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Xuefeng Bian,1,* Ting Guo,2,* Guojie Chen,2,* Dengyun Nie,2 Miao Yue,2 Yinxing Zhu,2 Mei Lin3 1Imaging Department, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, People’s Republic of China; 2Institute of Clinical Medicine, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, People’s Republic of China; 3Clinical Medical Laboratory, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mei Lin; Yinxing Zhu, Email trylm@ntu.edu.cn; lzp_zyx@163.comPurpose: This study aimed to construct targeting drug-loading nanocomposites (FA-FePt/DDP nanoliposomes) to explore their potential in ovarian cancer therapy and molecular magnetic resonance imaging (MMRI).Methods: FA-FePt-NPs were prepared by coupling folate (FA) with polyethylene-glycol (PEG)-coated ferroplatinum nanoparticles and characterized. Then cisplatin (DDP) was encapsulated in FA-FePt-NPs to synthesize FA-PEG-FePt/DDP nanoliposomes by thin film-ultrasonic method and high-speed stirring, of which MMRI potential, magnetothermal effect, and the other involved performance were analyzed. The therapeutic effect of FA-FePt/DDP nanoliposomes combined with magnetic fluid hyperthermia (MFH) on ovarian cancer in vitro and in vivo was evaluated. The expression levels of Bax and epithelial–mesenchymal transition related proteins were detected. The biosafety was also preliminarily observed.Results: The average diameter of FA-FePt-NPs was about 30 nm, FA-FePt/DDP nanoliposomes were about 70 nm in hydrated particle size, with drug slow-release and good cell-specific targeted uptake. In an alternating magnetic field (AMF), FA-FePt/DDP nanoliposomes could rapidly reach the ideal tumor hyperthermia temperature (42~44 °C). MRI scan showed that FA-FePt-NPs and FA-FePt/DDP nanoliposomes both could suppress the T2 signal, indicating a good potential for MMRI. The in vitro and in vivo experiments showed that FA-FePt/DDP-NPs in AMF could effectively inhibit the growth of ovarian cancer by inhibiting cancer cell proliferation, invasion, and migration, and inducing cancer cell apoptosis, much better than that of the other individual therapies; molecularly, E-cadherin and Bax proteins in ovarian cancer cells and tissues were significantly increased, while N-cadherin, Vimentin, and Bcl-2 proteins were inhibited, effectively inhibiting the malignant progression of ovarian cancer. In addition, no significant pathological injury and dysfunction was observed in major visceras.Conclusion: We successfully synthesized FA-FePt/DDP nanoliposomes and confirmed their good thermochemotherapeutic effect in AMF and MMRI potential on ovarian cancer, with no obvious side effects, providing a favorable strategy of integrated targeting therapy and diagnosis for ovarian cancer.Keywords: iron–platinum magnetic nanoparticles, ovarian cancer, DDP, molecular magnetic resonance imaging, folate

Yang Chen, Xiaoen Bian, Junnan Wang, Fang Yan, Jing Gao, Tao Sun Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People’s Republic of ChinaCorrespondence: Tao Sun, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, Jinan, Shandong, 250021, People’s Republic of China, Email suntaosdph@163.comPurpose: Chronic inflammatory pain is usually treated with oral non-steroidal anti-inflammatory drugs (NSAIDs). However, oral NSAIDs can cause some adverse events, and local preparation is an important alternative drug. Currently, small sample clinical studies show that loxoprofen sodium hydrogel patch (LX-P) has good analgesic and anti-inflammatory effects; however, there is a lack of real-world clinical research data.Patients and Methods: This study included 60 patients with chronic inflammatory pain. They were treated with LX-P without affecting their real-world treatment for two weeks.Results: After 2 weeks of continuous medication, 93.33% of the patients stated that the treatment was effective. Only 3.33% of the patients had a relapse after 4 weeks. Moreover, the swelling range and degree of swelling decreased markedly and the dysfunction of the pain site was markedly alleviated. The total satisfaction of patients after treatment reached 90.00%.Conclusion: In this real-world observational study, LX-P showed good efficacy and safety in patients with chronic inflammatory pain.Keywords: loxoprofen sodium hydrogel patch, real-world study, chronic inflammatory pain, non-steroidal anti-inflammatory drugs

