pediatric Orthopaedics, Shijiazhuang the Third Hospital, Hebei 050011, People’s Republic of China*These authors contributed equally to this workCorrespondence: Luping Ren Email renluping1122@163.comPurpose: We aimed to determine the relationship between the levels of glycated hemoglobin (HbA1c) and biomarkers of bone metabolism in patients with type 2 diabetes mellitus (T2DM), and whether HbA1c independently influences any of these biomarkers.Patients and Methods: A cohort study of 240 patients with T2DM was performed. Serum was obtained and used to measure HbA1c, total cholesterol (TC), triglycerides, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol (LDL-C), very-low-density lipoprotein-cholesterol, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), total protein, albumin, blood urea nitrogen (BUN), creatinine, serum 25-hydroxyvitamin D (25OHD), osteocalcin (OC), β-C-terminal cross-linked telopeptide of type I collagen (β-CTX), procollagen type 1 N-terminal propeptide (P1NP), or parathyroid hormone (PTH) concentrations. The participants were divided into three study groups according to HbA1c level: < 7%, 7– 9% and ≥ 9%. Chi-square testing and one-way analysis of variance were used to compare groups. The relationships between HbA1c and bone metabolism biomarker values were analyzed using linear correlation analysis and multiple linear regression analysis.Results: Age, duration of T2DM, and the concentrations of TC, LDL-C, apolipoprotein B, albumin, and BUN showed significant difference among the < 7%, 7– 9% and ≥ 9% HbA1c groups. Of the bone metabolism biomarkers, there were significant differences in serum 25-hydroxyvitamin D (25OHD) and osteocalcin (OC) among the groups. The correlation coefficients (r) for the relationships of HbA1c with 25OHD and OC were − 0.200 and − 0.183, respectively (P < 0.05). Regardless of adjustment for none, some, or all of the confounding factors (age, sex, and duration of T2DM), the 25OHD and OC concentrations were significantly lower in the HbA1c ≥ 9% group than in the HbA1c < 7% group. HbA1c showed no relationship with β-CTX, PINP, or PTH.Conclusion: T2DM patients with poorer glycemic control had lower concentrations of serum 25OHD and OC, suggesting that HbA1c is an independent risk factor for low 25OHD and OC.Keywords: diabetes mellitus type 2, bone metabolism, glycated hemoglobin

Chunhou Qi,1 Hongfei Gao,1 Qinghua Zhao,2 Lei Zhang3 1Department of Interventional Medicine, Linyi City Central Hospital, Yishui, Shandong, People’s Republic of China; 2Department of Emergency Medicine, Yishui County People’s Hospital, Yishui, Shandong, People’s Republic of China; 3Department of Interventional Radiology, Shandong Medical Imaging Research Institute, Affiliated to Shandong University, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Lei ZhangDepartment of Interventional Radiology, Shandong Medical Imaging Research Institute, Affiliated to Shandong University, 324 Jingwu Road, Jinan, Shandong, People’s Republic of ChinaTel +86-531-68776767Fax +86-531-87938550Email zhanglei0422@yeah.netObjective: To investigate the clinical safety, efficacy, therapeutic outcomes and risk factors of computed tomography-guided percutaneous cryoablation (CT-PCRA) for subcardiac hepatocellular carcinoma (HCC).Patients and Methods: In this study, patients with single HCC nodules located on the left lobe who subsequently underwent CT-PCRA were reviewed from July 2012 to August 2016. According to the definition of subcardiac HCC, the patients were grouped into the subcardiac HCC group (n=33) and the non-subcardiac HCC group (n=40). The technical success rates, tumour response rates, oncological outcomes including overall survival (OS) and recurrence-free survival (RFS) and complications were compared. Multivariate analysis was performed on clinicopathological variables to identify factors affecting long-term outcomes.Results: Seventy-three patients with subcardiac HCC were included in this study. After a median follow-up time of 37.8 months, 27.4% (20/73) of the patients died. The technical success and complete response rates were not significantly different between the two groups (p = 1.000; p = 0.590). The cumulative OS and RFS of the subcardiac HCC group were comparable to those of the non-subcardiac HCC group (p =0.820, p =0.922). Two major complications, intra-abdominal bleeding and right pleural effusion, were found at 2.2 and 3.1 months in the subcardiac HCC group, which were comparable with those in the non-subcardiac HCC group (p = 0.683). The multivariate analysis results showed that older age (hazard ratio [HR]: 2.382, 95% confidence interval [CI]: 1.884– 7.823; p = 0.038) and ALBI grade 2– 3 (HR: 3.398, 95% CI: 1.950– 6.058; p = 0.021) may be predictors of poor OS and that tumour size ≥ 3 cm in diameter (HR: 3.302, 95% CI: 2.232– 8.293; p = 0.012) may be a predictor of poor RFS.Conclusion: CT-PCRA for subcardiac HCC can be performed safely and efficiently and contribute to improving survival prognosis.Keywords: cryoablation, subcardiac location, hepatocellular carcinoma, therapeutic outcomes, risk factors

