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Ming Tang,1,2,&ast; Siyuan Wang,1,2,&ast; Yiwen Wang,1 Fanyi Zeng,1 Mianpeng Chen,1 Xindong Chang,1 Mingfei He,1 Qingqing Fang,1 Shiwu Yin1 1Department of Interventional Vascular Medicine, Hefei Hospital Affiliated to Anhui Medical University, The Second People’s Hospital of Hefei, Hefei City, Anhui Province, People’s Republic of China; 2The Fifth Clinical College of Medicine, Anhui Medical University, Hefei City, Anhui Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shiwu Yin, Department of Interventional Vascular Medicine, Hefei Hospital Affiliated to Anhui Medical University, The Second People’s Hospital of Hefei, 574 Changjiang East Road, Yaohai District, Hefei City, Anhui Province, 230011, People’s Republic of China, Email yinshiwu@126.comPurpose: Previous studies highlight paraspinal muscles’ significance in spinal stability. This study aims to assess paraspinal muscle predictiveness for postoperative recurrent lumbar disc herniation (PRLDH) after lumbar disc herniation patients undergo percutaneous endoscopic transforaminal discectomy (PETD).Patients and Methods: Retrospectively collected data from 232 patients undergoing PETD treatment at our institution between January 2020 and January 2023, randomly allocated into training (60%) and validation (40%) groups. Utilizing Lasso regression and multivariable logistic regression, independent risk factors were identified in the training set to construct a Nomogram model. Internal validation employed Enhanced Bootstrap, with Area Under the ROC Curve (AUC) assessing accuracy. Calibration was evaluated through calibration curves and the Hosmer-Lemeshow goodness-of-fit test. Decision curve analysis (DCA) and clinical impact curve (CIC) were employed for clinical utility analysis.Results: Diabetes, Modic changes, and ipsilesional multifidus muscle skeletal muscle index (SMI) were independent predictive factors for PRLDH following PETD (P< 0.05). Developed Nomogram model based on selected predictors, uploaded to a web page. AUC for training: 0.921 (95% CI 0.872– 0.970), validation: 0.900 (95% CI 0.828– 0.972), respectively. The Hosmer-Lemeshow test yielded χ2=5.638/6.259, P=0.688/0.618, and calibration curves exhibited good fit between observed and predicted values. DCA and CIC demonstrate clinical net benefit for both models at risk thresholds of 0.02– 1.00 and 0.02– 0.80.Conclusion: The Nomogram predictive model developed based on paraspinal muscle parameters in this study demonstrates excellent predictive capability and aids in personalized risk assessment for PRLDH following PETD.Keywords: lumbar disc herniation, percutaneous endoscopic transforaminal discectomy, postoperative recurrent lumbar disc herniation, predictive model

Di Zhang,1,&ast; Yu Guan,1,&ast; Xiuxiu Zhou,1 Mingzi Zhang,2 Yu Pu,1 Pengchen Gu,2 Yi Xia,1 Yang Lu,2 Jia Chen,2 Wenting Tu,1 Kunyao Huang,2 Jixin Hou,2 Hua Yang,2 Chicheng Fu,2 Qu Fang,2 Chuan He,2 Shiyuan Liu,1 Li Fan1 1Department of Radiology, Second Affiliated Hospital, Naval Medical University, Shanghai, People’s Republic of China; 2Scientific Research Department, Shanghai Aitrox Technology Corporation Limited, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li Fan; Shiyuan Liu, Department of Radiology, Second Affiliated Hospital, Naval Medical University, 415 Fengyang Road, Shanghai, 200003, People’s Republic of China, Tel +13564684699 ; +13761304518, Fax +86 21 63587668, Email czyxfl@smmu.edu.cn; radiology_cz@163.comPurpose: To develop a novel method for calculating small airway resistance using computational fluid dynamics (CFD) based on CT data and evaluate its value to identify COPD.Patients and Methods: 24 subjects who underwent chest CT scans and pulmonary function tests between August 2020 and December 2020 were enrolled retrospectively. Subjects were divided into three groups: normal (10), high-risk (6), and COPD (8). The airway from the trachea down to the sixth generation of bronchioles was reconstructed by a 3D slicer. The small airway resistance (RSA) and RSA as a percentage of total airway resistance (RSA%) were calculated by CFD combined with airway resistance and FEV1 measured by pulmonary function test. A correlation analysis was conducted between RSA and pulmonary function parameters, including FEV1/FVC, FEV1% predicted, MEF50% predicted, MEF75% predicted and MMEF75/25% predicted.Results: The RSA and RSA% were significantly different among the three groups (p< 0.05) and related to FEV1/FVC (r = − 0.70, p < 0.001; r = − 0.67, p < 0.001), FEV1% predicted (r = − 0.60, p = 0.002; r = − 0.57, p = 0.004), MEF50% predicted (r = − 0.64, p = 0.001; r = − 0.64, p = 0.001), MEF75% predicted (r = − 0.71, p < 0.001; r = − 0.60, p = 0.002) and MMEF 75/25% predicted (r = − 0.64, p = 0.001; r = − 0.64, p = 0.001).Conclusion: Airway CFD is a valuable method for estimating the small airway resistance, where the derived RSA will aid in the early diagnosis of COPD.Keywords: COPD, small airway disease, CT, fluid dynamics

Zekun Wang, Kangxiang Ji, Qi Fang Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, People’s Republic of ChinaCorrespondence: Zekun Wang; Qi Fang, Department of Neurology, The First Affiliated Hospital of Soochow University, No. 899 Pinghai Road, Gusu District, Suzhou, Jiangsu Province, 215031, People’s Republic of China, Tel +86-512-67972207, Email superzekun@126.com; fangqi_008@126.comBackground: Futile recanalization (FR) remains a significant challenge in patients with acute basilar artery occlusion (BAO) following successful endovascular treatment (EVT). This study aimed to investigate the predictive value of computed tomography perfusion (CTP)-based software (AutoMIStar; Apollo) for FR among BAO patients undergoing EVT.Methods: We analyzed a prospectively maintained database to identify consecutive BAO patients who achieved successful recanalization (modified Thrombolysis in Cerebral Infarction grade ≥ 2b) after EVT between January 2020 and September 2022. Clinical characteristics and imaging parameters from non-contrast CT, CT angiography, and CTP-AutoMIStar were collected for analysis. FR was defined as an unfavorable outcome (modified Rankin Scale score > 3) at 90 days despite successful recanalization. Multivariable stepwise logistic regression analysis was performed to identify independent predictors of FR.Results: Of the 54 patients included in this study, 24 (44.4%) experienced FR. In the univariate analysis, admission National Institutes of Health Stroke Scale score, posterior circulation Acute Stroke Prognosis Early CT Score, Basilar Artery on Computed Tomography Angiography (BATMAN) score, hypoperfusion intensity ratio, and perfusion deficit volume in delay time (DT) > 4 s, DT > 6 s, DT > 8 s, and all cerebral blood flow (CBF) thresholds were associated with FR (all P < 0.05). In the multivariate analysis, perfusion deficit volume in CBF < 35% (adjusted odds ratio [aOR] = 1.105, 95% confidence interval [CI]: 1.004– 1.215; P = 0.040) and BATMAN score (aOR = 0.662, 95% CI: 0.455– 0.964; P = 0.031) remained independent predictors of FR.Conclusion: Perfusion deficit volume in CBF < 35% on CTP-AutoMIStar imaging maps and BATMAN score are independent predictors of FR after EVT in BAO patients. There is a significant positive correlation between perfusion deficit volume in CBF < 35% and the occurrence of FR.Keywords: acute ischemic stroke, basilar artery occlusion, endovascular treatment, cerebral blood flow, computed tomography perfusion, futile recanalization

Xiyi Wang,1 Jing Shao,2 Aozhou Weng,1 Jiaqi Lian,1 Fule Weng,1 Qiong Fang,1 Yun Hu1 1School of Nursing, Shanghai Jiao Tong University, Shanghai, 200025, People’s Republic of China; 2Institute of Nursing Research and Department of Nursing of Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of ChinaCorrespondence: Yun Hu, School of Nursing, Shanghai Jiao Tong University, Shanghai, 200025, People’s Republic of China, Email huyunsy@shsmu.edu.cnBackground: The nursing workforce faces substantial challenges, particularly in the aftermath of the COVID-19 era. Developing an effective strategy for workforce maintenance and the strategic deployment of nurses is crucial.Purpose: This study aimed to explore and categorize nurses’ personality traits, with a focus on analyzing differences in their perceptions of the nursing work environment.Participants and Methods: Between January 2023 and February 2023, a multi-center cross-sectional study was carried out involving nurses from 12 tertiary hospitals actively engaged in frontline COVID-19 response duties. Through cluster sampling, surveys were distributed among eligible nursing staff, comprising a general information questionnaire, the Chinese Big Five Personality Questionnaire-Short Form, subjective evaluations of emergency nursing management, and the Chinese Nursing Work Environment Scale for Public Health Emergencies. Various statistical analyses, such as descriptive analysis, cluster analysis, non-parametric tests, and general linear model analysis, were employed to investigate the correlation between personality types and the perception of nursing work environments.Results: The analysis encompassed 1059 valid questionnaires, reflecting the experiences of frontline nurses. The majority of these nurses possessed 1– 5 years of experience, held junior professional titles, volunteered for their roles, and served as attending nurses. Categorization based on personality traits revealed three groups: resilient (35.60%), ordinary (16.15%), and distressed (48.25%) types. Significantly distinct perceptions of nursing work environments emerged among these categories, with resilient and ordinary types expressing notably higher satisfaction compared to the distressed group (H value = 256.487, p < 0.001).Conclusion: This study illustrates the connection between nurses’ perceived working environment and their personality traits. Nursing managers should factor in nurses’ personality traits when choosing and deploying frontline responders during public health emergencies. Prioritizing resilient-type nurses and crafting a supportive work environment that aligns with nurses’ characteristics is indispensable for an effective emergency response.Keywords: workforce management, cross-sectional studies, human resources, health system

