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Tianjie Zhang,1 Yan Liu,1 Dongwei Xu,2 Rui Dong,1 Ye Song1 1Department of Ultrasonography, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, 201318,People’s Republic of China; 2Department of Critical Care Medicine, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, People’s Republic of ChinaCorrespondence: Ye Song, Email songy_18@sumhs.edu.cnBackground: This study aims to evaluate the predictive value of bedside ultrasound evaluation of diaphragmatic dynamics in determining successful extubation outcomes for patients eligible for weaning.Methods: This prospective observational study was conducted on patients who were mechanically ventilated and ready for weaning during the spontaneous breathing trial (SBT). The diaphragm contraction and motion-related parameters of patients such as end inspiratory diaphragm thickness (DT-insp), end respiratory diaphragm thickness (DT-exp), diaphragm thickening fraction (DTF), diaphragmatic thickening fraction rapid shallow breathing index (DTF-RSBI), diaphragmatic excursion (DE), diaphragmatic excursion rapid shallow breathing index (DE-RSBI) were recorded and the association with failure in ventilatory extubation was analyzed. A receiver operating characteristic (ROC) curve was conducted to analyze the prediction of successful weaning.Results: Out of 95 patients, 14 (14.74%) died, and 68 (71.58%) were successfully extubated. There were significant differences between the two groups in all parameters except DT-exp. The results indicated that duration of mechanical ventilation (OR = 0.850, 95% CI: 0.770– 0.938, P = 0.001), DTF (OR = 1.214, 95% CI: 1.108– 1.330, P = 0.000), DTF-RSBI (OR = 0.917, 95% CI: 0.880– 0.954, P = 0.000), DE (OR = 127.02, 95% CI: 15.004– 1075.291, P = 0.000), DE-RSBI (OR = 0.752, 95% CI: 0.657– 0.861, P = 0.000) had predictive value for weaning. DTF and DE had a high sensitivity of 91.18%, 100%, respectively. Whereas, duration of mechanical ventilation, DTF-RSBI, DE-RSBI showed a high specificity of 81.48,85.19%, 81.48%. Considering all the above factors, the sensitivity was 88.24% and the specificity was 88.89%.Conclusion: Bedside ultrasound assessment of diaphragmatic parameters enables the detection of diaphragmatic dysfunction, thus proving valuable in predicting extubation success and facilitating a favorable weaning outcome.Keywords: diaphragmatic dynamics, bedside ultrasound, extubation, intensive care unit

Caixing Shi,1 Yueyao Li,2 Zhidong You,3 Yiran Tian,4 Xiaoyu Zhu,4 Hao Xu,4 Menghan Yang,4 Yutong Zhang,4 Rui Dong,4 Huirong Quan,4 Yongyi Shang,4 Xiaojin Li1 1School of Basic Medicine, Jining Medical University, Jining, 272067, People’s Republic of China; 2College of Integrated Chinese and Western Medicine, Jining Medical University, Jining, 272067, People’s Republic of China; 3School of Nursing, Jining Medical University, Jining, 272067, People’s Republic of China; 4School of Clinical Medicine, Jining Medical University, Jining, 272067, People’s Republic of ChinaCorrespondence: Xiaojin Li, School of Basic Medicine, Jining Medical University, No. 133 hehua Road, Taibai Lake New District, Jining, 272067, People’s Republic of China, Tel +8615265775150, Email jinli10221@163.comPurpose: Acute liver injury (ALI) is characterized by inflammation and oxidative stress (OS). Although mangiferin (MGF) has antioxidant and anti-inflammatory effects, its role in ALI remains unclear. Accordingly, we investigated the MGF molecular mechanism in carbon tetrachloride (CCl4)-induced ALI in vivo and in vitro.Materials and Methods: The CCl4 was utilized to induce ALI in mice. In vivo, the therapeutic effects of MGF on CCl4-induced liver injury were evaluated through biochemical assays and histomorphological analysis. Additionally, immunohistochemistry, immunofluorescence, ELISA and Western blotting were further applied to explore the mechanism. In vitro, The CCK-8 assay and flow cytometry were employed to investigate the protective effects of MGF against CCl4-induced toxicity in HepG2 cells, while mitochondrial reactive oxygen species levels and Western blotting were used to explore the biological effects and molecular mechanisms.Results: MGF treatment resulted in a reduction in serum levels of AST and ALT, diminished concentrations of TNF-α, IL-6, and IL-1β in liver tissue, and concurrently decreased cellular apoptosis. Furthermore, MGF pretreatment enhanced the activity of SOD and GSH while concurrently diminishing the MDA production. This study further demonstrated the upregulation of Nrf2, NQO1, and HO-1 protein expression levels, as well as the downregulation of p-p65 protein expression levels. In vitro investigations revealed that the mitigation of CCl4-induced inflammation and OS by MGF was mediated via the Nrf2- antioxidant response element (ARE) pathway, which was disrupted by ML385 in HepG2 cells.Conclusion: CCl4 can induce liver injury, while treatment with MGF mitigates ALI by inhibiting oxidative stress, inflammation, and apoptosis. The protective mechanism of MGF is mediated by the Nrf2-ARE pathway activation.Keywords: mangiferin, liver injury, oxidative stress, inflammation, Nrf2

Wei Qiang,1,* Mengyi Li,1,2,* Sucai Song,1,3 Ruiqing Dong,1 Tongxin Zhang,1 Xuna Kou,1 Yuan Wu,1 Zhaoxu Wang,1,4 Jiayue Liu,1 Juan Liu,1 Yi Wang,1 Xiaoyan Wu,1 Bingyin Shi,1 Hui Guo1 1Department of Endocrinology and Metabolism, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2Department of Endocrinology, Xi’an People’s Hospital, Xi’an, Shaanxi, 710100, People’s Republic of China; 3Department of Endocrinology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 4Department of Endocrinology, Luohe Central Hospital, Luohe, Henan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hui Guo, Department of Endocrinology and Metabolism, The First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta West Street, Xi’an, People’s Republic of China, Tel +86-13709292996, Fax +86-029-85323974, Email 13709292996@139.comIntroduction: The long-acting insulin analogue insulin degludec (IDeg) is increasingly recommended for type two diabetes (T2DM), yet clinical experience in China remains limited. This retrospective study aimed to delineate the initiation strategy for IDeg in Chinese hospitalized patients with T2DM.Methods: We retrospectively analyzed 217 Chinese hospitalized patients with T2DM who initiated IDeg from December 2018 to June 2020, calculating the initial dose and examining correlations between clinical characteristics and glucose profiles.Results: The initial IDeg doses ranged from 0.15 to 0.18 IU/kg·d, showing no association with clinical characteristics. During titration, mean blood glucose levels (MEAN) correlated positively with diabetes duration, age, and Glycosylated Hemoglobin (HbA1c), and negatively with body mass index (BMI), triglycerides (TG), and low-density lipoprotein (LDL). The coefficient of variation (CV) in glucose levels correlated positively with HbA1c and negatively with BMI and TG. The mean amplitude of glycemic excursions (MAGE) mirrored these trends, with additional negative correlations to estimated glomerular filtration rate (eGFR) and serum albumin (ALB). Notably, glycemic variability parameters did not correlate with the presence of diabetic ketoacidosis (DKA) at admission. Hypoglycemia was observed in 21 patients, with differences in MEAN and CV during titration being the only significant findings.Conclusion: The initial IDeg dosing was inadequate and not tailored to clinical features, and there were weak correlations between diabetes duration, age, BMI, eGFR, LDL, and ALB levels and glucose profile post-initiation.Keywords: T2DM, insulin degludec, glucose variability, insulin initiation

