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Yu Zhou,1,&ast; Huoying Cai,1,&ast; Lin Huang,1,&ast; Mingshan Wang,1 Ruiming Liu,2 Siwen Wang,1 Yuansen Qin,1 Chen Yao,1 Zuojun Hu1 1Division of Vascular Surgery, National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Disease, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 2Laboratory of Department of Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zuojun Hu; Chen Yao, Email huzuojun@mail.sysu.edu.cn; yaochen@mail.sysu.edu.cnBackground: Arteriosclerosis obliterans (ASO) is the leading cause of nontraumatic lower-extremity amputations. Multiple researches have suggested that circular RNAs (circRNAs) played vital regulatory functions in cancer and cardiovascular disease. Nevertheless, the underlying effect and pathological mechanism of circRNAs in the formation and progression of ASO are still indistinct.Methods and Results: This study used microarray analysis to investigate the expression portrait of circRNAs in normal lower extremity arteries and ASO arteries. Bioinformatics analysis was conducted using the KEGG database to study the enrichment of differentially expressed circRNAs (DE circRNAs) and predict their functions. The accuracy of microarray assay was verified by evaluating expression of the top 5 upregulated and 5 downregulated circRNAs (raw density of normal group ≥ 200) using RT-qPCR. A circRNA-miRNA-mRNA interaction network was further predicted using software. Compared to the normal lower extremity group, the ASO arteries with HE and EVG staining presented hyperplastic fibrous membrane and luminal stenosis. A total of 12,735 circRNAs were identified, including 1196 DE circRNAs with 276 upregulated and 920 downregulated in ASO group based on |log2(FC)| > 1 and padj < 0.05. Among selected 10 circRNAs, RT-qPCR confirmed that hsa_circ_0003266, hsa_circ_0118936 and hsa_circ_0067161 were upregulated while hsa_circ_0091934 and hsa_circ_0092022 were downregulated in ASO group (p < 0.05). GO analysis presented that the DE circRNAs were primarily enriched in protein binding, intracellular part and organelle organization. KEGG pathway analysis indicated that MAPK signaling pathway, human T-cell leukemia virus 1 infection, proteoglycans in cancer were associated with the DE circRNAs. The circRNA-miRNA-mRNA interactive network revealed that both mRNAs and miRNAs linked to circRNAs played an indispensable role in ASO.Conclusion: This study described the expression portrait of circRNAs in human ASO arteries, and revealed the molecular background for further investigations of the circRNA regulatory mechanism in the formation and progression of ASO.Keywords: arteriosclerosis obliterans, circular RNA, gene ontology analysis, pathway analysis, circRNA-miRNA-mRNA interaction network

Tianhui Gao,1,&ast; Cong Yao,1,&ast; Yuanyuan Shang,1 Renchun Su,1 Xuxia Zhang,1 Weicong Ren,1 Shanshan Li,1 Wei Shu,2 Yu Pang,1 Qi Li2 1Department of Bacteriology and Immunology, Beijing Key Laboratory for Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, People’s Republic of China; 2Clinical Center on Tuberculosis Control, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qi Li; Yu Pang, Beijing Chest Hospital, Capital Medical University, No. 97, Machang, Tongzhou District, Beijing, 101149, People’s Republic of China, Tel/Fax +86 010 6954 6690 ; +86 10 8950 9366, Email lq0703@hotmail.com; pangyupound@163.comPurpose: Unsatisfactory efficacies of currently recommended anti-Mycobacterium abscessus complex (MABC) treatment regimens have led to development of novel drugs to combat MABC infections. In this study, we evaluated in vitro antimicrobial activities of bedaquiline (BDQ) and four oxazolidinones against MABC isolates.Methods: The resazurin microplate assay was performed to determine minimum inhibitory concentrations (MICs) of BDQ and four oxazolidinones, including tedizolid (TZD), sutezolid (SZD), delpazolid (DZD), and linezolid (LZD), against 65 MABC isolates. A checkerboard method was used to investigate efficacies of various antimicrobial drug combinations.Results: BDQ MICs for MABC isolates ranged from < 0.031 to 1 μg/mL, while MIC50 and MIC90 values were 0.125 μg/mL and 0.25 μg/mL, respectively. TZD MIC50 and MIC90 values for MABC isolates were 1 μg/mL and 4 μg/mL, respectively, which were fourfold lower than corresponding LZD values (P < 0.001). DZD MIC90 values for MABC isolates was 8 μg/mL, which were 0.5-fold lower than corresponding LZD values (P < 0.01). MICs of BDQ, SZD, and LZD for M. abscessus subspecies massiliense isolates were significantly lower than corresponding MICs for M. abscessus subspecies abscessus isolates (P < 0.05). Notably, use of oxazolidinones (DZD, SZD, LZD, or TZD) with BDQ against MABC isolates led to reduction of the oxazolidinone median MIC range from 4 to 0.125 μg/mL to 1– 0.031 μg/mL.Conclusion: These results demonstrated excellent BDQ inhibitory activity against MABC isolates. TZD exhibited stronger antimicrobial efficacy against MABC isolates as compared to efficacies of DZD, SZD, and LZD. Importantly, MICs of oxazolidinones were markedly decreased when they were combined with BDQ, thus suggesting that combinations of BDQ and oxazolidinones may be effective treatments for MABC infections.Keywords: bedaquiline, tedizolid, oxazolidinones, susceptibility testing, Mycobacterium abscessus complex, delpazolid

Brandon Tejada,1,2 Roby Joehanes,1,2 Shih-Jen Hwang,1,2 Tianxiao Huan,1– 3 Chen Yao,1,2 Jennifer E Ho,4 Daniel Levy1,2,5 1Framingham Heart Study, Framingham, MA, USA; 2Population Sciences Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, USA; 3Ophthalmology and Visual Sciences, University of Massachusetts Medical School, Worcester, MA, USA; 4CardioVascular Institute and Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, Unites States; 5Boston University School of Medicine, Boston, MA, USACorrespondence: Daniel Levy, Framingham Heart Study, 73 Mt. Wayte Avenue, Suite 2, Framingham, MA, 01702, USA, Email Levyd@nih.govPurpose: Assessing an individual’s systemic inflammatory state is vital to understand inflammation’s role in cardiometabolic diseases and identify those at the greatest risk of disease. We generated global inflammation scores and investigated their associations with cardiometabolic risk factors and adverse outcomes.Patients and Methods: Aggregate Inflammation Scores (AIS) and Principal Component Analysis (PCA) scores were generated for 7287 Framingham Heart Study participants using up to 26 inflammation-related proteins, with higher scores reflecting a pro-inflammatory milieu. Multivariable regression and proportional hazards analyses were conducted to investigate the associations of inflammation with cardiometabolic risk factors and outcomes. The primary outcomes for cross-sectional analyses included age, cigarette smoking, fasting lipid and glucose levels, blood pressure, body mass index (BMI), and hypertension, diabetes, and obesity. For prospective analyses, new-onset hypertension, diabetes, obesity, cardiovascular disease and all-cause mortality were investigated.Results: Higher inflammation scores were associated with smoking and older age, higher BMI, systolic blood pressure, lipids, and glucose levels, and with greater odds of hypertension and diabetes after adjusting for age, sex, cohort, and BMI (all p < 0.001). Higher baseline scores were associated with greater odds of new-onset hypertension after adjusting for traditional risk factors (OR [95% CI] per one standard deviation [1-SD] increase, AIS: 1.33 [1.21– 1.47], PCA score: 1.26 [1.12– 1.42], p < 0.001). The AIS also was associated with new-onset diabetes (1.32 [1.14– 1.52], p < 0.001). Proportional hazards analyses revealed greater risk of new-onset cardiovascular disease events and all-cause mortality (HR [95% CI] per 1-SD, AIS: 1.25 [1.14– 1.37] and 1.32 [1.23– 1.42], PCA score: 1.22 [1.13– 1.33] and 1.40 [1.31– 1.49], p < 0.001).Conclusion: Global inflammation scores encompassing an array of pro- and anti-inflammatory proteins and pathways may enhance risk assessment for cardiometabolic diseases. The AIS and PCA scores provide further opportunities to investigate the mechanisms of inflammation-related risk of disease.Keywords: inflammation scores, cardiovascular disease, heart failure, pathways

Wei Fang,1,&ast; Yu Zhang,1,&ast; Sinian Li,1,&ast; Aiming Liu,2,&ast; Yin Jiang,2 Dandan Chen,1 Binbin Li,3 Can Yao,3 Rongchang Chen,1 Fei Shi3 1Key Laboratory of Shenzhen Respiratory Diseases, Institute of Shenzhen Respiratory Diseases, Shenzhen People’s Hospital (The First Affiliated Hospital of Southern University of Science and Technology, The Second Clinical Medical College of Jinan University), Shenzhen, Guangdong, People’s Republic of China; 2Shenzhen National Climate Observatory, Meteorological Bureau of Shenzhen Municipality, Shenzhen Key Laboratory of Severe Weather in South China, Shenzhen, Guangdong, People’s Republic of China; 3Emergency Department, Institute of Shenzhen Respiratory Diseases, Shenzhen People’s Hospital (The First Affiliated Hospital of Southern University of Science and Technology, The Second Clinical Medical College of Jinan University), Shenzhen, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Rongchang Chen; Fei Shi Email chenrc@vip.163.com; shi.fei@szhospital.comBackground: Reversible airflow obstruction (RO) and fixed airflow obstruction (FO) are two important clinical phenotypes of asthma. However, the relationship between air pollutant exposure and exacerbation of the two phenotypes is unknown.Objective: To study the effects of air pollutant exposure on exacerbation severity in asthma patients with or without FO.Methods: A total of 197 severe asthma patients were enrolled, and divided into two groups: the FO group (n=81) and the RO group (n=116). We collected the demographic data, laboratory parameters, pulmonary function test parameters, and the daily average concentrations of different air particles in Shenzhen on the different lag days of each subject. The receiver operating characteristic (ROC) curve was used to identify the effects of major air pollutants on the severity of asthma patients with RO.Results: Compared with the RO group, the FO group had fewer women, lower body mass index (BMI), longer disease duration, higher smoking history rate, allergic family history rate, FeNO level, and lower levels of large airway parameters. The median exposure levels of PM10 and PM2.5 in the severe RO subgroup were both higher than those in the mild-to-moderate RO subgroup on Lag0, 1 and 3, and the median exposure level of PM1 on Lag0 in the severe RO subgroup was significantly higher than that in the mild-to-moderate RO subgroup. Logistic regression modeling indicated exposure to PM2.5 and PM1.0 on Lag0, and PM10 on Lag0-2 were the independent risk factors for hospital admissions for asthma patients with RO. By performing an ROC curve analysis, PM2.5 on Lag0 (AUC = 0.645, p = 0.027) provided a best performance to predict severe asthma exacerbations with RO, with a sensitivity of 36.0% and a specificity of 91.2%.Conclusion: Short-term exposure to PM10, PM2.5 and PM1 may play a role in exacerbation severity among asthma patients with RO.Keywords: air particles, asthma, reversible airflow obstruction, fixed airflow obstruction