Ming Tang,1,2,&ast; Siyuan Wang,1,&ast; Yiwen Wang,1 Mianpeng Chen,1 Xindong Chang,1 Mingfei He,1 Qingqing Fang,1 Shiwu Yin1 1Department of Interventional Vascular Medicine, Hefei Hospital Affiliated to Anhui Medical University, The Second People’s Hospital of Hefei, Hefei City, Anhui Province, People’s Republic of China; 2The Fifth Clinical College of Medicine, Anhui Medical University, Hefei City, Anhui Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shiwu Yin, Department of Interventional Vascular Medicine, Hefei Hospital Affiliated to Anhui Medical University, The Second People’s Hospital of Hefei, 574 Changjiang East Road, Yaohai District, Hefei City, Anhui Province, 230011, People’s Republic of China, Email yinshiwu@126.comPurpose: To develop an individualized predictive model for postoperative recurrent lumbar disc herniation (PRLDH) in patients undergoing percutaneous endoscopic transforaminal discectomy (PETD) by considering postoperative activity factors.Patients and Methods: Retrospectively collected data from 612 LDH patients who underwent PETD in our institution from January 2017 to June 2023. They were divided into a training group (429 cases) and a validation group (183 cases). Lasso regression (Model 1) and random forest (Model 2) were applied for variable selection in the training group. The two models were compared in terms of discrimination (the area under curve, AUC), calibration (calibration curve), and clinical utility (decision curve analysis, DCA). Akaike information criterion (AIC) was used for model comparison, and internal validation employed 1000 times Bootstrap + 10-fold cross-validation. Finally, a Nomogram was constructed to display the results and uploaded to the web version.Results: Among 612 treated LDH patients, 66 (10.78%) developed PRLDH. Model 1, superior in AUC, calibration, DCA, and AIC over Model 2, was chosen as the predictive model. Logistic regression in the training group identified BMI, smoking, activity level score, time to first ambulation, diabetes, Modic change, and Pfirrmann grade as independent predictors of PRLDH. Model 1 exhibited a training group AUC of 0.813 (95% CI 0.753– 0.872) and a validation group AUC of 0.868 (95% CI 0.773– 0.962). At a Youden index of 0.50, sensitivity was 0.73, specificity was 0.77. Internal validation (1000 times Bootstrap + 10-fold cross-validation) for the training group showed accuracy of 0.889, kappa consistency of 0.112, and AUC of 0.757. The Hosmer-Lemeshow goodness-of-fit tests indicated good discriminative ability for Model 1 in both the training (χ2=2.895, P=0.941) and validation groups (χ2=8.197, P=0.414). The DCA and Nomogram are accessible at https://sofarnomogram.shinyapps.io/PRLDHNom/.Conclusion: The Nomogram predictive model, developed based on postoperative activity factors in this study, demonstrates excellent predictive capability, facilitating risk assessment for the occurrence of PRLDH after PETD.Keywords: Lumbar disc herniation, percutaneous endoscopic transforaminal discectomy, postoperative recurrent lumbar disc herniation, predictive model

Songsong Yu,1 Shuang Li,2 Jie Zhang,3 Qiuhong Fang4 1Department of Emergency, Emergency and Critical Care Medical Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People’s Republic of China; 2Department of Health Management Institute, NO.2 Medical Centre, Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China; 3Department of Infectious Diseases, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, People’s Republic of ChinaCorrespondence: Qiuhong Fang, Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gong Ti Nan Lu, Chaoyang District, Beijing, 100020, People’s Republic of China, Email fangmaster123@163.comObjective of the Study: Systemic glucocorticoid therapy can improve the outcomes of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). The study tried to investigate the use of glucocorticoids in AECOPD patients and the factors associated with the physicians’ choice.Methodology: Patients with AECOPD over two periods were divided by the year of 2017 when GOLD and ERS/ATS Guideline for COPD were updated. Data of patients regarding the study was retrieved from medical records. Descriptive statistical analysis was used for the illustration of glucocorticoids use, and hypothesis testing for comparison over the periods.Results: Between 2010 and 2016, the proportion of ICS use was 522/640 (81.6%) and 341/452 (75.4%) between 2017 and 2020. COPD severity (GOLD C/D classification), bronchial asthma, percentage of neutrophils, and higher PaCO2 were factors associated with physicians’ prescription of systemic glucocorticoids between 2010 and 2016. While the use of ICS at the stable stage, counts of neutrophils, and higher PaCO2 were influencing factors between 2017 and 2020. Over the two periods, 1-year recurrent rate decreased from 32.4% to 20.9%, with a significant statistical difference (P< 0.001).Conclusion: The optimized use of glucocorticoids was found after the publishment of 2017 ERS/ATS Guideline for COPD, this improvement was associated with a decreased 1-year recurrence rate among AECOPD patients at our institution, underscoring the positive impact of guideline updates on patient outcomes.Keywords: chronic obstructive pulmonary disease, acute exacerbation, glucocorticoids, treatment selection

Li-Jen Cheng,1 Benfa Gong,2 Christopher H Young,3 Prabhuram Krishnan,1 Ying Wang,2 Hui Wei,2 Chunlin Zhou,2 Shuning Wei,2 Yan Li,2 Qiuyun Fang,2 Jia Zhong,4 Eric Q Wu,5 Yingchang Mi,2 Jianxiang Wang2 1Medical Affairs, Astellas Pharma Singapore Pte. Ltd., Singapore; 2Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, People’s Republic of China; 3Advanced Informatics & Analytics, Astellas Pharma US Inc., Northbrook, IL, USA; 4Analysis Group, Inc., Beijing, People’s Republic of China; 5Analysis Group, Inc., Boston, MA, USACorrespondence: Jianxiang Wang, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, People’s Republic of China, Tel +86 13821389157, Email wangjx@ihcams.ac.cnIntroduction: For acute myeloid leukemia (AML), prognosis is particularly poor in patients harboring FMS-like tyrosine kinase 3 (FLT3) gene mutations, though routine screening for these mutations at diagnosis has been shown to be insufficient. The understanding of the impact of FLT3 mutations on treatment decisions is limited.Methods: In this retrospective, observational study, we investigated the key epidemiological characteristics, treatment patterns and responses among adult patients with newly diagnosed (ND) AML in China, who initiated treatment from January 1, 2015, to December 31, 2019, or progressed to relapsed/refractory (R/R) AML by December 31, 2020.Results: Of the 853 ND AML patients included, 63.4% were screened for FLT3 status, and 20.1% tested positive (FLT3MUT) at initial diagnosis. Of 289 patients who progressed to R/R AML during the study period, 24.9% were screened at the diagnosis of R/R AML, and 19.4% tested positive; 20.5% of screened patients changed FLT3 status at first diagnosis of R/R AML. Initial treatment regimens or treatment responses did not seem to differ in patients with ND AML by FLT3 mutation status. In patients with R/R AML, there was an apparent difference in second-line treatment choices by FLT3 mutation status; however, the number of FLT3-mutated patients were limited to demonstrate any meaningful distinction. FLT3-mutated R/R AML was associated with shorter relapse time.Conclusion: Study findings showed that there was a lack of routine testing for FLT3 mutations at first diagnosis of R/R AML, and initial treatment decisions did not differ by FLT3 mutation status. Given the clinical burden of FLT3MUT, likelihood of FLT3 status changes, and emerging FLT3 inhibitors, further routine FLT3 screening is needed to optimize treatment of R/R AML. Keywords: acute myeloid leukemia, epidemiology, real-world, retrospective study