Na Chen,1,2 Xuben Yu,3 Lu Li,1 Ping Yang,1 Rong Dong,1,4 Yizhen Huang,1,5 Xiao Ling,1,6 Qiaoqiao Shentu,1,7 Wenqiao Yu,8 Saiping Jiang1 1Department of Clinical Pharmaceutical, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, Hangzhou, People’s Republic of China; 3Department of Pharmacy, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 4Department of Clinical Pharmacy, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 5Department of Pharmacy, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China; 6Department of Pharmacy, The People’s Hospital of Yuhuan, Taizhou, People’s Republic of China; 7Department of Pharmacy, Dongyang Red Cross Hospital, Jinhua, People’s Republic of China; 8Department of Hepatobiliary and Pancreatic Surgery and Intensive Care Unit, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Saiping Jiang; Wenqiao Yu, Email j5145@zju.edu.cn; yuwenqiao1980@zju.edu.cnBackground: The population pharmacokinetics of nirmatrelvir/ritonavir (NIR/RIT) has not yet been described for critically ill adult patient.Purpose: This was a prospective observational population pharmacokinetic study of nirmatrelvir/ritonavir (NIR/RIT) in critically ill adult patients and identify optimal dosing regimens.Patients and Methods: The prescription of NIR/RIT is determined by the attending physician and ranges from 150mg/100mg to 300mg/100mg twice a day. Two to three serial blood samples were collected for each patient after the second doses. We developed and validated PK model for plasma NIR and plasma RIT. Monte Carlo dosing simulations were performed to assess target attainment.Results: We analyzed 89 plasma samples from 31 adult patients. The data were best described by a one-compartment model. Among the covariates tested on pharmacokinetic parameters, creatinine clearance (CrCL) and area under curve (AUC) of RIT had a significant effect on apparent clearance (CL/F) of NIR. Mean (SD) parameters estimates for the absorption rate constant (Ka), apparent distribution (V/F) and CL/F were 0.42 (0.10) h− 1. 36.5 (8.5) L, 3.6 (0.26) L/h, respectively. Dosing simulations showed that the target in vitro 90% effective concentration (EC90) was more likely to be achieved twice a day than once a day at the same daily dose of NIR. High CrCL, low AUC of RIT were associated with a reduced likelihood of NIR reaching the target EC90.Conclusion: Based on our dosing simulations, the initial dosage of NIR/RIT was 300mg/100mg twice a day in critically ill patients with CrCL> 45 mL/min; When CrCL in critically ill patients is between 15 and 45 mL/min, NIR/RIT is 150mg/100mg twice a day. The maintenance dose is adjusted according to CrCL and AUC of RIT, with the dosages varying between 75mg/100mg and 300mg/100mg.Keywords: nirmatrelvir, ritonavir, pharmacokinetics, critically ill, creatinine clearance

Tianjie Zhang,1 Yan Liu,1 Dongwei Xu,2 Rui Dong,1 Ye Song1 1Department of Ultrasonography, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, 201318, People’s Republic of China; 2Department of Critical Care Medicine, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, People’s Republic of ChinaCorrespondence: Ye Song, Email songye@tongji.edu.cnBackground: In recent years, diaphragm ultrasound (DUS) has been used to identify diaphragm dysfunction in the intensive care unit (ICU). However, there are few studies on DUS parameters to evaluate function, normal ranges, and influencing factors in population. The aim of this study is to provide a methodological reference for clinical evaluation of diaphragm function by measuring different DUS parameters in a healthy population.Methods: A descriptive study was conducted 212 (105 males, 107 females) subjects with normal spirometry underwent ultrasound imaging in this study. The diaphragm contraction and motion related parameters and shear wave velocity (SWV) were measured in the supine position. The effects of gender, age, body mass index (BMI) and lifestyle on diaphragm ultrasound parameters were analyzed.Results: The diaphragm thickness at end-expiration (DT-exp) was 0.14 ± 0.05 cm, the diaphragm thickness at end- inspiration (DT-insp) was 0.29± 0.10 cm, with thickening fraction (TF) was 1.11± 0.54. The diaphragm excursion (DE) was 1.68± 0.37cm and diaphragm velocity was 1.45± 0.41 cm/s during calm breathing. During deep breathing, the DE was 5.06± 1.40cm and diaphragm velocity was 3.20± 1.18 cm/s. The Diaphragm shear modulus—longitudinal view were Mean16.72± 4.07kPa, Max25.04± 5.58kPa, Min11.06± 3.88kPa, SD2.56± 0.98. The results of diaphragmatic measurement showed that the DT of males was significantly greater than that of females (P< 0.05), but there was no significant difference in TF. The DT-insp (r=0.155, P= 0.024) and the DT-exp (r=0.252, P=0.000) were positively correlated with age, and the DE during calm breathing was negatively correlated with age (r=− 0.218, P= 0.001) and BMI (r=− 00.280, P= 0.000). The DE (R=0.371, P=0.000) and velocity (R=0.368, P=0.000) during deep breathing were correlated with lifestyle.Conclusion: Our study provides normal reference values of the diaphragm and evaluates the influence of gender, age, body mass index and lifestyle on diaphragmatic morphology.Keywords: diaphragm, reference values, ultrasound, supine position

Junshuang Guo,1,2 Ruike Zhang,1 Ruirui Dong,1 Fan Yang,1 Yating Wang,1 Wang Miao1 1Neuro-Intensive Care Unit of the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 2Department of Immunology, School of Basic Medical Science, Central South University, Changsha City, Hunan Province, People’s Republic of ChinaCorrespondence: Wang Miao, Neuro-Intensive Care Unit of the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, 450000, People’s Republic of China, Email miaowang7211@126.comBackground: Machine learning (ML) is increasingly used in medical predictive modeling, but there are no studies applying ML to predict prognosis in Guillain-Barré syndrome (GBS).Materials and Methods: The medical records of 223 patients with GBS were analyzed to construct predictive models that affect patient prognosis. Least Absolute Shrinkage and Selection Operator (LASSO) was used to filter the variables. Decision Trees (DT), Random Forest (RF), Extreme Gradient Boosting (XGBoost), k-nearest Neighbour (KNN), Naive Bayes (NB), Neural Network (NN). Light Gradient Boosting Machine (LGBM) and Logistic Regression (LR) were used to construct predictive models. Clinical data from 55 GBS patients were used to validate the model. SHapley additive explanation (SHAP) analysis was used to explain the model. Single sample gene set enrichment analysis (ssGSEA) was used for immune cell infiltration analysis.Results: The AUCs (area under the curves) of the 8 ML algorithms including DT, RF, XGBoost, KNN, NB, NN, LGBM and LR were as follows: 0.75, 0.896 0.874, 0.666, 0.742, 0.765, 0.869 and 0.744. The accuracy of XGBoost (0.852) was the highest, followed by LGBM (0.803) and RF (0.758), with F1 index of 0.832, 0.794, and 0.667, respectively. The results of the validation set data analysis showed AUCs of 0.839, 0.919, and 0.733 for RF, XGBoost, and LGBM, respectively. SHAP analysis showed that the SHAP values of blood neutrophil/lymphocyte ratio (NLR), age, mechanical ventilation, hyporeflexia and abnormal glossopharyngeal vagus nerve were 0.821, 0.645, 0.517, 0.401 and 0.109, respectively.Conclusion: The combination of NLR, age, mechanical ventilation, hyporeflexia and abnormal glossopharyngeal vagus used to predict short-term prognosis in patients with GBS has a good predictive value.Keywords: Guillain-Barré syndrome, machine learning, prognosis, SHAP