Yunsheng Dong,1 Huahong Zhuang,1 Yan Hao,1 Lin Zhang,1 Qiang Yang,2 Yufei Liu,1 Chunxiao Qi,1 Shufang Wang1 1State Key Laboratory of Medicinal Chemical Biology, The Key Laboratory of Bioactive Materials, The College of Life Science, Nankai University, Tianjin, People’s Republic of China; 2Department of Spine Surgery, Tianjin Hospital, Tianjin, People’s Republic of ChinaCorrespondence: Qiang Yang No. 406 Jiefang Nan Road, Tianjin 300211, People’s Republic of ChinaEmail yangqiang1980@126.comShufang Wang No. 94 Weijin Road, Nankai District, Tianjin 300071, People’s Republic of ChinaEmail wangshufang@nankai.edu.cnIntroduction: Chronic trauma repair is an important issue affecting people’s healthy lives. Thermo-sensitive hydrogel is injectable in situ and can be used to treat large-area wounds. In addition, antioxidants play important roles in promoting wound repair.Methods: The purpose of this research was to prepare a novel thermo-sensitive hydrogel-poly(N-isopropyl-acrylamide)/poly(γ-glutamic acid) (PP) loaded with superoxide dismutase (SOD) to improve the effect for trauma treatment. The micromorphology of the hydrogel was observed by scanning electron microscope and the physical properties were measured. The biocompatibility of hydrogel was evaluated by MTT experiment, and the effect of hydrogel on skin wound healing was evaluated by in vivo histological staining.Results: Gelling behavior and differential scanning calorimeter outcomes showed that the PP hydrogels possessed thermo-sensitivity at physiological temperature and the phase transformation temperature was 28.2°C. The high swelling rate and good water retention were conducive to wound healing. The activity of SOD in vitro was up to 85% at 10 h, which was advantageous to eliminate the superoxide anion. MTT assay revealed that this hydrogel possessed good biocompatibility. Dressings of PP loaded with SOD (SOD-PP) had a higher wound closure rate than other treatments in vivo in diabetic rat model.Discussion: The SOD-PP thermo-sensitive hydrogels can effectively promote wound healing and have good application prospects for wound repair.Keywords: thermo-sensitive hydrogels, wound dressing, superoxide dismutase, poly(γ-glutamic acid)

Caifen Qi,1,2,* Shuangli Xu,1,* Maomao Wu,1 Shuo Zhu,1 Yanyan Liu,3 Hong Huang,1 Guijun Zhang,1 Jiabin Li,3 Xiaohui Huang1 1Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, Anhui, People’s Republic of China; 2Department of Pharmacy, The Anqing Affiliated Hospital of Anhui Medical University, Anqing, Anhui, People’s Republic of China; 3Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaohui HuangDepartment of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Meishan Road 81#, Hefei, Anhui 230032, People’s Republic of ChinaTel +86 138 5518 3138Email math2088@163.com Jiabin LiDepartment of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218#, Hefei, Anhui, People’s Republic of ChinaFax +86551 62922713Email lijiabin@ahmu.edu.cnObjectives: To explore the in vitro and in vivo antibacterial activity of linezolid/fosfomycin combination against vancomycin-susceptible and -resistant enterococci (VSE and VRE), and provide a theoretical basis for the treatment of VRE.Methods: The checkerboard method and time-kill curve study were used to evaluate the efficacy of linezolid combined with fosfomycin against VSE and VRE. The transmission electron microscopy (TEM) was employed to observe the cell morphology of bacteria treated with each drug alone or in combination, which further elucidate the mechanism of action of antibiotic combination therapy. The Galleria mellonella infection model was constructed to demonstrate the in vivo efficacy of linezolid plus fosfomycin for VSE and VRE infection.Results: The fractional inhibitory concentration index (FICI) values of all strains suggested that linezolid showed synergy or additivity in combination with fosfomycin against five of the six strains. Time-kill experiments demonstrated that the combination of linezolid-fosfomycin at 1×MIC or 2×MIC led to higher degree of bacterial killing without regrowth for all isolates tested than each monotherapy. TEM images showed that the combination treatment damaged the bacterial cell morphology more obviously than each drug alone. In the Galleria mellonella infection model, the enhanced survival rate of the combination treatment compared with linezolid monotherapy (P