Xiaohui Bian,1– 3,&ast; Jining He,1– 3,&ast; Rui Zhang,1– 3 Sheng Yuan,1– 3 Kefei Dou1– 4 1Cardiometabolic Medicine Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 3State Key Laboratory of Cardiovascular Disease, Beijing, People’s Republic of China; 4National Clinical Research Center for Cardiovascular Diseases, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Kefei Dou, Cardiometabolic Medicine Center, National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, A 167 Beilishi Road, Xicheng District, Beijing, 100037, People’s Republic of China, Tel +86-13801032912, Fax +86-10-6831-3012, Email drdoukefei@126.comBackground: Chronic low-grade inflammation is the common mechanism of both atherosclerosis and type 2 diabetes mellitus (T2DM), and systemic immune-inflammation index (SII) has been emerged as a novel and simple inflammatory biomarker. However, the association between SII and glycemic metabolism and their synergetic effect on the prognosis of coronary artery disease (CAD) patients remains unclear.Methods: A total of 8602 patients hospitalized for percutaneous coronary intervention (PCI) were included. The primary endpoint was major adverse cardiovascular events (MACE), including all-cause death, myocardial infarction (MI), and target vessel revascularization. According to the optimal cut-off value of SII for MACEs, patients were grouped into higher levels of SII (SII-H) and lower levels of SII (SII-L) and further divided by the concomitance of T2DM into four groups: SII-H/T2DM, SII-H/Non-T2DM, SII-L/T2DM, SII-L/Non-T2DM.Results: During a median 2.4-year follow-up, 522 MACEs occurred. The optimal cut-off value of SII for MACEs was 502.5. A 1-unit increase of SII (transformed by natural logarithm) was associated with a 29% increase of MACE risks in the T2DM cohort [adjusted hazard ratio (HR): 1.29, 95% confidence interval (CI): 1.03 to 1.61, P = 0.024], while had no effect in the non-T2DM cohort (HR: 1.03, 95% CI: 0.80 to 1.34, P = 0.800). Compared to those in SII-H/T2DM group, patients in SII-H/Non-T2DM, SII-L/T2DM, SII-L/Non-T2DM had significantly decreased risk of MACEs [adjusted HR: 0.77, 95% CI: 0.61 to 0.98, P = 0.036; adjusted HR: 0.66, 95% CI: 0.50 to 0.87, P = 0.003; adjusted HR: 0.58, 95% CI: 0.45 to 0.74, P < 0.001; respectively]. Multivariable Cox regression analysis also indicated the highest risk in T2DM patients with higher levels of SII than others (P for trend < 0.001).Conclusion: In this large-scale real-world study, diabetic patients with elevated SII levels were associated with worse clinical outcomes after PCI.Keywords: systemic immune-inflammation index, type 2 diabetes mellitus, coronary artery disease, percutaneous coronary intervention

Kailin Xing,1,&ast; Xinyu Bian,2,&ast; Dongmin Shi,3,&ast; Shuangshuang Dong,1 Hongxin Zhou,1 Shuxiu Xiao,4 Jinjin Bai,4 Weizhong Wu1,4 1Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Shanghai, 200032, People’s Republic of China; 2Department of Radiation Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210000, People’s Republic of China; 3Department of Medical Oncology, Shanghai Changzheng Hospital, Shanghai, 200072, People’s Republic of China; 4Clinical Center for Biotherapy, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weizhong Wu, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, People’s Republic of China, Tel +86-21-60268628, Fax +86-21-64037181, Email wu.weizhong@zs-hospital.sh.cnBackground: MicroRNA-612 (miR-612) has been proven to suppress the formation of invadopodia and inhibit hepatocellular carcinoma (HCC) metastasis by hydroxyacyl-CoA dehydrogenase alpha subunit (HADHA)-mediated lipid reprogramming. However, its biological roles in HCC cell ferroptosis remain unclear.Methods and Results: In this study, we found that HCC cells with high metastatic potential were more resistant to ferroptosis, indicating that ferroptosis is related to HCC metastasis. The levels of lipid reactive oxygen species (ROS) were found to be much lower in HCC cells with high metastatic potential by flow cytometry (FCM). We used HCC cells with miR-612 overexpression/knockout and HADHA overexpression/knockdown to test cell viability after stimulation with RSL3. HCC cells overexpressing miR-612 were more sensitive to ferroptosis, and miR-612 could increase lipid ROS levels. Furthermore, colony formation assays and Transwell assays showed that miR-612 could inhibit the proliferation and metastasis of HCC cells by promoting ferroptosis. We next confirmed that miR-612 influenced HCC cell ferroptosis by regulating HADHA. HADHA could upregulate the expression of key enzymes in the mevalonate (MVA) pathway. HADHA overexpression upregulated the expression of CoQ10 and decreased polyunsaturated fatty acid (PUFA) levels and lipid peroxide abundance. miR-612 also suppressed HCC cell proliferation and metastasis by enhancing RSL3- and lovastatin-induced ferroptosis in vivo.Conclusion: Overall, miR-612 promotes ferroptosis in HCC cells and affects HCC proliferation and metastasis by downregulating CoQ10 and increasing cellular PUFA levels and lipid peroxides via the HADHA-mediated MVA pathway.Keywords: HCC, Ferroptosis, miR-612, HADHA, MVA pathway