Jidong Guo,1,2,&ast; Qiang Li,1,&ast; Xuxia Zhang,2 Cong Yao,2 Rongmei Liu,1 Yu Pang,2 Mengqiu Gao1 1Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, 101149, People’s Republic of China; 2Department of Bacteriology and Immunology, Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, 101149, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: : Yu PangDepartment of Bacteriology and Immunology, Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing, 101149, People’s Republic of ChinaTel/Fax +86-10-8950 9162Email pangyupound@163.comMengqiu GaoDepartment of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing, 101149, People’s Republic of ChinaTel/Fax +86-10-8950 9322Email gaomqwdm@aliyun.comIntroduction: Interferon-γ release assays (IGRAs) can have high false-negative rates for active tuberculosis (TB) cases. Here we investigated factors, including potential anti-inflammatory mechanisms, that contributed to false-negative IGRA results.Methods: We established two cohorts. In the first cohort, we reviewed IGRA results for confirmed TB cases diagnosed in our hospital in 2018. Cases with false-negative IGRA results were analysed to identify factors contributing to false-negative results. In the second cohort, we prospectively studied IL-10 expression levels in peripheral blood mononuclear cells (PBMCs) of IGRAs-positive and IGRAs-negative TB cases after antigenic stimulation to correlate IL-10 expression with IGRAs results.Results: Of 1232 culture-confirmed TB cases, 1124 produced true-positive IGRA results and 108 had false-negative IGRA results. Multivariate logistic regression analysis identified glucocorticoid use and extrapulmonary TB as independent risk factors for false-negative IGRA results. Notably, IL-10 expression of the IGRA-negative group was significantly up-regulated as compared to that of the IGRA-positive group. The average cell supernatant IL-10 concentration of the IGRA-negative group was 4.77 pg/mL, a value that was statistically greater than the IGRA-positive group concentration (1.47 pg/mL, P = 0.007). After PBMCs pretreatment with BRD6989 (to enhance IL-10 secretion), average IFN-γ concentrations in cell supernatants from the IGRA-positive group significantly decreased from 59.73 pg/mL to 33.79 pg/mL (P = 0.011). By contrast, addition of AS101 (to inhibit IL-10 secretion) to false-negative group PBMCs led to an increase of average IFN-γ concentration in cell supernatants from 19.01 pg/mL to 45.10 pg/mL (P = 0.030), a result that was inversely correlated with IL-10 concentration.Conclusion: Our data demonstrate that increased IL-10 secretion by PBMCs is inversely correlated with IGRA assay results in culture-confirmed TB patients. Glucocorticoids use and extrapulmonary TB are significantly associated with false-negative IGRA results. Combination testing to measure IL-10 secretion and IFN-γ release is recommended to improve IGRAs specificity.Keywords: tuberculosis, interferon-γ release assay, interleukin 10

Si Sun,1,* Weipu Mao,1– 3,* Shuchun Tao,1,* Xiangyu Zou,4 Shengwei Tian,1 Siwei Qian,1 Chi Yao,1 Guangyuan Zhang,1,2 Ming Chen1– 3 1Department of Urology, Zhongda Hospital, Southeast University, Nanjing, 210009, People’s Republic of China; 2Surgical Research Center, Institute of Urology, Southeast University Medical School, Nanjing, 210009, People’s Republic of China; 3Department of Urology, Nanjing Lishui District People’s Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing, 211200, People’s Republic of China; 4Department of Urology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ming Chen; Guangyuan ZhangDepartment of Urology, Zhongda Hospital, Southeast University, No. 87 Dingjiaqiao, Hunan Road, Gulou District, Nanjing, 210009, People’s Republic of ChinaTel +86-139 13009977; +86-139 51658634Fax +86-139 13009977; +86-139 51658634Email mingchenseu@126.com; zgy0879@qq.comBackground: Polycyclic aromatic hydrocarbons (PAHs) exposure may cause various diseases. However, the association between PAHs exposure and kidney stones remains unclear. The purpose of this study was to examine the relationship between PAHs and the risk of kidney stones in the US population.Methods: The study included a total of 30,442 individuals (≥ 20 years) from the 2007– 2012 National Health and Nutrition Examination Survey (NHANES). Nine urinary PAHs were included in this study. Logistic regression and dose–response curves were used to evaluate the association between PAHs and the risk of kidney stones.Results: We selected 4385 participants. The dose–response curves showed a significant positive association between total PAHs, 2-hydroxynaphthalene, 1-hydroxyphenanthrene, 2-hydroxyphenanthrene, 9-hydroxyfluorene and the risk of kidney stones after adjusting for confounding factors. Compared with the low group, an increased risk of kidney stones was observed in the high group of total PAHs [OR (95% CI), 1.32 (1.06– 1.64), P=0.013], 2-hydroxynaphthalene [OR (95% CI), 1.37 (1.10– 1.71), P=0.005], 1-hydroxyphenanthrene [OR (95% CI), 1.24 (1.00– 1.54), P=0.046] and 9-hydroxyfluorene [OR (95% CI), 1.36 (1.09– 1.70), P=0.007].Conclusion: High levels of PAHs were positively associated with the risk of kidney stones in the US population.Keywords: polycyclic aromatic hydrocarbons, kidney stones, NHANES, cross-sectional survey

Zhenrui Xue,1– 3,* Minli You,2,3,* Ping Peng,1– 3,* Haoyang Tong,2,3 Wanghong He,2– 4 Ang Li,4 Ping Mao,1– 3 Ting Xu,1 Feng Xu,2,3 Chunyan Yao1 1Department of Transfusion Medicine, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, 400038, People’s Republic of China; 2The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, 710049, People’s Republic of China; 3Bioinspired Engineering and Biomechanics Center (BEBC), Xi’an Jiaotong University, Xi’an, 710049, People’s Republic of China; 4Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, 710049, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chunyan Yao; Feng XuDepartment of Transfusion Medicine, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, 400038, People’s Republic of ChinaTel +64 389 619 2922Email yao_yao24@yahoo.com; fengxu@mail.xjtu.edu.cnPurpose: Detection of single-base mutations is important for real-time monitoring of tumor progression, therapeutic effects, and drug resistance. However, the specific detection of single-base mutations from excessive wild-type background sequences with routine PCR technology remains challenging. Our objective is to develop a simple and highly specific qPCR-based single-base mutation detection method.Methods: Using EGRF T790M as a model, gold nanoparticles at different concentrations were separately added into the Taqman-MGB qPCR system to test specificity improvement, leading to the development of the optimal Taqman-MGB nanoPCR system. Then, these optimal conditions were used to test the range of improvement in the specificity of mutant-type and wild-type templates and the detection limit of mutation abundances in a spiked sample.Results: The Taqman-MGB nanoPCR was established based on the traditional qPCR, with significantly suppressed background noise and improved specificity for single-base mutation detection. With EGFR T790M as a template, we demonstrated that our Taqman-MGB nanoPCR system could improve specificity across a wide concentration range from 10− 9 μM to 10 μM and detect as low as 0.95% mutation abundance in spiked samples, which is lower than what the traditional Taqman-MGB qPCR and existing PCR methods can detect. Moreover, we also proposed an experimentally validated barrier hypothesis for the mechanism of improved specificity.Conclusion: The developed Taqman-MGB nanoPCR system could be a powerful tool for clinical single-base mutation detection.Keywords: nanoparticle-assisted PCR, point mutation, gold nanoparticle, specificity

Ling Huo,1,* Yao Tan,2,* Shu Wang,3 Cuizhi Geng,4 Yi Li,5 XiangJun Ma,6 Bin Wang,2 YingJian He,1 Chen Yao,2,7 Tao Ouyang1 1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Breast Center, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China; 2Department of Biostatistics, Peking University First Hospital, Beijing, People’s Republic of China; 3Department of Breast Center, Peking University People’s Hospital, Beijing, People’s Republic of China; 4The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 5Shunyi District Health Care Hospital for Women and Children of Beijing, Beijing, People’s Republic of China; 6Haidian Maternal and Child Health Hospital, Beijing, People’s Republic of China; 7Peking University Clinical Research Institute, Peking University Health Science Center, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chen YaoPeking University First Hospital, Xicheng District, Beijing, 100034, People’s Republic of ChinaTel +86 18610640562Email yaochen@hsc.pku.edu.cnTao OuyangPeking University Cancer Hospital & Institute, Haidian District, Beijing, 100142, People’s Republic of ChinaTel +86 010 88121122Email ouyanghongtao@263.netPurpose: This study aimed to establish and evaluate the usefulness of a simple, practical, and easy-to-promote machine learning model based on ultrasound imaging features for diagnosing breast cancer (BC).Materials and Methods: Logistic regression, random forest, extra trees, support vector, multilayer perceptron, and XG Boost models were developed. The modeling data set of 1345 cases was from a tertiary class A hospital in China. The external validation data set of 1965 cases were from 3 tertiary class A hospitals and 2 primary hospitals. The area under the receiver operating characteristic curve (AUC) was used as the main evaluation index, and pathological biopsy was used as the gold standard for evaluating each model. Diagnostic capability was also compared with that of clinicians.Results: Among the six models, the logistic model showed superior diagnostic efficiency, with an AUC of 0.771 and 0.906 and Brier scores of 0.181 and 0.165 in the test and validation sets, respectively. The AUCs of the clinician diagnosis and the logistic model were 0.913 and 0.906. Their AUCs in the tertiary class A hospitals were 0.915 and 0.915, respectively, and were 0.894 and 0.873 in primary hospitals, respectively.Conclusion: The externally validated logical model can be used to distinguish between malignant and benign breast lesions in ultrasound images. Compared with clinician diagnosis, the logistic model has better diagnostic efficiency, making it potentially useful to assist in screening, particularly in lower level medical institutions.Trial Registration: http://www.clinicaltrials.gov. ClinicalTrials.gov ID: NCT03080623.Keywords: breast cancer, machine learning, diagnostic accuracy, patient stratification, screening modalities, ultrasound imaging

Min Xu,1,2,* Chong Yao,3,* Wei Zhang,1 Shen Gao,1 Hao Zou,1 Jing Gao1,4 1School of Pharmacy, Second Military Medical University, Shanghai, 200433, People’s Republic of China; 2Department of Pharmacy, Changzheng Hospital, Shanghai, 200003, People’s Republic of China; 3Clinical Pharmacy Center, Department of Pharmacy, Chinese PLA General Hospital, Beijing, 100850, People’s Republic of China; 4State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jing Gao; Hao ZouSchool of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Yangpu District, Shanghai, People’s Republic of ChinaTel +86-10-6687-4665Email gjsmmu@126.com; haozou@smmu.edu.cnPurpose: Nanocarriers, with a high drug loading content and good safety, to achieve desirable therapeutic effect are always the goals for industry and research.Methods and Results: In the present study, we developed a docetaxel loaded poly-2-oxazoline polymer micellar system which employed poly-2-butyl-2 oxazoline and poly-2-methyl-2 oxazoline as the hydrophobic chain and hydrophilic chain, respectively. This micellar system achieves a high load up to 25% against the docetaxel, and further demonstrates an IC50 as low as 40% of the commercialized docetaxel injection in vitro and a double maximum tolerated dose in MCF-7 cells in vivo.Conclusion: The high drug loading content, superior safety, and considerable anti-cancer activity make this newly developed docetaxel loaded poly(2-oxazoline) micelle go further in future clinical research.Keywords: poly(2-oxazoline)s, micelle, docetaxel, high loading, anti-cancer activity