Zhaoli Geng,1– 3 Renping Dong,3 Xinlin Li,1,2 Xinyi Xu,1,2 Lin Chen,1,2 Xu Han,1,2 Dongxu Liu,1,2 Yi Liu1,2 1Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China; 2Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, 250012, People’s Republic of China; 3Department of Stomatology, Qingdao West Coast New Area People’s Hospital, Qingdao, Shandong, 266400, People’s Republic of ChinaCorrespondence: Yi Liu, Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, No. 44-1 Wenhua Road West, Jinan, Shandong, 250012, People’s Republic of China, Tel +86-531-88381630, Email yiliu@sdu.edu.cnBackground: Implants are widely used in the field of orthopedics and dental sciences. Titanium (TI) and its alloys have become the most widely used implant materials, but implant-associated infection remains a common and serious complication after implant surgery. In addition, titanium exhibits biological inertness, which prevents implants and bone tissue from binding strongly and may cause implants to loosen and fall out. Therefore, preventing implant infection and improving their bone induction ability are important goals.Purpose: To study the antibacterial activity and bone induction ability of titanium–copper alloy implants coated with nanosilver/poly (lactic-co-glycolic acid) (NSPTICU) and provide a new approach for inhibiting implant-associated infection and promoting bone integration.Methods: We first examined the in vitro osteogenic ability of NSPTICU implants by studying the proliferation and differentiation of MC3T3-E1 cells. Furthermore, the ability of NSPTICU implants to induce osteogenic activity in SD rats was studied by micro-computed tomography (micro-CT), hematoxylin-eosin (HE) staining, masson staining, immunohistochemistry and van gieson (VG) staining. The antibacterial activity of NSPTICU in vitro was studied with gram-positive Staphylococcus aureus (Sa) and gram-negative Escherichia coli (E. coli) bacteria. Sa was used as the test bacterium, and the antibacterial ability of NSPTICU implanted in rats was studied by gross view specimen collection, bacterial colony counting, HE staining and Giemsa staining.Results: Alizarin red staining, alkaline phosphatase (ALP) staining, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis showed that NSPTICU promoted the osteogenic differentiation of MC3T3-E1 cells. The in vitro antimicrobial results showed that the NSPTICU implants exhibited better antibacterial properties. Animal experiments showed that NSPTICU can inhibit inflammation and promote the repair of bone defects.Conclusion: NSPTICU has excellent antibacterial and bone induction ability, and has broad application prospects in the treatment of bone defects related to orthopedics and dental sciences.Keywords: nanosilver/PLGA coating, implant infection, antibacterial, osteogenesis, titanium copper alloy

Shi-Tong Diao, Run Dong, Jin-Min Peng, Yan Chen, Shan Li, Shu-Hua He, Yi-Fan Wang, Bin Du, Li Weng On behalf of the China Critical Care Clinical Trials Group (CCCCTG)Medical Intensive Care Unit, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Li Weng, Medical Intensive Care Unit, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, 1 Shuai Fu Yuan, Beijing, 100730, People’s Republic of China, Email wengli@gmail.comBackground: Sepsis surveillance was important for resources allocation, prevention, and development of health policy.Objective: The aim of the study was to validate a modified International Classification of Diseases (ICD)-10 based algorithm for identifying hospitalized patients with sepsis.Methods: We retrospectively analyzed a prospective, single-center cohort of adult patients who were consecutively admitted to one medical ICU ward and ten non-ICU wards with suspected or confirmed infections during a 6-month period. A modified ICD-10 based algorithm was validated against a reference standard of Sequential Organ Failure Assessment (SOFA) score based on Sepsis-3. Sensitivity (SE), specificity (SP), positive predictive value (PPV), negative predictive value (NPV), and areas under the receiver operating characteristic curves (AUROCs) were calculated for modified ICD-10 criteria, eSOFA criteria, Martin’s criteria, and Angus’s criteria.Results: Of the 547 patients in the cohort, 332 (61%) patients met Sepsis-3 criteria and 274 (50%) met modified ICD-10 criteria. In the ICU setting, modified ICD-10 criteria had SE (84.47%), SP (88.57%), PPV (95.60), and NPV (65.96). In non-ICU settings, modified ICD-10 had SE (64.19%), SP (80.00%), PPV (80.33), and NPV (63.72). In the whole cohort, the AUROCs of modified ICD-10 criteria, eSOFA, Angus’s criteria, and Martin’s criteria were 0.76, 0.75, 0.62, and 0.62, respectively.Conclusion: This study demonstrated that modified ICD-10 criteria had higher validity compared with Angus’s criteria and Martin’s criteria. Validity of the modified ICD-10 criteria was similar to eSOFA criteria. Modified ICD-10 algorithm can be used to provide an accurate estimate of population-based sepsis burden of China.Keywords: sepsis, validation, International Classification of Diseases, administrative health data, identification

Mingyuan Li,1 Meng Li,1 Xinyi Li,1 Wanhui Shao,1 Xiujuan Pei,2 Ruyue Dong,1 Hongmeng Ren,1 Lin Jia,1 Shiqin Li,1 Wenlin Ma,1 Yi Zeng,1 Yun Liu,1 Hua Sun,1 Peng Yu1 1College of Biotechnology/Tianjin Enterprise Key Laboratory for Application Research of Hyaluronic Acid, Tianjin University of Science & Technology, Tianjin, 300457, People’s Republic of China; 2Tianjin Shiji Kangtai Biomedical Engineering Co.,Ltd, Tianjin, 300462, People’s Republic of ChinaCorrespondence: Hua Sun; Peng Yu, Email sunhua@tust.edu.cn; yupeng@tust.edu.cnPurpose: In the present study, we prepared collagen liposomes with the addition of polyol, which is expected to not only increase the solubility of collagen but also improve skin penetration.Methods: Collagen liposomes were prepared by the film dispersion method, and their characteristics, integrity and biosafety were evaluated by Fourier transform infrared spectroscopy (FTIR), UV-VIS spectroscopy, polyacrylamide gel electrophoresis (SDS-PAGE), dynamic light scattering (DLS) and transmission electron microscope (TEM). The transdermal absorption of collagen and collagen liposomes were tested by an ex vivo horizontal Valia-Chien diffusion cell system.Results: We first demonstrated that collagen extracted from bovine Achilles tendon was type I collagen. The results of DLS measurement and TEM observation showed that the collagen liposomes were spherical in shape with average diameter (75.34± 0.93 nm) and maintained high stability at low temperature (4°C) for at least 42 days without toxicity. The encapsulation rate of collagen liposomes was 57.80 ± 0.51%, and SDS-PAGE analysis showed that collagen was intact in liposomes. Finally, permeability studies indicated that the collagen-loaded liposomes more easily penetrated the skin compared to collagen itself.Conclusion: This study proposed a new method to improve the bioavailability and permeability of bovine type I collagen, which improves the applicability of collagen in biomedicine, cosmeceuticals and pharmaceutical industries.Graphical Abstract: Keywords: collagen, liposome, physicochemical properties of collagen, skin penetration, drug delivery

