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Shiyang Wang, Binhe Tian, Hanping Wang Division of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, People’s Republic of ChinaCorrespondence: Hanping Wang, Division of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, People’s Republic of China, Tel +86010-69158760, Email wanghanping78@163.comObjective: This study aimed to investigate the risk factors for immune checkpoint inhibitor (ICI)-related colitis and its impact on prognosis in the treatment of lung cancer.Methods: This retrospective, single-center, observational study included lung cancer patients who received ICIs treatment between January 2016 and January 2022. The correlation between immune-related colitis and prognosis was evaluated. Kaplan-Meier analysis was used to compare the median overall survival (OS).Results: Among the lung cancer patients treated with ICIs, the incidence of colitis was 5.88% (35/595). The severity of colitis was graded as follows: grade 1 (8 cases), grade 2 (15 cases), grade 3 (9 cases), and grade 4 (3 cases). Except for the 1 case that resulted in death due to grade 4 adverse events, the remaining patients showed significant improvement after corticosteroid intervention. Among the 35 patients with ICI-related colitis, complete remission was not achieved. Partial remission was observed in 11 cases, disease stability in 16 cases, disease progression in 7 cases, and death in 1 case. Among the included patients, 19 chose to continue ICI treatment after symptom relief. The overall survival for all participants was 34 months (IQR: 24– 36), while the overall survival for those who received ICI treatment again was 36 months (IQR: 32-NA), and for those who did not receive ICI treatment again was 32 months (IQR: 21– 35). Kaplan-Meier survival curve analysis showed that patients who received ICI treatment again had significantly better overall survival compared to other patients.Conclusion: Immune-related colitis remains a significant concern in lung cancer patients treated with ICIs and requires close monitoring and timely intervention. Restarting treatment after symptom relief can provide additional benefits for patients.Keywords: lung cancer, immune checkpoint inhibitors, colitis, risk factors, prognosis

Shaoqiu Zhang,1,&ast; Qun Zhang,2,&ast; Jian Wang,1,3,&ast; Yifan Pan,4 Zhiyi Zhang,5 Yu Geng,1 Bei Jia,1 Bing Tian,2 Yali Xiong,1 Xiaomin Yan,1 Jie Li,1,3– 5 Huali Wang,6 Rui Huang,1,3– 5 Chao Wu1,3– 5 1Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China; 2Department of Infectious Diseases, Affiliated Zhongda Hospital of Southeast University, Nanjing, Jiangsu, People’s Republic of China; 3Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, People’s Republic of China; 4Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 5Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 6Department of General Practice, Nanjing Second Hospital, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chao Wu; Rui Huang, Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, No. 321 Zhongshan Road, Nanjing, Jiangsu, 210008, People’s Republic of China, Tel +86-25-83105890, Fax +86-25-83307115, Email dr.wu@nju.edu.cn; doctor_hr@126.comBackground: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging epidemic infectious disease with high mortality rate. This study aimed to investigate the association of red blood cell distribution width (RDW) and mortality risk in hospitalized SFTS patients.Methods: Clinical data of SFTS patients was retrospectively collected from three hospitals between October 2010 and August 2022. Cox proportional hazards model was used to identity the risk factors for fatal outcome. The predictive value of RDW for fatal outcome was evaluated by the receiver operating characteristic (ROC) analysis and Kaplan–Meier methods.Results: Of 292 patients, the median age was 61.5 years. Non-survivors showed higher RDW value than survivors (13.6% vs.13.0%, P < 0.001). The mortality rate was 44.8% in patients with elevated RDW compared to 18.4% of patients with normal RDW, with a relative risk (RR) of 2.439. Elevated RDW was an independent risk factor of mortality (hazards ratio: 1.167, P = 0.019). Patients with elevated RDW had a higher cumulative mortality than patients with normal RDW. The area under the ROC curve (AUC) of RDW for the prediction of mortality was 0.690 (P < 0.001).Conclusion: Elevated RDW was associated with higher mortality risk for patients hospitalized for SFTS. RDW may be helpful for risk stratification in SFTS patients.Keywords: severe fever with thrombocytopenia syndrome, red blood cell distribution width, prognosis, survival

Liuping Cui,1,2 Ran Liu,1 Fubo Zhou,1 Yumei Liu,1 Bing Tian,1 Ying Chen,2,&ast; Yingqi Xing1,3,4,&ast; 1Department of Vascular Ultrasound, Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Neurology, The First Hospital of Jilin University, Changchun, People’s Republic of China; 3Beijing Diagnostic Center of Vascular Ultrasound, Beijing, People’s Republic of China; 4Center of Vascular Ultrasound, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yingqi Xing, Department of Vascular Ultrasonography, Xuanwu Hospital, Capital Medical University, 45 Changchun Road, Beijing, Xicheng District, 100053, People’s Republic of China, Tel +86-18610047846, Email xingyq2009@sina.comPurpose: Intraplaque neovascularization, assessed using contrast-enhanced ultrasound (CEUS), is associated with ischemic stroke. It remains unclear whether detection of intraplaque neovascularization combined with color Doppler ultrasound (CDUS) provides additional value compared with CDUS alone in assessing ischemic stroke risk. Therefore, we investigated the clinical value of combined CEUS, CDUS, and clinical features for ischemic stroke risk stratification.Patients and Methods: We recruited 360 patients with ≥ 50% carotid stenosis between January 2019 and September 2022. Patients were examined using CDUS and CEUS. Covariates associated with ischemic stroke were identified using multivariate logistic regression analysis. The discrimination and calibration were verified using the C-statistic and Hosmer–Lemeshow test. The incremental value of intraplaque neovascularization in the assessment of ischemic stroke was analyzed using the Delong test.Results: We analyzed the data of 162 symptomatic and 159 asymptomatic patients who satisfied the inclusion and exclusion criteria, respectively. Based on multivariate logistic regression analysis, we constructed a nomogram using intraplaque neovascularization, degree of carotid stenosis, plaque hypoechoicity, and smoking status, with a C-statistic of 0.719 (95% confidence interval [CI]: 0.666– 0.768) and a Hosmer–Lemeshow test p value of 0.261. The net reclassification index of the nomogram was 0.249 (95% CI: 0.138– 0.359), and the integrated discrimination improvement was 0.053 (95% CI: 0.029– 0.079). Adding intraplaque neovascularization to the combination of CDUS and clinical features (0.672; 95% CI: 0.617– 0.723) increased the C-statistics (p=0.028).Conclusion: Further assessment of intraplaque neovascularization after CDUS may help more accurately identify patients at risk of ischemic stroke. Combining multiparametric carotid ultrasound and clinical features may help improve the risk stratification of patients with ischemic stroke with ≥ 50% carotid stenosis.Plain Language Summary: We studied whether using contrast-enhanced ultrasound (CEUS) to detect intraplaque neovascularization could help better determine the risk of ischemic stroke. We compared the combined use of color Doppler ultrasound (CDUS) and CEUS with CDUS alone in patients with more than 50% carotid narrowing. Our findings showed that combining clinical details, CDUS, and CEUS was more effective (0.719 vs 0.672). This means that CEUS provides extra insight when gauging ischemic stroke risk compared with CDUS alone. This could help in accurately identifying patients at high risk of stroke. However, more extensive studies are needed to fully understand the role of these tests in the evaluation of stroke risk. Keywords: atherosclerosis, contrast-enhanced ultrasound, vulnerable plaque, carotid ultrasound