C Linda Campbell,1,2,* Renqiang Yu,3,4 Fengzhi Li,1 Qin Zhou,3 Daozhen Chen,4 Ce Qi,1,2 Yongxiang Yin,5 Jin Sun1,2,* 1State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; 2School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; 3Department of Neonatology, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi 214002, China; 4Department of Central Lab, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi 214002, China; 5Department of Pathology, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi 214002, China *These authors contributed equally to this work Purpose: The antioxidant resveratrol (RSV) has low bioavailability and can reach the colon to access the gut microbial ecosystem. RSV administration together with high-fat diet prevented abnormal changes of intestinal microbiota. However, whether or not RSV can reshape the intestinal microbiota of obese mice and alleviate obesity-related diseases remains to be studied. This study aimed to explore the role of RSV in alleviating high-fat-induced obesity and its relationship with oxidative stress and gut microbiota.Methods: Male C57BL/6 mice were divided into five groups and administered for 16 weeks with: standard diet (CON), high-fat diet (60% energy for lard, HFD), and HFD with low, medium, and high dose of RSV, 50, 75, and 100 mg/kg body weight administered daily via drinking water, respectively.Results: Medium and high RSV treatment significantly prevented body weight gain, decreased relative weight of liver and adipose tissue compared with HFD (P0.8 P

Zhihuang Zheng,1,* Guoying Deng,2,* Chenyang Qi,3 Yuyin Xu,3 Xijian Liu,4 Zhonghua Zhao,3 Zhigang Zhang,3 Yuening Chu,1 Huijuan Wu,3 Jun Liu1 1Department of Nephrology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; 2Trauma Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; 3Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China; 4Department of Chemical Engineering and Technology, College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai, China *These authors contributed equally to this work Objectives: Acute kidney injury (AKI) is a growing global health concern, and is associated with high rates of mortality and morbidity in intensive care units. Se is a trace element with antioxidant properties. This study aimed to determine whether porous Se@SiO2 nanospheres could relieve oxidative stress and inflammation in ischemia/reperfusion (I/R)-induced AKI. Methods: Male 6- to 8-week-old C57bl/6 mice were divided into four groups: sham + saline, sham + Se@SiO2, I/R + saline, and I/R + Se@SiO2. Mice in the I/R groups experienced 30 minutes of bilateral renal I/R to induce an AKI. Porous Se@SiO2 nanospheres (1 mg/kg) were intraperitoneally injected into mice in the I/R + Se@SiO2 group 2 hours before I/R, and the same dose was injected every 12 hours thereafter. Hypoxia/reoxygenation (H/R) was used to mimic I/R in vitro. PBS was used as a control treatment. Human kidney 2 cells were seeded into 12-well plates (5×105 cells/well) and divided into four groups: control + PBS group, control + Se@SiO2 group, H/R + PBS group, and H/R + Se@SiO2 group (n=3 wells). We then determined the expression levels of ROS, glutathione, inflammatory cytokines and proteins, fibrosis proteins, and carried out histological analysis upon kidney tissues.Results: In vitro, intervention with porous Se@SiO2 nanospheres significantly reduced levels of ROS (P

Hao Chen,1–3,* Lan Li,2,3,* Yanyan Liu,4 Maomao Wu,2,3 Shuangli Xu,2,3 Guijun Zhang,2,3 Caifen Qi,2,3 Yan Du,2,3 Mingli Wang,5 Jiabin Li,4 Xiaohui Huang2,3 1Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; 2Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; 3Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; 4Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; 5Department of Microbiology, Anhui Medical University, Hefei, Anhui, China *These authors contributed equally to this work Objectives: Linezolid combination therapy is recommended for the treatment of Staphylococcus aureus (S. aureus) infections. However, the optimal regimen of the combination therapy for S. aureus is unknown. The objective of this study was to investigate the antibacterial activity, post-antibiotic effect (PAE), and post-antibiotic subminimum inhibitory concentration (MIC) effect (PA-SME) of linezolid alone and in combination with fosfomycin against eleven clinical isolates of S. aureus.Methods: The synergistic effects and antibacterial activity of linezolid and fosfomycin were assessed by checkerboard and time-kill assays. To determine the PAE and PA-SME, S. aureus strains in the logarithmic phase of growth were exposed for 1, 2, and 3 hours to the antibiotics, alone and in combination. Recovery periods of test strains were evaluated using viable counting after dilution.Results: Synergistic effects were observed for eight strains and no antagonism was found with any combination. Moreover, linezolid combined with fosfomycin at 4x MIC showed the best synergistic antibacterial effect, and this effect was retained after 24 hours. In addition, both the antibiotics alone and in combination showed increased PAE and PA-SME values in a concentration- and time-dependent manner.Conclusion: Linezolid combined with fosfomycin exerted a good antibacterial effect against S. aureus, and the combinations have significant PAE and PA-SME. Keywords: linezolid, fosfomycin, PAE, PA-SME, combination

