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Taoying Lu,1– 3 Mingyue Fan,1 Jianxiong Cai,4 Aolin Liu,1 Qianwen Xie,2,3 Xiaowen Zhou,1 Bei Chang,1 Lingjia Yin,2,3,5 Guli Jiang,6 Bin Sun,7 Wenyi Tang,7 Darong Wu4 1The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2Outcome Assessment Research Team in Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 3Outcome Assessment Research Team in Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, People’s Republic of China; 4State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 5Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden; 6Department of Scientific Research, Guangzhou Cadre Health Management Center, Guangzhou, People’s Republic of China; 7Department of Traditional Chinese Medicine, Guangzhou Cadre Health Management Center, Guangzhou, People’s Republic of ChinaCorrespondence: Darong Wu, State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 111 Dade Road, Guangzhou, 510120, People’s Republic of China, Tel +86 13808869436, Email darongwu@gzucm.edu.cnBackground: Dampness syndrome is a basic syndrome of many major and chronic diseases. Early screening and identification of dampness syndrome are important. The Dampness Syndrome Scale of Chinese Medicine (DSSCM) was developed to measure the occurrence and severity of dampness syndrome. The measurement characteristics of the DSSCM should be further validated. The objective of this study is to evaluate the reliability and validity of the DSSCM based on a cross-sectional survey.Methods: The development of DSSCM was based on the traditional Chinese medicine (TCM) theory, expert consensus and clinical investigations. Participants were recruited from Guangdong Provincial Hospital of Chinese Medicine and Guangzhou Cadre Health Management Center in Guangdong Province, China. All participants completed the baseline questionnaire and DSSCM. The reliability of the DSSCM was evaluated by internal consistency reliability and test–retest reliability. The factor structure was tested with confirmatory factor analysis (CFA), while discriminant validity was evaluated by calculating the difference between the total score of the DSSCM and its four dimensions for participants with or without dampness syndrome. We used a clinician’s diagnosis of dampness syndrome as a criterion to evaluate the criterion validity. Multivariate regression analysis was used to analyze the associations among gender, age, height, and weight and dampness syndrome.Results: A total of 880 participants were enrolled for psychometric validation and 869 participants were included in the final analyses after exclusion. The mean age of the participants was 42.62± 12.86 years. The Cronbach’s alpha coefficients for the four dimensions of the DSSCM were 0.809, 0.891, 0.816 and 0.780. The ICCs for the four dimensions of the DSSCM were 0.806, 0.674, 0.780 and 0.760. For validity, the results showed that the DSSCM had good content validity, discriminant validity and criterion validity. For the CFA, the root mean square error of approximation (RMSEA) was 0.091; the standardized root mean square residual (SRMR) was 0.074; the comparative fit index (CFI) was 0.766; and the Tucker–Lewis index (TLI) was 0.745. Weight was found to be associated with the total scores of the DSSCM and its three dimensions.Conclusion: The DSSCM has good reliability and validity to support its use as a tool for assessing the severity of dampness syndrome. This study provides empirical evidence for future updates to the DSSCM.Keywords: dampness syndrome, dampness syndrome scale of Chinese medicine, reliability, validity

Hongwei Huang,1 Jiacheng Mo,2 Gui Jiang,2 Zheng Lu1 1Intensive Care Unit, Guangxi Hospital Division of the First Affiliated Hospital, Sun Yat-Sen University, Nanning, Guangxi, 530022, People’s Republic of China; 2Intensive care unit, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530021, People’s Republic of ChinaCorrespondence: Zheng Lu, Intensive Care Unit, Guangxi Hospital Division of the First Affiliated Hospital, Sun Yat-sen University, Nanning, Guangxi, 530022, People’s Republic of China, Email iculuzheng@163.comPurpose: To evaluate the long-term efficacy and cost-efficiency of blood purification (BP) in severe acute pancreatitis (SAP) through single-center data.Patients and Methods: A total of 155 SAP patients were collected and followed up for 6 months. The participants were divided into control (49 cases) and BP group (106 cases) according to whether they received BP treatment or not. The primary outcomes were 6-month mortality, length of hospital stay, and hospitalization costs. Propensity score matching (PSM) analysis was performed based on various factors such as gender, age, etiology, SOFA score, JSS score, and creatinine value on day 1.Results: There were significant differences in all baseline data between BP and control groups (p< 0.05). However, there was a significant difference in the mortality, length of hospital stay, hospital costs and infection aggravation rate the in outcome data for 6-months (all p< 0.05). BP was not considered a death factor in any adjusted models, with p-values ranging from 0.81 to 0.93. The results of subgroup analysis after PSM showed that BP mode had no significant impact on prognostic indicators, but the length of ICU stay and total costs were significantly increased (all p< 0.001). There was no significant difference in mortality among the cases that did not require early intervention after 6 months (p=0.487). However, the patients in BP group had longer ICU stays (p=0.001) and higher hospitalization costs (p< 0.001) compared to the control group.Conclusion: The utilization of BP therapy did not decrease the 6-month mortality in SAP patients. Additionally, BP therapy has a significant impact on the duration of ICU stay or hospitalization expenses. However, the effectiveness and cost-efficiency of this therapy are unsatisfactory, and early intervention does not enhance survival benefits. Furthermore, there was no substantial variation in survival benefits between continuous veno-venous hemofiltration (CVVH) alone and compound BP.Keywords: severe acute pancreatitis, blood purification, long-term efficacy, cost-efficiency

Ruxian Wei,&ast; Huimei Lv,&ast; Gaiying Jiang, Xueqing Wang, Nan Zhang, Songjia Guo Nephrology Department, Shanxi Provincial People’s Hospital, Taiyuan, 030001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ruxian Wei, Nephrology Department, Shanxi Provincial People’s Hospital, No. 29, Shuangtasi Street, Taiyuan, 030001, People’s Republic of China, Email weiruxian_x@163.comObjective: The Chronic Kidney Disease Management Centre (CKDMC) primarily focuses on developing a new system for early screening, standardised diagnosis, treatment, and the long-term follow-up management of patients with chronic kidney disease (CKD) to enhance CKD prevention and management. Nurses play a pivotal role in the comprehensive management of CKD, contributing considerably to the improvement of patient survival. Consequently, this study constructs an evaluation index system for nursing positions in the CKDMC, delineating the required competencies of nurses and providing a foundation for their targeted training.Methods: A literature review and semi-structured interviews were used to develop the competency evaluation index system for nursing positions at the CKDMC. The Delphi method, involving expert correspondence, was employed over two rounds of inquiry with 16 experts, focusing on screening, modifying, and refining the indicators at all levels.Results: The response rates for the first and second rounds of the questionnaire were 100% and 93.8%, respectively, with expert authority coefficients of 0.73 for both rounds. The finalised competency evaluation index system includes 3 primary indicators (theoretical knowledge, practical skills, and professional attitude), 10 secondary indicators, and 44 tertiary indicators.Conclusion: The study successfully established a CKD specialist nurse competency evaluation index system comprising 3 primary, 10 secondary, and 44 tertiary indicators. The consensus among experts was high, rendering the results scientific, objective, and reliable. This system can serve as a basis for the training, selection, and competency evaluation of nursing professionals in CKDMCs.Keywords: chronic kidney disease, management centre, competency, index system

Wenna Zhang,1– 3 Xin Cai,1– 3 Jiayao Sun,2– 4 Weiwei Wang,2– 4 Jingfang Zhao,2– 4 Qing Zhang,1– 3 Guoliang Jiang,1– 3,5 Zheng Wang1– 3,5 1Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, People’s Republic of China; 3Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, People’s Republic of China; 4Department of Medical Physics, Shanghai Proton and Heavy Ion Center, Shanghai, People’s Republic of China; 5Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, People’s Republic of ChinaCorrespondence: Guoliang Jiang; Zheng Wang, Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, No. 4365 Kangxin Road, Pudong, Shanghai, 201315, People’s Republic of China, Email guoliang.jiang@sphic.org.cn; zheng.wang@sphic.org.cnPurpose: Carbon ion radiotherapy (CIRT) has emerged as a promising treatment modality for hepatocellular carcinoma (HCC). However, evidence of using the pencil beam scanning (PBS) technique to treat moving liver tumors remains lacking. The present study investigated the efficacy and toxicity of PBS CIRT in patients with HCC.Methods: Between January 2016 and October 2021, 90 consecutive HCC patients treated with definitive CIRT in our center were retrospectively analyzed. Fifty-eight patients received relative biological effectiveness-weighted doses of 50– 70 Gy in 10 fractions, and 32 received 60– 67.5 Gy in 15 fractions, which were determined by the tumor location and normal tissue constraints. Active motion-management techniques and necessary strategies were adopted to mitigate interplay effects efficiently. Oncologic outcomes and toxicities were evaluated.Results: The median follow-up time was 28.6 months (range 5.7– 74.6 months). The objective response rate was 75.0% for all 90 patients with 100 treated lesions. The overall survival rates at 1-, 2- and 3-years were 97.8%, 83.3% and 75.4%, respectively. The local control rates at 1-, 2- and 3-years were 96.4%, 96.4% and 93.1%, respectively. Radiation-induced liver disease was not documented, and 4 patients (4.4%) had their Child–Pugh score elevated by 1 point after CIRT. No grade 3 or higher acute non-hematological toxicities were observed. Six patients (6.7%) experienced grade 3 or higher late toxicities.Conclusion: The active scanning technique was clinically feasible to treat HCC by applying necessary mitigation measures for interplay effects. The desirable oncologic outcomes as well as favorable toxicity profiles presented in this study will be a valuable reference for other carbon-ion centers using the PBS technique and local effect model-based system, and add to a growing body of evidence about the role of CIRT in the management of HCC.Keywords: hepatocellular carcinoma, carbon ion radiotherapy, pencil beam scanning, local effect model