Jing Huang,1 Hongxia Sun,2 Bei Tian2 1Department of Nursing, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 2Department of Nursing, Shanghai Pudong New Area Zhoupu Hospital (Shanghai Health Medical College Affiliated Zhoupu Hospital), Shanghai, 201318, People’s Republic of ChinaCorrespondence: Bei Tian, Department of Nursing, Shanghai Pudong New Area Zhoupu Hospital (Shanghai Health Medical College Affiliated Zhoupu Hospital), No. 1500 Zhou yuan Road, Pudong New District, Shanghai, 201318, People’s Republic of China, Tel +86-18121216302, Email 18121216302@163.comIntroduction: This study aims to explore the thought, feelings and perceptions of male nursing students and male nursing professionals in the nursing profession.Methods: This present study used a qualitative research design to explore the feelings, thoughts, and opinions of male nursing students (first to fourth years) and male nursing professionals about their perception of the nursing profession. The study recruited 11 male nursing students and 11 male nursing professionals using a purposive sampling method. Data were collected via semi-structured individual interviews using qualitative open-ended inquiries consisting of seven questions. The data were analysed using thematic perspectives.Results: The analysis revealed three themes: (a) perceiving gender varieties, (b) taking apparent advantage of masculine characteristics, and (c) taking an equal perspective. Male students’ replies to their professional gender attitudes were that there was no distinct line among the gender-related advantages and disadvantages according to whether they were first to fourth-year students.Conclusion: Male nursing students and professionals believe that nursing is equally appropriate for both men and women, and they could employ masculine characteristics to thrive in their professional development.Keywords: male nurses, professional development, interventional nursing, semi-structured, masculine

Yong Ling,1,&ast; Xuejiao Hu,1,&ast; Guansheng Zheng,1 Weitao Ye,2 Kaixuan Yuan,1 Long Ye,1 Weiye Huang,3 Benshun Tian,1 Bing Gu1 1Department of Clinical Laboratory Medicine, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, 510000, People’s Republic of China; 2Department of Radiology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, 510000, People’s Republic of China; 3Department of Pathology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, 510000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Benshun Tian; Bing Gu, Department of Laboratory Medicine, Guangdong Provincial People’s Hospital, 106 Zhongshan 2nd Road, Yuexiu District, Guangzhou, Guangdong, 510000, People’s Republic of China, Email tbs20161017@163.com; gb20031129@163.comAbstract: Scrub typhus is a vector-borne infectious disease caused by Orientia tsutsugamushi. Accurate and timely diagnosis at the early infection stage could save the patients’ lives. Traditional technologies were limited to rapidly and successfully detecting Orientia tsutsugamushi due to poor specificity, especially in the condition of atypical symptoms. The technology of Metagenomic next-generation sequencing (mNGS) is amenable to finding the real pathogen because it holds potential as a diagnostic platform for unbiased pathogen identification and precision medicine. Herein, we reported two clinical case reports relative to the Orientia tsutsugamushi infection diagnosed by mNGS. We hope these two cases will improve clinical diagnosis.Keywords: scrub typhus, metagenomic next-generation sequencing, Orientia tsutsugamushi

Xiaoyu Zhu,1 Ran Li,1 Yu Zhu,1 Jia Zhou,1 Junchao Huang,1 Yanfang Zhou,1 Jinghui Tong,1 Ping Zhang,1 Xingguang Luo,2 Song Chen,1 Yanli Li,1 Baopeng Tian,1 Shu-Ping Tan,1 Zhiren Wang,1 Xiaole Han,1 Li Tian,3 Chiang-Shan R Li,2 Yun-Long Tan1 1Psychosomatic Department, Beijing HuiLongGuan Hospital, Beijing, People’s Republic of China; 2Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA; 3Institute of Biomedicine and Translational Medicine, Department of Physiology, Faculty of Medicine, University of Tartu, Tartu, EstoniaCorrespondence: Yun-Long Tan, Psychosomatic Department, Beijing HuiLongGuan Hospital, Beijing, People’s Republic of China, Tel +86-10-83024319, Fax +86-10-62710156, Email yltan21@126.comObjective: Accumulating evidence suggested that immune system activation might be involved in the pathophysiology of schizophrenia. The neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), platelet/lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) can measure inflammation. This study aimed to investigate the inflammatory state in patients with schizophrenia by using these indicators.Methods: In this study, the complete blood count data for 187 continuing hospitalized patients with schizophrenia and 187 age- and sex-matched healthy participants was collected annually from 2017 to 2019. Platelet (PLT), lymphocyte (LYM), monocyte (MON) and neutrophil (NEU) counts were aggregated and NLR, MLR, PLR, and SII were calculated. Using a generalized linear mixed model, we assessed the impact of age, sex, diagnosis, and sampling year on the above indicators and evaluated the interaction between the factors.Results: According to the estimation results of the generalized linear mixed model, the NLR increased by 0.319 (p = 0.004), the MLR increased by 0.037 (p < 0.001), and the SII increased by 57.858 (p = 0.018) in patients with schizophrenia. Data after two years of continuous antipsychotic treatment showed that the NLR and MLR were higher in patients with schizophrenia than those in healthy controls, while the PLT and LYM counts were decreased in patients with schizophrenia. The schizophrenia diagnosis was correlated to the MON and LYM count, NLR, MLR, and SII (p < 0.05).Conclusion: The differences in these markers were stable and cannot be eliminated by a full course of treatment. This study provides impetus for the inflammatory hypothesis of schizophrenia.Keywords: schizophrenia, systemic immune-inflammation index, neutrophil/lymphocyte ratio, monocyte/lymphocyte ratio, platelet/lymphocyte ratio

Bei Tian,1 Zhongping Ning,2 Pingan Tu3 1Department of Nursing, Shanghai Pudong New Area Zhoupu Hospital (Zhoupu Hospital Affiliated with Shanghai Medical College of Health), Shanghai, 201318, People’s Republic of China; 2Department of Cardiology, Shanghai Pudong New Area Zhoupu Hospital (Zhoupu Hospital Affiliated with Shanghai Medical College of Health), Shanghai, 201318, People’s Republic of China; 3Vice President Office, Shanghai Pudong New Area Zhoupu Hospital (Zhoupu Hospital Affiliated with Shanghai Medical College of Health), Shanghai, 201318, People’s Republic of ChinaCorrespondence: Pingan Tu, Vice President Office, Shanghai Pudong New Area Zhoupu Hospital (Zhoupu Hospital Affiliated with Shanghai Medical College of Health), No. 1500 Zhouyuan Road, Pudong New District, Shanghai, 201318, People’s Republic of China, Tel +86-18121216136, Email shanghai5288@hotmail.com Zhongping Ning, Department of Cardiology, Shanghai Pudong New Area Zhoupu Hospital (Zhoupu Hospital Affiliated with Shanghai Medical College of Health), No. 1500 Zhouyuan Road, Pudong New District, Shanghai, 201318, People’s Republic of China, Tel +86-021-68135590, Email ningzpsh@163.comAbstract: During the coronavirus disease 2019 (COVID-19) outbreak in Shanghai with the Omicron variant in March 2022, locally accessible hospitals and healthcare centres encountered difficulties quickly responding to a demand for hospitals that were rapidly increasing, optimizing clinical results and controlling the infection. In this commentary, we summarize the management strategies of patients in a temporary COVID-19 specialized hospital during the outbreak in Shanghai, China. The present commentary was considered eight characteristics of management system, including general idea, infection prevention team, and efficient time management, and preventive and protective measures management, strategies for the management of infected patients, disinfection management, drug supply management strategies, and medical waste management. Following eight characteristics, the temporary COVID-19 specialized hospital operated effectively for 21 days. A total of 9674 patients were admitted, 7127 cases (73.67%) were cured and discharged, and 36 were transferred to designate hospitals for better treatment. Twenty-five management staff, 1130 medical, nursing staff, 565 logistics staff, and 15 volunteers participated in the temporary COVID-19 specialized hospital, and no infection prevention team member was infected. We speculated that these management strategies could be potential references for public health emergencies.Keywords: novel coronavirus infection, specialized hospital, management strategies, Omicron variant, outbreak