Qinchang Chen,1,2,* Qingui Chen,3,* Yanchen Ye,1,2 Ridong Wu,1,2 Shenming Wang,1,2 Chen Yao1,2 1Department of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China; 2National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China; 3Department of Medical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shenming Wang; Chen YaoDepartment of Vascular Surgery; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Road 2, Guangzhou, 510080, People’s Republic of ChinaEmail shenmingwang@hotmail.com; yaochen@mail.sysu.edu.cnObjective: To investigate the characteristics and prognosis of abdominal or thoracic aortic aneurysm (AAA or TAA) patients admitted to intensive care unit (ICU) postoperatively.Methods: Patients admitted to ICU postoperatively with a primary diagnosis of AAA or TAA were screened in the eICU Collaborative Research Database, which contained data from multiple ICUs throughout the continental United States in 2014 and 2015. Baseline characteristics and comorbidities and were investigated and factors associated with ICU mortality were explored using univariable logistic regression. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the prognosis predictive performance of the widely used severity scoring system APACHE IVa.Results: A total of 974 patients including 677 AAA and 297 TAA patients admitted to ICU postoperatively were included. Compared with TAA, AAA patients had a significantly higher median age (72 versus 64 years, P< 0.001). 89.07% AAA and 84.51% TAA patients underwent elective surgery (P=0.046), 8.71% AAA and 31.99% TAA patients were with aortic dissection (P< 0.001), and 10.19% AAA and 2.36% TAA patients suffered from rupture of aortic aneurysm (P< 0.001). Hypertension requiring treatment was the most common comorbidity (57.31% for AAA and 61.95% for TAA). TAA patients had significantly higher ICU mortality (9.43% versus 2.36%, P< 0.001) than AAA. Several factors were found to be significantly associated with ICU mortality, including urgent surgery, with aortic dissection, rupture of aortic aneurysm, TAA, and a higher APACHE IVa score on ICU admission. APACHE IVa showed a good predictive performance for ICU mortality with an area under the ROC curve of 0.9176 (95% CI 0.8789– 0.9390).Conclusion: The prognosis of aortic aneurysm patients admitted to ICU postoperatively is yet to improve, and factors associated with prognosis are mainly related to the condition itself. APACHE IVa can be used for prognosis prediction.Keywords: vascular surgery, intensive critical care, epidemiology

Bin Wang,1 Junkai Lai,1 Xiaoyan Yan,2 Feifei Jin,1 Bin Yi,3 Caixia An,3 Yuanxiao Li,4 Chen Yao1,2 1Department of Biostatistics, Peking University First Hospital, Beijing, People’s Republic of China; 2Peking University Clinical Research Institute, Beijing, People’s Republic of China; 3Children’s Emergency Center, Gansu Provincial Maternity and Child-Care Hospital, Lanzhou, People’s Republic of China; 4Department of Pediatric Gastroenterology, Second Hospital of Lanzhou University, Lanzhou, People’s Republic of ChinaCorrespondence: Chen YaoPeking University First Hospital, Xicheng District, Beijing 100034, People’s Republic of ChinaTel +86 18610640562Email yaochen@hsc.pku.edu.cnObjective: This study aims to comprehensively evaluate the characteristics of clinical drug trials to facilitate the collection of evidence for COVID-19 drug treatments.Methods: A retrospective analysis of 910 trials retrieved on August 7, 2020.Results: A total of 910 registered clinical trials with at least one drug intervention were evaluated. The number of registrations (32.4%, 295) from the United States accounted for nearly one-third of the total and far exceeded that of other countries individually. Furthermore, the peak number of trials were registered in April (34.3%, 312). Over half of the trials (51.2%, 466) are in the recruitment phase, and only 4.2% (38) of the trials have been completed. The median (interquartile range) estimated enrollment is 127 (59, 365). In 39% (355) of trials, the estimated enrollment is less than 100 participants. A total of 94.5% (790) of the trials use randomization in the allocation, 82.7% (753) use a parallel intervention mode, and 52.2% (475) use masking. A total of 287 drug names have been standardized and mapped. “Hydroxychloroquine” is the leading drug among the registered trials (7.47%, 68). Among the main countries contributing to investigations on “hydroxychloroquine”, the United States ranks first with 36.76% (25) of the trials.Conclusion: The designs of COVID-19 clinical drug trials have greatly improved in terms of the implementation of randomization and, particularly, blinding methods. In terms of drug reuse, the number of drug types has greatly increased, and hundreds of drugs have been used for efficacy screening. The emergence of large-sample registration trials is expected to address the uncertainty regarding the current clinical efficacy of some drugs.Keywords: COVID-19, clinical trials, investigation, intervention, drug, treatment

Hui Yang,1 Wei Sun,2 Pei Ma,1 Chunsuo Yao,1 Yannan Fan,1 Shuyi Li,1 Jiqiao Yuan,1 Ziqian Zhang,1 Xuyu Li,1 Mingbao Lin,1 Qi Hou1 1State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 2Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Mingbao Lin; Qi Hou Tel +86-10-63165192; +86-10-63165191Email mingbaolin@imm.cams.cn; houq@imm.ac.cnBackground: Perilla frutescens (L.) Britt., a classic medicinal plant, has been demonstrated to have anti-inflammatory and anti-allergic effects in asthma. Perilla leaves extract (PLE) exerted significant therapeutic effect against allergic asthma inflammation through Syk inhibition. But the active chemical ingredients from PLE are complex and unclear, it is difficult to fully elucidate its pharmacological mechanisms.Methods: A method was established for rapid screening and characterization of active ingredients from PLE that targeted Syk, with which three potential active ingredients were identified. By using OVA-induced allergic asthma mouse model in vivo, OVA-induced human PBMCs inflammation model and DNP-IgE/BSA-induced RBL-2H3 cells model in vitro, the effects and mechanisms of PLE and its active components were evaluated.Results: Using Syk-affinity screening method, roseoside (RosS), vicenin-2 (Vic-2) and rosmarinic acid (RosA) were identified from PLE. In vitro, PLE and its ingredients showed significant inhibitory activities against Syk, with their mixture (Mix, prepared by RosS, Vic-2 and RosA in accordance with their ratio in Syk-conjugated beads bound fraction) showing a stronger inhibitory activity. RosS, Vic-2 and RosA also showed significant effects on allergic asthma, and a synergistic effect of Mix was observed. Moreover, treatment with PLE, RosS, Vic-2, RosA, and Mix significantly inhibited the expression and phosphorylation of Syk, PKC, NF-κB p65, and cPLA2 in allergic mice lung tissue and in RBL-2H3 cells.Conclusion: PLE may alleviate allergic airway inflammation partly through the multiple components synergistic targeting on Syk and its downstream inflammatory pathway.Keywords: allergic airway inflammation, multi-component, PLE, Syk, synergistic effect

Lingxia Niu,1,* Chunlin Yao,1,* Yu Wang,1 Yan Sun,1 Juan Xu,2 Yun Lin,1 Shanglong Yao1 1Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, People’s Republic of China; 2School of Medicine and Health Management, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430022, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yun Lin; Shanglong YaoDepartment of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277# Jiefang Avenue, Wuhan 430022, Hubei, People’s Republic of ChinaTel +86 13986288403; +86 13886128437Fax +86 27 85726970Email franklinyun@hust.edu.cn; yaoshanglong@hust.edu.cnPurpose: This study examined whether different neuromuscular-blocking agents (NMBAs) work differently on the short-term outcomes of gastric cancer patients in terms of laboratory test results and severity of postoperative illness, and whether the effect is dose-related.Patients and Methods: Data of 1643 adult patients receiving gastric cancer surgery were analyzed by employing generalized linear models (GLMs), to explore the effects of different NMBAs on neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), lymphocyte–monocyte ratio (LMR) at postoperative day 1 (POD1), POD3, POD7, and return to intended oncologic therapy (RIOT), among others. We adjusted multiple covariants, including patient-, anesthesia-, and surgical complexity-related risk factors.Results: Without adjusting dosage of NMBAs, POD1NLR, POD1PLR (P < 0.05), POD3NLR, POD7NLR, POD3 lymphocytes, POD7LMR (P < 0.01) in gastric cancer patients administered with benzylisoquinoline NMBAs worsened, and the administration of aminosteroidal NMBAs was associated with less risk of transfer to ICU (P < 0.01); without adjusting the types of NMBAs, the highest dose of NMBAs postponed the RIOT (P < 0.05) and was negatively associated with POD3NLR, POD7NLR and POD7LMR (P < 0.01), and increased risk of postoperative transfer to ICU (P < 0.01). When patients given benzylisoquinolines were re-divided in terms of five equal quintiles, from low to high dose, RIOT was delayed and POD7LMR decreased significantly in the fourth and fifth quintile groups as compared to the first quintile group. A higher risk for postoperative transfer to ICU was found in the fifth quintile group as compared to the first quintile group.Conclusion: Patients with gastric cancer given benzylisoquinoline NMBAs had more unfavorable short-term outcomes, such as more severe inflammation and increased risk of transfer to ICU than their counterparts administered aminosteroidal NMBAs, and the effect of benzylisoquinolines was dose-related. The effect of aminosteroids on short-term outcomes was not dose-related in the dosage range we used.Keywords: neuromuscular-blocking agents, benzylisoquinoline, aminosteroid, short-term postoperative outcomes, gastric cancer surgery

Xiaoyan Sun, Lingzi Liu, Hui Zou, Caixia Yao, Zhengyu Yan, Baofen Ye Key Laboratory of Biomedical Functional Materials, School of Science, China Pharmaceutical University, Nanjing, Jiangsu 210009, People’s Republic of ChinaCorrespondence: Baofen YeKey Laboratory of Biomedical Functional Materials, School of Science, China Pharmaceutical University, Nanjing, Jiangsu 210009, People’s Republic of ChinaTel +86 13951725591Email baofen_ye@163.comBackground: Particle-based drug delivery systems (DDSs) have a demonstrated value for drug discovery and development. However, some problems remain to be solved, such as limited stimuli, visual-monitoring.Aim: To develop an intelligent multicolor DDSs with both near-infrared (NIR) controlled release and macroscopic color changes.Materials and Methods: Microparticles comprising GO/pNIPAM/PEGDA composite hydrogel inverse opal scaffolds, with dextran and calcium alginate hydrogel were synthesized using SCCBs as the template. The morphology of microparticle was observed under scanning electron microscopy, and FITC-dextran-derived green fluorescence images were determined using a confocal laser scanning microscope. During the drug release, FITC-dextran-derived green fluorescence images were captured using fluorescent inverted microscope. The relationship between the power of NIR and the drug release rate was obtained using the change in optical density (OD) values. Finally, the amount of drug released could be estimated quantitatively used the structural color or the reflection peak position.Results: A fixed concentration 8% (v/v) of PEGDA and 4mg/mL of GO was chosen as the optimal concentration based on the balance between appropriate volume shrinkage and structure color. The FITC-dextran was uniformly encapsulated in the particles by using 0.2 wt% sodium alginate. The microcarriers shrank because of the photothermal response and the intrinsic fluorescence intensity of FITC-dextran in the microparticles gradually decreased at the same time, indicating drug release. With an increasing duration of NIR irradiation, the microparticles gradually shrank, the reflection peak shifted toward blue and the structural color changed from red to orange, yellow, green, cyan, and blue successively. The drug release quantity can be predicted by the structural color of microparticles.Conclusion: The multicolor microparticles have great potential in drug delivery systems because of its vivid reporting color, excellent photothermal effect, and the good stimuli responsivity.Keywords: drug delivery, microparticles, color change, graphene oxide, photothermal effect