Jinyu Hu,1,&ast; Yuanyi Xiao,1,&ast; Guilin Jiang,2 Xiaorong Hu2 1School of Graduate and Clinical Medicine, Jiangxi University of Chinese Medicine, Nanchang City, People’s Republic of China; 2Department of Clinical Medicine, The Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang City, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaorong Hu; Guilin Jiang, The Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang City, Jiangxi Province, People’s Republic of China, Email 414496410@qq.com; j1333070957788@163.comBackground: Acupuncture is considered an important means of analgesic, which has been widely used in chronic pelvic pain syndrome (CPPS) management and treatment in recent years, published a large number of related documents. However, the relevant literature in this field has not been summarized and quantitatively analyzed. Therefore, this study aims to analyze the hotspots and predicting future research trends of acupuncture on pelvic pain syndrome.Methods: Search for the relevant publications of the web of science database from 2000 to 2022 about the treatment of acupuncture on chronic pelvic pain syndrome. The Citespace software and VosViewer software are used to analyze the visualization of the countries, institutions, authors, keywords and references and references in the literature.Results: A total of 173 publications were included. The annual number of essays gradually showed an overall growth trend over time. Medicine magazine is the most published journal in this field. J UROLOGY and Acupunct Med are the most cited journals and the most influential magazines; The most active and influential country is China, and the most produced institutions are Beijing University of Chinese Medicine; The most produced authors are Liu Zhishun. The most cited and most influential authors are Nickel JC and Armour M; keywords and cited reference analysis show that the quality of life, mechanism research, alternative medicine and electro-acupuncture will be the scientific hotspot of acupuncture treatment for chronic pelvic pain syndrome.Conclusion: This study shows that acupuncture on CPPS is increasingly valued and recognized. The future research hotspots will focus on the effects and mechanisms. In the future, more high-quality animal basic research will be required to explore the exact mechanism of acupuncture on CPPS. In addition, different parameters of acupuncture such as electric-acupuncture, stimulating frequency, duration and strength are also the focus of future research. More clinical trials are required to verify its safety and effectiveness.Keywords: acupuncture, chronic pelvic pain syndrome, bibliometrics, CiteSpace

Guanghui Jiang,&ast; Cuicui Sheng,&ast; Luxia Yan,&ast; Zipeng Wang, Qing Wang, Rui Chen, Ying Zhao Department of Neurology, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ying Zhao; Rui Chen, Email zhaoying772023@163.com; chenrui5980@163.comPurpose: To explore the relationship between the serum level of S100 calcium-binding protein, beta chain (S100β) and Parkinson’s disease (PD) with depression.Patients and Methods: A total of 145 patients with PD and 60 healthy controls matched for sex, age, and years of education in our hospital were selected. Fluorescence quantitative immunochromatography was used to quantify the level of S100β in serum. Clinical manifestations were assessed by Unified Parkinson’s Disease Rating Scale part-III (UPDRS-III), Hoehn & Yahr (H-Y) stage and 17-item Hamilton Rating Scale for Depression (HAMD-17). According to the results of HAMD-17, PD patients were divided into PD with depression group and PD without depression group. The relationship between serum S100β and HAMD-17 scores in PD patients with depression was investigated through correlation analysis and multivariate regression analysis, and receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of serum S100β.Results: The level of serum S100β in PD with depression group was significantly higher than that in PD without depression group and control group. In PD patients with depression, serum S100β level was positively correlated with UPDRS-III score, H-Y Scale and HAMD-17 score. The HAMD-17 score was positively correlated with the UPDRS-III and H-Y scales, and the increase in the HAMD-17 score was associated with women. Elevated serum S100β level and UPDRS-III score are independent risk factors for PD with depression. Analysis of receiver operating characteristic (ROC) curves showed that the serum S100β level with a cutoff of 0.28 ng/mL distinguished patients with PD with or without depression with an area under the ROC curve (AUC) of 0.742, sensitivity of 0.696, and specificity of 0.779.Conclusion: The serum S100β level could be a biomarker of PD with depression.Keywords: Parkinson’s disease, depression, S100β, risk factors

Jiali Xia, Guan Jiang Department of Dermatology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, People’s Republic of ChinaCorrespondence: Guan Jiang, Department of Dermatology, The Affiliated Hospital of Xuzhou Medical University, 99 West Huai Hai Road, Xuzhou, Jiangsu, 221002, People’s Republic of China, Tel +86 181 6877 7336, Email dr.guanjiang@xzhmu.edu.cnAbstract: Eruptive pruritic papular porokeratosis (EPPP) is a subtype of porokeratosis (PK). EPPP is characterized by intense itching and challenging to treat in some cases. Herein, for the first time, a case of successful relief of EPPP treated with abrocitinib was reported. A 75-year-old male with a 60-year history of PK suddenly experienced severe itching in the past 6 months. The patient’s use of antihistamines, prednisone, vitamin A derivatives, vitamin D derivatives, and tripterygium wilfordii showed poor efficacy. Abrocitinib is a highly selective JAK1 inhibitor, and JAK1 appears to play a crucial role in pruritic diseases. Abrocitinib can quickly relieve itching within 24 hours. Before abrocitinib treatment, the visual analog scale (VAS) score was 10, the 12-item pruritus severity scale (12-PSS) score was 19, and the dermatology life quality index (DLQI) score was 18. Abrocitinib (100 mg) was taken orally once a day. After 1 month of oral administration of abrocitinib, the skin lesions gradually subsided, pruritus was relieved, and no adverse side effects occurred. The VAS, 12-PSS, and DLQI scores of the patient decreased to 2, 3, and 4, respectively. This report suggests a potential therapeutic benefit of abrocitinib in managing EPPP. However further investigations with larger sample sizes and controlled studies are necessary to validate its efficacy as a clinical therapy.Keywords: eruptive pruritic papular porokeratosis, porokeratosis, abrocitinib, pruritus, itch, JAK inhibitors

Xiaoxia Tang,1 Yizhuo Zhang,2 Xinyu Dong,2 Guixing Jiang,2 Defei Hong,2,&ast; Xiaolong Liu2,&ast; 1Operating Room, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2General Surgery, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaolong Liu; Defei Hong, Email hahapoint1234@sina.com; hongdefi@163.comAbstract: At present, the average five-year survival rate of liver cancer in China is only 12.1%. The reason for this association lies in the diagnosis at its middle or/and advanced stage of liver cancer for lacking special clinical symptoms in almost 70% of patients without the chance of effective surgical resection. Epidemiological studies have shown that there are only 30% of patients with an initial diagnosis of liver cancer have the opportunity to undergo radical surgery. Therefore, systematic and comprehensive treatment would play an important role in liver cancer treatment at its middle or/and advanced stage, and the related therapeutic schedule still needs further improvement and optimization. We applied a gene-targeted drug of Icaritin soft capsule in the treatment of a liver cancer patient at its advanced stage. And the level of AFP was found to decrease to 6.4ng/mL from 10.86ng/mL; meanwhile, MRI showed that the primary tumor significantly reduced in size, with shrinking of the hepatogastric space, hepatic aortic side, and renal artery side lymph nodes. After treatment with TACE and Icaritin, the patient had no discomfort and no longer experienced abdominal pain and bloating and gained three kilograms of weight. The therapeutic effect of Icaritin-targeted drugs was completely demonstrated during the later treatment follow-up. That is to say, the multiple anti-tumor characteristics of Icaritin with good safety were fully displayed in this case, and it can be used in combination with other drugs to treat hepatocellular carcinoma in the clinical setting. The results show that Icaritin can put some effects on the combined treatment of patients with liver cancer.Keywords: HCC, patient, systematic and comprehensive treatment, Icaritin, gene-targeted

Yuhong Tang,1,&ast; Jun Cao,1,&ast; Rui Peng,1 Xingkang Mao,1 Bingbing Su,1 Hao Tang,1 Daoyuan Tu,1 Jie Zhou,1 Guoqing Jiang,1 Shengjie Jin,1 Qian Wang,1 Chen Zhang,2 Renjie Liu,1 Chi Zhang,1,3 Dousheng Bai1,3 1Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China; 2The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China; 3General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dousheng Bai; Chi Zhang, Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, 98 West Nantong Road, Yangzhou, 225000, People’s Republic of China, Email drbaidousheng@yzu.edu.cn; zc17212850@163.comIntroduction: Immune checkpoint therapy (ICIs) effectively improves the prognosis of advanced (stage III/IV) hepatocellular carcinoma (HCC) patients. However, its objective response rate (ORR) is below 20%, significantly limiting ICI use in advanced HCC patients. The level of tumour immune infiltration influences ICI response rate. Recent studies have found ubiquitinase to be an important factor that regulates tumour immune infiltration. Therefore, the aim of this study is to explore the key ubiquitination genes that regulate immune infiltration in advanced HCC and further validate them.Methods: A biotechnological process was performed as a means of classifying 90 advanced HCC patients into three immune subtypes and identifying associations with immune infiltration in the co-expressed modules. Ubiquitination-related genes were then screened with WGCNA. Gene enrichment analysis was performed for the target module and 30 hub genes were screened out by protein–protein interaction network (PPI). ssGSEA, single-gene sequencing and the MCP counter were used for exploring immune infiltration. TIDE score was applied for predicting drug efficacy and GSEA was used for exploring potential pathways. Finally, GRB2 expression in HCC tissue was validated by in vitro experiments.Results: GRB2 expression was found to have a significant correlation with the pathological stage and prognosis of HCC patients and a positive correlation with immune infiltration and tumour mutation burden (TMB). In addition, significant correlations with the efficacy of ICIs, sorafenib and transarterial chemoembolization (TACE) were identified. GRB2 was found to be most significantly associated with the JAK-STAT signalling pathway and cytosolic DNA sensing pathway. Finally, it was found that GRB2 expression is closely related to the prognosis, tumour size and TMN stage.Conclusion: A significant association was observed between the ubiquitinated gene GRB2 and the prognosis and immune infiltration of advanced HCC patients and it may potentially be used for predicting therapy efficacy in advanced HCC patients in the future.Keywords: ubiquitination, growth factor receptor-binding protein 2, liver cancer, tumour-infiltrating immune cells