Na Wu, Ying Wan, Lu Song, Chen Qi, Zhenguo Liu, Jing Gan Department of Neurology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China Background: Levodopa-induced dyskinesia (LID) is a troublesome problem in the treatment of Parkinson’s disease (PD). The mechanisms of LID are still mysterious. Recently, the interaction between Shp-2 and D1 dopamine receptor (D1R) has been identified to be indispensable in the D1R-mediated extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation and the occurrence of LID. However, the role of Shp-2 in the D1R-mediated signaling pathway of dyskinetic rat models is not fully clear. We designed this study with the purpose of exploring the role of D1R/Shp-2 complex in the D1R-mediated signaling pathway in the occurrence of LID.Materials and methods: The 6-hydroxydopamine (6-OHDA) was injected unilaterally to produce the rat models of PD. Successful PD rat models were randomly divided into three groups to receive the treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) + benserazide, L-DOPA + benserazide + D1R antagonist (SCH23390) or D1R agonist (SKF38393). Abnormal involuntary movements were assessed in different groups during the treatment. The interaction between D1R and Shp-2 was confirmed in the sham and LID rats through the methods of coimmunoprecipitation. In addition, the levels of p-Shp-2, p-ERK1/2 and p-mTOR were determined by Western blot in different groups.Results: After the treatment with L-DOPA + benserazide for 22 days, PD rats presented with dyskinesia. D1R agonist, SKF38393, induced similar involuntary movements in PD rats. In contrast, the dyskinetic movements were not induced by coadministration of L-DOPA + D1R antagonist (SCH23390). The interaction between D1R and Shp-2 in the normal rats was kept stable after the long-term use of L-DOPA. Moreover, we found that the pulsatile levodopa administration induced hyperphosphorylation of Shp-2, ERK1/2 and mTOR, while the coadministration of L-DOPA and D1R antagonist, SCH23390, did not induce the hyperphosphorylation of these proteins.Conclusion: These data verified the existence of D1R/Shp-2 complex and its crucial role in the D1R-mediated signaling pathway in dyskinetic rats. Focus on the D1R/Shp-2 complex might be a potential treatment of LID in the future. Keywords: Parkinson’s disease, dyskinesia, levodopa, D1 receptors, Shp-2

Ding Zhou,1,* Chao Qi,2,* Yi-Xuan Chen,1 Ying-Jie Zhu,2 Tuan-Wei Sun,2 Feng Chen,2 Chang-Qing Zhang1 1Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Jiaotong University, 2State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Hydroxyapatite (HAP; Ca10(PO4)6(OH)2) and whitlockite (WH; Ca18Mg2(HPO4)2(PO4)12) are widely utilized in bone repair because they are the main components of hard tissues such as bones and teeth. In this paper, we synthesized HAP and WH hollow microspheres by using creatine phosphate disodium salt as an organic phosphorus source in aqueous solution through microwave-assisted hydrothermal method. Then, we prepared HAP/chitosan and WH/chitosan composite membranes to evaluate their biocompatibility in vitro and prepared porous HAP/chitosan and WH/chitosan scaffolds by freeze drying to compare their effects on bone regeneration in calvarial defects in a rat model. The experimental results indicated that the WH/chitosan composite membrane had a better biocompatibility, enhancing proliferation and osteogenic differentiation ability of human mesenchymal stem cells than HAP/chitosan. Moreover, the porous WH/chitosan scaffold can significantly promote bone regeneration in calvarial defects, and thus it is more promising for applications in tissue engineering such as calvarial repair compared to porous HAP/chitosan scaffold. Keywords: hydroxyapatite, whitlockite, chitosan, osteogenic differentiation, rat critical calvarial defect, tissue engineering