Liangshun You,1,* Cunying Yao,1,2,* Fan Yang,3 Qing Yang,4 Jianping Lan,5 Xiaolu Song,5 Jianping Shen,6 Xianfu Sheng,6 Xiaohui Chen,7 Huifen Tang,7 Huifang Jiang,8 Haiying Wu,8 Shenxian Qian,3 Haitao Meng1 1Department of Hematology, The First Affiliated Hospital of Medical School of Zhejiang University, Hangzhou, People’s Republic of China; 2Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 3Department of Hematology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Medical School of Zhejiang University, Hangzhou, People’s Republic of China; 5Department of Hematology, Zhejiang Provincial People’s Hospital, Hangzhou, People’s Republic of China; 6Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 7Department of Hematology, The Affiliated Hospital, Hangzhou Normal University, Hangzhou, People’s Republic of China; 8Department of Hematology, Tongde Hospital of Zhejiang Province, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haitao Meng; Shenxian Qian Email menghait2004@zju.edu.cn; sxqian@hotmail.comBackground: Candida tropicalis is the most common non-albicans Candida species identified in immunocompromised patients, which often appears with high mortality. However, data on the outcomes of treatment for Candida tropicalis fungemia in patients with neutropenia remain limited.Methods: In the present study, 90 neutropenic adult patients with proven Candida tropicalis fungemia, who received initial antifungal therapy, were retrospectively analyzed.Results: These results revealed that the overall 8-day and 30-day mortality among patients in the entire data set were 22.2% and 33.3%, respectively. However, there was no significant difference between the survival and death group, in terms of baseline characteristics. The univariate analysis of risk factors identified the treatment with azole as a predictor of mortality, while treatments that containing amphotericin B were associated with reduced mortality. In addition, the survival rate on day 30 was observed in 60.7% (17/28) of patients who were initially treated with echinocandins, while this was observed in 86.4% (19/22, P= 0.039) and 100% (13/13, P= 0.024) of patients treated with amphotericin B plus echinocandins and amphotericin B, respectively.Conclusion: These data indicate for the first time that the initial therapy with amphotericin B-based agents was associated with a better survival rate and could be assessed as the optimal strategy for the treatment of Candida tropicalis fungemia in patients with neutropenia.Keywords: Candida tropicalis, candidemia, hematological malignancy, neutropenia, amphotericin B, echinocandins

Lingling Li,1,2,* Qinchang Chen,1,* Qingui Chen,3 Ridong Wu,1 Shenming Wang,1 Chen Yao1 1Department of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 2Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People’s Republic of China; 3Department of Medical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shenming Wang; Chen YaoDepartment of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Road 2, Guangzhou, People’s Republic of ChinaEmail shenmingwang@hotmail.com; yaochen@mail.sysu.edu.cnPurpose: The aim of this study was to evaluate the association between blood glucose within 24 hours after intensive care unit (ICU) admission and prognosis.Patients and Methods: A retrospective cohort study was conducted using data from a large critical care database. Patients who had a length of ICU stay ≥ 24 hours and at least two blood glucose records within 24 hours after ICU admission were included and hospital mortality was chosen as the primary outcome. The average, minimum, and maximum blood glucose within 24 hours after ICU admission were a priori selected as exposures and associations between each exposure and outcomes were assessed after adjusted for potential confounders.Results: A total of 14,237 patients were included finally with an average age of 62.9± 17.7 years and a mean SAPS II on admission of 34 (26– 44). Among the study population, 20.2% (2872/14,237) had uncomplicated diabetes, and 6.7% (953/14,237) had complicated diabetes. Lowest hospital mortality rate was observed in the stratum with an average blood glucose ranged 110– 140 mg/dL, a minimum blood glucose ranged 80– 110 mg/dL, and a maximum blood glucose ranged 110– 140 mg/dL. After adjusted for confounders including age, sex, disease severity scores and comorbidities, an average blood glucose ranged 110– 140 mg/dL, a minimum blood glucose ranged 80– 110 mg/dL, and a maximum blood glucose ranged 110– 140 mg/dL were associated with the lowest risk of hospital mortality. Consistent results were found among patients without diabetes in the subgroup analyses stratified by diabetes.Conclusion: A range of 110– 140 mg/dL for average and maximum blood glucose and a range of 80– 110 mg/dL for minimum blood glucose within 24 hours after ICU admission predicted better prognosis especially among patients without diabetes.Keywords: blood glucose, critical care, mortality, retrospective studies

Ping Mao,1,2,* Ping Peng,1,* Zhiyong Liu,3 Zhenrui Xue,1 Chunyan Yao1 1Department of Transfusion Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, People’s Republic of China; 2Department of Clinical Laboratory, Sichuan Provincial Crops Hospital of Chinese People’s Armed Police Forces, Leshan, Sichuan, 614000, People’s Republic of China; 3Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chunyan YaoDepartment of Transfusion Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), No. 30 Gaotanyan Street, Chongqing 400038, People’s Republic of ChinaTel/Fax +86 23 6876 5475Email yao_yao24@yahoo.comBackground: Methicillin-resistant Staphylococcus aureus (MRSA) is a common pathogen of hospital infection with multi-drug resistant characteristics. Its spread and epidemic pose great challenges to nosocomial infection control. This study was aimed to identify risk factors for hospital-acquired MRSA (HA-MRSA) infections and investigate its clinical outcome, developing infection control strategies and improving patient outcomes.Methods: A retrospective case-case-control study was conducted to compare patients in Southwest Hospital, Chongqing, People’s Republic of China from January 2018 to December 2018 with control patients. In this study, 251 patients with MRSA nosocomial infection, 339 patients with methicillin-sensitive Staphylococcus aureus strains (MSSA) nosocomial infection, and 300 patients with non-Staphylococcus aureus infection were included.Results: Multivariate analysis showed that presence of central venous catheters (odds ratio [OR], 1.932; 95% confidence interval [CI], 1.074–3.477; P=0.028), sputum suction (OR, 2.887; 95% CI, 1.591–5.240; p

Qianling Lu,1,* Xinyu Dai,1,* Peng Zhang,1,* Xiao Tan,2 Yuejiao Zhong,3 Cheng Yao,4 Mei Song,4 Guili Song,4 Zhenghai Zhang,4 Gang Peng,5 Zhirui Guo,6 Yaoqi Ge,7 Kangzhen Zhang,7 Yuntao Li7 1Department of Neurology, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China; 2Department of Emergency, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China; 3Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China; 4Office of Academic Research, Kizilsu Kirghiz Autonomous Prefecture People’s Hospital, Atush, China; 5Department of Neurosurgery, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China; 6Department of Geratology, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China; 7Department of General Practice, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China *These authors contributed equally to this work Background: Thermoresponsive nanoparticles have become an attractive candidate for designing combined multimodal therapy strategies because of the onset of hyperthermia and their advantages in synergistic cancer treatment. In this paper, novel cetuximab (C225)-encapsulated core-shell Fe3O4@Au magnetic nanoparticles (Fe3O4@Au-C225 composite-targeted MNPs) were created and applied as a therapeutic nanocarrier to conduct targeted magneto-photothermal therapy against glioma cells. Methods: The core-shell Fe3O4@Au magnetic nanoparticles (MNPs) were prepared, and then C225 was further absorbed to synthesize Fe3O4@Au-C225 composite-targeted MNPs. Their morphology, mean particle size, zeta potential, optical property, magnetic property and thermal dynamic profiles were characterized. After that, the glioma-destructive effect of magnetic fluid hyperthermia (MFH) combined with near-infrared (NIR) hyperthermia mediated by Fe3O4@Au-C225 composite-targeted MNPs was evaluated through in vitro and in vivo experiments. Results: The inhibitory and apoptotic rates of Fe3O4@Au-C225 composite-targeted MNPs-mediated combined hyperthermia (MFH+NIR) group were significantly higher than other groups in vitro and the marked upregulation of caspase-3, caspase-8, and caspase-9 expression indicated excellent antitumor effect by inducing intrinsic apoptosis. Furthermore, Fe3O4@Au-C225 composite-targeted MNPs-mediated combined hyperthermia (MFH+NIR) group exhibited significant tumor growth suppression compared with other groups in vivo. Conclusion: Our studies illustrated that Fe3O4@Au-C225 composite-targeted MNPs have great potential as a promising nanoplatform for human glioma therapy and could be of great value in medical use in the future. Keywords: Fe3O4@Au-C225 composite-targeted magnetic nanoparticles, U251 cells, human glioma therapy, magnetic fluid hyperthermia, near-infrared hyperthermia

Haijun Shen,1 Fang Li,1 Dongxia Wang,1 Zhihan Yang,1 Chunfang Yao,1 Yang Ye,1 Xiaona Wang2 1Department of Preventive Medicine and Public Health Laboratory Science, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China; 2Department of Internal Medicine of Jiangsu University Hospital Workers, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, China Background and object: Polyelectrolyte microcapsule is a promising candidate for multifunctional drug delivery system. However, the lack of reports about animal experiments have greatly slowed down their development for drug delivery. We engineered biodegradable chitosan–alginate polyelectrolyte multilayer capsule filled with bovine serum albumin gel (BSA-gel-capsule). Herein, we demonstrated their applicability for local chemotherapy, a means of treating local or regional malignancies by direct administration of anti-tumor agents to tumor sites. Method: Doxorubicin (DOX) was loaded in BSA-gel-capsules and DOX-resistant cell line (MCF-7/ADR cells) was employed for antitumor studies in vitro. The cytotoxicity, cellular uptake and distribution of DOX from BSA-gel-capsules were studied. Afterwards, MCF-7/ADR xenografts tumor model was established in nude mice. The in vivo antitumor efficacy of DOX-loaded BSA-gel-capsules by intratumor injection was then evaluated. Result: Compared with free DOX, more effective cytotoxicity against MCF-7/ADR cells after treatment with DOX-loaded BSA-gel-capsules was revealed, demonstrating the positive reversal effect on drug-resistance. Thereafter, the more cellular uptake and nucleus distribution of DOX from BSA-gel-capsules in MCF-7/ADR cells provided convincing explanation for the reversal effect. DOX-loaded BSA-gel-capsules displayed remarkably more antitumor efficacy than free DOX in MCF-7/ADR cell-xenografted mice. Finally, the high DOX accumulation and prolonged retention in tumor site after local administration of DOX-loaded BSA-gel-capsules was demonstrated, displaying the unique advantages of BSA-gel-capsules for local chemotherapy. Conclusion: These findings indicate that DOX-loaded BSA-gel-capsules should be considered a potential candidate for the treatment of drug-resistant breast cancer. This paper provides a feasibility for the local chemotherapy of polyelectrolyte microcapsules, which will be a big step towards their application as drug delivery vehicles. Keywords: polyelectrolyte capsule, bovine serum albumin, layer-by-layer, pH-responsive, intratumor injection, multidrug resistance

Xiaoyu Wang,1,2* Zongguang Tai,1* Jing Tian,1* Wei Zhang,3 Chong Yao,1 Lijuan Zhang,1 Yuan Gao,1 Quangang Zhu,1 Jing Gao,4 Shen Gao1 1Department of Pharmaceutics, Changhai Hospital, Second Military Medical University, Shanghai, 2Department of Pharmaceutics, ChengDu Military General Hospital, ChengDu, 3Department of Pharmaceutics, Shanghai Pulmonary Hospital, Tongji University, Shanghai, 4Department of Pharmaceutical Science, School of Pharmacy, Second Military Medical University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Cationic oligopeptide as a nonviral gene delivery vector has aroused much research interest recently, but its further application is limited by its low transfection efficiency. In the present study, we have created a high-efficiency gene vector by using octa-d-arginine and tetra-l-histidine to form a disulfide cross-linked chimeric polypeptide and used this vector to deliver the therapeutic gene tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) to see whether the gene could be transferred and could exert antitumor effects in vitro and in vivo. The result showed that the newly designed vector was able to condense DNA into nanosized polyplexes effectively, thus facilitating its transmembrane transport, promoting its endosomal escape, and finally enabling degradation within the cell. Our study has demonstrated that this chimeric polypeptide is an effective gene carrier in cancer therapy. Keywords: reducible polypeptide, disulfide bond, octa-d-arginine, tetra-l-histidine, TRAIL