Rong Dong,1 Youyou Yan,2 Xiaokang Zeng,3 Nengming Lin,1,2 Biqin Tan1 1Department of Clinical Pharmacy, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China; 2Translational Medicine Research Center, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 31006, People’s Republic of China; 3Department of Critical Care Medicine, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 31006, People’s Republic of ChinaCorrespondence: Biqin Tan, Department of Clinical Pharmacy, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Room 207, No. 5 Building, Hangzhou, People’s Republic of China, Tel +86-571-56007824, Fax +86-571-56005600, Email biqintan@zju.edu.cn Nengming Lin, Department of Clinical Pharmacy, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Room 903, No. 7 Building, Hangzhou, People’s Republic of China, Tel/Fax +86-571-56005600, Email lnm1013@zju.edu.cnAbstract: Ibrutinib is the first-in-class Bruton tyrosine kinase (BTK) inhibitor that has revolutionized the treatment of B cell malignancies. Unfortunately, increased incidences of cardiotoxicity have limited its use. Despite over a decade of research, the biological mechanisms underlying ibrutinib cardiotoxicity remain unclear. In this review, we discuss the pharmacological properties of ibrutinib, the incidence and mechanisms of ibrutinib-induced cardiotoxicity, and practical management to prevent and treat this condition. We also synopsize and discuss the cardiovascular adverse effects related to other more selective BTK inhibitors, which may guide the selection of appropriate BTK inhibitors.Keywords: ibrutinib, cardiotoxicity, BTK inhibitors, atrial fibrillation, cardio-oncology

Yalan Li,1,&ast; Na Li,1,&ast; Jiajing Liu,1 Tieshan Wang,2 Ruijuan Dong,3 Dongyu Ge,3 Guiying Peng1 1Department of Immunology and Microbiology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3Experimental Teaching Center, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guiying Peng, Email penggy@bucm.edu.cnObjective: Ulcerative colitis (UC) as one of the intractable diseases in gastroenterology seriously threatens human health. Respiratory pathology is a representative extraintestinal manifestation of UC affecting the quality of life of patients. Gegen Qinlian Decoction (GQD) is a classical traditional Chinese medicine prescription for UC or acute lung injury. This study was aimed to reveal the therapeutic effect of GQD on UC and its pulmonary complications and uncover its molecular mechanism mediated by myeloid cells and microbiota.Methods: Mice with DSS-induced colitis were orally administrated with GQD. Overall vital signs were assessed by body weight loss and disease activity index (DAI). Pulmonary general signs were evaluated by pulmonary pathology and lung function. The mechanism of GQD relieving UC was characterized by detecting myeloid cells (neutrophils, macrophages, inflammatory monocytes, and resident monocytes) in colonic and lung tissues, related inflammatory cytokines, as well as the microbiota in bronchoalveolar lavage fluid (BALF) and feces.Results: GQD significantly reduced weight loss, DAI scores, and lung injury but improved the lung function of colitis mice. The DSS-induced colonic and concurrent pulmonary inflammation were also alleviated by GQD, as indicated by the down-regulated expressions of inflammatory cytokines (TNF-α, IL-1β, IL-6, CCR2, and CCL2) and the suppressed recruitment of neutrophils and inflammatory monocytes. Meanwhile, GQD greatly improved intestinal microbiota imbalance by enriching Ruminococcaceae UCG-013 while decreasing Parabacteroides, [Eubacterium]_fissicatena_group, and Akkermansia in the feces of colitis mice. Expectantly, GQD also restored lung microbiota imbalance by clearing excessive Coprococcus 2 and Ochrobactrum in the BALF of colitis mice. Finally, significant correlations appeared between GQD-mediated specific bacteria and inflammatory cytokines or immune cells.Conclusion: GQD could alleviate UC by decreasing excessive inflammatory myeloid cells and cytokines, and reshaping the microbiota between the colon and lung, which contributes to clarifying the mechanism by which GQD ameliorates colitis-associated pulmonary inflammation.Keywords: Gegen Qinlian Decoction, ulcerative colitis, lung and intestinal microbiota, pulmonary inflammation, myeloid cells

Pengyun Yan, Kui Zhang, Jian Cao, Ran Dong Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Ran DongDepartment of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, People’s Republic of ChinaTel +86-10-64456411Fax +86-10-64442234Email dongran6618@hotmail.comBackground: The relationship between abnormal left ventricular (LV) structure and adverse outcomes has been confirmed in diverse patient groups in previous studies. However, it remains uncertain whether LV structure has predictive implications in heart failure with reduced ejection fraction (HFrEF) patients with coronary artery bypass grafting (CABG).Methods: This study retrospectively enrolled patients who had HFrEF and underwent CABG between January 2013 and July 2019. According to LV hypertrophy (LVH) and LV enlargement (LVE) assessed by echocardiography, patients were classified into four LV structure types: (-)LVH/(-)LVE, (+)LVH/(-)LVE, (-)LVH/(+)LVE, and (+)LVH/(+)LVE.Results: A total of 435 consecutive patients (mean age: 59.4 ± 9.6 years; 14.9% female) were enrolled in the present study. Examined independently, either LVH (p < 0.001) or LVE (p < 0.001) was independently associated with postoperative mortality in multivariate analysis. When LVH and LVE were analyzed in combination, the risk of mortality after CABG was lowest in (-)LVH/(-)LVE and increased with (+)LVH/(-)LVE (odds ratio [OR]: 7.525; 95% confidence interval [CI]: 1.827– 30.679, p = 0.004), (-)LVH/(+)LVE (OR: 7.253; 95% CI: 1.950– 27.185, p = 0.003), and (+)LVH/(+)LVE (OR: 9.547; 95% CI: 2.726– 34.805, p < 0.001), independent of other risk factors. Adding LV structural types to the baseline model gained an incremental effect on the predictive value for postoperative mortality (AUC: baseline model, 0.838 vs baseline model + LV structural types, 0.901, p for comparison = 0.010; category‐free net reclassification improvement (NRI): 0.764, p < 0.001; integrated discrimination improvement (IDI): 0.061, p = 0.007).Conclusion: LVH and LVE were associated with an increased risk of postoperative mortality after CABG in patients with HFrEF. Categorizing LV structural patterns with LVH and LVE contributes to risk stratification and provides incremental predictive ability. Routine echocardiographic assessment of LVH and LVE is needed in clinical practice.Keywords: left ventricular hypertrophy, left ventricular enlargement, postoperative death, coronary artery bypass grafting, heart failure with reduced ejection fraction