Siqi Huang, Zhiming Yu, Yang Zhang, Chusheng Qi, Shifeng Zhang MOE Key Laboratory of Wooden Material Science and Application, Beijing Forestry University, Beijing, China Abstract: In order to fabricate antimicrobial carboxymethyl chitosan–nanosilver (CMC-Ag) hybrids with controlled silver release, this study demonstrated comparable formation via three synthetic protocols: 1) carboxymethyl chitosan (CMC) and glucose (adding glucose after AgNO3), 2) CMC and glucose (adding glucose before AgNO3), and 3) CMC only. Under principles of green chemistry, the synthesis was conducted in an aqueous medium exposed to microwave irradiation for 10 minutes with nontoxic chemicals. The structure and formation mechanisms of the three CMC-Ag hybrids were explored using X-ray diffraction, ultraviolet-visible spectroscopy, transmission electron microscopy, and Fourier-transform infrared analyses. Additionally, antimicrobial activity and in vitro silver release of the three synthesized hybrids were investigated in detail. The results revealed that a large number of stable, uniform, and small silver nanoparticles (AgNPs) were synthesized in situ on CMC chains via protocol 1. AgNPs were well dispersed with narrow size distribution in the range of 6–20 nm, with mean diameter only 12.22±2.57 nm. The addition of glucose resulted in greater AgNP synthesis. The order of addition of glucose and AgNO3 significantly affected particle size and size distribution of AgNPs. Compared to CMC alone and commercially available AgNPs, the antimicrobial activities of three hybrids were significantly improved. Of the three hybrids, CMC-Ag1 synthesized via protocol 1 exhibited better antimicrobial activity than CMC-Ag2 and CMC-Ag3, and showed more effective inhibition of Staphylococcus aureus than Escherichia coli. Due to strong coordination and electrostatic interactions between CMC and silver and good steric protection provided by CMC, CMC-Ag1 displayed stable and continuous silver release and better performance in retaining silver for prolonged periods than CMC-Ag2 and CMC-Ag3. Keywords: carboxymethyl chitosan/nanosilver hybrids, green synthesis, formation mechanism, controlled silver release, antimicrobial effect

Weilin Yu,1,* Tuan-Wei Sun,2,3,* Chao Qi,2,3 Zhenyu Ding,1 Huakun Zhao,1 Shichang Zhao,1 Zhongmin Shi,1 Ying-Jie Zhu,2,3 Daoyun Chen,1 Yaohua He1,4 1Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 2State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 3University of Chinese Academy of Sciences, Beijing, 4School of Biomedical Engineering, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China *These authors contributed equally to this work Abstract: Biomaterials with high osteogenic activity are desirable for sufficient healing of bone defects resulting from trauma, tumor, infection, and congenital abnormalities. Synthetic materials mimicking the structure and composition of human trabecular bone are of considerable potential in bone augmentation. In the present study, a zinc (Zn)-doped mesoporous hydroxyapatite microspheres (Zn-MHMs)/collagen scaffold (Zn-MHMs/Coll) was developed through a lyophilization fabrication process and designed to mimic the trabecular bone. The Zn-MHMs were synthesized through a microwave-hydrothermal method by using creatine phosphate as an organic phosphorus source. Zn-MHMs that consist of hydroxyapatite nanosheets showed relatively uniform spherical morphology, mesoporous hollow structure, high specific surface area, and homogeneous Zn distribution. They were additionally investigated as a drug nanocarrier, which was efficient in drug delivery and presented a pH-responsive drug release behavior. Furthermore, they were incorporated into the collagen matrix to construct a biomimetic scaffold optimized for bone tissue regeneration. The Zn-MHMs/Coll scaffolds showed an interconnected pore structure in the range of 100–300 µm and a sustained release of Zn ions. More importantly, the Zn-MHMs/Coll scaffolds could enhance the osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells. Finally, the bone defect repair results of critical-sized femoral condyle defect rat model demonstrated that the Zn-MHMs/Coll scaffolds could enhance bone regeneration compared with the Coll or MHMs/Coll scaffolds. The results suggest that the biomimetic Zn-MHMs/Coll scaffolds may be of enormous potential in bone repair and regeneration. Keywords: drug delivery, mesoporous hydroxyapatite microspheres, zinc, biomimicry, scaffold, bone regeneration