Chong Yao,1,* Zongguang Tai,1,* Xiaoyu Wang,1,* Jiyong Liu,1 Quangang Zhu,1,2 Xin Wu,3 Lijuan Zhang,1 Wei Zhang,4 Jing Tian,1 Yuan Gao,1 Shen Gao1 1Department of Pharmaceutics, Changhai Hospital, Second Military Medical University, 2Department of Pharmacy, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, 3Department of Pharmaceutics, Shanghai First People’s Hospital, Shanghai Jiaotong University School of Medicine, 4Department of Pharmaceutics, Shanghai Pulmonary Hospital, Shanghai Tongji University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Low efficiency and significant toxicity are the main obstacles to successful gene delivery. We have developed a cationic reduction-responsive vector based on a disulfide cross-linked stearylated polyarginine peptide modified with histidine (C-SHR) for DNA delivery. The structure of the C-SHR was characterized, and the in vitro and in vivo transfection efficiency and cytotoxicity of C-SHR/plasmid DNA complexes were examined. Compared with non-cross-linked stearylated polyarginine peptide (SHR), C-SHR increased the intracellular uptake and dissociation behavior of the complexes. In addition, the gene transfection efficiency of C-SHR/plasmid DNA complexes in HEK293 and HeLa cells was improved and was comparable with that of bPEI-25K/plasmid DNA complexes, and the cytotoxicity of C-SHR was significantly less than that of bPEI-25K. Importantly, the in vivo gene transfection efficiency of C-SHR/plasmid DNA complexes was five fold higher than that of SHR/plasmid DNA complexes, suggesting that C-SHR is an efficient non-viral vector for DNA delivery.Keywords: polyarginine, histidine, stearyl, reduction-responsive, peptide, DNA delivery

Xin Wu,1,2,* Zongguang Tai,1,* Quangang Zhu,3,* Wei Fan,4 Baoyue Ding,5 Wei Zhang,1,6 Lijuan Zhang,1 Chong Yao,1 Xiaoyu Wang,1 Xueying Ding,2 Qin Li,2 Xiaoyu Li,2 Gaolin Liu,2 Jiyong Liu,1 Shen Gao1 1Department of Pharmaceutics, Changhai Hospital, Second Military Medical University, 2Department of Pharmaceutics, Shanghai First People’s Hospital, Shanghai Jiaotong University School of Medicine, 3Department of Pharmaceutics, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 4Department of Pharmaceutics, The 425th Hospital of PLA, Sanya, People’s Republic of China; 5Department of Pharmaceutics, Medical College of Jiaxing University, Jiaxing, People’s Republic of China; 6Department of Pharmaceutics, The 522nd Hospital of PLA, Luoyang, People’s Republic of China *These authors contributed equally to this work Abstract: Ligand-mediated prostate cancer (PCa)-targeting gene delivery is one of the focuses of research in recent years. Our previous study reported the successful preparation of aptamer-modified nanoparticles (APT-NPs) in our laboratory and demonstrated their PCa-targeting ability in vitro. However, the mechanism underlying this PCa-targeting effect and their anticancer ability in vivo have not yet been elucidated. The objective of this study was to assess the feasibility of using APT-NPs to deliver micro RNA (miRNA) systemically to PCa cells, to testify their tumor-targeting efficiency, and to observe their biodistribution after systemic administration to a xenograft mouse model of PCa. In addition, the effect of APT depletion and endocytosis inhibitors on cellular uptake was also evaluated quantitatively in LNCaP cells to explore the internalization mechanism of APT-NPs. Finally, blood chemistry, and renal and liver function parameters were measured in the xenograft mouse model of PCa to see whether APT-NPs had any demonstrable toxicity in mice in vivo. The results showed that APT-NPs prolonged the survival duration of the PCa tumor-bearing mice as compared with the unmodified NPs. In addition, they had a potential PCa-targeting effect in vivo. In conclusion, this research provides a prototype for the safe and efficient delivery of miRNA expression vectors to PCa cells, which may prove useful for preclinical and clinical studies on the treatment of PCa. Keywords: miRNA, aptamer, polyamidoamine, prostate-specific membrane antigen, targeted delivery, prostate cancer

Chang Yao,1 Matt Hedrick,1 Gyan Pareek,2 Joseph Renzulli,2 George Haleblian,2 Thomas J Webster3 1Nanovis LLC, West Lafayette, IN, 2Section of Minimally Invasive Urology, Alpert Medical School, Brown University, Providence, RI, 3Department of Chemical Engineering and Program in Bioengineering, Northeastern University, Boston, MA, USA Abstract: Although showing much promise for numerous tissue engineering applications, polyurethane and poly-lactic-co-glycolic acid (PLGA) have suffered from a lack of cytocompatibility, sometimes leading to poor tissue integration. Nanotechnology (or the use of materials with surface features or constituent dimensions less than 100 nm in at least one direction) has started to transform currently implanted materials (such as polyurethane and PLGA) to promote tissue regeneration. This is because nanostructured surface features can be used to change medical device surface energy to alter initial protein adsorption events important for promoting tissue-forming cell functions. Thus, due to their altered surface energetics, the objective of the present in vivo study was to create nanoscale surface features on a new polyurethane and PLGA composite scaffold (by soaking the polyurethane side and PLGA side in HNO3 and NaOH, respectively) and determine bladder tissue regeneration using a minipig model. The novel nanostructured scaffolds were further functionalized with IKVAV and YIGSR peptides to improve cellular responses. Results provided the first evidence of increased in vivo bladder tissue regeneration when using a composite of nanostructured polyurethane and PLGA compared with control ileal segments. Due to additional surgery, extended potentially problematic healing times, metabolic complications, donor site morbidity, and sometimes limited availability, ileal segment repair of a bladder defect is not optimal and, thus, a synthetic analog is highly desirable. In summary, this study indicates significant promise for the use of nanostructured polyurethane and PLGA composites to increase bladder tissue repair for a wide range of regenerative medicine applications, such as regenerating bladder tissue after removal of cancerous tissue, disease, or other trauma. Keywords: polyurethane, poly-lactic-co-glycolic acid, nanotechnology, nanostructured features, in vivo

Xiaochao Qu,1,2,* Cuiping Yao,2,* Jing Wang,2 Zheng Li,2 Zhenxi Zhang,21Life Sciences Research Center, School of Life Sciences and Technology, Xidian University, Xi'an, Shaanxi, China; 2Key Laboratory of Biomedical Information Engineering of Education Ministry, Institute of Biomedical Analytical Technology and Instrumentation, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, China *These authors contributed equally to this workPurpose: Due to the efficient bioconjugation and highly photothermal effect, gold nanoparticles can stain receptor-overexpressing cancer cells through specific targeting of ligands to receptors, strongly absorb specific light and efficiently convert it into heat based on the property of surface plasmon resonance, and then induce the localized protein denaturation and cell death.Methods: Two gold nanoparticle–antibody conjugates, gold-BerH2 antibody (anti-CD30 receptor) and gold-ACT1 antibody (anti-CD25-receptor), were synthesized. Gold-BerH2 conjugates can specifically bind to the surface of L-428 Hodgkin's cells, and gold-ACT1 conjugates were used for the control. The gold nanoparticle-induced L-428 cell-killing experiments were implemented with different experimental parameters.Results: At a relatively low concentration of gold and short incubation time, the influence of cytotoxicity of gold on cell viability can be overlooked. Under laser irradiation at suitable power, the high killing efficiency of gold-targeted L-428 cells was achieved, but little damage was done to nontargeted cancer cells.Conclusion: Gold nanoparticle-mediated photothermal therapy provides a relatively safe therapeutic technique for cancer treatment.Keywords: gold nanoparticle–antibody conjugates, surface plasmon resonance, laser irradiation, selective destruction, photothermal treatment, cancer

Hao Xu, Chen Liu, Jiansheng Mei, Cuiping Yao, Sijia Wang, Jing Wang, Zheng Li, Zhenxi ZhangKey Laboratory of Biomedical Information Engineering of Education Ministry, Institute of Biomedical Analytical Technology and Instrumentation, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, Shannxi, People’s Republic of ChinaPurpose: As a precursor of the potent photosensitizer protoporphyrin IX (PpIX), 5-aminolevulinic acid (5-ALA), was conjugated onto cationic gold nanoparticles (GNPs) to improve the efficacy of photodynamic therapy (PDT).Methods: Cationic GNPs reduced by branched polyethyleneimine and 5-ALA were conjugated onto the cationic GNPs by creating an electrostatic interaction at physiological pH. The efficacy of ALA-GNP conjugates in PDT was investigated under irradiation with a mercury lamp (central wavelength of 395 nm) and three types of light-emitting diode arrays (central wavelengths of 399, 502, and 621 nm, respectively). The impacts of GNPs on PDT were then analyzed by measuring the intracellular PpIX levels in K562 cells and the singlet oxygen yield of PpIX under irradiation.Results: The 2 mM ALA-GNP conjugates showed greater cytotoxicity against K562 cells than ALA alone. Light-emitting diode (505 nm) irradiation of the conjugates caused a level of K562 cell destruction similar to that with irradiation by a mercury lamp, although it had no adverse effects on drug-free control cells. These results may be attributed to the singlet oxygen yield of PpIX, which can be enhanced by GNPs.Conclusion: Under irradiation with a suitable light source, ALA-GNP conjugates can effectively destroy K562 cells. The technique offers a new strategy of PDT.Keywords: nonradiative energy transfer, photodamage, protoporphyrin IX, selective destruction, singlet oxygen sensor green reagent, surface plasmon resonance

ErratumQu X, Yao C, Wang J, Li Z, Zhang Z. International Journal of Nanomedicine. 2012;7:6095–6103. The caption for Figure 4 was incorrect in the published paper. The correct Figure 4 caption is as follows:Figure 4 Photothermal treatments of L-428 cells with gold-BerH2 conjugates. (A) Without laser irradiation; (B) with 532 nm laser irradiation with 50 mW, 5 pulses.Read the original article

Aninwene II GE, Yao C, Webster TJ. Enhanced osteoblast adhesion to drug-coated anodized nanotubular titanium surfaces. Int J Nanomedicine. 2008;3(2):257–264.There is a mistake in the Drug coating section of the Materials and methods. In the paper it is written as follows:“For simple physical adsorption, 120 μL of either penicillin/streptomycin (Hyclone, Logan, UT, USA; 5 μg/mL) or dexamethasone (Sigma, St. Louis, MO, USA; 5 μg/mL) solutions were placed onto each unanodized or anodized titanium for 3 days at room temperature.”But the text should be written as:“For simple physical adsorption, 120 μL of either penicillin/streptomycin (Hyclone, Logan, UT, USA; 6.25 mg penicillin and 10 mg streptomycin per mL) or dexamethasone (Sigma, St. Louis, MO, USA; 5 mg/mL) solutions were placed onto each unanodized or anodized titanium for 3 days at room temperature.”Read the original article