Yulan Dong, Qianqian Chen, Bin Tian, Jing Li, Jin Li, Zhidong Hu Department of Clinical Laboratory, Tianjin Medical University General Hospital, Tianjin, People’s Republic of ChinaCorrespondence: Zhidong Hu, Department of Clinical Laboratory, Tianjin Medical University General Hospital, No. 154 Anshan Road, Heping District, Tianjin, People’s Republic of China, Tel +86 022-60814202, Email huzhidong27@126.comBackground: Due to limitations of traditional microbiological methods and the presence of the oropharyngeal normal flora, there are still many pathogens that cause lower respiratory tract infections (LRTIs) cannot be detected. Metagenomic next-generation sequencing (mNGS) has the potential capacity to solve this problem.Methods: This retrospective study successively reviewed 77 patients with LRTI and 29 patients without LRTI admitted to Tianjin Medical University General Hospital, China from August 2020 to June 2021. Pathogens in bronchoalveolar lavage fluid (BALF) specimens were detected adopting mNGS and traditional microbiological assays. The diagnostic performance of pathogens was compared between mNGS and BALF culture. The value of mNGS for aetiological and clinical impact investigation in LRTI was also evaluated.Results: Among 77 patients with LRTI, 22.1%, 40.3%, and 65.0% of cases were detected as definite or probable pathogens by culture, all conventional microbiological tests, and mNGS, respectively. Using the final diagnosis as a gold standard, mNGS exhibited a sensitivity of 76.6% (95% confidence interval [CI], 65.6– 85.5%), which was considerably superior to that of BALF culture (76.6% vs 18.2%; P < 0.01); specificity of 79.3% (95% CI, 60.3– 92.0%), which was similar (79.3% vs 89.7%; P = 0.38); positive-predictive value of 90.8% (95% CI, 81.0– 96.5%), and negative-predictive value of 56.1% (95% CI, 39.7– 71.5%). According to our data, mNGS identified potential microorganisms in 66.7% (42/63) of culture-negative samples. Among 59 patients with pathogens identified by mNGS, conventional microbiological methods confirmed pathogenic infections in less than half (28/59) cases. Within the 77 patients, 34 (44.2%) patients received pathogen-directed therapy, 7 (9.1%) patients underwent antibiotic adjustment, and 3 (3.9%) patients stopped using antibiotics due to mNGS results.Conclusion: mNGS exhibits high accuracy in diagnosing LRTI, and combine with traditional microbiological tests, causative pathogens can be detected in approximately 70.0% of cases, thus yields a positive effect on antibiotic application.Keywords: LRTIs, mNGS, pathogens, culture, diagnosis, infection

Jingwen Lyu,1,2,&ast; Qianyun Deng,2,&ast; Rongqing Li,3 Benshun Tian,1,2 Yunhu Zhao,2 Xuejiao Hu,2 Maohua Zhou,2 Bing Gu2 1Xuzhou Key Laboratory of Laboratory Diagnostics, School of Medical Technology, Xuzhou Medical University, Xuzhou, 221004, People’s Republic of China; 2Laboratory Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510000, People’s Republic of China; 3Jiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, 221004, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Maohua Zhou; Bing Gu, Laboratory Medicine, Guangdong Provincial People’s Hospital, 106 Zhongshan 2nd Road, Yuexiu District, Guangzhou, Guangdong, 510000, People’s Republic of China, Tel +86-20-83827812-62462, Email zhoumaohua@gdph.org.cn; gb20031129@163.comBackground: Pneumonia produced by coinfection with Pneumocystis jirovecii (PJ) and cytomegalovirus (CMV) in infants and young children without timely diagnosis and treatment is often fatal due to the limitations of traditional tests. More accurate and rapid diagnostic methods for multiple infections are urgently needed.Case Presentation: Here, we report a case of a 2-month-old boy with pneumonia caused by Pneumocystis jirovecii (PJ) and cytomegalovirus (CMV) without HIV infection. Chest computed tomography (CT) showed massive exudative consolidation in both lungs. Microscopic examination of stained sputum and smear specimens and bacterial and fungal culture tests were all negative, and CMV nucleic acid and antibody tests were positive. After a period of antiviral and anti-infective therapy, pulmonary inflammation was not relieved. Subsequently, sputum and venous blood samples were analysed by metagenomic next-generation sequencing (mNGS), and the sequences of PJ and CMV were acquired. The patient was finally diagnosed with pneumonia caused by PJ and CMV coinfection. Anti-fungal combined with anti-viral therapy was given immediately. mNGS re-examination of bronchoalveolar lavage fluid (BALF) also revealed the same primary pathogen. Therapy was stopped due to the request of the patient’s guardian. Hence, the child was discharged from the hospital and eventually died.Conclusion: This case emphasizes the combined use of mNGS and traditional tests in the clinical diagnosis of mixed lung infections in infants without HIV infection. mNGS is a new adjunctive diagnostic method that can rapidly discriminate multiple causes of pneumonia.Keywords: metagenomic next-generation sequencing, Pneumocystis jirovecii, cytomegalovirus, pneumonitis, HIV-negative

Wang Liu,1,&ast; Yu Zeng,1,&ast; Yanda Li,2,&ast; Nanhong Li,3 Min Peng,1 Junfen Cheng,1 Binbin Tian,4 Mingdi Chen5 1Department of Respiration, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, People’s Republic of China; 2Department of Internal Medicine, Central People’s Hospital of Zhanjiang, Zhanjiang, Guangdong, People’s Republic of China; 3Department of Pathology and Pathophysiology, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 4Department of Critical Care Medicine, Central People’s Hospital of Zhanjiang, Zhanjiang, Guangdong, People’s Republic of China; 5Department of Critical Care Medicine, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mingdi Chen; Binbin Tian Email 724877563@qq.com; 1169855063@qq.comBackground: In December 2019, coronavirus disease 2019 (COVID-19) caused by a novel coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2; previously known as 2019-nCoV) emerged in Wuhan, China, and caused many infections and deaths. At present, there are no specific drugs for the etiology and treatment of COVID-19. A combination of traditional Chinese and western medicine is proposed to treat COVID-19, in which Huang Lian Jie Du decoction (HLJDD) is recommended for the treatment of COVID-19 in many provinces in China and has been widely used in the clinic. This study explored the potential targets of HLJDD in the treatment of COVID-19 based on network pharmacology.Methods: First, the chemical composition and targets of HLJDD and COVID-19-related targets were obtained through the TCMSP, UniProt, GeneCards and OMIM databases. Second, HLJDD target and HLJDD-COVID-19 target networks were constructed via the STRING database and Cytoscape software. Finally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the HLJDD-COVID-19 targets was applied via the DAVID database.Results: Our study identified a total of 67 active ingredients of HLJDD and 204 targets of HLJDD. A total of 502 COVID-19-related targets were obtained, of which 47 were intersecting targets of HLJDD and COVID-19. A total of 179 GO terms and 77 KEGG terms, including the TNF signaling pathway, NF-κB signaling pathway and HIF-1 signaling pathway, were identified.Conclusion: The present study explored the potential targets and signaling pathways of HLJDD during the treatment of COVID-19, which may provide a basis for the research and development of drugs for the treatment of COVID-19.Keywords: Huang Lian Jie Du decoction, coronavirus disease 2019, COVID-19, SARS-CoV-2, network pharmacology, traditional Chinese medicine