Yongan Wang,1,&ast; Na Li,1,&ast; Qiuyi Li,1 Zirui Liu,1 Yalan Li,1 Jingwei Kong,1 Ruijuan Dong,2 Dongyu Ge,2 Jie Li,3 Guiying Peng1 1Department of Immunology and Microbiology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Experimental Teaching Center, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3Department of Respiratory Medicine, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guiying Peng; Jie Li Email penggy@bucm.edu.cn; lijie2007@126.comPurpose: Chronic obstructive pulmonary disease (COPD), a prevalent obstructive airway disease, has become the third most common cause of death globally. Xuanbai Chengqi decoction (XBCQ) is a traditional Chinese medicine prescription for the acute exacerbation of COPD. Here, we aimed to reveal the therapeutic effects of XBCQ administration and its molecular mechanisms mediated by Th17/Treg balance and gut microbiota.Methods: We determined the counts of Th17 and Treg cells in the serum of 15 COPD and 10 healthy subjects. Then, cigarette smoke extract-induced COPD mice were gavaged with low, middle, and high doses of XBCQ, respectively. Weight loss, pulmonary function and inflammation, Th17/Treg ratio, and gut microbiota were measured to evaluate the efficacy of XBCQ on COPD.Results: COPD patients had a higher Th17/Treg ratio in the serum than healthy controls, which was consistent with the results in the lung and colon of COPD mice. The middle dose of XBCQ (M-XBCQ) significantly decreased the weight loss and improved the pulmonary function (FEV0.2/FVC) in COPD mice. Moreover, M-XBCQ alleviated lung inflammation by rectifying the Th17/Treg imbalance, reducing the expressions of TNF-α, IL-1β, and MMP-9, and suppressing inflammatory cells infiltration. Meanwhile, M-XBCQ greatly improved the microbial homeostasis in COPD mice by accumulating probiotic Gordonibacter and Akkermansia but inhibiting the growth of pathogenic Streptococcus, which showed significant correlations with pulmonary injury.Conclusion: Oral M-XBCQ could alleviate COPD exacerbations by reshaping the gut microbiota and improving the Th17/Treg balance, which aids in elucidating the mechanism through which XBCQ as a therapy for COPD.Keywords: XBCQ, COPD, intestinal microbiota, Th17/Treg, pulmonary inflammation

Jin Peng,1 Ruiying Dong,1 Jianfen Jiao,1 Min Liu,1 Xi Zhang,1 Hualei Bu,1 Ping Dong,2 Shasha Zhao,3 Naidong Xing,4 Shuai Feng,5 Xingsheng Yang,1 Beihua Kong1 1Department of Obstetrics and Gynecology, Qilu hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 2Department of Anesthesiology, Qilu Hospital, Shandong University, Jinan, People’s Republic of China; 3Department of Clinical Nutrition, Qilu Hospital, Shandong University, Jinan, People’s Republic of China; 4Department of Urology, Qilu Hospital, Shandong University, Jinan, People’s Republic of China; 5Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People’s Republic of ChinaCorrespondence: Xingsheng YangDepartment of Obstetrics and Gynecology, Qilu Hospital, Shandong University, No. 107 West Wenhua Road, Jinan, 250001, People’s Republic of ChinaEmail xingshengyang@sdu.edu.cnObjective: Enhanced recovery after surgery (ERAS) protocol has widely gained acceptance in gynecological surgery. Its safety and efficacy should be evaluated fully via well-designed, randomized, control trials. The main objective of our study is to compare the ERAS protocol with the conventional perioperative care program after gynecological oncology. Furthermore, the secondary objectives of our study are the identification of markers that allow us to evaluate the effectiveness of the application of ERAS elements in the modulation of the body’s response to surgical stress.Methods: Patients with gynecological tumors indicated for surgery were randomly assigned to either the ERAS group or the conventional group. The ERAS protocol included short fasting time, fluid restriction, early oral feeding, reduced opioid consumption and immediate mobilization after surgery. The primary endpoint was the reduction of hospital stay in the ERAS group. The day of first flatus, postoperative nausea and vomiting (PONV), maximum pain score by the visual analogue scale (VAS) and complication, readmission rate, reoperation rate, postoperative mortality, total hospital cost and systemic inflammatory response (SIR) were secondary endpoints.Results: A total of 130 patients in gynecological tumor surgery were enrolled (ERAS = 65, conventional = 65). The ERAS group had faster bowel function recovery, significantly less pain, less PONV, shorter hospital stay, and less total hospital costs. SIR markers were estimated and screened out that postoperative platelet, neutrophil-lymphocyte-ratio (NLR) and platelet-lymphocyte-ratio (PLR) were significantly lower in ERAS groups compared to conventional groups.Conclusion: The implementation of ERAS protocol is safe and enhances postoperative recovery after gynecological oncology surgery. We firstly reveal the beneficial effect of ERAS protocols on the alleviation of postoperative SIR, which is a reflection of the magnitude of surgical trauma. Postoperative platelet, NLR or PLR could be the novel and inexpensive markers to assess how ERAS protocols modulate gynecological oncology surgery.Trial Registration: The trial was registered in ClinicalTrials.gov (NCT03629626).Keywords: ERAS, enhanced recovery after surgery, systemic inflammatory response, gynecological oncology surgery, NLR, neutrophil-lymphocyte-ratio, PLR, platelet-lymphocyte-ratio

Xu Lin,1,* Pei Wang,1 Ding-Wei Liu,2 Yu-Wei Guo,1 Chun-Hui Xie,3 Bin Wang,1,* Rui Dong,4 Li-Xin Sun,1 Ming-Shan Wang,1 Yan-Lin Bi1 1Department of Anesthesiology, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, People’s Republic of China; 2Department of Laboratory, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, People’s Republic of China; 3Department of Anesthesiology, Weifang Medical University, Weifang, People’s Republic of China; 4Department of Anesthesiology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan-Lin Bi; Ming-Shan WangDepartment of Anesthesiology, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, People’s Republic of ChinaTel +86 186 6167 5610; +86 186 61675608Email yanlinbi68@sina.cn; wmsqingdao@163.comPurpose: Postoperative delirium (POD) is common in elderly patients undergoing laparoscopic surgery for gastric and colorectal malignancies. POD may be affected by different fraction of inspired oxygen (FiO2). The purpose of this study was to compare the effects of different FiO2 on POD.Patients and Methods: A randomized, double-blind controlled trial was performed in Qingdao Municipal Hospital Affiliated to Qingdao University. A total of 662 patients aged 65 to 85 years old underwent isolated laparoscopic radical gastrectomy, radical resection of colon cancer, or radical resection of rectal cancer only. A random number table method was used to divide the patients into two groups: 40% FiO2 (group A) and 80% FiO2 (group B). The primary endpoint was the incidence of POD, which was assessed by the Confusion Assessment Method (CAM) twice daily during the first 7 postoperative days, and POD severity was measured by the Memorial Delirium Assessment Scale (MDAS). The secondary endpoints were the intraoperative regional cerebral oxygen saturation (rSO2), Bispectral (BIS) index, invasive arterial blood pressure (IABP), oxygen saturation (SpO2), end-tidal carbon dioxide partial pressure (PETCO2), the number of atelectasis cases and visual analogue scale (VAS) scores on days 1– 7 after surgery.Results: The incidence of POD was 19.37% (122/630), including 20.38% (64/314) in group A and 18.35% (58/316) in group B. No statistical significance was found in the incidence of POD between the two groups (P > 0.05); compared with group B, SpO2, rSO2 and PaO2 decreased at T2 to T4 time point (P < 0.01), and the incidence of postoperative atelectasis decreased (P < 0.05) in group A.Conclusion: The incidence of POD was not significantly affected by different FiO2 and the incidence of postoperative atelectasis was decreased at low FiO2.Keywords: intraoperative oxygen concentration, postoperative delirium, malignancy