Yu Pu,1,&ast; Xiuxiu Zhou,1,&ast; Di Zhang,1,&ast; Yu Guan,1,&ast; Yi Xia,1 Wenting Tu,1 Yang Lu,2 Weidong Zhang,2 Chi-Cheng Fu,2 Qu Fang,2 Geertruida H de Bock,3 Shiyuan Liu,1 Li Fan1 1Department of Radiology, Changzheng Hospital, Naval Medical University, Shanghai, People’s Republic of China; 2Department of Scientific Research, Shanghai Aitrox Technology Corporation Limited, Shanghai, People’s Republic of China; 3Department of Epidemiology, University Medical Center Groningen, Groningen, the Netherlands&ast;These authors contributed equally to this workCorrespondence: Shiyuan Liu; Li Fan, Department of Radiology, ChangZheng Hospital, Naval Medical University, No. 415 Fengyang Road, Shanghai, 200003, People’s Republic of China, Tel +86 21 81886012 ; Tel +86 21 81886012, Fax +86 21 63587668, Email cjr.liushiyuan@vip.163.com; fanli0930@163.comPurpose: To explore optimal threshold of FEV1% predicted value (FEV1%pre) for high-risk chronic obstructive pulmonary disease (COPD) using the parameter response mapping (PRM) based on machine learning classification model.Patients and Methods: A total of 561 consecutive non-COPD subjects who were screened for chest diseases in our hospital between August and October 2018 and who had complete questionnaire surveys, pulmonary function tests (PFT), and paired respiratory chest CT scans were enrolled retrospectively. The CT quantitative parameter for small airway remodeling was PRM, and 72 parameters were obtained at the levels of whole lung, left and right lung, and five lobes. To identify a more reasonable thresholds of FEV1% predicted value for distinguishing high-risk COPD patients from the normal, 80 thresholds from 50% to 129% were taken with a partition of 1% to establish a random forest classification model under each threshold, such that novel PFT-parameter-based high-risk criteria would be more consistent with the PRM-based machine learning classification model.Results: Machine learning-based PRM showed that consistency between PRM parameters and PFT was better able to distinguish high-risk COPD from the normal, with an AUC of 0.84 when the threshold was 72%. When the threshold was 80%, the AUC was 0.72 and when the threshold was 95%, the AUC was 0.64.Conclusion: Machine learning-based PRM is feasible for redefining high-risk COPD, and setting the optimal FEV1% predicted value lays the foundation for redefining high-risk COPD diagnosis.Keywords: chronic obstructive pulmonary disease, computed tomography, pulmonary function test, quantitative imaging, artificial intelligence

Xiaoxu Han,1 Xiaobo Yu,2 Ying Han,3 Qian Fang,3 Congle Shen,3 Hui Liu,1 Peng Wang,1 Yajie Wang,3 Xin Li1 1Department of Integrated Traditional Chinese and Western Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China; 2State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences-Beijing (PHOENIX Center), Beijing Institute of Lifeomics, Beijing, 102200, People’s Republic of China; 3Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of ChinaCorrespondence: Yajie Wang, Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, 8 Jingshundong Street, Chaoyang District, Beijing, 100015, People’s Republic of China, Email wangyajie@ccmu.edu.cn Xin Li, Department of Integrated Traditional Chinese and Western Medicine, Beijing Ditan Hospital, Capital Medical University, 8 Jingshundong Street, Chaoyang District, Beijing, 100015, People’s Republic of China, Tel +86-1084322130, Email leaxin@ccmu.edu.cnPurpose: Vaccination reduces the incidence of severe COVID-19 and death and effectively limits viral spread. Concerns have been raised about COVID-19 vaccine responses in the large population of HIV-infected patients. This study aims to explore the safety and immunogenicity of the inactivated COVID-19 vaccine in people living with HIV (PLWH).Patients and Methods: All participants in this study already had their second dose of an inactivated COVID-19 vaccine at least 14 days earlier, without a history of SARS-CoV-2 infection. The primary safety outcomes were the incidence of adverse reactions and changes in CD4+ T-cell counts. SARS-CoV-2 IgG and neutralizing antibody responses to the D614G variant and delta variant were measured for immune response assessment.Results: Forty-seven HIV-infected patients and 18 healthy donors (HDs) were enrolled in this study. Adverse reactions were mild or self-limiting and were reported in 19.1% of HIV-infected patients. Most PLWH developed antibody responses against the inactivated COVID-19 vaccine. The longitudinal analysis of antibody responses in PLWH (median interval between detection and complete vaccination, 59 days) showed that antibodies were maintained for at least three months, though their titers were reduced. However, the antibody-positive rates in PLWH were significantly lower than those in HDs. Additionally, compared to HDs (Geomean titers (GMT) of 165 for D614G and GMT of 72 for delta), the neutralizing antibody titers against the two variants in PLWH (GMT of 43 for D614G and GMT 13 for delta) were decreased significantly (p = 0.018 and p < 0.001, respectively). HIV-infected patients with CD4+T-cell counts ≤ 350 cells/μL appeared to exhibit a poor antibody response to inactivated vaccination.Conclusion: Inactivated COVID-19 vaccines appear to be efficacious in PLWH. However, antibody responses in HIV-infected patients are inferior to those in healthy individuals, especially PLWH with lower CD4+T-cell counts.Keywords: human immunodeficiency virus, coronavirus disease 2019, inactivated vaccines, immunogenicity, safety

Shijiao Ma,1 Chenchen Gu,1 Junjie Xu,1 Jinxin He,2 Shuli Li,1 Haolan Zheng,1 Bo Pang,1 Ying Wen,1 Qiaojun Fang,3 Weiquan Liu,1 Jiesheng Tian1 1State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, People’s Republic of China; 2College of Veterinary Medicine, Shanxi Agriculture University, Taigu, Shanxi, 030801, People’s Republic of China; 3CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, People’s Republic of ChinaCorrespondence: Weiquan Liu; Jiesheng Tian, Tel/Fax +8610-62732676 ; +8610-62731440, Email weiquan8@cau.edu.cn; tianhome@cau.edu.cnPurpose: Nanoparticles (NPs) decorated with functional ligands are promising candidates for cancer diagnosis and treatment. However, numerous studies have shown that chemically coupled targeting moieties on NPs lose their targeting capability in the biological milieu because they are shielded or covered by a “protein corona”. Herein, we construct a functional magnetosome that recognizes and targets cancer cells even in the presence of protein corona.Methods: Magnetosomes (BMPs) were extracted from magnetotactic bacteria, M. gryphiswaldense (MSR-1), and decorated with trastuzumab (TZ) via affibody (RA) and glutaraldehyde (GA). The engineered BMPs are referred to as BMP-RA-TZ and BMP-GA-TZ. Their capacities to combine HER2 were detected by ELISA, the quantity of plasma corona proteins was analyzed using LC-MS. The efficiencies of targeting SK-BR-3 were demonstrated by confocal laser scanning microscopy and flow cytometry.Results: Both engineered BMPs contain up to ∼ 0.2 mg TZ per mg of BMP, while the quantity of HER2 binding to BMP-RA-TZ is three times higher than that binding to BMP-GA-TZ. After incubation with normal human plasma or IgG-supplemented plasma, GA-TZ-containing BMPs have larger hydrated radii and more surface proteins in comparison with RA-TZ-containing BMPs. The TZ-containing BMPs all can be targeted to and internalized in the HER2-overexpressing breast cancer cell line SK-BR-3; however, their targeting efficiencies vary considerably: 50– 75% for RA-TZ-containing BMPs and 9– 19% for GA-TZ-containing BMPs. BMPs were incubated with plasma (100%) and cancer cells to simulate human in vivo environment. In this milieu, BMP-RA-TZ uptake efficiency of SK-BR-3 reaches nearly 80% (slightly lower than for direct interaction with BMP-RA-TZ), whereas the BMP-GA-TZ uptake efficiency is < 17%.Conclusion: Application of the RA scaffold promotes and orients the arrangement of targeting ligands and reduces the shielding effect of corona proteins. This strategy improves the targeting capability and drug delivery of NP in a simulated in vivo milieu.Keywords: affibody, protein corona, magnetosomes, human epidermal growth factor receptor 2, HER2

Zhen-Ni Liu,1– 3 Xue Wu,1– 3 Qian Fang,1– 3 Zi-Xuan Li,1– 3 Guo-Qing Xia,1– 3 Jun-Nan Cai,1– 3 Xiong-Wen Lv1– 3 1Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, People’s Republic of China; 2The Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, Hefei, People’s Republic of China; 3Institute for Liver Diseases of Anhui Medical University, Hefei, People’s Republic of ChinaCorrespondence: Xiong-Wen LvSchool of Pharmacy, Anhui Medical University, 81 Mei Shan Road, Hefei, Anhui Province, 230032, People’s Republic of ChinaEmail lyuxw@ahmu.edu.cnBackground: Alcoholic liver disease (ALD) is liver damage caused by long-term drinking. Inflammation plays a central role in the progression of ALD. CD73 is a ubiquitously expressed glycosylphosphatidylinositol-anchored glycoprotein that is a key enzyme that converts ATP into adenosine. Evidence has shown that CD73 plays an important role in many diseases, but the role and mechanism of CD73 in alcohol-induced liver injury and inflammation is still unclear.Methods: The alcohol-induced liver injury and inflammation mouse model was established. The rAAV9-CD73 was used to overexpress CD73. Isolation of primary macrophages (MΦ) from the liver was conducted. The effects of CD73 on alcohol-induced liver injury and inflammation were evaluated by quantitative real‑time PCR, Western blotting, ELISA, and immunohistochemical assay. Flow cytometry was used to detect the cell cycle and apoptosis.Results: Our results showed that overexpression of CD73 can reduce alcohol-induced liver damage, lipid accumulation, and the secretion of inflammatory cytokines. pEX3-CD73 can promote RAW264.7 cells proliferation and inhibit apoptosis via suppressing the activation of TLR4/MyD88/NF-κB signaling pathway. Inhibition of TLR4 further enhanced the anti-inflammatory effect of overexpression of CD73.Conclusion: Overexpression of CD73 can reduce alcohol-induced liver injury and inflammation. CD73 may serve as a potential therapeutic target for ALD.Keywords: CD73, alcohol-induced liver injury and inflammation, TLR4/MyD88/NF-κB signaling pathway, apoptosis, RAW264.7 cells