Yu-Xin Wang,1,&ast; Feng-Lian Li,1,&ast; Li-Xin Du,1 Jun-Fang Liu,2 Li-Gang Huo,1 Shu-Qing Li,3 Bin Tian1 1Department of Clinical Laboratory, Hengshui Fifth People’s Hospital, Hengshui City, 053000, People’s Republic of China; 2Department of Pathology, Hengshui Fifth People’s Hospital, Hengshui City, 053000, People’s Republic of China; 3Department of cardiothoracic surgery, Hengshui Fifth People’s Hospital, Hengshui City, 053000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Feng-Lian LiDepartment of Clinical Laboratory, Hengshui Fifth People’s Hospital, No. 1638 Shengli West Road, Hengshui City, Hebei Province, 053000, People’s Republic of ChinaTel +86 318-2316645Email fenglianlidr@163.comObjective: The aim of this study was to quantify the expression of melanoma-antigen family A proteins (MAGE-A) and New York esophageal squamous cell carcinoma-1 (NY-ESO-1) in breast cancer and establish the prognosis of breast cancer patients with MAGE-A and NY-ESO-1 co-expression.Methods: A total of 122 patients with breast cancer were recruited for this study. Their clinicopathological data were collected retrospectively, and the MAGE-A and NY-ESO-1 expressions in paraffin-embedded specimens from the 122 patients were evaluated using immunohistochemical analysis. In addition, the survival states of the patients were recorded.Results: Fifty-four patients (44.26%) were MAGE-A positive and 46 (37.70%) were NY-ESO-1 positive. Interestingly, 22 of the 46 NY-ESO-1-positive cases co-expressed MAGE-A. The expression of MAGE-A was positively associated with estrogen-receptor status (χ2 = 4.026, p = 0.045) and human epidermal growth factor receptor 2 status (χ2 = 5.482, p = 0.019), while the expression of NY-ESO-1 was positively associated with p53 expression (χ2 = 4.541, p = 0.033). Of the 122 patients, the lowest survival rate was observed in patients with NY-ESO-1 (+)/MAGE-A (+), with a 5-year survival rate of 59.09% and a median survival of 97 months.Conclusion: The results showed that MAGE-A and NY-ESO-1 were frequently expressed in breast cancer patients. The co-expression of MAGE-A and NY-ESO-1 occurred in about 18% of these patients, and it may indicate a poor prognosis.Keywords: breast cancer, cancer/testis antigens, MAGE-A, NY-ESO-1, co-expression

Chenyang Zhuang,1,&ast; Zixiang Wang,1,&ast; Weisin Chen,1 Bo Tian,1 Juan Li,1,2 Hong Lin1,2 1Department of Orthopedics, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Department of Orthopedics, Shanghai Geriatrics Center, Fudan University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Juan LiDepartment of Orthopedics, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai, 200032, People’s Republic of ChinaTel/Fax +86 21 6404 1990Email li_juan1983@outlook.comHong LinDepartment of Orthopedics, Shanghai Geriatrics Center, Fudan University, No. 2560 Chunshen Road, Shanghai, 201104, People’s Republic of ChinaEmail lin.hong1@zs-hospital.sh.cnPurpose: Osteoporosis and endplate damage, two primary orthopedic disorders that have adverse effects on the quality of life of older adults, may have some previously unknown relationship. The purpose of this study was to determine the potential association between osteoporosis and endplate damage with two specific imaging scoring systems and analyze the underlying mechanisms.Patients and Methods: A cross-sectional study including 156 patients with degenerative disc disease (DDD) who visited our department in 2018 was performed. Data including age, sex, body mass index, Hounsfield unit (HU) values utilizing computed tomography (CT), and total endplate scores (TEPSs) using magnetic resonance imaging (MRI) of all patients were retrospectively collected and analyzed. The average HU value and TEPS of L1–L4 were used to represent the degrees of bone mineral density (BMD) and endplate damage, respectively. Patients with an HU value < 110 were defined as having osteoporosis and placed in the low-BMD group; otherwise, they were placed in the normal-BMD group. Multivariate logistic regression models were used to determine the independent factors of endplate damage.Results: The TEPSs in the low-BMD group were significantly higher (6.4 ± 1.6 vs 5.0 ± 0.9, p < 0.001) overall and in every segment of L1–L4 (p < 0.01). A significant negative correlation was found between TEPS and HU values (p < 0.001). The HU value (odds ratio [OR] 0.221; 95% confidence interval [CI], 0.148– 0.295, p < 0.001), age (OR 0.047; 95% CI, 0.029– 0.224, p < 0.001), and BMD (OR 3.796; 95% CI, 2.11– 7.382, p < 0.05) were independent factors influencing endplate damage.Conclusion: A significantly positive correlation was observed between osteoporosis and endplate damage, indicating the requirement for a more comprehensive therapeutic regimen for treating patients with DDD complicated with osteoporosis.Keywords: degenerative disc diseases, bone mineral density, computed tomography, magnetic resonance imaging

Yulan Weng, 1 Jiulong Li, 1 Xingcheng Ding, 2 Binqiang Wang, 1 Shang Dai, 1 Yulong Zhou, 3 Renjiang Pang, 1 Ye Zhao, 1 Hong Xu, 1 Bing Tian, 1, 3 Yuejin Hua 1 1MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang University, Hangzhou, People’s Republic of China; 2Zhejiang Runtu Chemical Research Institute, Shaoxing, People’s Republic of China; 3Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, School of Chemistry and Chemical Engineering, Shihezi University, Shihezi, Xinjiang, People’s Republic of ChinaCorrespondence: Bing TianZhejiang University Zijingang Campus West Part, A403 Biophysics Building, 866 Yuhangtang Road, Hangzhou 310058, People’s Republic of ChinaTel/Fax +86-571-86971215Email tianbing@zju.edu.cnBackground: Biodegradation of toxic organic dye using nanomaterial-based microbial biocatalyst is an ecofriendly and promising technique.Materials and Methods: Here, we have investigated the novel properties of functionalized Au-Ag bimetallic nanoparticles using extremophilic Deinococcus radiodurans proteins (Drp-Au-AgNPs) and their degradation efficiency on the toxic triphenylmethane dye malachite green (MG).Results and Discussion: The prepared Drp-Au-AgNPs with an average particle size of 149.8 nm were capped by proteins through groups including hydroxyl and amide. Drp-Au-AgNPs demonstrated greater degradation ability (83.68%) of MG than D. radiodurans cells and monometallic AuNPs. The major degradation product was identified as 4-(dimethylamino) benzophenone, which is less toxic than MG. The degradation of MG was mainly attributed to the capping proteins on Drp-Au-AgNPs. The bimetallic NPs could be reused and maintained MG degradation ability (> 64%) after 2 cycles.Conclusion: These results suggest that the easily prepared Drp-Au-AgNPs have potential applications as novel nanomedicine for MG detoxification, and nanomaterial for biotreatment of a toxic polyphenyl dye-containing wastewater.Keywords: bimetallic nanoparticles, Deinococcus radiodurans, biodegradation, toxic triphenylmethane dye, malachite green, detoxification