Peng He,1 Xin Li,2 Xiaohan Guo,1 Xingchen Bian,1 Rui Wang,1 Yue Wang,1 Sijing Huang,1 Mengya Qi,1 Yuanxia Liu,3 Meiqing Feng1 1Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, People’s Republic of China; 2Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 3Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Department of Pathology, Shanghai, People’s Republic of ChinaCorrespondence: Meiqing Feng, Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, People’s Republic of China, Tel +86 21 51980035, Email fmq@fudan.edu.cn Yuanxia Liu, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Department of Pathology, Shanghai, People’s Republic of China, Email lyuyx@126.comIntroduction: LYSC98 is a novel vancomycin derivative used for gram-positive bacterial infections. Here we compared the antibacterial activity of LYSC98 with vancomycin and linezolid in vitro and in vivo. Besides, we also reported the pharmacokinetic/pharmacodynamic (PK/PD) index and efficacy-target values of LYSC98.Methods: The MIC values of LYSC98 were identified through broth microdilution method. A mice sepsis model was established to investigate the protective effect of LYSC98 in vivo. Single-dose pharmacokinetics of LYSC98 was studied in thigh-infected mice and liquid chromatography–tandem mass spectrometry (LC-MS/MS) method was used to determine LYSC98 concentration in plasma. Dose fractionation studies were performed to evaluate different PK/PD indices. Two methicillin-resistant Staphylococcus aureus (MRSA) clinical strains were used in the dose ranging studies to determine the efficacy-target values.Results: LYSC98 showed a universal antibacterial effect in Staphylococcus aureus with a MIC range of 2– 4 μg/mL. In vivo, LYSC98 demonstrated distinctive mortality protection in mice sepsis model with an ED50 value of 0.41– 1.86 mg/kg. The pharmacokinetics results displayed maximum plasma concentration (Cmax) 11,466.67− 48,866.67 ng/mL, area under the concentration–time curve from 0 to 24 h (AUC0– 24) 14,788.42− 91,885.93 ng/mL·h, and elimination half-life (T1/2) 1.70– 2.64 h, respectively. Cmax/MIC (R2 0.8941) was proved to be the most suitable PK/PD index for LYSC98 to predict its antibacterial efficacy. The magnitude of LYSC98 Cmax/MIC associated with net stasis, 1, 2, 3 and 4 - log 10 kill were 5.78, 8.17, 11.14, 15.85 and 30.58, respectively.Conclusion: Our study demonstrates that LYSC98 is more effective than vancomycin either in killing vancomycin-resistant Staphylococcus aureus (VRSA) in vitro or treating S. aureus infections in vivo, making it a novel and promising antibiotic. The PK/PD analysis will also contribute to the LYSC98 Phase I dose design.Keywords: LYSC98, vancomycin derivative, pharmacokinetics and pharmacodynamics, Staphylococcus aureus, murine thigh infection model

New pharmacologic advances in the treatment of diabetes include SGLT-2 inhibitors, which have been demonstrated in randomized-controlled clinical trials to reduce overall and cardiac-specific mortality and slow progression of chronic kidney disease. Euglycemic diabetic ketoacidosis is a rare but life-threatening complication associated with the use of SGLT-2 inhibitors. Here we describe a case of severe euglycemic diabetic ketoacidosis after lower extremity bypass in a patient taking an SGLT-2 inhibitor. Awareness of this potential complication is essential as these novel agents are increasingly used in patients with cardiovascular disease.

Hao Zhao,1 Jun Li,1 Xin Yan,2 Xinchao Bian1 1Department of Neurosurgery, Zibo Central Hospital, Zibo City, Shandong Province, 255036, People’s Republic of China; 2Department of Ultrasound, Central Hospital Affiliated to Shandong University, Zibo City, Shandong Province, 255036, People’s Republic of ChinaCorrespondence: Xinchao BianDepartment of Neurosurgery, Zibo Central Hospital, Zibo City, Shandong Province, 255036, People’s Republic of ChinaEmail xinchaobiantrap@163.comPurpose: LncRNA MAFG-AS1 plays critical roles in several types of cancer, while its role in glioblastoma (GBM) is unknown. By analyzing the TCGA dataset, we observed the upregulation of MAFG-AS1 in GBM. This study aimed to investigate the involvement of MAFG-AS1 in GBM cancer.Methods: The expression levels of MAFG-AS1, mature miR-34a, and miR-34a precursor in GBM and paired non-tumor tissues of 56 GBM patients were determined by RT-qPCR. Correlations are analyzed using linear regression. Overexpression of MAFG-AS1 was achieved in GBM cells, followed by measurement of the expression levels of mature miR-34a, miR-34a precursor, DICER and Drosha by RT-qPCR. The roles of MAFG-AS1 and miR-34a in regulating GBM cell proliferation were evaluated by CCK-8 assay. Flow cytometry was performed to explore the role of MAFG-AS1 and miR-34a in regulating the apoptosis and cell cycle of GBM cells. Cell scratch experiment was performed to determine the role of MAFG-AS1 and miR-34a in regulating the migration of GBM cells. Subcutaneous tumor animal model was used for in vivo study. The expressions levels of BCL-2 and caspase-3 were detected by Western blot analysis.Results: MAFG-AS1 was upregulated in GBM, while mature miR-34a was downregulated in GBM. Interestingly, MAFG-AS1 was inversely correlated with mature miR-34a but not miR-34a precursor across GBM tissues. In GBM tissues, the overexpression of MAFG-AS1 did not affect the expression levels of miR-34a precursor but reduced the expression levels of mature miR-34a. MAFG-AS1 promoted the expression of DICER and Drosha in GBM cells. Moreover, the overexpression of MAFG-AS1 promoted the proliferation of GBM cells and reduced the inhibitory effects of miR-34a on cell proliferation but did not affect cell cycle, apoptosis and migration. The overexpression of MAFG-AS1 promoted the progression of GBM in vivo by promoting the proliferation of GBM cells while miR-34a reversed the effect of overexpression of MAFG-AS1.Conclusions: MAFG-AS1 may suppress the maturation of miR-34a to promote GBM cell proliferation.Keywords: glioblastoma, MAFG-AS1, miR-34a, maturation