Jing Gan, Chen Qi, Zhenguo LiuDepartment of Neurology, Xinhua Hospital affiliated to Shanghai Jiao Tong University Medical School, Shanghai, People’s Republic of ChinaBackground: The role of N-Methyl-D-aspartate (NMDA) receptors is critical to the development of l-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in Parkinson’s disease (PD). Ca2+/calmodulin-dependent protein kinase II (CaMKII) is thought to regulate the expression and activation of NMDA receptors in LID, but the interaction between LID and CaMKII-modulated NMDA receptor activity is not clear so far.Methods: We used 6-hydroxydopamine-lesioned rats to create PD rat model, and at least 21 days of L-DOPA was administrated followed with or without microinjection of CaMKII inhibitor KN-93 into the lesioned striatum of all the PD rats and sham rats. A surface receptor cross-linking assay was used to distinguish expression of striatal NMDA receptors in surface and intracellular compartments.Results: L-DOPA treatment enhanced surface levels of GluN1 expression and reduced its intracellular expression, but did not change total levels of GluN1 protein in the lesioned striatum. In contrast, L-DOPA decreased GluN2A surface expression but increased its intracellular expression. L-DOPA increased GluN2B expression preferentially in the surface compartment. We also found that L-DOPA increased CaMKII autophosphorylation at T286 in striatal neurons. The inhibition of CaMKII by microinjecting CaMKII inhibitor KN-93 into the lesioned striatum largely reversed the L-DOPA-induced changes in three subunits. In addition, dyskinetic behaviors of animals were observed alleviated after treatment of KN-93.Conclusion: Our research indicates that long-term L-DOPA administration activates CaMKII in striatal neurons. Activated CaMKII is involved at least in part in mediating L-DOPA-induced changes of NMDA receptors surface/intracellular expression.Keywords: glutamate, GluN1, GluN2A, GluN2B, dopamine, KN-93

Jing Gan,1 Chen Qi,1 Li-Min Mao,2 Zhenguo Liu11Department of Neurology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China; 2Department of Basic Medical Science, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USABackground: N-methyl-D-aspartate (NMDA) receptors play a central role in glutamatergic synaptic transmission in the mammalian brain and are linked to the pathophysiology and symptomatology of Parkinson's disease (PD). However, changes in NMDA receptor expression in distinct subcellular compartments in PD have not been elucidated. In this study, we investigated changes in subcellular expression of NMDA receptors in striatal neurons in a rodent PD model.Methods: Intracranial injection of the neurotoxin 6-hydroxydopamine (6-OHDA) was selectively lesioned into the nigrostriatal dopaminergic pathway in adult Sprague Dawley rats, which is a common rat model of PD. A surface receptor crosslinking assay was conducted to examine the response of individual NMDA receptor subunits to dopamine depletion in isolated and confined surface and intracellular compartments of striatal neurons.Results: In PD rats where 6-OHDA was selectively lesioned, surface expression of NMDA receptor GluN1 subunits as detected by surface protein crosslinking assays was increased in the striatum. In contrast, intracellular levels of GluN1 were decreased in the lesioned region. The NMDA receptor GluN2B subunit was elevated in its abundance in the surface pool of the lesioned striatum, while intracellular GluN2B levels were not altered. GluN2A subunits in both surface and intracellular fractions remained stable. In addition, total cellular levels of striatal GluN1 and GluN2A were not changed in lesioned tissue, while total GluN2B proteins showed an increase.Conclusion: These results demonstrate the differential sensitivity of principal NMDA receptor subunits to dopamine depletion. GluN1 and GluN2B expression in the distinct surface compartment underwent upregulation in striatal neurons after selective lesions of the dopaminergic pathway by 6-OHDA.Keywords: glutamate, excitatory amino acid, NMDA, GluN, dopamine, 6-hydroxydopamine, caudate putamen, nucleus accumbens

The experimental B(GT) strengths of the 59Fe excited states were employed to determine the transition strengths which greatly contribute 59Fe stellar β–decay at typical carbon shell burning temperature. The result has been compared with the theoretical rates FFN (Fuller-Fowler-Newman) and LMP (Langanke&Martinez-Pinedo). Impact of the newly determined rate on the synthesis of cosmic γ emitter 60Fe has also been studied using one-zone model calculation. Our results show 59Fe stellar β−decay rate plays an important role in the 60Fe nucleosynthesis. However the uncertainty of the decay rate is rather large due to the error of B(GT) strength that requires further studies.