Yan Liang,1 Jing Zhang,1 Baocheng Tian,1 Zimei Wu,2 Darren Svirskis,2 Jingtian Han1 1School of Pharmacy, Binzhou Medical University, Yantai 264003, Shandong Province, People’s Republic of China; 2School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New ZealandCorrespondence: Jingtian HanSchool of Pharmacy, Binzhou Medical University, 346 Guanhai Road, Yantai 264003, People’s Republic of ChinaTel +86-535-6913317Fax +86-535-6913718Email hanjingtian002@163.comDarren SvirskisSchool of Pharmacy, University of Auckland, 85 Park Road, Grafton, Auckland, New ZealandTel +64-9-923 1158Email d.svirskis@auckland.ac.nzAim: Sequential treatment with paclitaxel (PTXL) and gemcitabine (GEM) is considered clinically beneficial for non-small-cell lung cancer. This study aimed to investigate the effectiveness of a nano-system capable of sequential release of PTXL and GEM within cancer cells.Methods: PTXL-ss-poly(6-O-methacryloyl-d-galactopyranose)-GEM (PTXL-ss-PMAGP-GEM) was designed by conjugating PMAGP with PTXL via disulfide bonds (-ss-), while GEM via succinic anhydride (PTXL:GEM=1:3). An amphiphilic block copolymer N-acetyl-d-glucosamine(NAG)-poly(styrene-alt-maleic anhydride)58-b-polystyrene130 acted as a targeting moiety and emulsifier in formation of nanostructures (NLCs).Results: The PTXL-ss-PMAGP-GEM/NAG NLCs (119.6 nm) provided a sequential in vitro release of, first PTXL (redox-triggered), then GEM (pH-triggered). The redox- and pH-sensitive NLCs readily distributed homogenously in the cytoplasm. NAG augmented the uptake of NLCs by the cancer cells and tumor accumulation. PTXL-ss-PMAGP-GEM/NAG NLCs exhibited synergistic cytotoxicity in vitro and strongest antitumor effects in tumor-bearing mice compared to NLCs lacking pH/redox sensitivities or free drug combination.Conclusion: This study demonstrated the abilities of PTXL-ss-PMAGP-GEM/NAG NLCs to achieve synergistic antitumor effect by targeted intracellularly sequential drug release.Keywords: sequential release, redox-sensitive, pH-sensitive, synergistic efficiency, combination drug delivery, gemcitabine, paclitaxel

Cheng Zheng,1,2,* Jiachang Cai,3,* Haizhou Liu,1,4,* Shufang Zhang,5 Li Zhong,1,6 Nanxia Xuan,1 Hongwei Zhou,3 Kai Zhang,1 Yesong Wang,1 Xijiang Zhang,2 Baoping Tian,1 Zhaocai Zhang,1 Changming Wang,2 Wei Cui,1 Gensheng Zhang1 1Department of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, People’s Republic of China; 2Department of Critical Care Medicine, Taizhou Municipal Hospital, Taizhou, Zhejiang, People’s Republic of China; 3Clinical Microbiology Laboratory, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, People’s Republic of China; 4Department of Critical Care Medicine, Zhejiang Rehabilitation Hospital, Hangzhou, Zhejiang, People’s Republic of China; 5Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, People’s Republic of China; 6Department of Critical Care Medicine, Huzhou First People’s Hospital, Huzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Gensheng ZhangDepartment of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, People’s Republic of ChinaTel +86-571-8778-3636Fax +86-571- 87022776Email genshengzhang@zju.edu.cnPurpose: Although the enterococcal bloodstream infections (EBSI) are often observed in clinic, the mixed-EBSI are few reported. The aim of this study was to investigate the clinical characteristics and risk factors of mixed-EBSI in comparison with monomicrobial EBSI (mono-EBSI).Methods: A single-center retrospective observational study was performed between Jan 1, 2013 and Dec 31, 2018 in a tertiary hospital. All patients with EBSI were enrolled, and their data were collected by reviewing electronic medical records.Results: A total of 451 patients with EBSI were enrolled including 157 cases (34.8%) with mixed-EBSI. The most common co-pathogens were Coagulase-negative Staphylococcus (26.86%), followed by Acinetobacter baumannii (23.43%) and Klebsiella pneumoniae (8.57%). In multivariable analysis, burn injury (adjusted odds ratio [aOR], 7.39; 95% confidence interval [CI], 2.69–20.28), and length of prior hospital stay (aOR, 1.01; 95% CI, 1.00–1.02) were associated with mixed-EBSI. Patients with mixed-EBSI developed with more proportion of septic shock (19% vs. 31.8%, p=0.002), prolonged length of intensive care unit (ICU) stay [9(0,25) vs. 15(2.5,36), p

Shanshan Gao, Baocheng Tian, Jingtian Han, Jing Zhang, Yanan Shi, Qingzhi Lv, Keke LiSchool of Pharmacy, Binzhou Medical University, Yantai, People’s Republic of chinaBackground: Nanostructured lipid carriers (NLCs) are emerging as attractive drug carriers in transdermal drug delivery. The surface modification of NLCs with cell-penetrating peptides (CPPs) can enhance the skin permeation of drugs.Purpose: The objective of the current study was to evaluate the ability of the cell-penetrating peptide (CPP) polyarginine to translocate NLCs loaded with lornoxicam (LN) into the skin layers and to evaluate its anti-inflammatory effect.Methods: The NLCs were prepared using an emulsion evaporation and low temperature solidification technique using glyceryl monostearates, triglycerides, DOGS-NTA-Ni lipids and surfactants, and then six histidine-tagged polyarginine containing 11 arginine (R11) peptides was modified on the surface of NLCs.Results: The developed NLCs formulated with LN and R11 (LN-NLC-R11) were incorporated into 2% HPMC gels. NLCs were prepared with a particle size of (121.81±3.61)–(145.72±4.78) nm, and the zeta potential decreased from (−30.30±2.07) to (−14.66±0.74) mV after the modification of R11 peptides. The encapsulation efficiency and drug loading were (74.61±1.13) % and (7.92±0.33) %, respectively, regardless of the surface modification. Cellular uptake assays using HaCaT cells suggested that the NLC modified with R11 (0.02%, w/w) significantly enhanced the cell internalization of nanoparticles relative to unmodified NLCs (P

Paulo Rodolfo Tagliari Barbisan,1 Marina Gonçalves Monteiro Viturino,1 Fernanda Maria Silveira Souto,1 Bo Tian,2,3 Roberto Damian Pacheco Pinto,1 Lucas Barasnevicius Quagliato,1 Maurício Abujamra Nascimento,1 Rosane Silvestre de Castro,1 Carlos Eduardo Leite Arieta1 1Department of Ophthalmology, State University of Campinas, Campinas, São Paulo, Brazil; 2Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA; 3Department of Ophthalmology and Visual Sciences, University of Massachusetts Medical School, Worcester, MA, USA Purpose: To assess potential vascular, structural, and functional changes to the macula in patients with keratoconus that underwent ultraviolet A (UVA)–riboflavin-mediated corneal collagen cross-linking (CXL) therapy.Patients and methods: Seventeen eyes from 17 patients of age 16 years or older with keratoconus undergoing CXL treatment were studied. The same eye served as its own control (before CXL vs after CXL). Eyes were evaluated in terms of best-corrected visual acuity (BCVA), refractive error, intraocular pressure, Amsler grid, retinography, fluorescein angiography, autofluorescence, and spectral domain optical coherence tomography (SD-OCT) prior to CXL and 7 and 30 days after treatment. Multifocal electroretinography (mfERG) was recorded prior to and 7 days after CXL.Results: Mean (SD) BCVA by logMAR chart was 0.47 (±0.12) pre-CXL, 0.55 (±0.15) 7 days post-CXL (P=0.57), and 0.46 (±0.10) 30 days post-CXL (P=0.87). Mean (SD) SD-OCT central macular thickness (µm) was 253.62 (±20.9) pre-CXL, 260.5 (±18.7) 7 days post-CXL (P=0.48), and 256.44 (±21.6) 30 days post-CXL (P=0.69). In 12 eyes, mfERG revealed a statistically significant increase (P=0.0353) in P1 latency (ms) of ring four from the pre-CXL period (39.45±2.05) to 7 days post-CXL (41.04±1.28) period. Regression analysis showed that the increase in P1 latency was correlated with the increase in central macular thickness (P=0.027). Furthermore, nine patients experienced a significant decrease in P1 amplitudes of rings 1 (P=0.0014), 2 (P=0.0029), 3 (P=0.0037), 4 (P=0.0014), and 5 (P=0.0012) from pre-CXL to 7 days post-CXL.Conclusion: In this pilot study, most of the patients exhibited slight changes in their mfERG parameters and OCT thickness, despite a lack of vascular abnormalities observed on fluorescein angiography/autofluorescence imaging, no alteration in BCVA, and no reports of symptoms. These changes could, therefore, be categorized as a mild subclinical effect of the corneal cross-linking procedure. Keywords: keratoconus, light damage, multifocal electroretinogram, UVA, phototoxicity, crosslinking