Tao Wang,1,2 Zhandong Wang,1 Wenxia Qi,1 Ganggang Jiang,1 Gang Wang2 1Gansu University of Chinese Medicine, Lanzhou, 730020, People’s Republic of China; 2Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou, 730020, People’s Republic of ChinaCorrespondence: Gang Wang, Email wanggangyishi6565@gszy.edu.cnAbstract: Rheumatoid arthritis (RA) is a persistent systemic autoimmune disease with the hallmarks of swelling of the joint, joint tenderness, and progressive joint destruction, which may cause synovial inflammation and pannus as a basic pathological change, resulting in joint malformations and serious disorders. At present, the precise etiology and mechanism of pathogenesis of RA are unknown. The imbalance of immune homeostasis is the origin of RA. Hippo pathway is widely expressed in a range of cell lineages and plays a fundamental role in maintaining the immune steady state and may be involved in the pathogenic mechanism of RA. This study reviews the progress of Hippo pathway and its main members in the pathogenesis of RA from three aspects: regulating the maintenance of autoimmune homeostasis, promoting the pathogenicity of synovial fibroblasts and regulating the differentiation of osteoclasts. The study also presents a new way to recognize the pathogenesis of rheumatoid arthritis, which is favorable for finding a new way for treating the rheumatoid arthritis.Keywords: Hippo pathway, rheumatoid arthritis, pathogenesis, immune cell

Lu Liu,1,&ast; Xiaojiu Zhang,1,2,&ast; Nan Jiang,3,&ast; Yufeng Liu,1 Qing Wang,1 Guanghui Jiang,1 Xuejing Li,4 Liandong Zhao,1 Qijin Zhai1 1Department of Neurology, Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, People’s Republic of China; 2Department of Neurology, Hongze People’s Hospital, Huai’an, Jiangsu, People’s Republic of China; 3Department of Neurology, Lianshui PEople’s Hospital Affiliated to Kangda College of Nanjing Medical University, Huai’an, Jiangsu, People’s Republic of China; 4Rehabilitation Centre, Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liandong Zhao; Qijin Zhai, Email zld18796201519@163.com; qjzhai1983@163.comPurpose: The plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory biomarker of cerebral microbleeds (CMBs) and may be related to the occurrence, development, and prognosis of cognitive impairment. The present study aimed to investigate the impact of plasma Lp-PLA2 level on the cognitive impairment in patients with CMBs.Methods: In this study, 213 patients with CMBs confirmed by 3.0 T brain magnetic resonance imaging (MRI) were analyzed. Lp-PLA2 levels were determined by magnetic particle chemiluminescence immunoassay technology, and cognitive function was assessed using the Montreal Cognitive Assessment Scale (MoCA). The cognitive functions of patients with CMBs were divided into three groups according to the MoCA scale, including normal cognition (NC), mild cognitive impairment (MCI), and moderate-severe cognitive impairment (MSCI). Clinical, laboratory and radiological data of the three groups were analysed. The relationship between plasma Lp-PLA2 and MoCA score in patients with CMBs was investigated through rank correlation analysis and multivariate regression analysis, and receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of Lp-PLA2.Results: CMBs were detected in 213 (30.2%) of 705 patients who underwent 3.0 T MRI. Multiple comparisons showed that plasma Lp-PLA2 in patients with CMBs with normal cognitive scores was significantly lower than that in the other two groups with cognitive impairment (p < 0.05). In the single factor correlation analysis, high level of plasma Lp-PLA2 was negatively correlated with the decrease of MoCA score in patients with CMBs (r =− 0.389, p < 0.01). Multivariate regression analysis showed that high plasma Lp-PLA2 was an independent risk factor for a low MoCA score in patients with CMBs (odds ratio [OR]=1.014; 95% confidence interval [CI], 1.002– 1.026; p=0.025).Conclusion: A high level of plasma Lp-PLA2 is positively correlated with the generation of cognitive impairment in patients with CMBs and negatively correlated with the degree of impairment. Plasma Lp-PLA2 is an important indicator of cognitive impairment in patients with CMBs and may provide a therapeutic target for preventing CMB-induced cognitive impairment.Keywords: cerebral microbleeds, lipoprotein-associated phospholipase A2, cognitive impairment, risk factors, cerebral small vessel disease

Yuyuan Zhang,1,&ast; Zaoqu Liu,1,&ast; Jie Li,1 Xin Li,1 Mengjie Duo,2 Siyuan Weng,1 Peijie Lv,3 Guozhong Jiang,4 Caihong Wang,5 Yan Li,6 Shichao Liu,6 Zhen Li1 1Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 3Department of Radiology, Zhengzhou University First Affiliated Hospital, Zhengzhou, Henan, People’s Republic of China; 4Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 5Department of Magnetic Resonance Imaging, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 6Department Cardiology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhen Li, Email lzlyct620@163.comIntroduction: Mutation patterns have been extensively explored to decipher the etiologies of hepatocellular carcinoma (HCC). However, the study and potential clinical role of mutation patterns to stratify high-risk patients and optimize precision therapeutic strategies remain elusive in HCC.Methods: Using exon-sequencing data in public (n=362) and in-house (n=30) cohorts, mutation signatures were extracted to decipher relationships with the etiology and prognosis in HCC. The proteomics (n=159) and cell-line transcriptome data (n=1019) were collected to screen the implication of sensitive drugs. A novel multi-step machine-learning framework was then performed to construct a classification predictor, including recognizing stable reversed gene pairs, establishing a robust prediction model, and validating the robustness of the predictor in five independent cohorts (n=900).Results: Two heterogeneous mutation signature clusters were identified, and a high-risk prognosis cluster was recognized for further analysis. Notably, mutation signature cluster 1 (MSC1) was featured by activated anti-tumor immune and metabolism dysfunctional states, higher genomic instability (high TMB, SNV neoantigen, indel neoantigens, and total neoantigens), and a dismal prognosis. Notably, MSC performed as an independent risk factor than clinical traits (eg, stage, vascular invasion). Additionally, afatinib and canertinib were recognized which might have potential therapeutic implications in MSC1, and the targets of these drugs presented a higher expression in both gene and protein levels in HCC.Discussion: Our studies may provide a promising platform for improving prognosis and tailoring therapy in HCC.Keywords: hepatocellular carcinoma, mutation signature, gene pairs, precision therapy, machine learning, prognosis

Hua Xiao,&ast; Xia Yu,&ast; Yuanyuan Shang, Ruyan Ren, Yi Xue, Lingling Dong, Liping Zhao, Guanglu Jiang, Hairong Huang National Clinical Laboratory on Tuberculosis, 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&ast;These authors contributed equally to this workCorrespondence: Hairong Huang, Beijing Key Laboratory for Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, No. 97 Ma Chang, Tongzhou District, Beijing, 101149, People’s Republic of China, Tel +86-10-89509159, Fax +86-10-89509160, Email huanghairong@tb123.orgBackground: Sudapyridine (WX-081) has exhibited equivalent efficacy than its counterpart parent drug bedaquiline (BDQ) but better safety profile against Mycobacterium tuberculosis (Mtb). Our study was aimed to evaluate in vitro activity of WX-081 against the clinical isolates of Mtb with different drug-resistance profiles and the intracellular bactericidal activity against the reference strain.Methods: The minimum inhibitory concentrations (MICs) of WX-081 and BDQ were tested against 114 Mtb clinical isolates. The intracellular activity of WX-081 and BDQ against the Mtb reference strain H37Rv in THP-1 cells was also evaluated in parallel.Results: The MICs for WX-081 of the enrolled isolates ranged from 0.0156 μg/mL to 1 μg/mL. The MIC50 and MIC90 of WX-081 were, respectively, 0.25 μg/mL and 0.5 μg/mL, with 95.6% of the enrolled strains having MICs ≤ 0.25 μg/mL. For a given strain, the MIC value of WX-081 was generally equivalent to or 2-fold than MIC of BDQ. The intracellular bacterial killing was acquired with the tested drug concentrations that were presumed attainable during clinical usage.Conclusion: WX-081 exhibited potent efficacy against the clinical isolates in vitro. The intracellular killing effect of sudapyridine against the reference strain supports its potential efficacy in treating TB patients.Keywords: tuberculosis, sudapyridine, bedaquiline, antibacterial activity

Xin Zhang,1– 3 Xiangbo Bu,4 Wenyu Jia,1,2 Yu Ying,1,2 Shanrong Lv,1,2 Guan Jiang1,2 1Department of Dermatology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, People’s Republic of China; 2Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China; 3Department of Dermatology, Xuzhou Children’s Hospital, Xuzhou Medical University, Xuzhou, Jiangsu, 221000, People’s Republic of China; 4Department of Orthopaedics, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, Jiangsu, 221009, People’s Republic of ChinaCorrespondence: Guan Jiang, Email dr.guanjiang@xzhmu.edu.cnIntroduction: Nanophototherapy has emerged as a novel and promising therapeutic strategy for cancer treatment; however, its efficacy in dermatological tumors and precancerous lesions remains severely limited. This study aimed to use the gas-liquid injection technique to fully utilize the synergistic photodynamic therapy (PDT)/photothermal therapy (PTT) of nanomaterials to enhance the antitumor effect.Methods: A novel oxygen-generating nanocomposite (TSL-IR820-CAT) was synthesized by encapsulating the photosensitizer IR820 and catalase (CAT) using a matrix encapsulation method based on thermosensitive liposomes (TSL).–The liquid injection technology enhances the treatment of cutaneous squamous cell carcinoma (cSCC). The combined PDT/PTT therapeutic effect of TSL-IR820-CAT on cSCC was investigated using in vivo and in vitro experiments.Results: TSL-IR820-CAT, with good stability, efficient drug release, and photothermal conversion ability, was successfully developed. Nanoparticles injected through a needle-free syringe efficiently accumulate in the tumor tissue. As TSL-IR820-CAT was consumed by A431 cells, some of it localized to the mitochondria and produced oxygen to relieve hypoxia, thereby enhancing the efficacy of PDT. PDT/PTT combination therapy resulted in irreversible apoptosis and inhibited cSCC growth. TSL-IR820-CAT coupled with gas-liquid injection was free from apparent systemic side effects.Conclusion: This article discusses new strategies and ideas for treating skin tumors and has significant application value.Keywords: skin squamous cell carcinoma, nanoparticles, gas-liquid injection technology, photodynamic therapy, photothermal therapy