Ling Jin,1,2,&ast; Kai Fan,1,2,&ast; Chunyan Yao,1,&ast; Yongjun Chang,1 Yang Wang,1 Jiawei Lu,1 Shaoqing Yu1,2 1Department of Otolaryngology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, People’s Republic of China; 2Department of Allergy,Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shaoqing Yu, Department of Otolaryngology, Tongji Hospital, School of Medicine, Tongji University, 389 Xincun Road, Putuo District, Shanghai, 200065, People’s Republic of China, Tel/Fax +8602166111042, Email yu_shaoqing@163.comPurpose: The treatment of chronic rhinosinusitis (CRS) is often a difficult and long-term behavior, so it is necessary to seek a local treatment method that can be used for a long time, and is safe and effective. Nasal saline irrigation after functional endoscopic sinus surgery (FESS) is currently recognized as a local treatment method, but it has no anti-inflammatory, anti-damage, and healing-promoting functions. To investigate the efficacy and safety of hydrogen-rich saline (HRS) for nasal irrigation after CRS surgery.Patients and Methods: A total of 61 patients after CRS completed the study. Subjects were randomly assigned to rinse the nasal cavity with HRS or normal saline (NS) after CRS. Participants were followed up once a week for 12 times, and were evaluated with visual analogue score (VAS), 22-item Sinonasal Outcomes Test (SNOT-22), and Lund-Kennedy endoscopy scores (LKES). The primary outcome was the VAS score of patients.Results: After 12 weeks of follow-up, the VAS scores of both groups decreased, and the HRS group (0.52± 0.85) was lower than the NS group (1.47± 1.55), P=0.005. The total number of cases with complete control (clinical cure) in the short-term efficacy evaluation was more in the HRS group (20/31) than in the NS group (11/30), P=0.03< 0.05. No obvious adverse reactions occurred in the two groups during the follow-up.Conclusion: This study found that HRS was more effective than NS alone in nasal irrigation after CRS surgery, and could shorten the time of nasal mucosal healing and epithelialization, with a higher rate of recent complete control.Keywords: physiological saline, hydrogen -rich saline, nasal irrigation, chronic rhinosinusitis, endoscopic sinus surgery

Wen-Jia Li,1,&ast; Chen Yao,2,&ast; Lu Han,1 Ji-Hong Zhou,1 Rui-Ming Pang2 1Department of Pulmonary and Critical Care Medicine, Shenzhen Bao’an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen City, People’s Republic of China; 2Department of Orthopedics and Traumatology, Shenzhen Bao’an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen City, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ji-Hong Zhou, Department of Pulmonary and Critical Care Medicine, Shenzhen Bao’an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen City, People’s Republic of China, Email zjh14569@163.com Rui-Ming Pang, Department of Orthopedics and Traumatology, Shenzhen Bao’an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen City, People’s Republic of China, Email prm1757607@163.comBackground: The associations between gut microbiota and chronic obstructive pulmonary disease (COPD) have gained increasing attention and research interest among scholars. However, it remains unclear whether gut microbiota serves as a causal factor for COPD or if it is a consequence of the disease. Therefore, we investigated the causal relationship between COPD and gut microbiota, with intention of providing novel insights and references for clinical diagnosis and treatment.Methods: Based on the genome-wide association study (GWAS) data, we employed MR-Egger regression, random-effects inverse variance-weighted (IVW) method, and weighted median method for bidirectional Mendelian randomization (MR) analysis. We conducted Cochran’s Q test for heterogeneity assessment and performed multivariable analysis, sensitivity analysis, and heterogeneity testing to validate the reliability and stability of results.Results: Utilizing MR analysis, mainly employing the IVW method, we detected a collective of 11 gut microbiota species that exhibited associations with COPD. Among them, Bacteroidia, family XIII, Clostridium innocuum group, Barnesiella, Collinsella, Lachnospiraceae NK4A136 group, Lachnospiraceae UCG004, Lachnospiraceae UCG010, and Bacteroidales were found to be protective factors for COPD. On the other hand, Holdemanella and Marvinbryantia were identified as risk factors for COPD. Individuals with elevated levels of Holdemanella exhibited a 1.141-fold higher risk of developing COPD compared to their healthy counterparts, and those with increased levels of Marvinbryantia had a 1.154-fold higher risk. Reverse MR analysis yielded no evidence indicating a causal relationship between gut microbiota and COPD occurrence.Conclusion: Our study established a causal link between 11 specific gut microbiota species and COPD, offering novel insights and valuable references for targeted therapies in the clinical management of COPD. However, our results were mainly based on the analysis of database, and further clinical studies are needed to clarify the effects of gut microbiota on COPD and its specific protective mechanism.Keywords: gut microbiota, COPD, bidirectional MR, causal, association

Jiong Li,1 Dongqin Lei,1 Yanbing Cao,2,3 Fuli Xin,2,3 Zhenxi Zhang,1 Xiaolong Liu,2,3 Ming Wu,2,3 Cuiping Yao1 1Key Laboratory of Biomedical Information Engineering of Ministry of Education, Institute of Biomedical Photonics and Sensing, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, 710049, 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, 350025, People’s Republic of China; 3Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, People’s Republic of ChinaCorrespondence: Ming Wu, Mengchao Hepatobiliary Hospital of Fujian Medical University, 312 Xi Hong Road, Fuzhou, 350025, People’s Republic of China, Email wmmj0419@163.com Cuiping Yao, School of Life Science and Technology, Xi’an Jiaotong University, 28 Xian Ning West Road, Xi’an, 710049, People’s Republic of China, Email zsycp@xjtu.edu.cnIntroduction: Photodynamic therapy (PDT) has attracted increasing attention in the clinical treatment of epidermal and luminal tumors. However, the PDT efficacy in practice is severely impeded by tumor hypoxia and the adverse factors associated with hydrophobic photosensitizers (PSs), including low delivery capacity, poor photoactivity and limited ROS diffusion. In this study, Pt nanozymes decorated two-dimensional (2D) porphyrin metal-organic framework (MOF) nanosheets (PMOF@HA) were fabricated and investigated to conquer the obstacles of PDT against hypoxic tumors.Materials and Methods: PMOF@HA was synthesized by the coordination of transition metal iron (Zr4+) and PS (TCPP), in situ generation of Pt nanozyme and surface modification with hyaluronic acid (HA). The abilities of hypoxic relief and ROS generation were evaluated by detecting the changes of O2 and 1O2 concentration. The cellular uptake was investigated using flow cytometry and confocal laser scanning microscopy. The SMMC-7721 cells and the subcutaneous tumor-bearing mice were used to demonstrate the PDT efficacy of PMOF@HA in vitro and in vivo, respectively.Results: Benefiting from the 2D structure and inherent properties of MOF materials, the prepared PMOF@HA could not only serve as nano-PS with high PS loading but also ensure the rational distance between PS molecules to avoid aggregation-induced quenching, enhance the photosensitive activity and promote the rapid diffusion of generated radical oxide species (ROS). Meanwhile, Pt nanozymes with catalase-like activity effectively catalyzed intratumoral overproduced H2O2 into O2 to alleviate tumor hypoxia. Additionally, PMOF@HA, with the help of externally coated HA, significantly improved the stability and increased the cell uptake by CD44 overexpressed tumor cells to strengthen O2 self-supply and PDT efficacy.Conclusion: This study provided a new strategy of integrating 2D porphyrin MOF nanosheets with nanozymes to conquer the obstacles of PDT against hypoxic tumors.Keywords: 2D porphyrin MOF, hypoxic relief, Pt nanozyme, photodynamic therapy

Lu Zhang,1– 3,&ast; Fei Teng,1,2,&ast; Huajie Xin,1,2 Wei Xu,1,2 Wei Wu,4 Chenguo Yao,3 Zhiqiang Wang1,2 1Key Laboratory for Biorheological Science and Technology of Ministry of Education (Chongqing University), Chongqing University Cancer Hospital, Chongqing, 400030, People’s Republic of China; 2Center of Thoracic Cancer, Chongqing University Cancer Hospital, Chongqing, 400030, People’s Republic of China; 3The State Key Laboratory of Power Transmission Equipment and System Security and New Technology, College of Electrical Engineering, Chongqing University, Chongqing, 400044, People’s Republic of China; 4College of Biological Engineering, Chongqing University, Chongqing, 400030, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lu Zhang; Zhiqiang Wang, Chongqing University Cancer Hospital, No. 181 Hanyu Road, Shapingba District, Chongqing, 400030, People’s Republic of China, Email luzhang_524@aliyun.com; zhiqiangwang@21cn.comAbstract: Patients diagnosed with glioma typically face a limited life expectancy (around 15 months on average), a bleak prognosis, and a high likelihood of recurrence. As such, glioma is recognized as a significant form of malignancy. Presently, the treatment options for glioma include traditional approaches such as surgery, chemotherapy, and radiotherapy. Regrettably, the efficacy of these treatments has been less than optimal. Nevertheless, a promising development in glioma treatment lies in the use of hydrogel nano-systems as sophisticated delivery systems. These nano-systems have demonstrated exceptional therapeutic effects in the treatment of glioma by various responsive ways, including temperature-response, pH-response, liposome-response, ROS-response, light-response, and enzyme-response. This study seeks to provide a comprehensive summary of both the therapeutic application of hydrogel nano-systems in managing glioma and the underlying immune action mechanisms. Keywords: glioma, hydrogel nano-system, immunotherapy, tumor immune microenvironment

Yueda Jihu,1,2,&ast; Ruobing Leng,1,&ast; Mengchang Liu,1,2 Hongjing Ren,1,2 Defu Xie,1,2 Chong Yao,1,2 Hong Yan1,2 1Clinical College of Medicine, Southwest Medical University, Lu zhou, People’s Republic of China; 2Department of Plastic and Burn Surgery, the Affiliated Hospital of Southwest Medical University, Lu zhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hong Yan, Email zxsswk@163.comIntroduction: Angiotensin (1– 7) (Ang-(1-7)) is an emerging component of the renin-angiotensin system (RAS) with effective anti-fibrosis properties and has been shown to interfere with epithelial-mesenchymal transition (EMT) by numerous studies. In recent years, EMT has been proposed as a new therapeutic target for skin fibrotic diseases such as keloids. However, the effect of Ang-(1-7) on EMT in skin is still unclear. Hence, the purpose of this study was to explore the effect of Ang-(1-7) on Transforming growth factor-β 1(TGF-β 1)–induced EMT of human immortalized keratinocytes HaCaT in vitro.Methods: The study involved the use of the human immortalized keratinocyte cell line (HaCaT). The cells were cultured in high-glucose DMEM medium with 10% fetal bovine serum and 1% penicillin-streptomycin. Four groups were created for experimentation: control group (Group C), TGF-β 1-treated group (Group T), Ang-(1-7)-treated group (Group A), and a group treated with both TGF-β 1 and Ang-(1-7) (Group A + T). Various assays were conducted, including a cell proliferation assay using CCK-8 solution, a scratch wound healing assay to evaluate cell migration, and Western blotting to detect protein expressions related to cell characteristics. Additionally, quantitative real-time polymerase chain reaction (PCR) was performed to analyze epithelial-mesenchymal transition (EMT) related gene expression levels. The study aimed to investigate the effects of TGF-β 1 and Ang-(1-7) on HaCaT cells.Results: We found that Ang-(1-7) not only reduced the migration of HaCaT cells induced by TGF-β 1 in vitro but also reduced the expression of α-SMA and vimentin, and restored the protein expression of E-cadherin and claudin-1. Mechanistically, Ang-(1-7) inhibits the phosphorylation levels of Smad2 and Smad3 in the TGF-β 1 canonical pathway, and suppresses the expression of EMT-related transcription factors (EMT-TFs) such as SNAI2, TWIST1, and ZEB1.Discussion: Taken together, our findings suggest that Ang-(1-7) inhibits TGF-β 1–induced EMT in HaCaT cells in vitro by disrupting the TGF-β 1-Smad canonical signaling pathway. These results may be helpful in the treatment of EMT in skin fibrotic diseases such as keloids.Keywords: angiotensin (1-7), epithelial-mesenchymal transition, transforming growth factor-β, keratinocytes