Jiulong Li,1 Bing Tian,1 Tao Li,1 Shang Dai,1 Yulan Weng,1 Jianjiang Lu,2 Xiaolin Xu,2 Ye Jin,1 Renjiang Pang,1 Yuejin Hua1 1Key Laboratory for Nuclear-Agricultural Sciences of Chinese Ministry of Agriculture and Zhejiang Province, Institute of Nuclear-Agricultural Sciences, Zhejiang University, Hangzhou, People’s Republic of China; 2Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, School of Chemistry and Chemical Engineering, Shihezi University, Xinjiang, People’s Republic of China Background: Biosynthesis of noble metallic nanoparticles (NPs) has attracted significant interest due to their environmental friendly and biocompatible properties.Methods: In this study, we investigated syntheses of Au, Ag and Au–Ag bimetallic NPs using protein extracts of Deinococcus radiodurans, which demonstrated powerful metal-reducing ability. The obtained NPs were characterized and analyzed by various spectroscopy techniques.Results: The D. radiodurans protein extract-mediated silver nanoparticles (Drp-AgNPs) were preferably monodispersed and stably distributed compared to D. radiodurans protein extract-mediated gold nanoparticles (Drp-AuNPs). Drp-AgNPs and Drp-AuNPs exhibited spherical morphology with average sizes of 37.13±5.97 nm and 51.72±7.38 nm and zeta potential values of -18.31±1.39 mV and -15.17±1.24 mV at pH 7, respectively. The release efficiencies of Drp-AuNPs and Drp-AgNPs measured at 24 h were 3.99% and 18.20%, respectively. During the synthesis process, Au(III) was reduced to Au(I) and further to Au(0) and Ag(I) was reduced to Ag(0) by interactions with the hydroxyl, amine, carboxyl, phospho or sulfhydryl groups of proteins and subsequently stabilized by these groups. Some characteristics of Drp-AuNPs were different from those of Drp-AgNPs, which could be attributed to the interaction of the NPs with different binding groups of proteins. The Drp-AgNPs could be further formed into Au–Ag bimetallic NPs via galvanic replacement reaction. Drp-AuNPs and Au–Ag bimetallic NPs showed low cytotoxicity against MCF-10A cells due to the lower level of intracellular reactive oxygen species (ROS) generation than that of Drp-AgNPs.Conclusions: These results are crucial to understand the biosynthetic mechanism and properties of noble metallic NPs using the protein extracts of bacteria. The biocompatible Au or Au–Ag bimetallic NPs are applicable in biosensing, bioimaging and biomedicine. Keywords: extreme bacterium, green synthesis, noble metallic nanoparticles, reactive oxygen species

Ketema Bizuwork Gebremedhin,1 Bingjie Tian,2 Chulei Tang,3 Xiaoxia Zhang,3 Engida Yisma,1,4 Honghong Wang3 1Department of Nursing and Midwifery, School of Allied Health Sciences, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia; 2Department of General Surgery, Affiliated Huashan Hospital of Fudan University, Shanghai, China; 3Department of Fundamental Nursing, Xiangya School of Nursing, Central South University, Changsha, China; 4School of Medicine, Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia Introduction: The global human immunodeficiency virus (HIV) epidemic disproportionately affects sub-Saharan African countries, including Ethiopia. Provider-initiated HIV testing and counseling (PITC) is a tool to identify HIV-positive pregnant women and an effective treatment and prevention strategy. However, its success depends upon the willingness of pregnant women to accept HIV testing.Objectives: To describe the level of acceptance of PITC and associated factors among pregnant women attending 8 antenatal care clinics in Adama, Ethiopia.Methods: Trained nursing students and employees from an HIV clinic conducted face-to-face structured interviews in private offices at the clinics from August to September, 2016.Results: Among the 441 respondents, 309 (70.1%) accepted PITC. Women with more antenatal care visits (odds ratio [OR] =2.59, 95% CI: 1.01–6.63), reported better quality of the PITC service (OR =1.91, 95% CI: 1.19–3.08), and higher level of knowledge on mother-to-child transmission (OR =1.82, 95% CI: 1.03–3.20), were more likely to accept PITC, while women who were older in age (OR =0.37, 95% CI: 0.19–0.74) and perceived negative attitudes from their partners toward HIV-positive results (OR =0.31, 95% CI: 0.10–0.94) were less likely to accept the PITC service.Conclusion: About one-third of pregnant women are not willing to accept PITC. When designing intervention program to improve the acceptance of PITC, we should take into consideration the personal factors, HIV-related knowledge, and attitude of women as well as institutional factors. Keywords: pregnant woman, HIV, provider initiated HIV testing and counseling (PITC), Ethiopia

Baocheng Tian,1 Qi Yan,1 Juan Wang,1 Chen Ding,2 Sixiang Sai1 1School of Pharmacy, Binzhou Medical University, Yantai, 2College of Life and Health Science, Northeastern University, Shenyang, People’s Republic of China Abstract: Candida commonly adheres to implanted medical devices and forms biofilms. Due to the minimal activity of current antifungals against biofilms, new drugs or drug-delivery systems to treat these persistent infections are urgently needed. In the present investigation, voriconazole-loaded nanostructured lipid carriers (Vrc-NLCs) were formulated for enhanced drug-delivery efficiency to C. albicans to increase the antifungal activity of Vrc and to improve the treatment of infectious Candida diseases. Vrc-NLCs were prepared by a hot-melt, high-pressure homogenization method, and size distribution, ζ-potential, morphology, drug-encapsulation efficiency, drug loading, and physical stability were characterized. The antifungal activity of Vrc-NLCs in vitro was tested during planktonic and biofilm growth in C. albicans. The mean particle size of the Vrc-NLCs was 45.62±0.53 nm, and they exhibited spheroid-like morphology, smooth surfaces, and ζ-potential of -0.69±0.03 mV. Encapsulation efficiency and drug loading of Vrc-NLCs were 75.37%±2.65% and 3.77%±0.13%, respectively. Physical stability results revealed that despite the low measured ζ-potential, the dispersion of the Vrc-NLCs was stable during their 3-week storage at 4°C. The minimum inhibitory concentration of Vrc-NLCs was identical to that of Vrc. However, the inhibition rate of Vrc-NLCs at lower concentrations was significantly higher than that of Vrc during planktonic growth in C. albicans in yeast-extract peptone dextrose medium. Surprisingly, Vrc-NLCs treatment reduced cell density in biofilm growth in C. albicans and induced more switches form hyphal cells to yeast cells compared with Vrc treatment. In conclusion, Vrc-NLCs maintain antifungal activity of Vrc and increase antifungal drug-delivery efficiency to C. albicans. Therefore, Vrc-NLCs will greatly contribute to the treatment of infectious diseases caused by C. albicans. Keywords: antifungal activity, Candida albicans, voriconazole, nanostructured lipid carriers, biofilms