Run Dong,1,2,* Min Liu,3,* Xiao-Xi Huang,4 Zheng Liu,4 Ding-Yuan Jiang,5 Hui-Juan Xiao,1 Jing Geng,5 Yan-Hong Ren,5 Hua-Ping Dai5 1Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Department of Respiratory Medicine, Capital Medical University, Beijing, People’s Republic of China; 2Department of Respiratory Medicine, Zhengzhou Central Hospital, Zhengzhou, People’s Republic of China; 3Department of Radiology, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 4Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Department of Medical Research, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China; 5Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital; National Clinical Research Center for Respiratory Diseases; Capital Medical University, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hua-Ping DaiDepartment of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing 100029, People’s Republic of ChinaEmail daihuaping@ccmu.edu.cnBackground: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial pneumonia. And, oxidation/antioxidant imbalance plays an important role in the progress of IPF. Fullerene is considered to be a novel “structural” antioxidant. This study aimed to explore if water-soluble C60 (C60(OH)22) can exhibit antifibrotic activity in its antioxidant role.Methods: Healthy C57BL/6J mice were randomly grouped and induced pulmonary fibrosis by intratracheal injection of bleomycin.Results: The survival rate of mice was observed and found that 10mg/kg was the optimal dose of water-soluble C60 for pulmonary fibrosis. We observed that water-soluble C60 can alleviate the severity of pulmonary fibrosis by observing the chest computed tomography, pulmonary pathology, and content of collagen, alpha smooth muscle actin and fibronectin in lung. Compared with bleomycin group, ROS, the content of TNF-α in BALF, and the number of fibroblasts was significantly decreased and the number of type Ⅱ alveolar epithelial cells was increased after treatment with C60.Conclusion: Therefore, thanks to its powerful antioxidant action, water-soluble C60 can reduce the severity of pulmonary fibrosis induced by bleomycin in mice.Keywords: pulmonary fibrosis, bleomycin, water-soluble C60, mice

Chunjie Liu, 1,* Siyu Tian, 2,* Jiangbo Bai, 2 Kunlun Yu, 2 Lei Liu, 3 Guoli Liu, 4 Ruiyi Dong, 5 Dehu Tian 2 1Department of Orthopedics, Tangshan Workers Hospital, Tangshan, Hebei 063000, People’s Republic of China; 2Department of Hand Surgery, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, People’s Republic of China; 3Department of Orthopedics, Changping District Hospital, Beijing 102200, People’s Republic of China; 4Department of Orthopedics, The Second Hospital of Tangshan, Tangshan, Hebei 063000,People’s Republic of China; 5Department of Orthopedics, Cangzhou Integrated Traditional Chinese and Western Medicine Hospital, Cangzhou, Hebei 061001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dehu TianDepartment of Hand Surgery, The Third Affiliated Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang, Hebei 050017, People’s Republic of ChinaTel +86-151-3056-6366Fax +86-311-8860-3818Email tiandehu_1961@126.comBackground: Adhesion after tendon injury is a common complication in clinical practice. The lack of effective prevention mechanisms seriously affects the functional rehabilitation of patients. This research aimed to optimise the amniotic membrane and explain the mechanism of tendon–amniotic membrane by imitating the tendon sheath to construct a multilayer electrospun polycaprolactone (PCL) nanofibre membrane.Materials and Methods: Fresh amnions were subjected to freezing and vacuum drying. The two surfaces of freeze-dried amnions were coated with PCL nanofibres by electrospinning, thereby forming a multilayer composite membrane and constructing a growth factor-sustained release system conforming to the tendon-healing cycle. The new materials were characterised, and the biological effects on tenocytes and fibroblasts were evaluated. The tendon injury model of New Zealand rabbits was constructed to observe the effects on tendon adhesion and healing.Results: After freezing and vacuum drying, fresh amnions were found to effectively remove most of the cell components but retained the active components TGF-β 1, bFGF, VEGF, and PDGF, as well as the fibrous reticular structure of the basement membrane. After coating with PCL nanofibres, a composite membrane mimicking the structure of the tendon sheath was constructed, thereby strengthening the tensile strength of the amnion. By up-regulating the phosphorylation of ERK1/2 and SMAD2/3, the adhesion and proliferation of tenocytes and fibroblasts were promoted, and collagen synthesis was enhanced. In the rabbit tendon repair model, the composite membrane effectively isolated the exogenous adhesion tissue and promoted endogenous tendon healing.Conclusion: The composite membrane mimicking the structure of tendon sheath effectively isolated the exogenous adhesion tissue and achieved good tendon slip. By slowly releasing the growth factors TGF-β 1, bFGF, VEGF and PDGF, the ERK1/2 and SMAD2/3 pathways were regulated. Consequently, endogenous tendon healing was promoted. This strategy can alternatively address the clinical problem of tendon adhesion.Keywords: amniotic membrane, electrospinning, nanofibers, composite membrane, tendon adhesion