Xiaoyan Bian,1,* Yuxia Guo,2,* Shixuan Guo,3,* Song Zhang,4,* Guisen Zhang,3 Lei Liu,4 Yajun Yang,5 Jun Liu6 1Department of Ocular Surface, Baotou Chaoju Eye Hospital, Baotou, 014060, People’s Republic of China; 2Department of Cataract Surgery, Ninghai Eye Hospital, Ningbo, 315615, People’s Republic of China; 3Department of Retina, Hohhot Chaoju Eye Hospital, Hohhot, 010050, People’s Republic of China; 4Department of Ophthalmology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, People’s Republic of China; 5Department of Cataract, Baotou Chaoju Eye Hospital, Baotou, 014060, People’s Republic of China; 6Department of Ophthalmology, Changzhi People’s Hospital, Changzhi, 046000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yajun YangDepartment of Cataract, Baotou Chaoju Eye Hospital, Baotou, 014060, People’s Republic of ChinaEmail yangyajun@chaojueye.comJun LiuDepartment of Ophthalmology, Changzhi People’s Hospital, Changzhi, 046000, People’s Republic of ChinaEmail yuanliu97@sina.comAim: To investigate the relationships between property of the visual quality, Strehl ratio (SR) and the degree of myopia.Methods: A total of 444 anatomically normal eyes of 222 adolescents were enrolled in the TYPE study. Based on spherical equivalent (SE), subjects were divided into four groups: emmetropia/control (SE: +0.75 to − 0.75 D), low myopia (SE: − 0.75 to − 3.00D), moderate myopia (SE: − 3.00 to − 5.00D), high myopia (SE:

Yajun Yang,1,* Guisen Zhang,2,* Song Zhang,3,* Xiaoyan Bian,1 Lao Qi,2 Shixuan Guo,2 Bozhou Zhang,1 Lei Liu4 1Cataract Department, Baotou Chaoju Eye Hospital, Baotou, 014060, People’s Republic of China; 2Retina Department, Hohhot Chaoju Eye Hospital, Hohhot, 010050, People’s Republic of China; 3Cataract Department, China Medical University, Shenyang, 110122, People’s Republic of China; 4Department of Ophthalmology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bozhou ZhangBaotou Chaoju Eye Hospital, Baotou, Inner Mongolia Autonomous Region, 014060, People’s Republic of ChinaEmail zhangbozhou@chaojueye.cnLei LiuThe First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110001, People’s Republic of ChinaEmail liuleijiao@163.comAim: To use OCTA to collect normative data describing the vascular perfusion of the macula and optic disc in adolescents.Methods: This cross-sectional, school-based study was conducted from Oct 15, 2019, to Nov 30, 2019, in Tuyou County, Baotou, China. All eligible participants underwent a comprehensive questionnaire and ocular examination. The vascular perfusion of the macula and optic disc was determined using a spectral-domain OCTA device.Results: A total of 570 anatomically normal eyes without a history of pathologic disease from 570 adolescents (mean ± SD age, 15.1 ± 1.9 years; 298 girls [52.3%]) were enrolled. In the macula, the mean ± SD perifoveal perfusion density (PD) of the superficial capillary plexus (SCP) and deep capillary plexus (DCP) was 44.2% ± 4.37% and 50.74% ± 3.98%, respectively. The mean ± SD foveal avascular zone (FAZ) was 0.32 mm2 ± 0.11 mm2. The mean ± SD peripapillary vessel density (PVD) was 54.98% ± 3.53%. The inferior hemiretinal SCP-PD, DCP-PD, FAZ, and PVD was larger in girls than boys (P = 0.006, P = 0.001, P < 0.001, and P = 0.006, respectively) Multiple regression analysis confirmed that sex independently affected the DCP-PD, FAZ, and PVD (P < 0.001, P < 0.001, and P = 0.029, respectively) and that axial length (AL) independently affected the FAZ area and PVD (P = 0.004 and P < 0.001, respectively).Conclusion: Quantitative studies of the perifoveal vasculature in adolescents should consider the patient’s sex and AL. Our findings may provide useful information for the understanding and the management of retinal perfusion in Chinese adolescents.Keywords: macula, optic disc, optical coherence tomography angiography, retinal perfusion