Chunlong Li,1 Yuexia Liu,2 Ning Yang,3 Zhihong Lan,4 Shumei Huang,3 Yunfan Wu,3 Xiaofen Ma,3 Guihua Jiang3 1Department of Medical Imaging, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’ s Republic of China; 2Department of Ultrasound, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’ s Republic of China; 3Department of Medical Imaging, Guangdong Second Provincial General Hospital, Guangzhou, People’s Republic of China; 4Department of Medical Imaging, Zhuhai City People’s Hospital, Zhuhai, People’s Republic of ChinaCorrespondence: Guihua Jiang; Xiaofen Ma, Email GH.jiang2002@163.com; xiaofenma12@163.comIntroduction: In recent years, people have gained a profound understanding of chronic insomnia disorder (CID), but the pathophysiological mechanism of CID is still unclear. There is some evidence that the locus coeruleus (LC) is involved in the regulation of wakefulness in CID, but there have been few studies using brain functional imaging. The purpose of this study was to evaluate the resting-state functional connectivity (FC) between the LC and other brain voxels in CID and whether these abnormal FC are involved in the regulation of wakefulness.Methods: A total of 49 patients with chronic insomnia disorder and 47 healthy controls (HC) matched for gender, age, and education were examined with rs-fMRI in this study. The LC was selected as the region of interest, and then seed-based analysis was conducted on the LC and other voxels to obtain the brain regions with abnormal FC. The correlation between the FC value of the abnormal connection area and the clinical scale score was analyzed.Results: Compared with the HC, the FC between the LC and right precuneus, right posterior cingulate cortex, left middle temporal gyrus, left calcarine, and right superior orbitofrontal cortex was significantly enhanced (p < 0.05, FDR correction), and the functional connectivity signal value between the locus coeruleus and left middle temporal gyrus was positively correlated with the Self-Rating Depression Scale (p = 0.021).Conclusion: The abnormal FC between the LC and multiple brain regions may contribute to a better understanding of the neurobiological mechanism of CID.Keywords: chronic insomnia disorder, default mode network, functional connectivity, locus coeruleus, seed-based analysis

Danfeng Wang,1,2 Shuhui Min,1,2 Xiao Lin,1,2 Guan Jiang1,2 1Department of Dermatology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China; 2First Clinical Medical College, Xuzhou Medical University, Xuzhou, People’s Republic of ChinaCorrespondence: Guan Jiang, Department of Dermatology, Affiliated Hospital of Xuzhou Medical University; First Clinical Medical College, Xuzhou Medical University, Xuzhou, People’s Republic of China, Email dr.guanjiang@xzhmu.edu.cnObjective: The aim of the present study was to investigate the association of single-nucleotide polymorphisms (SNPs) in the macrophage migration inhibiting factor (MIF), interferon-induced Helicase C domain 1 (IFIH1), interleukin-6 (IL6) genes, circulating levels with non-segmental vitiligo (NSV) susceptibility in the Chinese population, and to analyze the relationships between gene polymorphisms and clinical characteristics of vitiligo.Methods: In this study, genotyping was conducted in 155 patients with NSV and 117 unaffected controls using polymerase chain reaction and snapshot technique. Serum concentrations were determined by ELISA kit.Results: There were strong associations between IFIH1 H843R and IL6-572G/C polymorphisms and NSV susceptibility (p = 0.013; p = 0.009). In contrast to previous studies, we found no significant difference in the MIF-173G/C polymorphism between the two groups. In addition, the frequency of allelic distribution for MIF-173G/C in patients with active NSV was significantly higher than stable NSV (p = 0.011), and IFIH1 H843R with early-onset (≤ 20), active or family history of NSV was significantly higher than late-onset (> 20), stable or no family history of NSV (p = 0.033; p = 0.045; p = 0.039). Serum concentrations of MIF were higher in patients with active NSV, serum IFIH1 and IL6 concentrations were related to the presence of polymorphisms in patients with NSV (p = 0.009; p = 0.011).Conclusion: Our results suggested that IFIH1 H843R and IL6-572G/C gene polymorphisms and expression levels are obviously correlated with the onset of NSV. MIF-173G/C allele and serum concentrations may be associated with active NSV, and IFIH1 H843R allele may be associated with youth, active or family history of NSV.Keywords: vitiligo, MIF, IFIH1, IL6, single nucleotide polymorphism

Shoujun Xu,1,&ast; Meng Li,2,&ast; Chunlan Yang,3 Xiangling Fang,4 Miaoting Ye,4 Yunfan Wu,2 Binrang Yang,4 Wenxian Huang,4 Peng Li,1 Xiaofen Ma,2 Shishun Fu,2 Yi Yin,2 Junzhang Tian,2 Yungen Gan,1 Guihua Jiang2 1Department of Radiology, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of China; 2Department of Medical Imaging, Guangdong Second Provincial General Hospital, Guangzhou, People’s Republic of China; 3Department of Hematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of China; 4Department of Department of Children Healthcare, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of China&ast;These authors have contributed equally to this workCorrespondence: Guihua Jiang; Yungen Gan, Email jianggh@gd2h.org.cn; gdszgyg-1@126.comPurpose: This study used the graph-theory approach, degree centrality (DC) to analyze whole-brain functional networks at the voxel level in children with ASD, and investigated whether DC changes were correlated with any clinical variables in ASD children.Methods: The current study included 86 children with ASD and 54 matched healthy subjects Aged 2– 5.5 years. Next, chloral hydrate induced sleeping-state functional magnetic resonance imaging (ss-fMRI) datasets were acquired from these ASD and healthy subjects. For a given voxel, the DC was calculated by calculating the number of functional connections with significantly positive correlations at the individual level. Group differences were tested using two-sample t-tests (p < 0.01, AlphaSim corrected). Finally, relationships between abnormal DCs and clinical variables were investigated via Pearson’s correlation analysis.Results: Children with ASD exhibited low DC values in the right middle frontal gyrus (MFG) (p

Suting Chen,&ast; Fen Wang,&ast; Yi Xue, Fengmin Huo, Junnan Jia, Lingling Dong, Liping Zhao, Guanglu Jiang, Hairong Huang National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory for Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, China&ast;These authors contributed equally to this workCorrespondence: Hairong Huang, Email huanghairong@tb123.org; Guanglu Jiang, guanglu0725@126.comBackground: Nontuberculous mycobacteria (NTM) and their associated diseases remain neglected. Through minor modifications in our diagnostic algorithm, we observed an unexpected higher number of cultivable NTM isolates. Therefore, a retrospective study was performed thoroughly to investigate the effect of changed laboratory procedures on NTM isolation in a specialized tuberculosis hospital.Methods: NTM isolation rates and composition of NTM species were compared for the two diagnostic algorithms: (1) by using traditional p-nitrobenzoic acid (PNB) selective medium as a preliminary test to identify NTM isolates among the positive cultures (procedure I) and (2) by using the MPT64 antigen detection method to distinguish between Mycobacterium tuberculosis complex (MTBC) isolates and possible NTM isolates after a positive MGIT960 liquid culture (procedure II).Results: The NTM isolation rate in procedure II was significantly higher than the procedure I (18.08% vs 9.71%; P< 0.001). A noticeable increase in the ratio of NTM isolates among the identified mycobacteria was observed over the studied years (ie, from 58.18% in 2019 to 72.93% in 2021), which indicated a more precise prescription of species identification test after prompt information was provided in procedure II. In addition, the consistency of the identified species using multiple specimens from the same patient did not present a significant difference between the procedures.Conclusion: According to our study, NTM infection might be far more underestimated than it is. A diagnostic procedure combining MGIT960 culture and MPT64 antigen detection could timely and easily identify clues of NTM isolates and improve the diagnosis of NTM infections.Keywords: tuberculosis, nontuberculous mycobacteria, p-nitrobenzoic acid, MPT64 antigen, species

Jian-guo Zhang,1– 3,&ast; Shang-miao Fu,1,&ast; Fen Liu,1 Jian-guo Wan,4 Shu-bing Wu,4 Guang-hui Jiang,4 Wen-qiang Tao,1 Wen Zhou,4 Ke-jian Qian1 1Department of Critical Care Medicine, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Department of Infection, First Affiliated Hospital of Nanchang University, Nanchang, Jianxi, People’s Republic of China; 3Department of Critical Care Medicine, Linyi People’s Hospital, Linyi, Shandong, People’s Republic of China; 4Department of Critical Care Medicine, First Hospital of Nanchang, Nanchang, Jiangxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ke-jian Qian, Department of Critical Care Medicine, First Affiliated Hospital of Nanchang University, No. 17 YongwaiZheng Street, Nanchang, Jiangxi, 330006, People’s Republic of China, Email 361439919072@email.ncu.edu.cn Wen Zhou, Department of Critical Care Medicine, First Hospital of Nanchang, No. 128 Xiangshan North Road, Nanchang, Jiangxi, 330006, People’s Republic of China, Email doctor20210428@163.comPurpose: To investigate the correlation and prognostic significance of low triiodothyronine (T3) syndrome and norepinephrine dosage in patients with sepsis and septic shock.Methods: This single-center, retrospective, cohort study enrolled 169 patients with sepsis and septic shock that were admitted to the intensive care unit of First Hospital of Nanchang, Nanchang, China from June 2017 to July 2019. All included patients were followed up for 28 days or died, whichever was earlier. Patients with free T3 (FT3) of < 3.1 pmol/L were considered with low T3 syndrome. The correlation and prognostic significance of the FT3 and maximum dosage of norepinephrine (MDN) within 72 h, as well as other clinical indicators, were analyzed by using correlation analysis, principal component analysis, receiver operating characteristic curve, Youden index, and logistic regression.Results: A total of 138 patients were allocated to the low T3 group. FT3 inversely correlated with the Sequential Organ Failure Assessment (SOFA) score within 24 h, fluid resuscitation volume within 24 h, and lactic acid levels, and positively correlated with the mean arterial pressure. The critical values of age, SOFA, and MDN for predicting the 28-day mortality were 79.5 years, 8.5 points, and 0.61 μg/kg/min, respectively. The mortality of the low T3 and normal T3 groups was similar. Considering the MDN of 0.61 μg/kg/min as the cutoff value, the mortality between the two groups was significantly different.Conclusion: Among patients with sepsis and septic shock, FT3 was inversely correlated with the disease severity. An MDN ≥ 0.61 μg/kg/min within 72 h may be an important prognostic indicator.Keywords: euthyroid sick syndromes, low T3 syndrome, non-thyroidal illness syndrome, norepinephrine, sepsis, septic shock