Li Zhang1,2, Jingwen Huang1,2, Ran Dong3, Yun Feng1,2, Min Zhou1,2 1Department of Respiratory and Critical Care Medicine, Shanghai Institute of Respiratory Disease, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Respiratory Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Min ZhouDepartment of Pulmonary and Critical Care Medicine, Shanghai Institute of Respiratory Disease, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, No.197 Ruijin Er Road, Shanghai 200025, People’s Republic of ChinaTel +86 216 437 0045Fax +86 216 467 4301Email doctor_zhou_99@163.comPurpose: Leukotriene B4 (LTB4) is a major pro-inflammatory mediator that leads to the persistence of chronic inflammation in chronic obstructive pulmonary disease (COPD). The purpose of this study was to evaluate therapeutic potential of BLT1 antagonist for cigarette smoke (CS)-induced COPD and to explore the underlying mechanism.Materials and methods: In vitro, autophagy proteins were determined by Western blotting in RAW264.7 macrophages treated with U75302 (BLT1 antagonist) or autophagy inhibitor in cigarette smoke extract-induced inflammation. In vivo, C57BL/6J mice were randomly divided into three groups: Control group, CS group and CS+U75302 group. After 12-week exposure, histological analysis and lung function tests were performed to evaluate the inflammatory infiltration and emphysema. The expression of inflammatory cytokines was measured by real-time PCR and enzyme-linked immunosorbent assay. Immunohistochemical analysis and Western blotting detected the expression of autophagy-related proteins. Transmission electron microscopy (TEM) showed the alterations of autophagosomes and lysosomes.Results: Lower levels of inflammatory factors and autophagy markers were detected in U75302-treated cells and mice after CS exposure than control. In vitro, LC3 mRNA expression was elevated when treated with U75302. Autophagy inhibition resulted in augmented inflammatory response and autophagy proteins even with U75302 treatment. Furthermore, BLT1 antagonist decreased the number of lysosomes and autophagosomes in alveolar macrophages of mice and potentially enhanced the expression of transcriptional activation of transcription factor-EB (TFEB) in vitro and vivo.Conclusion: Insufficient autophagy of macrophages was associated with LTB4-mediated inflammation in CS-exposure models. BLT1 antagonist ameliorated inflammatory response through inducing autophagy.Keywords: cigarette smoke, inflammation, autophagy, BLT1 antagonist, COPD

Lin Zhu, Zhifei Liu, Ruijia Dong, Xiaojun Wang, Mingzi Zhang, Xiao Guo, Nanze Yu, Ang ZengDepartment of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, People’s Republic of ChinaBackground: Cutaneous melanoma is the most aggressive form of skin cancer. It accounts for approximately 5% of all cutaneous malignancies and is currently responsible for the majority of skin cancer-related deaths. However, the exact mechanisms responsible for the occurrence of melanoma, in particular the invasive growth in normal skin or muscle tissue, remain unknown.Materials and methods: miR-3662, a microRNA is a potential tumor suppressor targeting zinc finger E-box binding homeobox 1 (ZEB1), which functions as a key regulator of the epithelial-mesenchymal transition (EMT) process. This microRNA was identified using an online database (miRDB) and expression was confirmed by Western blot analysis. Quantitative polymerase chain reaction (qPCR) was used to examine whether miR-3662 inhibits the EMT process in the aggressive melanoma cell line, A375, through the modification of the expression of invasion-related genes in A375 cells. The effects of miR-3662 on the in vivo growth of A375 cells were examined in a nude mouse model.Results: Using virtual screening of the miRDB database, miR-3662 was shown to target the 3ʹ untranslated region (UTR) of the ZEB1 gene. Expression of miR-3662 via a lentivirus vector significantly decreased protein levels of ZEB1 and inhibited the growth of A375 cells in vitro and in vivo. The reduction in ZEB1 expression induced by miR-3662 resulted in EMT inhibition in A375 cells and decreased the relative expression of metastasis genes.Conclusion: Down-regulation of ZEB1’s expression via miR-3662 lentivirus vectors significantly decreased the in vitro and in vivo growth of the highly aggressive melanoma cell line A375.Keywords: melanoma, microRNA, proliferation, invasive growth, zinc finger E-box binding homeobox 1

Jiayu Li,1 Rong Dong,2 Jiali Yu,2 Sun Yi,2 Jingjing Da,2 Fuxun Yu,3 Yan Zha2 1Guizhou University School of Medicine, Guizhou University, 2Department of Nephrology, Guizhou Provincial People’s Hospital, 3Department of Central Laboratory, Guizhou Provincial People’s Hospital, Guiyang, China Objective: To explore the anti-inflammatory mechanism of IGF1R inhibitor in diabetic nephropathy.Methods: C57/BL6 mice were reared with high-fat diet for 8 weeks, then were injected 30 mg/kg streptozotocin intraperitoneally to induce type 2 diabetes. After 8 weeks, the type 2 diabetes nephropathy model was successfully set up the different drugs were administrated to mice with diabetes (insulin 1–2 U/day, benazepril 10 mg/kg per day intragastrically, IGF-1R inhibitor 30 mg/kg per day intragastrically). After 8 weeks drugs administration, all mice were collected the kidney tissue, measured levels of inflammatory factor (F4/80, TLR4and CD68) and fibrosis markers(αSMA, E-cadherin and SR) using immunohistochemistry and in situ hybridization.Results: The type 2 diabetes nephropathy model was built successfully, which along with increased urinary protein excretion rate and increased inflammatory infiltration, and the correlation was characterized by increased CD68+, F4/80+ cells and increased TLR4, αSMA, SR expression. IGF-1R inhibitors reversed this changes, but benazepril and insulin were without significant changes. The insulin decreased the expression level of IGF-1, and increased the levels of suppressor of cytokine signaling 2 (SOCS2). Benazepril and IGF-1R inhibitor were no significant changes like insulin.Conclusion: Inhibition of IGF1R was a more effective choice for inflammation treatment than Ben or Ins in diabetic kidney disease (DKD). The IGF1R inhibitor blocked pathological changes induced by the over-expression of IGF1 in DKD without up-regulating SOCS2 protein levels. Keywords: diabetes kidney disease, IGF1R inhibitor, insulin, SOCS2

Liang Xie,1,* Qingmin Li,2,* Ran Dong,3,* Kaishun Zhao,4 Yun Feng,1 Zhiyao Bao,1 Min Zhou1 1Department of Pulmonary and Critical Care Medicine, Shanghai Institute of Respiratory Disease, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; 2Department of Cardiology, Henan Provincial Peoples Hospital, Zhengzhou, China; 3Department of Respiratory Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China; 4Department of Respiratory Medicine, Jiading Central Hospital, Shanghai, China *These authors contributed equally to this work Background: Inflammation is an important cause of COPD. Alveolar macrophages are the major innate immune cells that have an important role in COPD pathology. Class A scavenger receptor (SR-A) is a pattern recognition receptor expressed on macrophages. This study investigates the role of SR-A in COPD progression via regulation of inflammation.Patients and methods: SR-A expression in COPD patients and control subjects (smokers and nonsmokers without COPD) was measured by immunohistochemistry, immunofluorescence, and real-time PCR. The cytokine levels in BAL were measured by enzyme-linked immunosorbent assay. To further prove our hypothesis, we treated RAW264.7 cells that overexpress SR-A with lipopolysaccharides, poly(I:C), cigarette smoke extract, and H1N1 influenza separated from patients for 24 h and examined the levels of inflammatory cytokines.Results: In both groups, COPD and smokers without COPD, SR-A expression level was upregulated in alveolar macrophages. SR-A mRNA level was positively correlated with inflammatory cytokines and negatively correlated with FEV1% predicted in COPD patients. In RAW-SR-A cells, level of inflammatory cytokines was significantly higher when compared with control ones.Conclusion: SR-A could increase inflammation stimulated by cigarette smoke extracts, bacteria, and virus, leading to long-term inflammation in COPD, and thus might be used as a new therapeutic target for COPD treatment. Keywords: chronic obstructive pulmonary disease, class A scavenger receptor, inflammation, cigarette smoke extract, lipopolysaccharides, poly(I:C), H1N1 influenza