Mancheng Xia,1 Haosen Yang,2 Yusheng Wang,1 Keqiang Yin,1 Xiaodong Bian,1 Jiawei Chen,1 Weibing Shuang3 1First Clinical Medical College, Shanxi Medical University, Taiyuan, People’s Republic of China; 2Kidney Transplantation Center, Shanxi Second People’s Hospital, Taiyuan, People’s Republic of China; 3Department of Urology, The First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of ChinaCorrespondence: Weibing ShuangDepartment of Urology, The First Hospital of Shanxi Medical University, No. 85, JieFang South Road, Yingze District, Taiyuan 030001, People’s Republic of ChinaEmail shuangweibing@126.comObjective: To develop and validate a nomogram for predicting the overall survival (OS) of renal cell carcinoma (RCC) patients after nephrectomy.Materials and Methods: In total, 488 patients with RCC who underwent nephrectomy at the Urology Department of the First Hospital of Shanxi Medical University between January 2013 and December 2018 were randomly divided into a development cohort (n = 344) and a validation cohort (n = 144). The development cohort was used to build a prediction model, and the validation cohort was used for validation. Single-factor and multifactor analyses were carried out with R software, and the nomogram, calibration chart, ROC curve and C index were constructed.Results: The median follow-up time of the development and validation cohorts was 34 months. The total 3-year and 5-year survival rates of the development cohort were 93.3% and 91.6%, respectively; those of the validation cohort were 92.4% and 91.0%, respectively. Cox univariate analysis of the development cohort showed that age, type 2 diabetes mellitus (T2DM), smoking history, type of surgery, T stage, N stage, M stage and Fuhrman nuclear grade were prognostic factors for OS in RCC patients undergoing nephrectomy. Cox multivariate analysis showed that T2DM, smoking history and T stage were independent prognostic factors for OS in RCC patients undergoing nephrectomy (P < 0.05). According to the univariate and multivariate analyses, a nomogram was constructed. In the development cohort, the C index of predicted OS was 0.875 (95% CI, 0.820– 0.930). The calibration curve of the 3-year and 5-year survival rates showed that the predicted value of the nomogram was consistent with the actual observed value. The area under the 3-year and 5-year survival ROC curves was 0.861 and 0.901, respectively. In the validation cohort, the C index was 0.880 (95% CI, 0.778– 0.982). The calibration curve of the 3-year and 5-year survival rates showed that the predicted value of the nomogram was consistent with the actual observed value. The area under the 3-year and 5-year survival ROC curves was 0.813 and 0.799, respectively.Conclusion: We developed and verified a new and accurate nomogram with available clinicopathological data that can effectively predict the OS of RCC patients after nephrectomy.Keywords: renal cell carcinoma, prognosis, nomogram, influencing factors

Yan Li1,2,*, Xiaohui Bian2,*, Shuyi Wei2, Meizhi He2, Yuelian Yang1 1Department of Gerontology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 2The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuelian YangDepartment of Gerontology, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Haizhu District, Guangzhou, Guangdong 510280, People’s Republic of ChinaTel +86 1 366 057 4670Email 61850306@qq.comAbstract: Pancreatic cancer (PC) is a devastating and lethal malignant disease and it is well known that there is a complex bidirectional relationship between PC and type 2 diabetes mellitus (T2DM). In order to more deeply summarize the relationship between them, this article summarizes the epidemiological data on the relationship between PC and T2DM in the past 5 years, and further explains the mechanism of interaction between them. Meanwhile, it also summed up the effects of drug therapy for T2DM on PC and the impact of T2DM on surgical resection of PC. Epidemiological studies clearly indicate that the risk of PC is increased in patients with T2DM. But increasing epidemiological data points out that PC also acts as a cause of T2DM and new-onset T2DM is sign and consequence of PC. Insulin resistance, hyperinsulinemia, hyperglycemia, and chronic inflammation are the mechanisms of T2DM-Associated PC. Metformin decreases the risk of PC, while insulin therapy increases the risk of PC. Besides, studies have shown that T2DM decreases the survival in patients with PC resection.Keywords: pancreatic cancer, type 2 diabetes, bidirectional relationship