Ronglin Wang,1,* Yuqian Li,1,* Gang Zhu,1,* Bo Tian,1 Wen Zeng,1 Yang Yang,2 Zhihong Li1 1Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, 2Department of Neurosurgery, The 451th hospital of PLA, Xi’an, Shaanxi, People’s Republic of China *These authors contributed equally to this work Background: Previous studies have demonstrated that long noncoding RNA cancer susceptibility candidate 2 (lncRNA CASC2) is frequently downregulated in several types of tumors and functions as a tumor-suppressive factor. However, the clinical significance and function of CASC2 in human glioma remain largely unknown. The purpose of this study was to identify the clinical values of CASC2, as well as investigate the potential molecular mechanisms in glioma. Methods: This retrospective study first analyzed the expression levels of CASC2 using quantitative real-time polymerase chain reaction. Then, CASC2 expression levels were associated with various clinicopathologic characteristics and the survival rate of patients with glioma. Finally, the function and underlying molecular mechanisms of CASC2 in human glioma were investigated in U251 cell line. Results: By quantitative real-time polymerase chain reaction analysis, our data showed that CASC2 expression was significantly downregulated in glioma tissues and cell lines (U87 and U251) compared to adjacent normal brain tissues or normal human astrocytes. Moreover, its expression negatively correlated with tumor grade in glioma patients. Furthermore, Kaplan–Meier curves with log-rank analysis revealed a close correlation between downregulated CASC2 and shorter survival time in glioma patients. In addition, Cox regression analysis indicated that CASC2 could be considered as an independent risk factor for poor prognosis. Finally, in vitro experiment demonstrated that CASC2 overexpression remarkably suppressed glioma cell proliferation, migration, and invasion through suppressing Wnt/β-catenin signaling pathway. Conclusion: This study suggested that CASC2 may potentially serve as a valuable diagnostic and prognostic biomarker and a therapeutic target for glioma patients. Keywords: glioma, lncRNA, CASC2, biomarker, Wnt/β-catenin

Yan Liang,1 Baocheng Tian,1 Jing Zhang,1 Keke Li,1 Lele Wang,1 Jingtian Han,1,* Zimei Wu2,* 1School of Pharmacy, Binzhou Medical University, 2School of Pharmacy, Yantai University, Yantai, China *These authors contributed equally to this work Abstract: Gemcitabine (GEM) and paclitaxel (PTX) are effective combination anticancer agents against non-small-cell lung cancer (NSCLC). At the present time, a main challenge of combination treatment is the precision of control that will maximize the combined effects. Here, we report a novel method to load GEM (hydrophilic) and PTX (hydrophobic) into simplex tumor-targeted nanostructured lipid carriers (NLCs) for accurate control of the ratio of the two drugs. We covalently preconjugated the dual drugs through a hydrolyzable ester linker to form drug conjugates. N-acetyl-D-glucosamine (NAG) is a glucose receptor-targeting ligand. We added NAG to the formation of NAG-NLCs. In general, synthesis of poly(6-O-methacryloyl-d-galactopyranose)–GEM/PTX (PMAGP-GEM/PTX) conjugates was demonstrated, and NAG-NLCs were prepared using emulsification and solvent evaporation. NAG-NLCs displayed sphericity with an average diameter of 120.3±1.3 nm, a low polydispersity index of 0.233±0.04, and accurate ratiometric control over the two drugs. A cytotoxicity assay showed that the NAG-NLCs had better antitumor activity on NSCLC cells than normal cells. There was an optimal ratio of the two drugs, exhibiting the best cytotoxicity and combinatorial effects among all the formulations we tested. In comparison with both the free-drug combinations and separately nanopackaged drug conjugates, PMAGP-GEM/PTX NAG-NLCs (3:1) exhibited superior synergism. Flow cytometry and confocal laser scanning microscopy showed that NAG-NLCs exhibited higher uptake efficiency in A549 cells via glucose receptor-mediated endocytosis. This combinatorial delivery system settles problems with ratiometric coloading of hydrophilic and hydrophobic drugs for tumor-targeted combination therapy to achieve maximal anticancer efficacy in NSCLC. Keywords: polymer–drug conjugate, nanostructured lipid carriers, combination treatment, ratiometric drug loading, cancer targeting

Bing Tian,1 Ri Liu,1 Shiyue Chen,1 Luguang Chen,1 Fang Liu,1 Guorong Jia,1 Yinmei Dong,1 Jing Li,1 Huaiwen Chen,2,3 Jianping Lu11Department of Radiology, 2Center of Clinical and Translational Medicine, Shanghai Changhai Hospital, The Second Military Medical University, 3Sunlipo Biotech Research Center for Nanomedicine, Shanghai, People’s Republic of ChinaBackground: Acute pancreatitis (AP) is an acute inflammatory condition of the pancreas. The symptoms, treatment, and prognosis of mild and severe AP are different, and severe AP is a potentially life-threatening disease with a high incidence of complications and high mortality rate. Thus, it is urgent to develop an effective approach to reliably discriminate between mild and severe AP.Methods: We have developed novel gadolinium-diethylenetriaminepentaacetic (Gd-DTPA)-loaded mannosylated liposomes (named thereafter M-Gd-NL) that preferably target macrophages in AP. The targeting ability of M-Gd-NL toward macrophages in AP and its ability to discriminate between mild and severe AP were evaluated.Results: The liposomes were of desired particle size (~100 nm), Gd-DTPA encapsulation efficiency (~85%), and stability. M-Gd-NL and non-targeted Gd-DTPA-loaded liposomes (Gd-NL) exhibited increased relaxivity compared with Gd-DTPA. Compared with Gd-NL and Gd-DTPA, M-Gd-NL showed increased uptake in macrophages, resulting in increased T1 imaging ability both in vitro (macrophage cell line) and in vivo (severe AP model). Importantly, M-Gd-NL had the ability to discriminate between mild and severe AP, as reflected by a significantly higher T1 magnetic resonance imaging signal in severe AP than in mild AP. M-Gd-NL did not show severe organ toxicity in rats.Conclusion: Our data suggest that M-Gd-NL had enhanced magnetic resonance imaging ability by targeting macrophages in AP and good ability to discriminate between mild and severe AP. We believe that M-Gd-NL could shed new light on the diagnosis of AP in the near future.Keywords: acute pancreatitis, Gd-DTPA, liposomes, macrophages, mannose receptors

Jiulong Li,1,* Qinghao Li,1,* Xiaoqiong Ma,2,* Bing Tian,1 Tao Li,1 Jiangliu Yu,1 Shang Dai,1 Yulan Weng,1 Yuejin Hua1 1Key Laboratory for Nuclear-Agricultural Sciences of Chinese Ministry of Agriculture and Zhejiang Province, Institute of Nuclear-Agricultural Sciences, Zhejiang University, 2Central Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China *These authors contributed equally to this work Abstract: Deinococcus radiodurans is an extreme bacterium known for its high resistance to stresses including radiation and oxidants. The ability of D. radiodurans to reduce Au(III) and biosynthesize gold nanoparticles (AuNPs) was investigated in aqueous solution by ultraviolet and visible (UV/Vis) absorption spectroscopy, electron microscopy, X-ray diffraction (XRD), dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). D. radiodurans efficiently synthesized AuNPs from 1 mM Au(III) solution in 8 h. The AuNPs were of spherical, triangular and irregular shapes with an average size of 43.75 nm and a polydispersity index of 0.23 as measured by DLS. AuNPs were distributed in the cell envelope, across the cytosol and in the extracellular space. XRD analysis confirmed the crystallite nature of the AuNPs from the cell supernatant. Data from the FTIR and XPS showed that upon binding to proteins or compounds through interactions with carboxyl, amine, phospho and hydroxyl groups, Au(III) may be reduced to Au(I), and further reduced to Au(0) with the capping groups to stabilize the AuNPs. Biosynthesis of AuNPs was optimized with respect to the initial concentration of gold salt, bacterial growth period, solution pH and temperature. The purified AuNPs exhibited significant antibacterial activity against both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria by damaging their cytoplasmic membrane. Therefore, the extreme bacterium D. radiodurans can be used as a novel bacterial candidate for efficient biosynthesis of AuNPs, which exhibited potential in biomedical application as an antibacterial agent. Keywords: Deinococcus radiodurans, gold nanoparticles, gold ions, reduction, antibacterial