Yang Qu, Zhengming Wang, Haohan Zhou, Mingyang Kang, Rongpeng Dong, Jianwu Zhao Department of Orthopedics, The Second Hospital of Jilin University, Changchun, People’s Republic of China Abstract: Degenerative lumbar disease (DLD) is a significant issue for public health. Posterior lumbar intervertebral fusion with cages (PLIFC) has high-level fusion rate and realignment on DLD. However, there are some complications following the surgery. Alginate oligosaccharides (AOS) have antioxidant and anti-inflammatory activities and may be suitable for infection therapy. MiR-155 is a biomarker associated with inflammatory and oxidative stress. AOS may promote PLIFC therapy by regulating miR-155. Pluronic nanoparticles and oligosaccharide nanomedicine of alginate sodium (ONAS) were prepared with ampicillin at size

Ran Dong,1,* Liang Xie,1,* Kaishun Zhao,2,* Qiurui Zhang,1 Min Zhou,1 Ping He3 1Department of Respiratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 2Department of Respiratory Medicine, Jiading Central Hospital, 3Department of Microbiology and Parasitology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: Evidence suggests that suppressor of cytokine signaling 1 (SOCS1) is crucial for the negative regulation of inflammation. We investigated the relationship between smoking, SOCS1, and leukotriene B4 (LTB4) in vitro and in clinical samples of COPD; besides which we detected the impact of LTB4 receptor 1 (BLT1) antagonist on inflammation.Methods: SOCS1 expression in bronchial mucosa was determined by immunohistochemistry and real-time polymerase chain reaction. We also detect SOCS1 and BLT1 expression in alveolar macrophages from bronchoalveolar lavage fluid (BALF) by real time-PCR, in addition to measuring the level of cytokines in BALF using enzyme-linked immunosorbent assay. In vitro, we investigated the expression of SOCS1 in cigarette smoke extract-induced mouse macrophage cell line RAW264.7 by real-time polymerase chain reaction and Western blot, and detected the level of cytokines in the supernatant by enzyme-linked immunosorbent assay. Then, we investigated the effects of BLT1 antagonist U-75302 on SOCS1 expression in these cells.Results: We obtained endobronchial biopsies (15 COPD patients and 12 non-COPD control subjects) and BALF (20 COPD patients and 20 non-COPD control subjects), and our results showed that SOCS1 expression significantly decreased in lung tissues from COPD patients. Inflammatory cytokines in BALF were higher in COPD and these inflammatory cytokines negatively correlate with SOCS1 levels. Further, the BLT1 antagonist restored SOCS1 expression and in turn inhibited inflammatory cytokine secretion in vitro.Conclusion: Long-term cigarette smoke exposure induced SOCS1 degradation and LTB4 accumulation, which was associated with emphysema and inflammation. A BLT1 antagonist might be a potential therapeutic candidate for the treatment of COPD. Keywords: treatment, LTB1 antagonist, endobronchial biopsies, BALF, inflammatory cytokines

The Internet of Things (IoT) promises many advantages in the control and monitoring of physical systems from both efficacy and efficiency perspectives. However, in the wrong hands, the data might pose a privacy threat. In this article, we consider the tradeoff between the operational value of data collected in the IoT and the privacy of consumers. We present a general framework for quantifying this tradeoff in the IoT, and focus on a smart grid application for a proof of concept. In particular, we analyze the tradeoff between smart grid operations and how often data are collected by considering a realistic direct-load control example using thermostatically controlled loads, and we give simulation results to show how its performance degrades as the sampling frequency decreases. Additionally, we introduce a new privacy metric, which we call inferential privacy. This privacy metric assumes a strong adversary model and provides an upper bound on the adversary’s ability to infer a private parameter, independent of the algorithm he uses. Combining these two results allows us to directly consider the tradeoff between better operational performance and consumer privacy.

We present optical and near-infrared high-contrast images of the transitional disk HD 100546 taken with the Magellan Adaptive Optics system (MagAO) and the Gemini Planet Imager (GPI). GPI data include both polarized intensity and total intensity imagery, and MagAO data are taken in Simultaneous Differential Imaging mode at Hα. The new GPI H-band total intensity data represent a significant enhancement in sensitivity and field rotation compared to previous data sets and enable a detailed exploration of substructure in the disk. The data are processed with a variety of differential imaging techniques (polarized, angular, reference, and simultaneous differential imaging) in an attempt to identify the disk structures that are most consistent across wavelengths, processing techniques, and algorithmic parameters. The inner disk cavity at 15 au is clearly resolved in multiple data sets, as are a variety of spiral features. While the cavity and spiral structures are identified at levels significantly distinct from the neighboring regions of the disk under several algorithms and with a range of algorithmic parameters, emission at the location of HD 100546 "c" varies from point-like under aggressive algorithmic parameters to a smooth continuous structure with conservative parameters, and is consistent with disk emission. Features identified in the HD 100546 disk bear qualitative similarity to computational models of a moderately inclined two-armed spiral disk, where projection effects and wrapping of the spiral arms around the star result in a number of truncated spiral features in forward-modeled images.

Film cooling protects high-temperature components and generates complex vortex structures through the interaction between the mainstream flow and the injected coolant. Additionally, the process of applying thermal barrier coatings introduces imperfect cooling holes. A numerical simulation study is conducted on two geometric configurations: inclined perfect and imperfect holes arranged in a single row on a flat plate to investigate the effects of flow field vortex structures and hole imperfections. The k-epsilon turbulent model is employed to analyse the impact of varying blowing ratios and defect positions on flow field structure and cooling efficiency, with vortex dynamics providing explanatory insights. As the blowing ratio increases, the kidney vortex associated with the perfect holes progressively detaches from the wall, reducing film cooling efficiency. The kidney vortex originates from the shear interaction between the mainstream and the impinging jet, predominantly influenced by the vortex stretching component. Imperfect holes influence the distribution state of the kidney vortex, with weakened roll-up phenomena observed at the IT4 defect location. Consequently, a noticeable enhancement in film cooling effectiveness is achieved near the proximal end of the hole. [ABSTRACT FROM AUTHOR]

We present H- and K-band imaging polarimetry for the PDS 66 circumstellar disk obtained during the commissioning of the Gemini Planet Imager (GPI). Polarization images reveal a clear detection of the disk in to the 0.″12 inner working angle (IWA) in the H band, almost three times closer to the star than the previous Hubble Space Telescope (HST) observations with NICMOS and STIS (0.″35 effective IWA). The centro-symmetric polarization vectors confirm that the bright inner disk detection is due to circumstellar scattered light. A more diffuse disk extends to a bright outer ring centered at 80 AU. We discuss several physical mechanisms capable of producing the observed ring + gap structure. GPI data confirm enhanced scattering on the east side of the disk that is inferred to be nearer to us. We also detect a lateral asymmetry in the south possibly due to shadowing from material within the IWA. This likely corresponds to a temporally variable azimuthal asymmetry observed in HST/STIS coronagraphic imaging.