Chuanxu Cai,1,2,* Xiqing Bian,3,* Mingshan Xue,1 Xiaoqing Liu,1 Haisheng Hu,1 Jingxian Wang,4 Song Guo Zheng,5 Baoqing Sun,1 Jian-Lin Wu31Department of Allergy and Clinical Immunology, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Department of Laboratory Medicine, Shenzhen People’s Hospital, Shenzhen, People’s Republic of China; 3State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macao, People’s Republic of China; 4Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China; 5Department of Internal Medicine, Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH, USA*These authors contributed equally to this workBackground and objective: The prevalence of asthma is greater than 20% in patients previously diagnosed with COPD. Patients with asthma–COPD overlap (ACO) are at risk of rapid progression of disease and severe exacerbations. However, in some patients with ACO, a clear distinction from COPD is very difficult by using physiological testing techniques. This study aimed to apply a novel metabolomic approach to identify the metabolites in sera in order to distinguish ACO from COPD.Methods: In the study, blood samples were collected from patients with COPD, ACO, and healthy controls. Cholamine derivatization-ultrahigh performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) was used to investigate serum metabolites of eicosanoids.Results: A clear intergroup separation existed between the patients with ACO and those with COPD, while ACO tends to have higher serum metabolic levels of eicosanoids. A robust Orthogonal Projections to Latent Structures-Discriminant Analysis (OPLS-DA) model was found for discriminating between ACO and COPD (R2Y =0.81, Q2=0.79). In addition, there is a significant correlation between some metabolites and clinical indicators, such as hydroxyeicosatetraenoic acids (HETEs), hydroperoxyeicosatetraenoic acids (HPETEs) and FEV1/FVC. The higher values of area under the receiver operating characteristic curves (ROC) of HETEs, which were metabolized from HPETEs through lipoxygenase (LOX), indicated that they should be the potential biomarkers to distinguish ACO from COPD.Conclusion: Eicosanoids can clearly discriminate different biochemical metabolic profiles between ACO and COPD. The results possibly provide a new perspective to identify potential biomarkers of ACO and may be helpful for personalized treatment.Keywords: metabolomics, COPD, asthma–COPD overlap, cholamine derivatization-UHPLC-Q-TOF/MS

Xiang Zhu,* Yuxi Liu,* Hongfang Huang, Yonghua Zhang, Saisai Huang, Weiwei Zhou, Xiaocui Bian, Shiren Shen, Su Cao Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, People’s Republic of China *These authors contributed equally to this work Purpose: Postoperative pain is a common clinical problem. In this study, we aimed to investigate the role of protein kinase C bII (PKCβII) in the progression of postoperative pain following skin/muscle incision and retraction (SMIR) surgery. Materials and methods: SMIR postoperative pain model was established in rats, akin to a clinical procedure. The expression level and location of p-PKCβII were observed in dorsal root ganglion (DRG) or spinal cord from SMIR-operated rats by Western blotting and immunofluorescence. In addition, the effects of PKCβII on the expression of protein gene product 9.5 (PGP9.5) or vascular endothelial growth factor (VEGF) were assessed by using pharmacological activator and inhibitor of PKCβII. Moreover, mechanical withdrawal threshold (MWT) was assessed before or after SMIR-operated rats were treated with inhibitor or activator of PKCβII. Results: The expression of PKCβII in DRG and spinal cord was significantly increased after SMIR surgery (P < 0.001, P < 0.01) and expression of PKCβII was located in the neurons of the spinal cord, and magnocellular neurons, non-peptide neurons, and peptide neurons in DRG. Besides, compared with skin/muscle incision group, retraction caused a marked increase in the expression of PKCβII and a significant decrease of MWT (P < 0.001, P < 0.05). The activator of PKCβII greatly increased the expression of PGP9.5 and VEGF (P < 0.05, P < 0.01) and enhanced MWT (P < 0.001), while inhibitor of PKCβII decreased the expression of PGP9.5 and VEGF and attenuated MWT (P < 0.05, P < 0.01, P < 0.001). Conclusion: Activation of PKCβII signaling pathways might be an important mechanism in the progression of postoperative pain. Keywords: postoperative persistent pain, neurons, PKCβII, PGP9.5, VEGF

Wenrui Wu,1,2,* Xingkang He,3,4,* Liya Yang,1,2 Qing Wang,1,2 Xiaoyuan Bian,1,2 Jianzhong Ye,1,2 Yating Li,1,2 Lanjuan Li1,2 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; 2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China; 3Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University Medical School, Hangzhou, China; 4Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden *These authors contributed equally to this work Background: The morbidity and mortality of pancreatic cancer vary considerably around the world. The aim of this study was to characterize and evaluate recent changes in incidence and incidence-based mortality in the USA. Methods: Incidence and incidence-based mortality data were based on the 18 Surveillance, Epidemiology, and End Results (SEER) registries through SEER*Stat software. We adopted joinpoint regression to analyze the temporal trends stratified by age, gender, ethnicity, stage, tumor site, and size. Results: Based on 18 SEER data sets, the age-adjusted incidence of pancreatic cancer increased from 11.85/100,000 in 2000 to 14.70/100,000 in 2014, increasing by an average annual percentage change (AAPC) of 1.6 (95% CI 1.5–1.8, p