Xiaochen Yang,1,2 Yangjing Zhao,3 Qixiang Shao,3 Guoqin Jiang1 1Department of Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, Jiangsu Province, People’s Republic of China; 2Department of Thyroid and Breast Surgery, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, 215300, Jiangsu Province, People’s Republic of China; 3Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu Province, People’s Republic of ChinaCorrespondence: Guoqin JiangDepartment of Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, 215004, People’s Republic of ChinaTel/Fax +86-512-67784797Email jiang_guoqin@suda.edu.cnQixiang ShaoJiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, 212013, People’s Republic of ChinaTel +86-511-80961661Fax +86-511-86102010Email shao_qx@ujs.edu.cnPurpose: Cytochrome b561 (CYB561) is a transmembrane protein and participates in ascorbate recycling and iron homeostasis. However, its role in breast cancer remains unclear.Patients and Methods: In this study, we explored the expression pattern and prognostic value of CYB561 in breast cancer through The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), PrognoScan and Kaplan–Meier Plotter and confirmed its mRNA expression in human breast cell lines. LinkedOmics, Metascape and Gene Expression Profiling Interactive Analysis (GEPIA2) databases were applied to investigate the co-expression genes and construct microRNA (miRNA) networks associated with CYB561. The correlations between CYB561 and immune infiltration cells and genes were also illustrated.Results: The CYB561 expression was upregulated in breast cancer tissues and cell lines and significantly correlated with the clinical features of breast cancer patients. High CYB561 expression was associated with poor survival and was an independent risk factor for overall and disease-specific survival. Functional enrichment analysis showed that CYB561 and its co-expressed genes were mainly enriched in lipid biosynthetic process, Wnt signaling pathway, Hippo signaling pathway, etc. The miRNA network analysis suggested that hsa-miR-497 was negatively correlated with CYB561 expression and was predicted to direct target CYB561. CYB561 expression was positively correlated with infiltrating levels of CD4+ T cells, neutrophils and dendritic cells in breast cancer. Subsequent analysis found that B cells could predict the outcome of breast cancer. Also, CYB561 showed strong correlations with diverse immune marker sets in breast cancer.Conclusion: CYB561 may serve as a potential prognostic biomarker and target for breast cancer. Our findings laid foundation for future research on molecular mechanisms of CYB561 in breast cancer.Keywords: cytochrome b561, breast cancer, prognosis, biomarker, immune infiltrates

Xia Yu,&ast; Fengmin Huo,&ast; Fen Wang,&ast; Shu’an Wen, Guanglu Jiang, Yi Xue, Lingling Dong, Liping Zhao, Rui Zhu, Hairong Huang National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory for Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hairong HuangBeijing Key Laboratory for Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beiguan St, No. 9, Tongzhou Qu, Beijing, 101149, People’s Republic of ChinaEmail huanghairong@tb123.orgBackground: The antimicrobial activities of some new oxazolidinones against slowly growing mycobacteria (SGM) have never been well evaluated.Methods: We evaluate the in vitro susceptibility of 20 reference strains and 157 clinical isolates, pertaining different SGM species, against four oxazolidinones, ie, delpazolid, sutezolid, tedizolid and linezolid. In addition, the association of linezolid resistance and mutations in 23srRNA, rplC, rplD were also tested.Results: Sutezolid presented the strongest antimicrobial activity against the clinical isolates of M. intracellulare than the other oxazolidinones, with MIC50 at 2 μg/mL and MIC90 at 4 μg/mL. MICs of sutezolid were usually 4- to 8-fold lower than these of linezolid against M. intracellulare and M. avium. The tested isolates of M. kansasii were susceptible to all of the four oxazolidinones. According to the multiple sequence alignment, novel 23srRNA mutations (A2267C and A2266G) in M. intracellulare and rplD mutations (Thr147Ala) in M. avium were identified in this study which have plausible involvement in rendering resistance against linezolid.Conclusion: This study showed that sutezolid harbors the strongest inhibitory activity against M. intracellulare, M. avium and M. kansasii in vitro, which provided important insights on the potential clinical application of oxazolidinones for treating SGM infections.Keywords: slowly growing mycobacteria, delpazolid, sutezolid, tedizolid, linezolid, antimicrobial activity

Qin Li,1,&ast; Jie Ren,2,&ast; Wei Liu,3 Guoqin Jiang,2 Rongkuan Hu1 1GenePharma Co., Ltd., Suzhou, 215125, Jiangsu, People’s Republic of China; 2Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, People’s Republic of China; 3Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guoqin JiangDepartment of General Surgery, The Second Affiliated Hospital, Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu, People’s Republic of ChinaTel +86-512-67784797Email jiang_guoqin@163.comRongkuan HuGenePharma Co., Ltd., 199 Dongping Street, Suzhou, 215125, Jiangsu, People’s Republic of ChinaTel +86-512-86668828Email rkhu@mail.ustc.edu.cnPurpose: The purpose of our research was to identify and evaluate synthetic phosphorothioate-modified CPG oligodeoxynucleotides (CPG-ODNs) activating innate and adaptive immune responses. Furthermore, combined treatment with CpG and an mRNA cancer vaccine was evaluated in melanoma models as a therapeutic approach.Methods: A molecular assay was used to screen new CpG molecules; mouse modeling and pathological analysis were used to confirm the antitumor effect of CpG alone or in combination with an mRNA vaccine. Finally, safety was assessed by monitoring blood biochemistry.Results: We first screened and identified a new CpG-B class ODN (CpG2018B) that effectively stimulated type II interferons in both mouse plasmacytoid dendritic cells (pDCs) and human peripheral blood mononuclear cells (PBMCs). In addition, CpG2018B promoted cytokine production mainly via toll-like receptor 9 (TLR9) pathways. We further demonstrated that intratumoral (IT) injection of CpG2018B inhibited melanoma growth in syngeneic models and could turn “cold” tumors into “hot” tumors. Then, CpG2018B and an mRNA-based neoantigen cancer vaccine were encapsulated in lipid nanoparticles (LNPs) and intratumorally injected into melanoma mouse models. Interestingly, vaccination with CpG or the mRNA vaccine alone could inhibit tumor growth, while combination of CpG with the mRNA vaccine enhanced the antitumor effect. Finally, we described the long-term safety and tolerability of CpG2018B and mRNA therapy in mice model.Conclusion: We identified a novel CpG-B class ODN to promote the immune response, and CpG combined with mRNA cancer vaccines is an attractive candidate approach for immunostimulatory sequence (ISS)-based therapeutic strategies.Keywords: CpG, IFN-γ, TLR9, mRNA vaccine, neoantigen

Yilan Xing,1,2 Shishun Fu,3 Meng Li,3 Xiaofen Ma,3 Mengchen Liu,3 Xintong Liu,2 Yan Huang,2 Guang Xu,2 Yonggang Jiao,2 Hong Wu,2 Guihua Jiang,1,3 Junzhang Tian1,3 1The Second School of Clinical Medicine, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Neurology of Guangdong Second Provincial General Hospital, Guangzhou, People’s Republic of China; 3Department of Medical Imaging of Guangdong Second Provincial General Hospital, Guangzhou, People’s Republic of ChinaCorrespondence: Junzhang Tian; Guihua JiangDepartment of Medical Imaging of Guangdong Second Provincial General Hospital, No. 466, Xingang Road, Guangzhou, People’s Republic of ChinaTel +86 20 89168701; +86 18620120333Email tianjunzhang2015@163.com; GH.jiang2002@163.comPurpose: The aim of this study was to compare regional homogeneity (ReHo) changes in Parkinson’s disease mild cognitive impairment (PD-MCI) patients with respect to normal controls (NC) and those with cognitively normal PD (PD-CN). Further, the study investigated the relationship between ReHo changes in PD patients and neuropsychological variation.Patients and Methods: Thirty PD-MCI, 19 PD-CN, and 21 NC subjects were enrolled. Resting state functional magnetic resonance imaging data of all subjects were collected, and regional brain activity was measured for ReHo. Analysis of covariance for ReHo was determined between the PD-MCI, PD-CN, and NC groups. Spearman rank correlations were assessed using the ReHo maps and data from the neuropsychological tests.Results: In comparison with NC, PD-CN patients showed significantly higher ReHo values in the right middle frontal gyrus (MFG) and lower ReHo values in the left supramarginal gyrus, bilateral inferior parietal lobule (IPL), and the right postcentral gyrus (PCG). In comparison with PD-CN patients, PD-MCI patients displayed significantly higher ReHo values in the right PCG, left middle occipital gyrus (MOG) and IPL. No significant correlation between ReHo indices and the neuropsychological scales was observed.Conclusion: Our finding revealed that decreases in ReHo in the default mode network (DMN) may appear before PD-related cognitive impairment. In order to preserve executive attention capacity, ReHo in the right MFG in PD patients lacking cognition impairment increased for compensation. PD-MCI showed increased ReHo in the left MOG, which might have been caused by visual and visual-spatial dysfunction, and increased ReHo in the left IPL, which might reflect network disturbance and induce cognition deficits.Keywords: Parkinson’s disease, mild cognitive impairment, ReHo, fMRI, DMN