Hao Wang,1,2 Shanhao Chen,1 Die Meng,1,2 Chunyan Wu,3 Junjie Zhu,4 Minlin Jiang,1,2 Jing Ning,1,2 Shengyu Wu,1,2 Lijia Wu,5 Jingjie Li,5 Bin Chen,1 Sha Zhao,1 Wei Li,1 Jia Yu,1,2 Qiyu Fang,1,2 Jun Zhu,1,2 Wencheng Zhao,1,2 Yayi He,1 Caicun Zhou1 1Department of Medical Oncology, Shanghai Pulmonary Hospital, Shanghai, 200433, People’s Republic of China; 2Medical School, Tongji University, Shanghai, 200433, People’s Republic of China; 3Pathology Department, Shanghai Pulmonary Hospital, Shanghai, 200433, People’s Republic of China; 4Surgery Department, Shanghai Pulmonary Hospital, Shanghai, 200433, People’s Republic of China; 5Genecast Biotechnology Co., Ltd, Wuxi City, Jiangsu, 214104, People’s Republic of ChinaCorrespondence: Yayi He; Caicun ZhouDepartment of Medical Oncology, Shanghai Pulmonary Hospital, No. 507 Zhengmin Road, Shanghai, People’s Republic of ChinaTel +86 13818828623; Tel +86 13818828623Email 2250601@qq.com; caicunzhoudr@126.comIntroduction: Nowadays, immune checkpoint blockades (ICBs) have been extensively applied in non-small cell lung cancer (NSCLC) treatment. However, the outcome of anti-program death-1/program death ligand-1 (anti-PD-1/PD-L1) therapy is not satisfying in EGFR-mutant lung adenocarcinoma (LUAD) patients and its exact mechanisms have not been fully understood. Since tumor mutation burden (TMB) and tumor immune phenotype had been thought as potential predictors for efficacy of ICBs, we further studied the TMB and immune phenotype in LUAD patients to explore potential mechanisms for poor efficacy of ICBs in EGFR positive mutated patients and to find possible factors that could impact the tumor immune phenotype which might uncover some new therapeutic strategies or combination therapies.Methods: We enrolled 223 LUAD patients who underwent surgery in our hospital. We evaluated TMB through targeted panel sequencing. The tumor immune phenotype, which could be divided into non-inflamed, intermediate and inflamed, was determined through immunohistochemistry using formalin-fixed paraffin-embedded samples. Enumeration data were analyzed by Chi-square test or Fisher exact test and shown as number (proportion). Logistic regression model was employed for univariate and multivariate analysis of the association between TMB levels and clinical characteristics.Results: The median TMB level was 4.0445 mutations/Mb. Multivariate analysis showed the TMB level was significantly associated with age (P=0.026), gender (P=0.041) and EGFR mutation status (P=0.015), and in EGFR-mutant patients we found a lower proportion of patients with mutated KRAS and BRCA2. Furthermore, we found patients with or without metastatic lesions would have different immune phenotype (P=0.007). And the mutational frequencies of ALK, CDKN2A, MAP2K1, IDH2 and PTEN were significantly different among three immune phenotypes.Conclusion: Low TMB level could be the reason for the poor efficacy of ICBs in patients having EGFR mutation. And mutational frequencies of KRAS and BRCA2 were lower in EGFR-mutant patients. Furthermore, ALK, CDKN2A, MAP2K1, IDH2 and PTEN might involve in the formation of immune phenotypes.Keywords: lung adenocarcinoma, EGFR mutation, tumor mutation burden, immune phenotype, immune checkpoint blockade

Zhao Wang,1 Xiaoxia Song,2 Qingbo Fang,3 Weige Xia,1 Aihua Luo2 1Department of Orthopedics, The Second Poverty Relief Hospital of Xinjiang Uygur Autonomous Region (The Fifth People′s Hospital of Xinjiang Uygur Autonomous Region), Urumqi, Xinjiang, People’s Republic of China; 2Department of Critical Care Medicine, The Second Poverty Relief Hospital of Xinjiang Uygur Autonomous Region (The Fifth People′s Hospital of Xinjiang Uygur Autonomous Region), Urumqi, Xinjiang, People’s Republic of China; 3Department of Vascular Surgery, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, People’s Republic of ChinaCorrespondence: Aihua LuoDepartment of Critical Care Medicine, The Second Poverty Relief Hospital of Xinjiang Uygur Autonomous Region (The Fifth People′s Hospital of Xinjiang Uygur Autonomous Region), No. 159, West Kashi Road, Urumqi, 830000, People’s Republic of ChinaTel +86-18116803983Email 33180536@qq.comPurpose: To investigate the association of polymorphism of IL-1β rs16944(T/C) with intervertebral disk degeneration (IDD), explore the possible mechanism and evaluate the predictive value of IL-1β for IDD.Patients and Methods: A total of 196 consecutive patients with IDD were recruited, and 196 healthy controls were matched to these patients based on sex and age (± 3 years). The polymorphisms of IL-1β rs16944(T/C), rs1143623(G/C), rs10490571(T/C) and rs2853550(A/G) were determined, and serum IL-1β, MMP-1, MMP-3, MMP-9 and a disintegrin-like and metalloproteinase with thrombospondin motif-4 (ADAMTS-4) levels were measured. Univariate analysis was performed with Student t-test or one-way ANOVA followed by post hoc and Chi-square test. Variables with two-sided P< 0.10 were included in multivariate analysis, which employed a backward stepwise logistic regression model. Receiver operating characteristic (ROC) curve was used to evaluate the predictive value.Results: Multivariate analysis showed that the polymorphism of IL-1β rs16944(T/C) was independently associated with IDD. The risk for IDD was significantly increased in TT and TC genotype compared with CC genotype, and the OR of TT genotype was higher than that of TC genotype. ANOVA analysis showed that serum concentration of IL-1β was highest in IL-1β rs16944 TT genotype, intermediate in TC genotype, and lowest in CC genotype. Similarly, serum concentrations of MMP-3 and ADAMTS-4 demonstrated the same tendency of TT > TC > CC genotype. Serum concentrations of MMP-1 and MMP-9 were higher in TT genotype than in TC and CC genotype. The area under curve (AUC) of IL-1β levels in predicting IDD was 0.788 (SE: 0.023, P=0.001, 95% CI: 0.742– 0.834), and the predictive value was modest with a sensitivity of 77.0% and a specificity of 75%.Conclusion: Polymorphism of IL-1β rs16944(T/C) affected IDD susceptibility through upregulation of serum levels of IL-1β and subsequent stimulation of ECM degradation. IL-1β levels could be applied in predicting IDD.Keywords: intervertebral disk degeneration, single-nucleotide polymorphisms, IL-1β, susceptibility, predictive value

Chen-miao Huang,1,2 Jia-jing Cai,1,2 Shao-wu Jin,1,2 Qi-cheng Lin,1,2 Qian-juan Fang,1,2 Ke Nan,1,2 Yuan Han,1,2 Wen-wei Ge,1,2 Yu Liu,1,2 Yuan-xiang Tao,1,3 Hong Cao,1,2 Jun Li1,2 1Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People’s Republic of China; 2Zhejiang Province Key Laboratory of Anesthesiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People’s Republic of China; 3Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, 07103, USACorrespondence: Jun Li; Hong CaoDepartment of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People’s Republic of ChinaTel/Fax +86 577-88002925 Email lijun0068@163.com; caohong1955@21cn.comObjective: Perioperative neurocognitive disorders (PND) are a common complication in the elderly. Histone deacetylases (HDACs) are a class of enzymes that control the acetylation status of intracellular proteins. Thus, we explored whether HDACs trigger the release of high mobility group box 1 (HMGB1) through altering the acetylation status in the hippocampi of aged mice.Materials and Methods: The effect of the Class IIa HDAC in PND was explored using an in vivo form of splenectomy. Sixteen-month-old healthy male C57BL/6J mice were randomly divided into five groups: control, anesthesia plus sham surgery, anesthesia plus splenectomy, LMK235 treatment, and PBS treatment. The hippocampi were harvested on either first, third, or seventh postoperative day. Cognitive function was assessed via a Morris water maze (MWM) test. Quantitative RT-PCR, Western blots and ELISAs were carried out to assess the targeted gene expression at transcriptional and translational levels.Results: Splenectomy led to a significant deficiency in spatial memory acquisition, marked decreases in mRNA and protein levels of HDAC4 and HDAC5 in the hippocampus, and increases in the levels of total HMGB1 and acetylated HMGB1. In a similar fashion to splenectomy, treatment with the HDAC4/5 inhibitor LMK235 produced impaired spatial memory and an increase in the expression of HMGB1 and its acetylated counterpart in the hippocampus.Conclusion: These results suggest that surgery leads to PND through class IIa HDAC downregulation-triggered HMGB1 release in hippocampus of aged mice. HDACs may be a potential therapeutic target for postoperative cognitive dysfunction.Keywords: postoperative cognitive dysfunction, hippocampus, HDAC4, HDAC5, HMGB1, neuroinflammation