Wenrui Wu,1,2 Daiqiong Fang,1,2 Ding Shi,1,2 Xiaoyuan Bian,1,2 Lanjuan Li1,2 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, 2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, People’s Republic of China Purpose: It is well demonstrated that being married is associated with a better prognosis in multiple types of cancer. However, whether the protective effect of marital status varied across race/ethnicity and gender in patients with hepatocellular carcinoma remains unclear. Therefore, we aimed to evaluate the roles of race/ethnicity and gender in this relationship.Patients and methods: We identified eligible patients from Surveillance, Epidemiology and End Results (SEER) database during 2004–2012. Overall and cancer-specific survival differences across marital status were compared by Kaplan–Meier curves. We also estimated crude hazard ratios (CHRs) and adjusted hazard ratios (AHRs) with 95% confidence intervals (CIs) for marital status associated with survival by race/ethnicity and gender in Cox proportional hazard models.Results: A total of 12,168 eligible patients diagnosed with hepatocellular carcinoma were included. We observed that married status was an independent protective prognostic factor for overall and cancer-specific survival. In stratified analyses by race/ethnicity, the AHR of overall mortality (unmarried vs married) was highest for Hispanic (AHR =1.25, 95% CI, 1.13–1.39; P

Pu Wang,1,* Yazhuo Qu,2,* Chuan Li,3 Li Yin,2 Caifei Shen,1 Wei Chen,3 Shiming Yang,4 Xiuwu Bian,2 Dianchun Fang11Institute of Gastroenterology, 2Institute of Pathology, 3Department of Radiology, Southwest Hospital, The Third Military Medical University, Chongqing, People’s Republic of China; 4Department of Gastroenterology, Xinqiao Hospital, The Third Military Medical University, Chongqing, People’s Republic of China*These authors contributed equally to this workPurpose: Nano dense-silica (dSiO2) has many advantages such as adjustable core–shell structure, multiple drug delivery, and controllable release behavior. Improving the gastric tumor-specific targeting efficiency based on the development of various strategies is crucial for anti-cancer drug delivery systems.Methods: Superparamagnetic iron oxide nanoparticles (SPION) were coated with dSiO2 as core–shell nanoparticles, and labeled with near infra-red fluorescence (NIRF) dye 800ZW (excitation wavelength: 778 nm/­emission wavelength: 806 nm) and anti-CD146 monoclonal antibody YY146 for magnetic resonance (MR)/NIRF imaging study in xenograft gastric cancer model. The morphology and the size of pre- and postlabeling SPION@dSiO2 core–shell nanoparticles were characterized using transmission electron microscopy. Iron content in SPION@dSiO2 nanoparticles was measured by inductively coupled plasma optical emission spectrometry. Fluorescence microscopy and fluorescence-activated cell sorter studies were carried out to confirm the binding specificity of YY146 and 800ZW–SPION@dSiO2–YY146 on MKN45 cells. In vivo and in vitro NIRF imaging, control (nanoparticles only) and blocking studies, and histology were executed on MKN45 tumor-bearing nude mice to estimate the affinity of 800ZW–SPION@dSiO2–YY146 to target tumor CD146.Results: 800ZW–SPION@dSiO2–YY146 nanoparticles were uniformly spherical in shape and dispersed evenly in a cell culture medium. The diameter of the nanoparticle was 20–30 nm with 15 nm SPION core and ~10 nm SiO2 shell, and the final concentration was 1.7 nmol/mL. Transverse relaxivity of SPION@dSiO2 dispersed in water was measured to be 110.57 mM-1·s-1. Fluorescence activated cell sorter analysis of the nanoparticles in MKN45 cells showed 14-fold binding of 800ZW–SPION@dSiO2–YY146 more than the control group 800ZW–SPION@dSiO2. Series of NIRF imaging post intravenous injection of 800ZW–SPION@dSiO2–YY146 demonstrated that the MKN45 xenograft tumor model could be clearly identified as early as a time point of 30 minutes postinjection. Quantitative analysis revealed that the tumor uptake peaked at 24 hours postinjection.Conclusion: This is the first successful study of functional nanoparticles for MR/NIRF imaging of cell surface glycoprotein CD146 in gastric cancer model. Our results suggest that 800ZW–SPION@dSiO2–YY146 nanoparticles will be applicable in tumor for image-guided therapy/surgery.Keywords: SPION, nanotechnology, EMT, SPION@dSiO2, xenograft, gastric cancer