Guiying Jiang,1,* Xueqian Wang,1,* Ying Zhou,1 Chenming Zou,2,3 Ling Wang,1 Wei Wang,1 Danya Zhang,1 Hanjie Xu,1 Jie Li,1 Fei Li,1 Danfeng Luo,1 Xiangyi Ma,1 Ding Ma,1 Songwei Tan,2 Rui Wei,1 Ling Xi1 1Department of Obstetrics & Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei Province, People’s Republic of China; 2Tongji School of Pharmacy, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei Province, People’s Republic of China; 3School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ling Xi; Rui WeiDepartment of Obstetrics & Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, People’s Republic of ChinaTel/Fax +86 27 83662688Email lxi@tjh.tjmu.edu.cn; weirui2018@tjh.tjmu.edu.cnBackground and Purpose: Cisplatin–paclitaxel (TP) combination chemotherapy as the first-line therapy for numerous cancers is hindered by its inadequate accumulation in tumors and severe side effects resulting from non-specific distribution. The aim of this study is to explore whether TMTP1-modified, cisplatin and paclitaxel prodrugs co-loaded nanodrug could improve cervical cancer chemotherapy and relieve its side effects through active and passive tumor targeting accumulation and controlled drug release.Methods: TDNP, with capacities of active targeting for tumors and controlled drug release, was prepared to co-deliver cisplatin and paclitaxel prodrugs. The characteristics were investigated, including the diameter, surface zeta potential, stability and tumor microenvironment (TME) dependent drug release profiles. Cellular uptake, cytotoxicity, drug accumulation in tumors, antitumor effects and safety analysis were evaluated in vitro and in vivo.Results: The oxidized cisplatin and the paclitaxel linked to the polymer achieved a high loading effciency of over 80% and TME-dependent sustained drug release. Moreover, TMTP1 modification enhanced cellular uptake of TDNP and further improved the cytotoxicity of TDNP in vitro. In vivo, TDNP showed an extended blood circulation and increased accumulation in SiHa xenograft models with the aid of TMTP1. More importantly, TDNP controlled tumor growth without life-threatening side effects.Conclusion: Our study provided a novel TP co-delivery platform for targeted chemotherapy of cervical cancer, which was promising to improve the therapeutic effcacy of TP and may also have application in other tumors.Keywords: TME-responsive, targeted co-delivery, combined chemotherapy, cervical cancer

Sun J, Chen C, Jiang G, Tian W, Li Y, Sun S. Int J Nanomedicine. 2014;9(1):1339–1346. An error during the preparation of Figure 3 for publishing led to the inadvertent creation of a duplicate region in figure part 3A on page 1342. The journal wishes to apologise for this error. The correct version of Figure 3 is shown below. Figure 3 The different Ki67 expressions detected by QD-IHC (A and C) and IHC (B and D) in the same specimens.Abbreviations: IHC, immunohistochemistry; QD-IHC, quantum dot-immunohistochemistry.Notes: (A and B) are the same specimens; (C and D) are the same specimens. Scale bar: 25 μm.

Suting Chen,1,* Tianlu Teng,1,2,* Zhuman Zhang,1 Yuanyuan Shang,1,2 Hua Xiao,1 Guanglu Jiang,1 Fen Wang,1 Junnan Jia,1 Lingling Dong,1 Liping Zhao,1 Naihui Chu,2 Hairong Huang1 1National Clinical Laboratory on Tuberculosis, 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; 2Department of Tuberculosis; Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hairong Huang; Naihui Chu Tel +86-10-89509159; +86-10-89509301Email nclhuang@ccmu.edu.cn; dongchu1994@sina.comObjective: Treatment choices for Mycobacterium abscessus (M. abscessus) infections are very limited, and the prognosis is generally poor. Effective new antibiotics or repurposing existing antibiotics against M. abscessus infection are urgently needed. Carbonyl cyanide 3-chlorophenylhydrazone (CCCP), a member of the lipophilic weak acid class, is known as an efflux pump inhibitor for Mycobacterium tuberculosis. The aim of this study was to determine the inhibitory activity of CCCP as a potential novel antibiotic against M. abscessus.Methods: A total of 47 reference strains of different mycobacterial species and 60 clinical isolates of M. abscessus were enrolled. In vitro inhibitory activity of CCCP was accessed using microplates alamar blue method with the reference and clinical isolates. The activity of CCCP against intracellular M. abscessus residing within macrophage was also evaluated by intracellular colony numerating assay.Results: CCCP exhibited good activity against M. abscessus clinical isolates in vitro, the minimum inhibitory concentration (MIC) ranged from 0.47 μg/mL to 3.75 μg/mL, with a MIC50 of 1.875 μg/mL and MIC90 of 3.75 μg/mL. At concentrations safe for the cells, CCCP exhibited highly intracellular bactericidal activities against M. abscessus and M. massiliense reference strains, with inhibitory rates of 84.8%± 8.8% and 72.5%± 13.7%, respectively. CCCP demonstrated bactericidal activity against intracellular M. abscessus that was comparable to clarithromycin, and concentration-dependent antimicrobial activity against M. abscessus in macrophages was observed. In addition, CCCP also exhibited good activities against most reference strains of rapidly growing mycobacterial species.Conclusion: CCCP could be a potential candidate of novel antimicrobiological agent to treat M. abscessus infection.Keywords: Mycobacterium abscessus, carbonyl cyanide 3-chlorophenylhydrazone, minimum inhibitory concentration, intracellular bactericidal activity

Qidong Zhou,1,2 Weihong Ding,1,2 Zhiyu Qian,1,2 Guangliang Jiang,3 Chuanyu Sun,1,2 Ke Xu1,2 1Department of Urology, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 3Department of Urology, Ruijin Hospital, Medical School of Shanghai Jiao Tong University, Shanghai, People’s Republic of ChinaCorrespondence: Ke XuDepartment of Urology, Huashan Hospital, Fudan University, No. 12 Middle Urumqi Road, Shanghai 200040, People’s Republic of ChinaTel/Fax +86 21 52887080Email drkexu@163.comObjective: Chronic psychological stress is common in patients with bladder cancer. An increasing number of evidence demonstrated that psychiatric disorder leads to worse prognostic outcomes in bladder cancer. This study was to investigate the effects of chronic psychological stress on the growth of bladder cancer and its potential mechanisms.Methods: A xenograft mouse model was established by subcutaneously implanting the human bladder cancer cell line T24 into nude mice. All of the tumor-bearing mice (N=20) were randomly separated into two groups. Mice in the control group were subjected to normal feeding conditions, while in another group, a chronic unpredictable mild stress (CUMS) model was established, in which mice were exposed to various types of stressors. Various analyses were performed on parameters including the tumor volume, tumor weight, expression of Caspase-3 and VEGF, proportion of Ki-67 positive cells (Ki-67 index), microvessel density (MVD) and serum concentrations of epinephrine and cortisol.Results: In the CUMS group, the growth of transplanted tumors was distinctly accelerated, with the weight of removed tumors at the end of experiment increased by 34.07% compared to that of the control. Serum levels of epinephrine and cortisol determined by ELISA were significantly increased by CUMS. Immunohistochemistry and Western blot analysis showed that the expression of Caspase-3 was downregulated, whereas the expression of VEGF was upregulated in the CUMS group. Meanwhile, CUMS could increase the Ki-67 index and MVD.Conclusion: Our research supports the hypothesis that CUMS could affect the growth of bladder cancer in nude mice, indicating that the intervention of chronic psychological stress may be a possible therapeutic strategy for bladder cancer.Keywords: bladder cancer, chronic unpredictable mild stress, tumor growth, cell proliferation, angiogenesis

Xiaoyang Hou,1,* Yingkai Tao,1,* Xinxin Li,1,* Yanyu Pang,1 Chunsheng Yang,2 Guan Jiang,1 Yanqun Liu1 1Department of Dermatology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, People’s Republic of China; 2Department of Dermatology, The Affiliated Huai’an Hospital of Xuzhou Medical University, The Second People’s Hospital of Huai’an, Huai’an 223002, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guan Jiang; Yanqun LiuDepartment of Dermatology, The Affiliated Hospital of Xuzhou Medical University, 99 West Huai Hai Road, Xuzhou, Jiangsu 221002, People’s Republic of ChinaEmail dr.guanjiang@xzhmu.edu.cn; xyfylyq@sohu.comObjective: Nanotechnology-based photodynamic therapy (PDT) is a relatively new anti-tumor strategy. However, its efficacy is limited by the hypoxic state in the tumor microenvironment. In the present study, a poly(lactic-co-glycolic acid) (PLGA) nanoparticle that encapsulated both IR820 and catalase (CAT) was developed to enhance anti-tumor therapy.Materials and Methods: HA-PLGA-CAT-IR820 nanoparticles (HCINPs) were fabricated via a double emulsion solvent evaporation method. Dynamic light scattering (DLS), transmission electron microscopy (TEM), laser scanning confocal microscopy, and an ultraviolet spectrophotometer were used to identify and characterize the nanoparticles. The stability of the nanoparticle was investigated by DLS via monitoring the sizes and polydispersity indexes (PDIs) in water, PBS, DMEM, and DMEM+10%FBS. Oxygen generation measurement was carried out via visualizing the oxygen bubbles with ultrasound imaging system and an optical microscope. Inverted fluorescence microscopy and flow cytometry were used to measure the uptake and targeting effect of the fluorescent-labeled nanoparticles. The live-dead method and tumor-bearing mouse models were applied to study the HCINP-induced enhanced PDT effect.Results: The results showed that the HCINPs could selectively target melanoma cells with high expression of CD44, and generated oxygen by catalyzing H2O2, which increased the amount of singlet oxygen, ultimately inhibiting tumor growth significantly.Conclusion: The present study presents a novel nanoplatform for melanoma treatment.Keywords: catalase, hyaluronic acid, IR820, photodynamic therapy, tumor hypoxia

Meiying Cui,1 Pan Li,1 Ying Mao,1 Lan Zhang,1 Peiyi Xia,1 Enjie Liu,1 Weiwei Wang,1 Jianying Zhang,2 Guozhong Jiang,1 Wencai Li1 1Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, Mainland China; Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Wencai Li; Guozhong JiangDepartment of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450002, People’s Republic of ChinaEmail liwencai@zzu.edu.cn; guozhongjiang@zzu.edu.cnBackground: Microsatellite instability (MSI) has been a hot topic in cancer research. Determining MSI status greatly aids tumor prognosis and treatment plans. However, MSI data for Asian cancer patients with prognostic information are scarce. Here, our aim was to clarify MSI status and its prognostic value in a large Chinese cohort with different tumors.Patients and Methods: Tissue samples from 600 Chinese cases, including 150 endometrial cancers, 150 colorectal cancers, 150 liver cancers and 150 gastric cancers, were used for IHC and MSI examinations. Two mononucleotide and three dinucleotide markers were used to analyze MSI status.Results: In total,17.3% (26/150) of endometrial cancer patients showed positive MSI,10.0% (15/150) in colorectal cancer, 2.7% (4/150) in liver cancer, and 2.7% (4/150) in gastric cancer. Tumor location (P < 0.001 for colorectal cancer) and clinical stage (P =0.038 for gastric cancer) showed significant correlations with MSI status in gastrointestinal carcinogenesis. The mismatch repair (MMR) deficiency was observed in 20 colorectal cases (13.3%) and was significantly more frequent in the MSI-positive group (P < 0.001). Interestingly, the prevalence of MSI-H was mostly occurred in early-stage tumors, and none was in late stage (stage IV). Meanwhile, low clinicopathological stage had significant correlation with longer survival in multiple cancers here.Conclusion: The incidence of microsatellite instability varies among different cancer types. And the prevalence of MSI-H mostly occurred early clinicopathological stage. In addition, our study provided a large Asian cohort screened by five loci PCR method and significantly increased knowledge on the prognostic significance of MSI in Asia.Keywords: microsatellite instability, endometrial cancer, colorectal cancer, liver cancer, gastric cancer