Hao Wang,1,2 Die Meng,1,2 Haoyue Guo,1,2 Chenglong Sun,1,2 Peixin Chen,1,2 Minlin Jiang,1,2 Yi Xu,1,2 Jia Yu,1,2 Qiyu Fang,1,2 Jun Zhu,1,2 Wencheng Zhao,1,2 Shengyu Wu,1,2 Sha Zhao,1 Wei Li,1 Bin Chen,1 Lei Wang,1 Yayi He1 1Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of China; 2Tongji University, School of Medicine, Shanghai, 200433, People’s Republic of ChinaCorrespondence: Yayi HeDepartment of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No 507 Zhengmin Road, Shanghai, 200433, People’s Republic of ChinaTel +86 13818828623Email 2250601@qq.comAbstract: Single-cell sequencing (SCS) which has an unprecedentedly high resolution is an advanced technique for cancer research. Lung cancer still has a high mortality and morbidity. For further understanding the lung cancer, SCS is also been applied to lung cancer research to investigate its heterogeneity, metastasis, drug resistance, tumor microenvironment and many other issues. In this review, we summarized lung cancer research using SCS and their research achievements.Keywords: single-cell sequencing, lung cancer, intratumoral heterogeneity, tumor microenvironment, lung cancer therapy

Qianyu Zhang,1,* Tong Wang,1,* Jiawei Jin,1,2 Xiaoqian Shi,2 Aiben Huang,3 Zhenru Ma,1 Jiujie Li,4 Shiyu Wang,4 Runlin Z. Ma,4,5 Qiuhong Fang1 1Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, People’s Republic of China; 2The Clinical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, People’s Republic of China; 3Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, People’s Republic of China; 4School of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China; 5State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qiuhong FangDepartment of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongren Tiyuchang South Road, Chaoyang District, Beijing 100020, People’s Republic of ChinaTel +86 10-85231451Fax +86 10-85231412Email fangmaster123@163.comRunlin Z. MaInstitute of Genetics and Developmental Biology, Chinese Academy of Sciences, S2-316 Building #2, West Beichen Road, Chaoyang District, Beijing 100101, People’s Republic of ChinaTel +86 10-64806599Fax +86 10-64806598Email rlma@genetics.ac.cnBackground: Chronic obstructive pulmonary disease (COPD), characterized by irreversible airflow limitation, is a highly prevalent lung disease worldwide and imposes increasing disease burdens globally. Emphysema is one of the primary pathological features contributing to the irreversible decline of pulmonary function in COPD patients, but the pathogenetic mechanisms remain unclear. Reticulocalbin 3 (Rcn3) is an endoplasmic reticulum (ER) lumen protein localized in the secretory pathway of living cells. Rcn3 in type II alveolar epithelial cell (AECIIs) has been reported to play a critical role in regulating perinatal lung development and bleomycin-induced lung injury-repair processes. We hypothesized that Rcn3 deficiency is associated with the development of emphysema during COPD, which is associated with the dysfunction of injury-repair modulated by alveolar epithelial cells.Materials and Methods: We examined Rcn3 expression in lung specimens from COPD patients and non-COPD control patients undergoing lung lobectomy or pneumonectomy. Two mouse models of emphysema were established by cigarette smoke (CS) exposure and intratracheal instillation of porcine pancreatic elastase (PPE). Rcn3 expression was detected in the lung tissues from these mice. Furthermore, conditional knockout (CKO) mice with Rcn3 deletion specific to AECIIs were used to explore the role of Rcn3 in PPE-induced emphysema progression. Rcn3 protein expression in lung tissues was evaluated by Western blot and immunohistochemistry. Rcn3 mRNA expression in lung tissues was detected by qPCR.Results: Rcn3 expression was significantly increased in the lung specimens from COPD patients versus non-COPD patients and the level of Rcn3 increase was associated with the degree of emphysema. Rcn3 expression were also significantly up-regulated in both CS-induced and PPE-induced emphysematous mouse lungs. Moreover, the selective ablation of Rcn3 in AECIIs significantly alleviated severity of the mouse emphysema in response to intratracheal installation of PPE.Conclusion: Our data, for the first time, indicated that suppression of Rcn3 expression in AECIIs has a beneficial effect on PPE-induced emphysema.Keywords: COPD, emphysema, Rcn3, type II alveolar epithelial cell

Guangjing Huang,1,2 Jie Chen,2 Jing Liu,2 Xiaoyan Zhang,2 Haijie Duan,2 Qian Fang3,4 1Department of Biomedicine, Medical College of Guizhou University, Guiyang, Guizhou, 550000, People’s Republic of China; 2Anesthesiology Department, Guizhou Provincial People’ s Hospital, Guiyang, Guizhou, 550000, People’s Republic of China; 3Medical College of Guizhou University, Guiyang, Guizhou, 550000, People’s Republic of China; 4Nursing Department, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, 550000, People’s Republic of ChinaCorrespondence: Qian Fang Email 403696864@qq.comObjective: The biological functions and molecular mechanisms of miR-935 have been widely investigated in various types of cancer. The aim of the present study was to explore the function of miR-935 in glioma.Methods: Bioinformatic analysis and quantitative real-time fluorescent PCR (qRT-PCR) were used to determine the expression of miR-935 in glioma tissues and glioma cell lines. Chi-square test was performed to analyze the relationship between the expression of miR-935 and clinical traits. CCK-8 assay, colony formation assay, cell cycle analysis and subcutaneous tumorigenesis model in nude mice were conducted to determine the effects of miR-935 on the proliferation of glioma cells both in vitro and in vivo. Wound healing and transwell assays were used to detect the effects of miR-935 on the migration and invasion of glioma cells in vitro. The relationship between miR-935 and HIF1α was analyzed using bioinformatics, luciferase reporter assay and Western blotting.Results: The expression of miR-935 was lower in glioma tissues than in the adjacent tissues, and in cell lines than in the normal human astrocytes (NHAs), and the low expression levels of miR-935 predicted a poor outcome. Exogenous overexpression of miR-935 inhibited the proliferation of glioma cells both in vitro and in vivo, and suppressed the migration and invasion of glioma cells in vitro. HIF1α was identified as the target of miR-935, whereas miR-935 overexpression decreased the expression of HIF1α and its target genes VEGF, MCL1 and GLUT1. Strikingly, overexpression of HIF1α significantly decreased the expression of miR-935, whereas silencing HIF1α increased the expression of miR-935. Similarly, HIF1α overexpression remarkably reversed the inhibitory effects of miR-935 on the proliferation, migration and invasion of glioma cells.Conclusion: Overall, present study reveals the presence of miR-935/HIF1α feedback loop in glioma, which inhibits the development of glioma. This feedback loop may be a potential target for the treatment of glioma.Keywords: glioma, miR-935, HIF1α, proliferation, migration

Quangang Fang, Haiyun Liu, Aiqun Zhou, Huaping Zhou, Zhiyong Zhang Department of Laboratory, Jiangxi Provincial People’s Hospital Affiliated to Nanchang University, Nanchang 330006, Jiangxi, People’s Republic of ChinaCorrespondence: Zhiyong ZhangDepartment of Laboratory, Jiangxi Provincial People’s Hospital Affiliated to Nanchang University, No. 92 Aiguo Road, Nanchang 330006, Jiangxi, People’s Republic of ChinaTel +86-791-86895951Email heo4hpd@163.comBackground: Many studies have confirmed that circular RNAs (circRNAs) play a key role in the biological progression of cancers. However, the function of a novel circRNA, circ_0046599, in hepatocellular carcinoma (HCC) progression has not been explored.Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to measure the expression of circ_0046599, microRNA (miR)-1258 and Ribophorin II (RPN2). Subcellular fractionation location assay was used to localize circ_0046599 in HCC cells. The circular characteristic of circ_0046599 was verified using Ribonuclease R (RNase R) digestion assay. Besides, cell counting kit 8 (CCK8) assay, colony formation assay, wound healing assay and transwell assay were used to detect cell proliferation, migration and invasion, respectively. The lactate production and glucose level were determined by Lactate and Glucose Assay Kits. Furthermore, the protein levels of glycolysis, metastasis and proliferation-related marker proteins, as well as RPN2 were tested by Western blot (WB) analysis. Moreover, dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were employed to confirm the interactions among circ_0046599, miR-1258 and RPN2. In addition, mice xenograft models were applied to observe the effect of circ_0046599 silencing on HCC tumor growth in vivo.Results: Circ_0046599 was highly expressed in HCC tissues and cells, and its knockdown could suppress HCC cell proliferation, migration, invasion and glycolysis process. MiR-1258 could be targeted by circ_0046599, and its inhibitor could invert the suppressing effect of circ_0046599 knockdown on HCC progression. Further, RPN2 was a target of miR-1258. Overexpressed RPN2 could reverse the inhibiting effect of miR-1258 overexpression on HCC progression. Also, knockdown of circ_0046599 could restrain HCC tumor growth in vivo.Conclusion: Our results provided new evidence that circ_0046599 could promote the progression of HCC by increasing RPN2 expression via sponging miR-1258.Keywords: HCC, circ_0046599, miR-1258, RPN2, progression