Xiaomei Bian,1 Su Liang,1 Jyothy John,1 Cheng-Hui Hsiao,1 Xin Wei,2 Dong Liang,1 Huan Xie1 1Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, 2Department of Chemistry, College of Science and Technology, Texas Southern University, Houston, TX, USA Purpose: Itraconazole (ITZ) is a synthetic triazole antifungal agent, which is widely used for treatment and prevention of fungal infections. The purpose of this study is to develop ITZ-loaded poly(lactic-co-glycolic acid) (PLGA) nanospheres (PLGA-ITZ-NS) as a new sustained-release formulation for intravenous ITZ administration. Materials and methods: PLGA-ITZ-NS were prepared by a nanoprecipitation method and optimized by modifying the surfactant poloxamer 188 concentration and PLGA:ITZ ratio. Their physicochemical properties, including size, zeta potential, external morphology and encapsulation efficiency, were characterized by dynamic light scattering (DLS), scanning electron microscopy (SEM) and high performance liquid chromatography (HPLC). The effect of the different selected lyoprotectants with various concentrations on NS particles size and surface charge were also assessed. Rapid and sensitive HPLC and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods were developed to determine ITZ concentrations in formulation and in rat plasma, respectively. Pharmacokinetics of the optimum PLGA-ITZ-NS formulation was compared with the former commercial Sporanox® injection formulation using rats as the animal model. Noncompartmental pharmacokinetic parameters were obtained by WinNonlin® software. Results: Optimal PLGA-ITZ-NS had a mean particle size of about 200 nm with a high homogeneity (polydispersity index ≈0.2), favorable zeta potential (approximately -20 to -30 mV) and encapsulation efficiency (72%). In addition, 2% w/v sucrose was selected as a lyoprotectant for NS freeze-drying. The newly developed LC-MS/MS assay was validated and found to be accurate and precise. The in vivo study showed that the NS formulation has a similar systemic bioavailability to Sporanox®while providing a sustained plasma level (>100 ng/mL) for up to 24 hours after intravenous administration. Conclusion: Our newly developed PLGA-ITZ-NS has shown great sustained release and comparable bioavailability with Sporanox®, therefore having the potential to be an alternative injectable formulation of ITZ. Keywords: itraconazole, poly(lactic-co-glycolic acid), PLGA, nanoparticle, sustained release, pharmacokinetics, intravenous injection

Nickel stable isotopes (δ60Ni) provide insight to Ni biogeochemistry in the modern and past oceans. Here, we present the first Pacific Ocean high‐resolution dissolved Ni concentration and δ60Ni data, from the US GEOTRACES GP15 cruise. As in other ocean basins, increases in δ60Ni toward the surface ocean are observed across the entire transect, reflecting preferential biological uptake of light Ni isotopes, however the observed magnitude of fractionation is larger in the tropical Pacific than the North Pacific Subtropical Gyre. Such surface ocean fractionation by phytoplankton should accumulate isotopically lighter Ni in the deep Pacific, yet we find that North Pacific deep ocean δ60Ni is similar to previously reported values from the deep Atlantic. Finally, we find that seawater dissolved δ60Ni in regions with hydrothermal input can be either higher or lower than background deep ocean δ60Ni, depending on vent geochemistry and proximity. Plain Language Summary: A habitable Earth relies on the growth of microscopic plants, called phytoplankton, in the ocean. Phytoplankton help regulate Earth's climate and their growth requires various nutrients in seawater, including a suite of metal elements such as iron, zinc, and nickel (Ni). These metals are called trace metals in the ocean because their concentrations are extremely low in seawater, yet they are essential micronutrients. Therefore, it is important to understand how much and how these elements are supplied to and removed out of the ocean, and how they are used by phytoplankton. To study this question, we analyzed Ni isotope ratios of hundreds of seawater samples collected from the Pacific Ocean—which is the ratio of naturally occurring Ni atoms with different numbers of neutrons and therefore slightly different masses. We find that surface seawater is more enriched in heavier Ni isotopes than the deep seawater, in particular around the tropical Pacific. The deep ocean has similar Ni isotope ratios across different ocean basins, from the Atlantic to the Pacific. Seawater Ni isotope ratios are impacted by rivers near Alaska, submarine volcanos near Hawaiʻi, and a submarine volcanic chain called the East Pacific Rise. Key Points: Enrichment of heavier Ni isotopes is observed in the surface ocean across the GP15 transect, particularly in the equatorial PacificNorth Pacific deep ocean Ni isotope composition is nearly homogeneous and similar to previously reported values from other ocean basinsHydrothermal activity can both decrease and increase seawater Ni isotope composition, depending on vent geochemistry and proximity [ABSTRACT FROM AUTHOR]

The toolbox to study the Universe grew on 14 September 2015 when the LIGO–Virgo collaboration heard a signal from two colliding black holes between 30 and 250 Hz. Since then, many more gravitational waves have been detected as detectors continue to increase sensitivity. However, the current and future interferometric detectors will never be able to detect gravitational waves below a few Hz due to oceanic activity on Earth. An interferometric space mission, the laser interferometer space antenna, will operate between 1 mHz and 0.1 Hz, leaving a gap in the decihertz band. To detect gravitational-wave signals also between 0.1 and 1 Hz, the Lunar Gravitational-wave Antenna will use an array of seismic stations. The seismic array will be deployed in a permanently shadowed crater on the lunar south pole, which provides stable ambient temperatures below 40 K. A cryogenic superconducting inertial sensor is under development that aims for fm/ √ Hz sensitivity or better down to several hundred mHz, and thermal noise limited below that value. Given the 10 6 m size of the Moon, strain sensitivities below 10 − 20 1/ √ Hz can be achieved. The additional cooling is proposed depending on the used superconductor technology. The inertial sensors in the seismic stations aim to make a differential measurement between the elastic response of the Moon and the inertial sensor proof-mass motion induced by gravitational waves. Here, we describe the current state of research toward the inertial sensor, its applications, and additional auxiliary technologies in the payload of the lunar gravitational-wave detection mission. [ABSTRACT FROM AUTHOR]