Yuru Guo,1 Yan Liu,2 Zehui Zhang,1 Menghan Chen,1 Dexian Zhang,1 Chunlian Tian,1 Mingchun Liu,1 Guotuo Jiang2 1Key Laboratory of Livestock Infectious Diseases in Northeast China, Ministry of Education, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, Liaoning, People’s Republic of China; 2Dalian Sanyi Animal Medicine Co., Ltd., Dalian, Liaoning, People’s Republic of ChinaCorrespondence: Mingchun Liu; Guotuo Jiang Tel/Fax +86 024 8848 7156; +86 411 6688 6289Email liumingchun@syau.edu.cn; jgt600@sina.comPurpose: This research aimed to investigate the antibacterial activity and potential mechanism of luteolin against T. pyogenes.Materials and Methods: The broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) of luteolin against various T. pyogenes strains. The potential mechanism of action of luteolin was elucidated through testing and analysing the luteolin-induced alterations of T. pyogenes in several aspects, including cell wall, cell membrane, protein expression, nucleic acid content, topoisomerase activity and energy metabolism.Results: The MIC values of luteolin against various T. pyogenes isolates and ATCC19411 were 78 μg/mL. The increased cell membrane permeability, destruction of cell wall integrity and TEM images after exposure to luteolin showed that the cell wall and membrane were damaged. The content of total protein and nucleic acid in T. pyogenes decreased significantly after treatment with luteolin (1/2 MIC) for 12, 24, and 36 h. Moreover, a hypochromic effect was observed in the absorption spectrum of luteolin when deoxyribonucleic acid (DNA) was added. In addition, after treatment with luteolin, a decrease in nicked or relaxed DNA content, which was catalysed by T. pyogenes-isolated DNA topoisomerase, was observed. In addition, the adenosine triphosphate (ATP) content in cells and the activity of succinate dehydrogenase (SDH) both decreased when T. pyogenes was exposed to different concentrations (1/4 MIC, 1/2 MIC, 1 MIC, 2 MIC) of luteolin for 1 h.Conclusion: Luteolin showed distinct antibacterial activity against T. pyogenes by multiple actions, which mainly include destroying the integrity of the cell wall and cell membrane, influencing the expression of proteins, inhibiting nucleic acid synthesis, and interfering with energy metabolism.Keywords: luteolin, Trueperella pyogenes, antibacterial activity, antibacterial mechanism

Jingjing Ge,1,2 Jingjing Yang,3 Jingjing Song,1 Guangyu Jiang,1,2 Yong Zheng1 1Faculty of Psychology, Southwest University, Chongqing, People’s Republic of China; 2Department of Humanities and Management, Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, People’s Republic of China; 3Department of Public Health and Management, Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Yong ZhengFaculty of Psychology, Southwest University, Chongqing, People’s Republic of ChinaTel +86 13667636167Fax + 86 23 68254139Email zhengy@swu.edu.cnPurpose: Past-negative time perspective (PNTP) can affect our everyday lives and is associated with negative emotions, unhealthy behaviors, rumination, anxiety, depression, and post-traumatic stress disorder (PTSD). Dispositional mindfulness may be able to reduce the negative effects of PNTP; however, few studies have investigated their relationship. Thus, the purpose of this study was to explore the effect dispositional mindfulness has on PNTP, as well as the mediating role of resilience and inner peace in this regard.Methods: This study investigated the cross-sectional relationship between self-reported mindfulness, resilience, inner peace, and PNTP. In order to further explore the relationship between mindfulness and PNTP, this study specially selected and analyzed the samples of 185 meditators and 181 non-meditators.Results: Correlation analysis revealed that mindfulness is significantly positively correlated with resilience and inner peace. Conversely, PNTP is significantly negatively correlated with mindfulness, resilience, and inner peace. Structural equation model analysis revealed that resilience and inner peace partially mediated the relationship between mindfulness and PNTP. Furthermore, a multi-group analysis showed that the mediating effects are different between meditators and non-meditators. For meditators, the effect of mindfulness on PNTP was fully mediated by resilience and inner peace. For non-meditators, the effect of mindfulness on PNTP was only partially mediated by resilience and inner peace.Conclusion: Based on the significant differences between the mediational models of meditators and non-meditators, we believe that dispositional mindfulness can negatively predict PNTP, and practicing meditation consistently improves dispositional mindfulness, resilience and inner peace and effectively reduces PNTP. Our findings indicate that a combination of mindfulness and PNTP could be used to design new psychological interventions to reduce the symptoms of mental health concerns such as negative bias, rumination, depression, anxiety, and PTSD.Keywords: psychological intervention, resilience, meditation, past-negative time perspective, unhealthy behaviors, inner peace

Jinghan Shi, 1,* Weiqing Gu, 2,* Yanfeng Zhao, 1 Junjie Zhu, 1 Gening Jiang, 1 Minwei Bao, 1 Jingyun Shi 3 1Department of Thoracic Surgery, Shanghai Pulmonary Hospital Affiliated to Tongji University, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Pulmonary Hospital Affiliated to Tongji University, Shanghai, People’s Republic of China; 3Department of Radiology, Shanghai Pulmonary Hospital Affiliated to Tongji University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Minwei BaoDepartment of Thoracic Surgery, Shanghai Pulmonary Hospital Affiliated to Tongji University, 507 Zhengmin Road, Shanghai 200433, People’s Republic of ChinaTel +86 138 1808 9090Email even0123@hotmail.comJingyun ShiDepartment of Radiology, Shanghai Pulmonary Hospital Affiliated to Tongji University, 507 Zhengmin Road, Shanghai 200433, People’s Republic of ChinaTel +86 136 7170 1139Email Shijingyun89179@126.comObjective: The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene is a key oncogenic driver in non-small cell lung cancer (NSCLC). This study analyzed the clinicopathological characteristics and prognostic significance of EML4-ALK fusion gene in patients with surgically resected adenocarcinoma.Methods: The clinicopathological characteristics of 1056 consecutive patients with surgically resected stage I–IIIA adenocarcinoma were collected from February 2014 to October 2014, and EML4-ALK rearrangement was detected using real-time polymerase chain reaction (RT-PCR) technology. To compare the imaging and pathological features, a propensity score matching (PSM) method was performed. The follow-up information was collected to evaluate the long-term outcomes of patients with EML4-ALK rearrangement.Results: The prevalence of EML4-ALK rearrangement was 6.6% in 1056 consecutive patients. A total of 70 EML4-ALK-positive and 210 EML4-ALK-negative patients were identified after PSM. Imaging and pathological analyses showed that EML4-ALK rearrangement was significantly associated with less ground-glass opacity (GGO) (adjusted OR=1.38, 95% CI=1.03– 1.85, Ptrend=0.029) and higher prevalence of non-invasive mucinous adenocarcinoma mucin-laden adenocarcinomas (non-IMA MLA, adjusted OR=6.79, 95% CI=2.69– 17.17, P< 0.001). EML4-ALK rearrangement was found to be an unfavorable prognostic factor for disease-free survival (DFS) in female patients (HR=2.26, 95% CI=1.13– 4.53, P=0.021).Conclusion: Our results suggest that adenocarcinomas harboring EML4-ALK fusion gene exhibit specific radiological and pathological characteristics compared with EML4-ALK-negative adenocarcinomas. In female patients, EML4-ALK rearrangement was associated with shorter DFS.Keywords: adenocarcinoma, non-small cell lung cancer, NSCLC, anaplastic lymphoma kinase, survival

Liang Wu,1 Hao Wang,2 Haomin Cai,1 Jiang Fan,1 Gening Jiang,1 Yayi He,3 Lei Jiang1 1Department of Surgery, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, People’s Republic of China; 2Medical School, Tongji University, Shanghai 200433, People’s Republic of China; 3Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, People’s Republic of ChinaCorrespondence: Yayi He; Lei Jiang Tel/fax +86 21 6511 5006Email 2250601@qq.com; leijiang2356@yahoo.comBackground: With the development of the surgical technique and experience of surgeons, uniportal VATS has been used in double sleeve lobectomy to treat non-small cell lung cancer (NSCLC). This retrospective study aims to evaluate the efficacy and safety of uniportal VATS in NSCLC treatment.Methods: We reviewed 42 NSCLC patients who underwent double sleeve lobectomy in Shanghai Pulmonary Hospital from June 2015 to November 2017. 21 patients received double sleeve lobectomy through uniportal VATS and 21 through conventional thoracotomy with large incision.Results: The characteristics of patients were similar between the two groups. The operation time was longer in the uniportal VATS group (p=0.021) and the drainage on postoperation day 1 was significantly less in the uniportal VATS group (p=0.004). Patients reported a lower postoperative pain level in the uniportal VATS group than in the thoracotomy group (p=0.002). No statistically significant difference showed in other aspects.Conclusion: Uniportal VATS double sleeve lobectomy for NSCLC treatment is safe and effective. Lower postoperative pain level was found in the uniportal VATS group. Its complication rate and postoperation survival were similar to the conventional thoracotomy approach with large incision. But a large randomized clinical trial is still necessary for further investigation.Keywords: sleeve lobectomy, uniportal video-assisted thoracic surgery, VATS, thoracotomy