Qun Fang,1,* Aijie Yang,2,* Anshan Dong,3 Ligang Zhao4 1Department of Emergency, Yidu Central Hospital of Weifang, Weifang, People’s Republic of China; 2Department of Radiotherapy, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, People’s Republic of China; 3Department of Gastroenterology, Weifang Second People’s Hospital, Weifang, People’s Republic of China; 4Department of General Surgery, PLA Rocket Force Characteristic Medical Center, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Anshan DongDepartment of Gastroenterology, Weifang Second People’s Hospital, 7 Yuanxiao Street, Weifang, Shandong 261000, People’s Republic of ChinaTel +8613573654782Email 36635854@qq.comObjective: This study aims to illustrate the role of circPDSS1 and the Wnt/β-catenin signaling in the development of colorectal cancer (CRC).Patients and Methods: Cancerous mucosa and normal paracancerous mucosa tissues more than 5 cm away from the tumor were surgically collected from 56 CRC patients. circPDSS1 levels in collected tissues and CRC cell lines were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The influence of circPDSS1 on clinical features of CRC patients was analyzed. After knockdown of circPDSS1 in HCT-8 and HCT-116 cells, phenotype changes were examined by Transwell, tube formation and wound healing assay. Western blot and rescue experiments were finally performed to uncover the role of circPDSS1 and the Wnt/β-catenin signaling in the development of CRC.Results: circPDSS1 was upregulated in CRC mucosa tissues than controls. High level of circPDSS1 predicted high rates of lymphatic metastasis and distant metastasis, and poor prognosis in CRC patients. Knockdown of circPDSS1 attenuated migratory ability and angiogenesis in CRC cells. Protein levels of key genes in the Wnt/β-catenin signaling, including β-catenin, GSK-3β, c-Myc, MMP-9 and cyclin D1 were downregulated in CRC cells transfected with sh-circPDSS1. Overexpression of β-catenin reversed the role of circPDSS1 in attenuating migratory ability and angiogenesis in CRC cells.Conclusion: Upregulated circPDSS1 in CRC is closely linked to lymphatic metastasis, distant metastasis and overall survival. It stimulates the migratory ability and angiogenesis in CRC cells via activating the Wnt/β-catenin signaling.Keywords: circPDSS1, Wnt/β-catenin, CRC, metastasis

Wenjia Lai,1,* Dan Li,2,3,* Qingsong Wang,4 Xiaohui Nan,2,3 Zhichu Xiang,2,3 Yan Ma,5 Ying Liu,2 Jiankui Chen,6 Jiesheng Tian,7 Qiaojun Fang2,3 1CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, People’s Republic of China; 2CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, People’s Republic of China; 3University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China; 4State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing 100871, People’s Republic of China; 5Aviation Service Department, Yantai Engineering & Technology College, Yantai 264000, People’s Republic of China; 6Clinical Laboratory, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, People’s Republic of China; 7State Key Laboratories for Agrobiotechnology and College of Biological Sciences, China Agricultural University, Beijing 100193, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiesheng TianState Key Laboratories for Agrobiotechnology and College of Biological Sciences, China Agricultural University, No. 2 Yuanmingyuan West Road, Haidian District, Beijing 100193, People’s Republic of ChinaTel +86 10-62731440Email tianhome@cau.edu.cn Qiaojun FangCAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No. 11 ZhongGuanCun Beiyitiao, Haidian District, Beijing 100190, People’s Republic of ChinaTel +86 10-82545562Email fangqj@nanoctr.cnPurpose: It is well known that when exposed to human blood plasma, nanoparticles are predominantly coated by a layer of proteins, forming a corona that will mediate the subsequent cell interactions. Magnetosomes are protein-rich membrane nanoparticles which are synthesized by magnetic bacteria; these have gained a lot of attention owing to their unique magnetic and biochemical characteristics. Nevertheless, whether bacterial magnetosomes have a corona after interacting with the plasma, and how such a corona affects nanoparticle–cell interactions is yet to be elucidated. The aim of this study was to characterize corona formation around a bacterial magnetosome and to assess the functional consequences.Methods: Magnetosomes were isolated from the magnetotactic bacteria, M. gryphiswaldense (MSR-1). Size, morphology, and zeta potential were measured by transmission electron microscopy and dynamic light scattering. A quantitative characterization of plasma corona proteins was performed using LC-MS/MS. Protein absorption was further examined by circular dichroism and the effect of the corona on cellular uptake was investigated by microscopy and spectroscopy.Results: Various serum proteins were found to be selectively adsorbed on the surface of the bacterial magnetosomes following plasma exposure, forming a corona. Compared to the pristine magnetosomes, the acquired corona promoted efficient cellular uptake by human vascular endothelial cells. Using a protein-interaction prediction method, we identified cell surface receptors that could potentially associate with abundant corona components. Of these, one abundant corona protein, ApoE, may be responsible for internalization of the magnetosome-corona complex through LDL receptor-mediated internalization.Conclusion: Our findings provide clues as to the physiological response to magnetosomes and also reveal the corona composition of this membrane-coated nanomaterial after exposure to blood plasma.Keywords: LC-MS/MS, cellular interaction, cellular uptake, biogenic magnetic nanoparticle

Qing Fang,* Siyi Jiang,* Chengyuan Li Department of Hematology, The Third Xiangya Hospital of Central South University, Changsha, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chengyuan LiThe Third Xiangya Hospital of Central South University, Tongzipo Road 138, Changsha 410013, People’s Republic of ChinaTel/Fax +86 073188618511Email lcy800097@163.comIntroduction: Evodiamine (Evo) is one of the main bioactive components derived from the drying mature fruit of the genus Evodia rutaecarpa (Juss.) Benth. Although Evo has shown its anti-cancer activity in several cancers, the effects on multiple myeloma (MM) remain unknown. In this study, we aim to investigate the cytotoxic role of Evo on MM cells.Methods: CCK-8 assay, apoptotic cell analysis, xenografted mice model, caspase activity assay and mitochondrial membrane potential assay were performed.Results: We found that Evo selectively inhibits cell proliferation and increases apoptosis rate in MM cells, but not in healthy B lymphocytes, in a time and dose-dependent manner. Evo treatment significantly activated caspase-3 and −9 in MM cells. Evo also increased cytochrome C expression and ROS production in cytosol in a dose-dependent manner, which was abolished by MitoTEMPO cotreatment. In addition, co-treatment with bortezomib and Evo showed a more potent reduction of cell viability and a higher apoptosis than that of bortezomib single treatment in U266 and RPMI8226 cells.Conclusion: We provided evidence to demonstrate that Evo selectively suppresses cell growth and increases apoptosis rate in MM cells through the intrinsic apoptosis pathway. Application of Evo and bortezomib might enhance the anti-cancer effect on MM cells.Keywords: evodiamine, mitochondria, intrinsic apoptosis, bortezomib, resistance

Yanmeizhi Wu,1 Jun Han,1 Kazakova Elena Vladimirovna,1 Shumei Zhang,2 Wenhua Lv,2 Yan Zhang,3 Esma Jamaspishvili,1 Jingxue Sun,1 Qingxiao Fang,1 Jingjing Meng,1 Hong Qiao1 1Department of Endocrinology, No.2 Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People’s Republic of China; 2Department of Epigenetics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang Province, People’s Republic of China; 3Department of Bioinformatics and Computational Epigenetics, College of Life and Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Province, People’s Republic of ChinaCorrespondence: Hong QiaoDepartment of Endocrinology, No.2 Affiliated Hospital of Harbin Medical University, No. 148 Baojian Road, Nangang District, Harbin, Heilongjiang Province, People’s Republic of ChinaTel +86 13945677355Email qhong0823@163.comIntroduction: PTC is not generally considered a lethal disease, but prone to recurrence as the prognosis. Hashimoto’s thyroiditis (HT) is an important factor that affects the prognosis of papillary thyroid carcinoma (PTC). It is crucial to find biomarkers to identify the combination of HT with PTC and to predict the prognosis.Methods: RNASeq data from the Cancer Genome Atlas (TCGA) database was used to screen differentially expressed genes (DEGs) of PTC with HT via the edgeR package of R software version 3.3.0. Also, the DEGs were applied to the DAVID web-based tool to determine the enrichment of gene functions via Gene Ontology (GO) analysis and to identify associated pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. By constructing protein interaction networks within Cytoscape software, we screened candidate genes and explored possible relationships with the clinical phenotype of PTC. Finally, additional thyroid tissue samples were collected to verify the results above.Results: After analyzing the RNA-Seq data of PTC patients from the Cancer Genomic Atlas, 497 differentially expressed PTC genes were found to be associated with HT, of which protein tyrosine phosphatase receptor type C (PTPRC), KIT, and COL1A1 were associated with tumor size and lymph node metastasis (p < 0.05). Verification of these results with another 30 thyroid tissues of clinical PTC patients revealed that the expression level of PTPRC in the PTC with HT group was higher than that in the PTC without HT group (p < 0.05) and the ROC curve showed a good discrimination (area under the curve = 0.846). However, the correlation with the clinical phenotype was not statistically significant (p > 0.05).Discussion: These data suggest that upregulation of PTPRC enhances the incidence of HT associated with PTC and is also predictive of a poor prognosis.Keywords: papillary thyroid carcinoma, Hashimoto’s thyroiditis, PTPRC, biomarker, prognosis