Guiyun Zhang,1 Yufeng Lu,2 Lin Qi,1 Chunli Yao1 1Department of Dermatology, The Second Hospital of Jilin University, Changchun, 130041, People’s Republic of China; 2Department of Thoracic Surgery, Sino-Japanese Friendship Hospital of Jilin University, Changchun, 130012, People’s Republic of ChinaCorrespondence: Chunli Yao, Department of Dermatology, The Second Hospital of Jilin University, Changchun, 130041, People’s Republic of China, Tel +86-431-81136244, Email ycl@jlu.edu.cnIntroduction: Rare studies have reported pilomatricoma in twins, and extremely rare cases showed lesions in the same part of the body position. We reported a case of monozygotic twins with pilomatricoma in the same location on the skin of the right upper extremity.Case Presentation: Seven-year-old monozygotic twins presented to our department with a palpable, painless, and solid mass in the subcutaneous tissue of the right upper limb. A 1.5-cm diameter nodule was seen on the anterolateral aspect of the right upper extremity of the twins. The node was irregular in shape, and upon palpation, the patients reported no noticeable tenderness. Following the administration of local anesthesia, the twins underwent surgical procedure to excise the solid mass. Finally, they were diagnosed with pilomatricoma based on the clinical and histopathological features. Complete surgical resection followed by primary closure was performed. During a follow-up period of three years, there has been no recurrence observed in the twins.Conclusion: We reported a case of monozygotic twins with pilomatricoma in the same location on the skin of the right upper arm. Our findings underscore the requirement of considering genetic factors in the diagnosis and treatment of the rare conditions.Keywords: pilomatricoma, pilomatrixoma, calcifying epithelioma of malherbe, case report

Changyu Yao,&ast; Jian Kong,&ast; Fei Xu, Shaohong Wang, Shilun Wu, Wenbing Sun, Jun Gao Department of Hepatobiliary Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100043, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenbing Sun; Jun Gao, Department of Hepatobiliary Surgery, Beijing Chao-Yang Hospital, Capital Medical University, No. 5 Jingyuan Road, Shijingshan District, Beijing, 100043, People’s Republic of China, Tel +86-010-51718382, Fax +86-010-51718372, Email sunwenbing@bjcyh.com; gaojun8430@163.comPurpose: Systemic inflammatory response syndrome (SIRS) is a common complication of radiofrequency ablation (RFA) for hepatic hemangiomas. RFA can cause hemolytic reactions during hepatic hemangioma ablation. However, the mechanisms underlying RFA-induced SIRS remain unclear.Methods: We established an orthotopic liver hemangioma model and performed radiofrequency ablation. The levels of interleukin (IL)-1β and IL-18 and the production of ROS were measured. The wet-to-dry lung ratio, inflammation score, and in vivo endothelial cell permeability were examined. GSDMD−/− mice were used to investigate the effect of heme-inducing SIRS. RNA sequencing (RNA-seq) was performed to identify the main pathways underlying heme-induced SIRS. Western blotting and immunoprecipitation were used to determine the changes and interactions of associated proteins.Results: The levels of heme, IL-1β, and IL-18 were significantly increased after RFA. The wet-to-dry lung ratio increased in hepatic hemangiomas after RFA, indicating that SIRS occurred. Heme induced increased levels of IL-1β and IL-18, cell death, wet-to-dry lung radio, and inflammation score in vitro and in vivo, indicating that heme induced SIRS and pyroptosis. Furthermore, GSDMD participates in heme-induced SIRS in mice, and GSDMD deletion in mice reverses the effect of heme. Heme regulates NLRP3 activation through the NOX4/ROS/TXNIP-TRX pathway, and an N-acetyl-L-cysteine (NAC) or NOX4 inhibitor (GLX351322) reverses heme-induced SIRS.Conclusion: Our findings suggest that heme induces endothelial cell pyroptosis and SIRS in mice and decreasing heme levels and ROS scavengers may prevent SIRS in hepatic hemangioma after RFA. Keywords: hemangioma, radiofrequency ablation, systemic inflammatory response syndrome, pyroptosis, endothelial cells

Introduction: Angiotensin (1-7) (Ang-(1-7)) is an emerging component of the renin-angiotensin system (RAS) with effective anti-fibrosis properties and has been shown to interfere with epithelial-mesenchymal transition (EMT) by numerous studies. In recent years, EMT has been proposed as a new therapeutic target for skin fibrotic diseases such as keloids. However, the effect of Ang-(1-7) on EMT in skin is still unclear. Hence, the purpose of this study was to explore the effect of Ang-(1-7) on Transforming growth factor-β1(TGF-β1)-induced EMT of human immortalized keratinocytes HaCaT in vitro., Methods: The study involved the use of the human immortalized keratinocyte cell line (HaCaT). The cells were cultured in high-glucose DMEM medium with 10% fetal bovine serum and 1% penicillin-streptomycin. Four groups were created for experimentation: control group (Group C), TGF-β1-treated group (Group T), Ang-(1-7)-treated group (Group A), and a group treated with both TGF-β1 and Ang-(1-7) (Group A + T). Various assays were conducted, including a cell proliferation assay using CCK-8 solution, a scratch wound healing assay to evaluate cell migration, and Western blotting to detect protein expressions related to cell characteristics. Additionally, quantitative real-time polymerase chain reaction (PCR) was performed to analyze epithelial-mesenchymal transition (EMT) related gene expression levels. The study aimed to investigate the effects of TGF-β1 and Ang-(1-7) on HaCaT cells., Results: We found that Ang-(1-7) not only reduced the migration of HaCaT cells induced by TGF-β1 in vitro but also reduced the expression of α-SMA and vimentin, and restored the protein expression of E-cadherin and claudin-1. Mechanistically, Ang-(1-7) inhibits the phosphorylation levels of Smad2 and Smad3 in the TGF-β1 canonical pathway, and suppresses the expression of EMT-related transcription factors (EMT-TFs) such as SNAI2, TWIST1, and ZEB1., Discussion: Taken together, our findings suggest that Ang-(1-7) inhibits TGF-β1-induced EMT in HaCaT cells in vitro by disrupting the TGF-β1-Smad canonical signaling pathway. These results may be helpful in the treatment of EMT in skin fibrotic diseases such as keloids., Competing Interests: The authors have stated explicitly that there are no conflicts of interest in connection with this article., (© 2024 Jihu et al.)

Introduction: We assessed the effect of Mycobacterium tuberculosis (MTB) bacterial load on Xpert MTB/RIF accuracy for detection of rifampicin (RIF)-resistant MTB in bronchoalveolar lavage fluid (BALF) specimens obtained at a national tuberculosis (TB) specialized hospital in Beijing, China., Methods: A retrospective study was conducted at Beijing Chest Hospital. Patients with symptoms suggestive of pulmonary TB who provided BALF specimens for routine MTB detection between June 2019 and July 2020 were enrolled in the study. Chi-square test and Student's t -test were used to compare results across groups stratified according to BALF bacterial load., Results: In total, 1125 patients with positive Xpert results who were enrolled in final analysis, 263 provided BALF specimens that tested positive for RIF-resistant MTB via Xpert MTB/RIF. The RIF-resistance rate of specimens with very low MTB bacterial load was 30.9%, a resistance rate significantly greater than rates obtained for groups with high (25.0%), medium (17.3%) and low (19.2%) MTB loads ( P <0.01). Notably, false-positive results obtained for the very low bacterial load group led to markedly reduced positive predictive value of Xpert MTB/RIF to provide correct RIF-resistance predictions for that group (67.1%, 95% CI: 56.1%-78.1%5) relative to the predictive value obtained for all other groups combined (about 90%, P <0.05). Sanger sequencing data obtained for 20 (32.8%) MTB isolates deemed RIF-resistant via Xpert (Probe E) lacked rpoB RRDR mutations. Meanwhile, of another group of 23 isolates deemed RIF-susceptible via DST but RIF-resistant via Xpert MTB/RIF, 20 isolate sequences (87.0%) lacked rpoB RRDR mutations, while sequences of the remaining 3 isolates harbored single rpoB RRDR mutations predicted to cause amino acid substitutions., Conclusion: Xpert MTB/RIF assay performed alarmingly poorly when used to detect RIF-resistant MTB in BALF specimens with very low bacterial loads. A high rate of Xpert probe E hybridization failure was the main driver of false-positive RIF-resistant results., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Qin et al.)

Background: Thermoresponsive nanoparticles have become an attractive candidate for designing combined multimodal therapy strategies because of the onset of hyperthermia and their advantages in synergistic cancer treatment. In this paper, novel cetuximab (C225)-encapsulated core-shell Fe 3 O 4 @Au magnetic nanoparticles (Fe 3 O 4 @Au-C225 composite-targeted MNPs) were created and applied as a therapeutic nanocarrier to conduct targeted magneto-photothermal therapy against glioma cells., Methods: The core-shell Fe 3 O 4 @Au magnetic nanoparticles (MNPs) were prepared, and then C225 was further absorbed to synthesize Fe 3 O 4 @Au-C225 composite-targeted MNPs. Their morphology, mean particle size, zeta potential, optical property, magnetic property and thermal dynamic profiles were characterized. After that, the glioma-destructive effect of magnetic fluid hyperthermia (MFH) combined with near-infrared (NIR) hyperthermia mediated by Fe 3 O 4 @Au-C225 composite-targeted MNPs was evaluated through in vitro and in vivo experiments., Results: The inhibitory and apoptotic rates of Fe 3 O 4 @Au-C225 composite-targeted MNPs-mediated combined hyperthermia (MFH+NIR) group were significantly higher than other groups in vitro and the marked upregulation of caspase-3, caspase-8, and caspase-9 expression indicated excellent antitumor effect by inducing intrinsic apoptosis. Furthermore, Fe 3 O 4 @Au-C225 composite-targeted MNPs-mediated combined hyperthermia (MFH+NIR) group exhibited significant tumor growth suppression compared with other groups in vivo., Conclusion: Our studies illustrated that Fe 3 O 4 @Au-C225 composite-targeted MNPs have great potential as a promising nanoplatform for human glioma therapy and could be of great value in medical use in the future., Competing Interests: Disclosure The authors declare no conflicts of interest in this work.