Background and purposePatients with unruptured intracranial aneurysms routinely undergo surveillance imaging to monitor growth. Angiography is the criterion standard for aneurysm diagnosis, but it is invasive. This study aimed to evaluate the accuracy and reproducibility of a 3D noncontrast black-blood MR imaging technique for unruptured intracranial aneurysm measurement in comparison with 3D-TOF and contrast-enhanced MRA, using 3D rotational angiography as a reference standard.Materials and methodsSixty-four patients (57.3 ± 10.9 years of age, 41 women) with 68 saccular unruptured intracranial aneurysms were recruited. Patients underwent 3T MR imaging with 3D-TOF-MRA, 3D black-blood MR imaging, and contrast-enhanced MRA, and they underwent 3D rotational angiography within 2 weeks. The neck, width, and height of the unruptured intracranial aneurysms were measured by 2 radiologists independently on 3D rotational angiography and 3 MR imaging sequences. The accuracy and reproducibility were evaluated by Bland-Altman plots, the coefficient of variance, and the intraclass correlation coefficient.Results3D black-blood MR imaging demonstrates the best agreement with DSA, with the smallest limits of agreement and measurement error (coefficients of variance range, 5.87%-7.04%). 3D-TOF-MRA had the largest limits of agreement and measurement error (coefficients of variance range, 12.73%-15.78%). The average coefficient of variance was 6.26% for 3D black-blood MR imaging, 7.03% for contrast-enhanced MRA, and 15.54% for TOF-MRA. No bias was found among 3 MR imaging sequences compared with 3D rotational angiography. All 3 MR imaging sequences had excellent interreader agreement (intraclass correlation coefficient, >0.95). 3D black-blood MR imaging performed the best for patients with intraluminal thrombus (n = 10).Conclusions3D black-blood MR imaging achieves better accuracy for aneurysm size measurements compared with 3D-TOF, using 3D rotational angiography as a criterion standard. This noncontrast technique is promising for surveillance of unruptured intracranial aneurysms.

Applications of photon upconverting nanoparticles (UCNPs) in biological imaging and solar energy conversion demand that their anti-Stokes luminescence be both tunable and efficient. Rational design of more efficient UCNPs requires an understanding of energy transfer (ET) between their lanthanide dopants, dynamics that are typically characterized by measuring luminescence lifetimes. Existing knowledge, however, cannot explain basic observations in lifetime experiments, such as their dependence on excitation power, significantly limiting the generality and reliability of lifetime measurements. Here, we elucidate the origins of the ET dynamics and luminescence lifetimes of Yb3+-, Er3+-co-doped NaYF4 UCNPs using time-resolved luminescence and novel applications of rate equations and stochastic simulations. Experiments and calculations consistently show that at high concentrations of Er3+, the luminescence lifetimes of UCNPs decrease as much as six-fold when excitation power densities are increased over 6 orders of magnitude. Since power-dependent lifetimes cannot be explained by intrinsic relaxation rates of individual transitions, we analyze lifetime data by treating each UCNP as a complex ET network. We find that UCNP ET networks exhibit four distinguishing characteristics of complex systems: collectivity, nonlinear feedback, robustness, and history dependence. We conclude that power-dependent lifetimes are the consequence of thousands of minor relaxation pathways that act collectively to depopulate and repopulate Er3+ emitting levels. These ET pathways are dependent on past excitation power because they originate from excited donors and excited acceptors; however, each transition has an unexpectedly small impact on lifetimes due to negative feedback in the network. This robustness is determined by systematically "knocking out", or disabling, ET transitions in kinetic models. Our classification of UCNP ET networks as complex systems explains why UCNP luminescence lifetimes do not match the intrinsic lifetimes of emitting states. In the future, UCNP networks may be engineered to rival the complexity of biological networks that pattern features with unmatched precision. ©

Black phosphorus (BP) as a promising two-dimensional (2D) material has gained great attention in nanoelectronic devices because of its intrinsic semiconductor characteristics. However, the poor material availability and solution processability have been major roadblocks that hinder its wider application in microelectronics. Herein, readily available, lost-cost BP was utilized as an effective component that was integrated via a facile solution process for the fabrication of bulk heterojunction organic solar cells (OSCs). An impressive fill factor (FF) of 74.2% and power conversion efficiency (PCE) of 10.5% were realized in the OSCs incorporating 10 wt% of BP in the active layer of the benchmark polymer donor PTB7-Th and PC71BM acceptor, corresponding to a 20% PCE enhancement compared to the BP-free binary devices. The efficiency enhancement can be attributed to BP's high hole carrier mobility that facilitates better carrier extraction and suppression of the recombination. BP has been further demonstrated to be effective in additional solar cells based on other photovoltaic (PV) materials, including non-fullerene OSCs. The successful incorporation of the inexpensive BP in the solution-based fabrication of OSCs opens the door for its application in high performance, low cost flexible electronics.

Background and purposeHigh-resolution 3T MR imaging can visualize intracranial atherosclerotic plaque. However, histologic validation is still lacking. This study aimed to evaluate the ability of 3T MR imaging to identify and quantitatively assess intracranial atherosclerotic plaque components ex vivo with histologic validation.Materials and methodsFifty-three intracranial arterial specimens with atherosclerotic plaques from 20 cadavers were imaged by 3T MR imaging with T1, T2, and proton-density-weighted FSE and STIR sequences. The signal characteristics and areas of fibrous cap, lipid core, calcification, fibrous tissue, and healthy vessel wall were recorded on MR images and compared with histology. Fibrous cap thickness and maximum wall thickness were also quantified. The percentage of areas of the main plaque components, the ratio of fibrous cap thickness to maximum wall thickness, and plaque burden were calculated and compared.ResultsThe signal intensity of the lipid core was significantly lower than that of the fibrous cap on T2-weighted, proton-density, and STIR sequences (P < .01) and was comparable on T1-weighted sequences (P = 1.00). Optimal contrast between the lipid core and fibrous cap was found on T2-weighted images. Plaque component mean percentages were comparable between MR imaging and histology: fibrous component (81.86% ± 10.59% versus 81.87% ± 11.59%, P = .999), lipid core (19.51% ± 10.76% versus 19.86% ± 11.56%, P = .863), and fibrous cap (31.10% ± 11.28% versus 30.83% ± 8.51%, P = .463). However, MR imaging overestimated mean calcification (9.68% ± 5.21% versus 8.83% ± 5.67%, P = .030) and plaque burden (65.18% ± 9.01% versus 52.71% ± 14.58%, P < .001).ConclusionsEx vivo 3T MR imaging can accurately identify and quantitatively assess intracranial atherosclerotic plaque components, providing a direct reference for in vivo intracranial plaque imaging.

© 2015 Zhang et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Pu