Baixia Zhang,1 Wei Du,2 Kang Gan,1 Qigen Fang,2 Xu Zhang21Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 2Department of Head Neck and Thyroid, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan Province, People’s Republic of ChinaBackground: The main goal of this study was to evaluate the prognosis of young patients with oral squamous cell carcinoma (SCC) with a focus on the value of the pretreatment neutrophil-to-lymphocyte ratio (NLR).Materials and methods: Young (≤40 years old) patients with oral SCC were retrospectively enrolled, and each young patient was matched with an old (≥60 years old) oral SCC patient. Associations between the NLR and clinicopathological variables were analyzed by the chi-square test, and the Kaplan–Meier method was used to analyze recurrence-free survival (RFS) and disease-specific survival (DSS) rates.Results: A total of 103 young patients were enrolled, and compared to the old group, the young group had a significantly lower NLR value (p=0.012). In the young group, the 5-year RFS and DSS rates were 82% and 85%, respectively. In the old group, the 5-year RFS and DSS rates were 65% and 71%, respectively, and the differences between the groups were significant (both p2.56, the 5-year DSS rate was 76%. This difference was significant (p=0.020). A further Cox model analysis confirmed that the NLR was an independent prognostic factor for DSS.Conclusion: Young patients with oral SCC have a better prognosis than old oral SCC patients, and the NLR is significantly associated with DSS in young patients.Keywords: oral squamous cell carcinoma, young patient, head and neck cancer, neutrophil-to-lymphocyte ratio, survival analysis

BackgroundTo systematically review the clinical value of 18F-DCFPyL prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) in the diagnosis of prostate cancer (PCa).MethodsLiterature concerning 18F-DCFPyL PSMA PET/CT in the diagnosis of prostate cancer published from 2015 to 2020 was electronically searched in the databases including PubMed and Embase. Statistical analysis was carried out with STATA 15 software, and the quality of included studies was tested with quality assessment of diagnostic accuracy studies (QUADAS) items. The heterogeneity of the included data was tested.ResultsIn total, nine pieces of literature involving 426 patients met the inclusion criteria. The heterogeneity of the study group was not obvious. The SEN, SPE, LR+, LR−, DOR as well as AUC of 18F-DCFPyL PSMA PET/CT diagnosis of prostate cancer were 0.91, 0.90, 8.9, 0.10, 93, and 0.93. The pooled DR of 18F-DCFPyL labeled PSMA PET/CT in PCa was 92%. The pooled DR was 89% for PSA≥0.5 ng/ml and 49% for PSA < 0.5ng/ml.Conclusion18F-DCFPyL PSMA PET/CT had good sensitivity and specificity for the diagnosis of prostate cancer. The DR of 18F-DCFPyL PSMA PET/CT was correlated with PSA value. Further large-sample, high-quality studies were needed.

Sen Zheng,1,* Huita Wu,2,* Fei Wang,1,* Jie Lv,1 Jing Lu,1 Qinliang Fang,1 Fuqiang Wang,1 Yuyan Lu,1 Sheng Zhang,1 Yaping Xu,3 Qing Bao,1 Chengrong Xie,1 Zhenyu Yin11Department of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen 361004, Fujian, People’s Republic of China; 2Department of Oncology, Zhongshan Hospital, Xiamen University, Xiamen 361004, Fujian, People’s Republic of China; 3Key laboratory of functional and clinical translational medicine, Xiamen Medical College, Xiamen 361004, Fujian, People’s Republic of China*These authors contributed equally to this workBackground: Due to the high recurrence and metastasis rate, the clinical outcomes of patients with hepatocellular carcinoma (HCC) are still unsatisfactory. Hepatitis B virus X-interacting protein (HBXIP) has been reported to play crucial roles in carcinogenesis.Purpose: We aimed to reveal the functional significance and underlying mechanism of HBXIP in HCC metastasis.Methods: Cell transwell assay, in vivo metastasis model, real-time PCR, western blot analysis, luciferase reporter and chromatin immunoprecipitation assays were applied.Results: Here, we detected the HBXIP expression level and determined its clinical significance in HCC. We found that HBXIP was significantly upregulated in HCC tissues, and correlated with vascular invasion, tumor metastasis and worse prognosis of HCC patients. HBXIP enhanced cell migration and invasion in vitro, and promoted the metastasis of HCC in vivo. Furthermore, we confirmed that HBXIP increased MMP15 expression through association with proto-oncogene c-myc. Depletion of c-myc abolished HBXIP-mediated MMP-15 upregulation. We also observed a positive correlation between HBXIP and MMP15 expression in HCC tissues.Conclusion: Our results establish a novel function for HBXIP-MMP15 regulation in HCC metastasis and suggest its candidacy as a new prognostic biomarker and therapeutic target for HCC metastasis.Keywords: c-myc, MMP15, HBXIP, metastasis

Guangyan Cheng,1 Fei Liu,1 Xinyu Niu,1 Qigen Fang2 1Department of Oral Medicine, Stomatology Center, The First affiliated hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Department of Head Neck and Thyroid, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, People’s Republic of China Background: To analyze the value of the pretreatment neutrophil-to-lymphocyte ratio (NLR) in the survival of patients with parotid cancer.Methods: In total, 249 patients were enrolled. Information including age, sex, pretreatment NLR, and pathologic variables such as, tumor stage, intraparotid node (IPN) metastasis, and follow-up findings was extracted and analyzed.Results: IPN metastasis was noted in 45 (18.1%) patients, and the mean NLR was 2.48, with a range from 1.5 to 6.1. The NLR was significantly associated with tumor stage, disease stage, and disease grade. A total of 73 patients died of the disease, and the 10 -year disease-specific survival (DSS) rate was 62%. In patients with an NLR

Fei Wang,1,2 Huita Wu,3 Sheng Zhang,4 Jing Lu,1 Yuyan Lu,1 Ping Zhan,1 Qinliang Fang,1 Fuqiang Wang,1 Xiuming Zhang,5 Chengrong Xie,1 Zhenyu Yin11Department of Hepatobiliary Surgery, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital, Xiamen University, Xiamen, Fujian, People’s Republic of China; 2The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 3Department of Oncology, Zhongshan Hospital, Xiamen University, Xiamen, Fujian, People’s Republic of China; 4Department of Pathology, Hubei Cancer Hospital, Wuhan, Hubei, People’s Republic of China; 5Department of Biomaterials, College of Materials, Xiamen University, Xiamen, Fujian, People’s Republic of ChinaBackground: Hepatocellular carcinoma (HCC) is one of the most frequent cancers and the third leading cause of cancer-related deaths. It has been reported that lysosomal associated transmembrane protein LAPTM4B expression is significantly upregulated in human cancers and closely associated with tumor initiation and progression.Purpose: We aimed to reveal the relevance of LAPTM4B and the pathogenesis of HCC. Methods: Cell viability assessment, colony formation assay, in vivo xenograrft model, microarray, real-time PCR, immunofluorescence and western blot analysis were applied.Results: Our results demonstrated that LAPTM4B promoted HCC cell proliferation in vitro and tumorigenesis in vivo. Additionally, upon starvation conditions, LAPTM4B facilitated cell survival, inhibited apoptosis and induced autophagic flux. Expression profiling coupled with gene ontology (GO) analysis revealed that 159 gene downregulated by LAPTM4B silencing was significantly enriched in response to nutrient and some metabolic processes. Moreover, LAPTM4B activated ATG3 transcription to modulate HCC cell apoptosis and autophagy.Conclusion: Our findings demonstrate that LAPTM4B acts as an oncogene that promotes HCC tumorigenesis and autophagy, and indicate that LAPTM4B may be used as a novel therapeutic target for HCC treatment.Keywords: autophagy, apoptosis, LAPTM4B, ATG3

Abstract Problems in unsteady aerodynamics and aeroacoustics can sometimes be formulated as integral equations, such as the boundary integral equations. Numerical discretization of integral equations in the time domain often leads to so-called March-On-in-Time (MOT) schemes. In the literature, the temporal basis functions used in MOT schemes have been largely limited to low-order shifted Lagrange basis functions. In order to evaluate the accuracy and effectiveness of the temporal basis functions, a Fourier analysis of the temporal interpolation schemes is carried out. Based on the Fourier analysis, the spectral resolutions of various temporal basis functions are quantified. It is argued that hybrid temporal basis functions be used for interpolation of the numerical solution and its derivatives with respect to time. Stability of the proposed hybrid schemes is studied by a matrix eigenvalue method. Substantial improvement in accuracy and efficiency by using the hybrid temporal basis functions for time domain integral equations is demonstrated by numerical examples. Compared with the traditional temporal basis functions, the use of hybrid basis functions keeps numerical errors low for a larger frequency range given the same time step size. Conversely, for a given range of frequency of interest, a larger time step can be used with the hybrid temporal basis functions, resulting in an increase in computational efficiency and, at the same time, a reduction in memory requirement.