Purpose: Plasmonic nanostructure-mediated photothermal therapy (PTT) is a promising alternative therapy for the treatment of skin cancer and other diseases. However, the insufficient efficiency of PTT at irradiation levels tolerable to tissues and the limited biodegradability of nanomaterials are still crucial challenges. In this study, a novel nanosystem for PTT based on liposome-nanoparticle assemblies (LNAs) was established., Materials and Methods: Thermal-sensitive liposomes (TSLs) encapsulating cantharidin (CTD) were coated with gold nanoparticles (GNPs) and used in near-infrared (NIR) illumination-triggered PTT and thermally induced disruption on A431 cells., Results: The coated GNPs disintegrated into small particles of 5-6 nm after disruption of TSLs, allowing their clearance by the liver and kidneys. CTD encapsulated in the TSLs was released into cytoplasm after PTT. The released CTD increased the apoptosis of PTT-treated tumor cells by blocking the heat shock response (HSR) and inhibiting the expression of HSP70 and BAG3 inhibiting the expression of HSP70 and BAG3 with the synergistic enhancement of CTD, the new nanosystem CTD-encapsulated TSLs coated with GNPs (CTD-TSL@GNPs) had an efficient PTT effect using clinically acceptable irradiation power (200 mW//cm 2 ) on A431 cells., Conclusion: The developed CTD-TSL@GNPs may be a promising PTT agent for clinical skin cancer therapy., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Purpose: As a promising photodynamic therapy (PDT) agent, Al(III) phthalocyanine chloride tetrasulfonic acid (AlPcS 4 ) provides deep penetration into tissue, high quantum yields, good photostability, and low photobleaching. However, its low delivery efficiency and high binding affinity to serum albumin cause its low penetration into cancer cells, further limiting its PDT effect on gastric cancer. In order to improve AlPcS 4 /PDT effect, the AlPcS 4 delivery sys tems with different drug carriers were synthesized and investigated., Materials and Methods: Gold nanorods, cationic liposomes, and Pluronic ® F127 nanomicellars were used to formulate the AlPcS 4 delivery systems. The anticancer effect was evaluated by CCK-8 assay and colony formation assay. The delivery efficiency of AlPcS 4 and the binding affinity to serum proteins were determined by fluorescence intensity assay. The apoptosis and necrosis ability, reactive oxygen species and singlet oxygen generation, mitochondrial transmembrane potential and ([Ca 2+ ] i ) concentration were further measured to evaluate the mechanism of cell death., Results: The series of synthesized AlPcS 4 delivery systems with different drug carriers improve the limited PDT effect in varying degrees. In contrast, AlPcS 4 complex with gold nanorods has significant anticancer effects because gold nanorods are not only suitable for AlPcS 4 delivery, but also exhibit enhanced singlet oxygen generation effect and photothermal effect to induce cell death directly. Moreover, AlPcS 4 complex with cationic liposomes shows the potent inhibition effect because of its optimal AlPcS 4 delivery efficiency and ability to block serum albumin. In addition, AlPcS 4 complex with Pluronic F127 exhibits inferior PDT effect but presents lower cytotoxicity, slower dissociation rate, and longer retention time of incorporated drugs; thus, F127-AlPcS 4 is used for prolonged gastric cancer therapy., Conclusion: The described AlPcS 4 drug delivery systems provide promising agents for gastric cancer therapy., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Purpose: Pulsed-laser irradiation of light-absorbing gold nanoparticles (AuNPs) attached to cells transiently increases cell membrane permeability for targeted molecule delivery. Here, we targeted EGFR on the ovarian carcinoma cell line OVCAR-3 with AuNPs. In order to optimize membrane permeability and to demonstrate molecule delivery into adherent OVCAR-3 cells, we systematically investigated different experimental conditions., Materials and Methods: AuNPs (30 nm) were functionalized by conjugation of the antibody cetuximab against EGFR. Selective binding of the particles was demonstrated by silver staining, multiphoton imaging, and fluorescence-lifetime imaging. After laser irradiation, membrane permeability of OVCAR-3 cells was studied under different conditions of AuNP concentration, cell-incubation medium, and cell-AuNP incubation time. Membrane permeability and cell viability were evaluated by flow cytometry, measuring propidium iodide and fluorescein isothiocyanate-dextran uptake., Results: Adherently growing OVCAR-3 cells can be effectively targeted with EGFR-AuNP. Laser irradiation led to successful permeabilization, and 150 kDa dextran was successfully delivered into cells with about 70% efficiency., Conclusion: Antibody-targeted and laser-irradiated AuNPs can be used to deliver molecules into adherent cells. Efficacy depends not only on laser parameters but also on AuNP:cell ratio, cell-incubation medium, and cell-AuNP incubation time., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background and Objectives: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is one of the leading causes of hospitalization and is associated with considerable mortality, for which clinicians are seeking useful and easily obtained biomarkers for prognostic evaluation. This study aimed to determine the potential role of the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) as prognostic makers for hospital mortality in patients with AECOPD., Methods: We included 303 patients with AECOPD in this retrospective study. Clinical characteristics, NLR, PLR, and serum levels of C-reactive protein (CRP) and other data were collected. Relationships between NLR/PLR and CRP were evaluated by Pearson's correlation test. Receiver operating characteristics curve and the area under the curve (AUC) were used to assess the ability of NLR and PLR to predict hospital mortality in patients with AECOPD., Results: Mean levels of NLR and PLR of all patients with AECOPD were 7.92±8.79 and 207.21±148.47, respectively. NLR levels correlated with serum CRP levels ( r =0.281, P <0.05). The overall hospital mortality rate was 12.21% (37/303). Levels of NLR and PLR were signifi-cantly higher among non-survivors compared to survivors of AECOPD (both P <0.05). At a cut-off value of 6.24, the sensitivity and specificity of the NLR in predicting hospital mortality were 81.08% and 69.17%, respectively, with an AUC of 0.803. At a cut-off of 182.68, the corresponding sensitivity, specificity and AUC of PLR were 64.86%, 58.27%, and 0.639. The combination of NLR, PLR, and CRP increased the prognostic sensitivity., Conclusion: NLR and PLR levels were increased in non-survivor patients with AECOPD, and the NLR may be simple and useful prognostic marker for hospital mortality in patients with AECOPD. More studies should be carried out to confirm our findings., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Drug delivery to ischemic myocardium is an enormous challenge. This work aimed to characterize cardiac delivery behaviors of mono-polyethylene glycosylated (PEGylated) conjugates and long-circulating liposomes (L-Lps) with Radix Ophiopogonis polysaccharide (ROP) as drug. The results showed that compared to native ROP, 32-, 52-, and 45-fold increases in blood half-life were achieved by 20-kDa PEG mono-modified ROP (P(20k)-R), 40-kDa PEG mono-modified ROP (P(40k)-R), and ROP-loaded L-Lp, respectively. With comparable blood pharmacokinetics, ROP-loaded L-Lp showed both significantly higher targeting efficacy and drug exposure in infarcted myocardium than P(40k)-R. With regard to P(20k)-R, both its targeting efficacy and its level in infarcted myocardium at 3 hours postdose were comparable to P(40k)-R, but its level in blood and myocardium reduced obviously faster. As a whole, the results indicate that both loading in L-Lps and mono-PEGylation are effective in targeting drug to ischemic myocardium, but the former appears to induce stronger effects.

Although PEGylation plays an important role in drug delivery, knowledge about the distribution behavior of PEGylated drugs in ischemic myocardia is rather limited compared to nanoparticles. This work therefore aims to characterize the targeting behavior of the anti-myocardial ischemic mono-PEGylated conjugates of Radix Ophiopogonis polysaccharide (ROP) in two clinically relevant animal models, ie, the myocardial infarction (MI) model and the ischemia/reperfusion (IR) model. To determine the effect of the molecular size of conjugates, two representative conjugates (20- and 40-kDa polyethylene glycol mono-modified ROPs), with hydrodynamic size being approximately and somewhat beyond 10 nm, respectively, were studied in parallel at three time points postdose after a method for determining them quantitatively in biosamples was established. The results showed that the cardiac distribution of the two conjugates was significantly enhanced in both MI and IR rats due to the enhanced permeability and retention effect induced by ischemia. In general, the cardiac targeting efficacy of the conjugates in MI and IR rats was approximately 2; however, different changing in targeting efficacy with time was observed between MI and IR rats and also between the conjugates. Although the enhanced permeability and retention effect-based targeting efficacy for mono-PEGylated ROPs was not high, they, as dissolved macromolecules, are prone to diffusion in the cardiac interstitium space, and thus, facilitate the drug to reach perfusion-deficient and nonperfused areas. These findings are helpful in choosing the cardiac targeting strategy.

Current orthopedic implants have functional lifetimes of only 10-15 years due to a variety of reasons including infection, extensive inflammation, and overall poor osseointegration (or a lack of prolonged bonding of the implant to juxtaposed bone). To improve properties of titanium for orthopedic applications, this study anodized and subsequently coated titanium with drugs known to reduce infection (penicillin/streptomycin) and inflammation (dexamethasone) using simple physical adsorption and the deposition of such drugs from simulated body fluid (SBF). Results showed improved drug elution from anodized nanotubular titanium when drugs were coated in the presence of SBF for up to 3 days. For the first time, results also showed that the simple physical adsorption of both penicillin/streptomycin and dexamethasone on anodized nanotubular titanium improved osteoblast numbers after 2 days of culture compared to uncoated unanodized titanium. In addition, results showed that depositing such drugs in SBF on anodized titanium was a more efficient method to promote osteoblast numbers compared to physical adsorption for up to 2 days of culture. In addition, osteoblast numbers increased on anodized titanium coated with drugs in SBF for up to 2 days of culture compared to unanodized titanium. In summary, compared to unanodized titanium, this preliminary study provided unexpected evidence of greater osteoblast numbers on anodized titanium coated with either penicillin/streptomycin or dexamethasone using simple physical adsorption or when coated with SBF; results which suggest the need for further research on anodized titanium orthopedic implants possessing drug-eluting nanotubes.

There are more than 30,000 orthopedic implant revision surgeries necessary each year in part due to poor implant fixation with juxtaposed bone. A further emphasis on the current problems associated with insufficient bone implant performance is the fact that many patients are receiving hip implants earlier in life, remaining active older, and that the human lifespan is continuously increasing. Collectively, it is clear that there is a strong clinical need to improve implant performance through proper, prolonged fixation. For these reasons, the objective of the present in vitro study was to improve the performance of titanium (Ti), one of the most popular orthopedic implant materials. Accordingly, the proliferative response of osteoblasts (bone-forming cells) on novel nanostructured Ti/PLGA (poly-lactic-co-glycolic acid) composites was examined. This study showed that nano-topography can be easily applied to Ti (through anodization) and porous PLGA (through NaOH chemical etching) to enhance osteoblast cell proliferation which may lead to better orthopedic implant performance. This straight forward application of nano-topography on current bone implant materials represents a new direction in the design of enhanced biomaterials for the orthopedic industry.

Bioactive coatings are in high demand to increase the functions of cells for numerous medical devices. The objective of this in vitro study was to characterize osteoblast (bone-forming cell) adhesion on several potential orthopedic polymeric materials (specifically, polyetheretherketone, ultra-high molecular weight polyethylene, and polytetrafluoroethylene) coated with either titanium or gold using a novel Ionic Plasma Deposition process which creates a surface-engineered nanostructure (with features below 100 nm). Results demonstrated that compared to currently-used titanium and uncoated polymers, polymers coated with either titanium or gold using Ionic Plasma Deposition significantly increased osteoblast adhesion. Qualitative cell morphology results supported quantitative adhesion results as increased osteoblast cell spreading was observed on coated polymers compared to uncoated polymers. In this manner, this in vitro study strongly suggests that Ionic Plasma Deposition should be further studied for creating nanometer surface features on a wide variety of materials to enhance osteoblast functions necessary for orthopedic applications.