Qigen Fang,1 Fei Liu,2 Dongjie Seng3 1Department of Head and Neck, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China; 2Department of Oral Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; 3Department of Ear, Nose, and Throat, Affiliated Children Hospital of Zhengzhou University, Zhengzhou, China Background: The goal of this study was to investigate the long-term oncologic outcome of parotid mucoepidermoid carcinoma (MEC) in pediatric patients. Patients and methods: Patients

Fang Q, Yang A, Dong A, Zhao L. Onco Targets Ther. 2020;13:6329–6337. The Editor and Publisher of OncoTargets and Therapy wish to retract the published article. Concerns were raised regarding the integrity of the data presented in Figure 1 and the % values reported in Table 1. The authors responded to our queries and agreed there were errors with the data but were unable to verify their original data and have therefore agreed to retract the article. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”. This retraction relates to this paper

BackgroundContrast-enhanced ultrasound (CEUS) is an examination mode for detecting blood vessels in tissues, and it has been gradually used in the diagnosis of kidney cancer in recent years. This study explores the value of contrast-enhanced ultrasound in the clinical diagnosis of renal cancer, and provides an accurate and effective method for clinical diagnosis of renal cancer.MethodsCEUS and RCC were selected as the keywords. Searching the PubMed and Embase from 2007 to 2020, the original data were abstracted and performed heterogeneity test with the Meta-Disc software. The weighted sensitivity, specificity, positive likelihood ratio and negative likelihood ratio were calculated, as well as the summary receiver operating characteristic (SROC) curve. Further estimated the diagnostic value of CEUS in the research of renal cancer by calculating the area under the curve (AUC). The quality of evidence in researches was evaluated by QUADAS items. Meta-disc, Review Manager 5.3, and STATA 13 were used.ResultsA total of 20 studies were adopted for Meta-analysis. The weighted sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 0.97, 0.86, 6.8, 0.04 and 171, respectively; and AUC was 0.97. The results showed that there was high heterogeneity.ConclusionCEUS technology has a good diagnostic value for RCC.

Minzhi Zhao,* Haiyun Li,* Yan Ma, He Gong, Shu Yang, Qiaojun Fang, Zhiyuan Hu Chinese Academy of Sciences Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, People’s Republic of China *These authors contributed equally to this work Abstract: Abraxane (Abr), a US Food and Drug Administration-approved albumin-bound nanoparticle applied for the treatment of non-small-cell lung cancer, has been reported to be more effective than paclitaxel (PTX). To further understand the molecular mechanisms that produce this superior drug efficacy of Abr, a quantitative proteomic approach has been applied to investigate the global protein expression profiles of lung cancer cell A549 treated with Abr and PTX. Only one protein, namely, glucosamine 6-phosphate N-acetyltransferase 1 (GNA1), showed significant differential expression (P

Gaozhi Chen,1,* Lili Jiang,2,* Lili Dong,2 Zhe Wang,1 Fengli Xu,2 Ting Ding,3 Lili Fu,1 Qilu Fang,1 Zhiguo Liu,1,4 Xiaoou Shan,2 Guang Liang1 1Chemical Biology Research Center, School of Pharmaceutical Sciences, 2Department of Pediatrics, The 2nd Affiliated Hospital, 3Department of Pharmacy, The 5th Affiliated Hospital, Wenzhou Medical University, Lishui, Zhejiang, People's Republic of China; 4Wenzhou Undersun Biotchnology Co, Ltd, Wenzhou, Zhejiang, People's Republic of China *These authors contribute equally to this work Abstract: Sepsis, a typically acute inflammatory disease, is the biggest cause of death in ICU (intensive care unit). Novel anti-inflammatory alternatives are still in urgent need. In this study, we designed and synthesized 30 indole-2-one and 7-aza-2-oxindole derivatives based on the skeleton of tenidap, and their anti-inflammatory activity was determined by evaluating the inhibitory potency against lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF)-α and interleukin (IL)-6 release in RAW264.7 macrophages. Quantitative SAR (structure–activity relationship) analysis revealed that a high molecular polarizability and low lipid/water partition coefficient (ALogP) in indole-2-one are beneficial for anti-inflammatory activity. Moreover, compounds 7i and 8e inhibited the expression of TNF-α, IL-6, COX-2, PGES, and iNOS in LPS-stimulated macrophages, and 7i exhibited a significant protection from LPS-induced septic death in mouse models. These data present a series of new indole-2-one compounds with potential therapeutic effects in acute inflammatory diseases. Keywords: anti-inflammation, macrophages, sepsis

Yali Zhang,1,2,* Chengguang Zhao,1,2,* Wenfei He,2,* Zhe Wang,2 Qilu Fang,2 Bing Xiao,2 Zhiguo Liu,2 Guang Liang,2 Shulin Yang1 1School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu, People's Republic of China; 2Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, University Town, Wenzhou, Zhejiang, People's Republic of China *These authors contributed equally to this work Abstract: Sepsis is a systemic inflammatory response syndrome and is mainly caused by lipopolysaccharides (LPS) – a component of the cell walls of gram-negative bacteria, via toll-like receptor 4–mitogen-activated protein kinases/nuclear factor-kappa B-dependent proinflammatory signaling pathway. Here, we synthesized 26 asymmetric monocarbonyl analogs of curcumin and evaluated their anti-inflammatory activity by inhibiting the LPS-induced secretion of tumor necrosis factor-α and interleukin-6 in mouse RAW264.7 macrophages. Five active compounds (3a, 3c, 3d, 3j, and 3l) exhibited dose-dependent inhibition against the release of tumor necrosis factor-α and interleukin-6, and they also showed much higher chemical stability than curcumin in vitro. The anti-inflammatory activity of analogs 3a and 3c may be associated with their inhibition of the phosphorylation of extracellular signal-regulated kinase and the activation of nuclear factor-kappa B. In addition, 3c exhibited significant protection against LPS-induced septic death in vivo. These results indicate that asymmetrical monocarbonyl curcumin analogs may be utilized as candidates for the treatment of acute inflammatory diseases. Keywords: sepsis, inflammatory cytokines, anti-inflammation, quantitative structure–activity relationship

Qiuhong Fang,1,2 Nancy A Schulte,3 Huijung Kim,4 Tetsu Kobayashi,5 Xingqi Wang,2 Anna Miller-Larsson,6 Elisabet Wieslander,6 Myron L Toews,3 Xiangde Liu,2 Stephen I Rennard21Pulmonary and Critical Care Department, Beijing Shijitan Hospital, Capital Medical University, Beijing, People's Republic of China; 2Pulmonary, Critical Care, Sleep and Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; 3Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA; 4Pulmonary and Critical Care Division, WonKwang University, Kunpo Medical Center, Seoul, Republic of Korea; 5Mie University Graduate School of Medicine, Tsu City, Japan; 6AstraZeneca R&D Molndal, Molndal, SwedenBackground: The balance between production and degradation of extracellular matrix is crucial in maintaining normal tissue structure. This study was designed to investigate the effect of budesonide on fibroblast-mediated tissue repair and remodeling.Methods: Using human fetal lung fibroblasts in a three-dimensional collagen gel culture system, we investigated the effect of budesonide (1–1000 nM) on collagen gel contraction and degradation in the presence or absence of inflammatory cytokines (interleukin-1β and tumor necrosis factor α; 5 ng/mL each) and, in order to activate latent proteases, serine protease trypsin 0.25 µg/mL. The effects of budesonide on metalloproteinase production and activation were also investigated.Results: Inflammatory cytokines significantly inhibited collagen gel contraction mediated by lung fibroblasts. Budesonide counteracted the effect of cytokines in a concentration-dependent manner (to 50%, P < 0.01). Budesonide 100 nM almost completely inhibited the release and mRNA expression of metalloproteinase-1, metalloproteinase-3, and metalloproteinase-9 induced by the cytokines (P < 0.05). Exposure to the cytokines plus trypsin increased collagen degradation and conversion of the metalloproteinases to lower molecular weight forms corresponding to their active forms. Budesonide blocked both enhanced collagen degradation (P < 0.01) and suppressed trypsin-mediated conversion of cytokine-induced metalloproteinase-9 and metalloproteinase-3 to lower molecular weight forms. Similar effects were observed with dexamethasone 1 µM, suggesting a class effect.Conclusion: These findings demonstrate that budesonide directly modulates contraction of collagen gels and can decrease collagen degradation under inflammatory conditions. The mechanism of this effect is through suppressing gene expression, release, and activation of metalloproteinases. By modulating the release and activity of metalloproteinases, inhaled budesonide may be able to modify airway tissue repair and remodeling.Keywords: metalloproteinase, budesonide, tissue remodeling