Taiyuan Li,1,* Li Deng,2,* Xin He,1 Gongan Jiang,1 Fang Hu,1 Shanping Ye,1 Yu You,3 Jinzhong Duanmu,1 Hua Dai,4 Guodong Huang,1 Cheng Tang,1 Xiong Lei1 1Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, People’s Republic of China; 2Department of Diagnostic Medical Sonography, Jiangxi Pingxiang People’s Hospital, Pingxiang 337000, Jiangxi, People’s Republic of China; 3Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, People’s Republic of China; 4Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiong LeiDepartment of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, People’s Republic of ChinaTel +86-791-88694893Fax +86-791-88692745Email leixionglinty@126.comBackground: Metastasis is the main cause for gastric cancer (GC)-related deaths. Better understanding of GC metastatic mechanism would provide novel diagnostic markers and therapeutic targets. Though it has been reported that mammalian sterile-20-like kinase 4 (MST4) exerts the oncogenic role in other tumors, the prognostic value and biological role of MST4 in GC are still unknown.Methods: The expression level of MST4 in GC was analyzed by using TCGA database. Then, Western blot and polymerase chain reaction (PCR) were used to determine the MST4 expression in GC tissues and cell lines. Immunohistochemistry was performed to investigate the expression of proteins in human GC tissues, and its correlation with clinicopathologic parameters as well as the prognosis for patients with GC was analyzed. In addition, the biological function and its molecular mechanism of MST4 in GC were investigated by in vitro and in vivo assays.Results: It demonstrated that MST4 expression was significantly upregulated in GC tissues and cell lines. High expression of MST4 was correlated with aggressive clinicopathological parameters such as lymph node metastasis, lymphovascular invasion (all P < 0.05). GC patients with high MST4 expression had both shorter overall survival (OS) and disease-free survival (DFS) than those with low MST4 expression (all P < 0.05). MST4 expression was an independent and significant risk factor for OS and DFS of GC patients (all P < 0.05). Results of functional experiments showed that MST4 could promote GC cells migration, invasion in vitro and metastasis in vivo. In terms of mechanism, MST4 promoted metastasis by facilitating epithelial–mesenchymal transition (EMT) through activating Ezrin pathway in GC. Further studies indicate that down-regulated miR-124-3p expression contributes to upregulated MST4 expression in GC.Conclusion: Our data showed that MST4 predicts poor prognosis and promotes metastasis by facilitating epithelial–mesenchymal transition in GC. Therefore, our study suggests that MST4 can be used as a valuable prognostic biomarker and a potential therapeutic target in GC.Keywords: MST4, gastric cancer, prognosis, epithelial-mesenchymal transition, metastasis

Zhiwei Chen,1,* Shengping Shen,1,* Wenbo Shi,1,* Gening Jiang,2 Xin Wang,3 Hong Jian,1 Zhen Zhou,1 Zhengping Ding,1 Shun Lu11Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People’s Republic of China; 2Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, Shanghai 200433, People’s Republic of China; 3Department of Thoracic Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China*These authors contributed equally to this workObjective: This multicenter, open-label, single-arm, phase II trial evaluated the efficacy and safety of an intercalated combination of erlotinib and gemcitabine/cisplatin or carboplatin in patients with stage IIIA non-small-cell lung cancer (NSCLC).Registration: This trial is registered with ClinicalTrials.gov, number NCT01297101.Methods: The primary endpoint was the objective response rate (ORR), which includes complete response (CR) and partial response (PR), assessed using RECIST version 1.0 in the intention-to-treat population. Adverse events (AEs) were graded by the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Secondary endpoints included the disease control rate, disease-free survival (DFS), overall survival (OS), and safety. Between April 1, 2011, and July 31, 2014, 39 patients with stage IIIA NSCLC received two cycles of intercalated use of erlotinib with gemcitabine/cisplatin or carboplatin.Results: Eighteen patients (46.15%) achieved a PR and no patient achieved a pathologic CR, resulting in an ORR of 46.15% (95% CI 30–63%). Median DFS was 20 months (95% CI 5.26–50.61) and median OS was 25 months (95% CI 15.57–33.39). Patients with EGFR mutations (n=7) had a higher ORR than those with wild-type EGFR (n=9) (85.71% vs 55.56%, P=0.00). Most AEs were CTCAE grade 1 or 2; there were no cases of increased hematologic toxicity or erlotinib-emergent interstitial lung disease observed.Conclusion: Two cycles of intercalated neoadjuvant therapy with erlotinib and gemcitabine/cisplatin or carboplatin were effective and safe for patients with stage IIIA NSCLC. This approach should be further explored in larger randomized controlled trials given the lack of a consensus about the best treatment for stage IIIA NSCLC.Keywords: non-small-cell lung cancer, NSCLC, neoadjuvant, erlotinib, gemcitabine, platinum, objective response rate, progression-free survival, overall survival

Tingting Zhang,1,2 Guanglu Jiang,1,2 Shu’an Wen,1,2 Fengmin Huo,1,2 Fen Wang,1,2 Hairong Huang,1,2 Yu Pang1,21National Clinical Laboratory on Tuberculosis, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, People’s Republic of China; 2Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, People’s Republic of ChinaBackground: The purpose of this work was to assess the activity of para-aminosalicylic acid (PAS) in combination with isoniazid (INH) against clinical isolates of Mycobacterium tuberculosis (MTB).Materials and methods: A total of 72 MTB isolates with differential in vitro drug susceptibilities were included in this study, comprising 24 pan-susceptible, 24 MDR-TB, and 24 extensively drug-resistant (XDR) isolates. A microplate alamarBlue assay was performed to identify the minimal inhibitory concentrations (MICs) of MTB isolates. Results: The MIC50 of INH was 4 mg/L, and that of PAS was 0.063 mg/L against MTB isolates when single drug used. The combined use of INH and PAS resulted in 16-fold and 8-fold decrease in MIC50 for INH and PAS, respectively. The INH-PAS revealed synergistic activity in 94.4% of the isolates. In addition, there was no significant difference in the FIC index of the INH-PAS combination among individual isolates harboring different susceptibility pattern (P>0.05).Conclusion: The synergy between INH and PAS is demonstrated using non-multidrug-resistant (non-MDR) and MDR-TB strains, which will provide clinicians with useful hints to reuse this combination for treatment of TB patients in clinical practice.Keywords: Mycobacterium tuberculosis, isoniazid, para-aminosalicylic acid, synergy

Jinghan Shi, Yang Yang, Yanfeng Zhao, Junjie Zhu, Xiao Song, Gening Jiang Department of Thoracic Surgery, Shanghai Pulmonary Hospital affiliated to Tongji University, Shanghai, China Objectives: A retrospective study was performed to investigate the association between EGFR mutations and visceral pleural invasion (VPI), and evaluate the prognostic value of EGFR in resected non-small-cell lung cancer (NSCLC) patients with VPI.Materials and methods: Clinicopathological characteristics and follow-up information were collected from 508 consecutive patients with surgically resected stage I–III NSCLC, and EGFR mutations were detected based on real-time PCR technology. Significant results (P

Yi-jun Lyu,1,2,* Fang Shen,3,* Yun Yan,4,5 Ming-zhu Situ,4,5 Wei-zhu Wu,1,2 Guo-qiang Jiang,3 Ya-ya Chen4,5 1Department of Thyroid and Breast Surgery, Ningbo Medical Center Lihuili Eastern Hospital, Ningbo 315040, Zhejiang, China; 2Department of Thyroid and Breast Surgery, Taipei Medical University Ningbo Medical Center, Ningbo 315040, Zhejiang, China; 3Department of Orthopaedic Surgery’s Spine Division, The Affiliated Hospital of Medical School of Ningbo University, Ningbo 315020, Zhejiang, China; 4Department of Ultrasound, Ningbo Medical Center Lihuili Eastern Hospital, Ningbo 315040, Zhejiang, China; 5Department of Ultrasound, Taipei Medical University Ningbo Medical Center, Ningbo 315040, Zhejiang, China *These authors contributed equally to this work Objective: Ultrasound-guided fine-needle aspiration biopsy (US-FNAB) is a safe and effective method of screening malignant thyroid nodules such as papillary thyroid carcinoma. However, not much data are available regarding the diagnostic efficacy of US-FNAB for papillary thyroid microcarcinoma (≤10 mm in diameter). We aim to compare the diagnostic efficacy of US-FNAB on thyroid nodules between two groups divided by a diameter of 10 mm by correlating the cytological results of US-FNAB with the histopathologic diagnoses in selected patients. Patients and methods: Eight hundred twenty-two thyroid nodules (Group A: diameter ≤10 mm, n=620; Group B: diameter >10 mm, n=202) from 797 patients treated between March 2014 and June 2017 were retrospectively evaluated. Only nodules with Thyroid Imaging Reporting and Data System (TIRADS) categories 4–6 were enrolled and sampled by US-FNAB, followed by surgical resection. Results: According to The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) diagnostic categories, 94 thyroid nodules were classified as I, III and IV, and were excluded from the analysis. The resultant 728 thyroid nodules from 721 patients were analyzed. The malignant tendency (TBSRTC V and VI) rates on US-FNAB were 88.2% and 84.6% (P=0.202) in Group A and Group B, respectively, and the malignant rates were 89.5% and 86.9% (P=0.330), respectively, on histopathology. There was a high concordance between cytology and histopathology diagnoses (kappa value =0.797), and no statistical difference in terms of US-FNAB accuracy was found between the two groups (P=0.533). Conclusion: For thyroid nodules of TIRADS category 4–6, the diagnostic efficacy of US-FNAB is similar for thyroid nodules either smaller or greater than 10 mm in their maximum diameter. Keywords: ultrasound-guided fine-needle aspiration biopsy, thyroid nodules, microcarcinoma, histopathology, cytopathology

Zichang Zhao,1,2,* Wei Shen,2,* Hanbin Zhu,3,* Lin Lin,4 Gening Jiang,1 Yongzhe Zhu,5 Hongyuan Song,2 Liang Wu1 1Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China; 2Department of Ophthalmology, Changhai Hospital, Second Military Medical University, Shanghai, China; 3Company 11 of Student Brigade, Second Military Medical University, Shanghai, China; 4Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai, China; 5Department of Microbiology, Second Military Medical University, Shanghai, China *These authors contributed equally to this work Background: Previous preclinical and clinical studies have demonstrated that zoledronate might inhibit neointimal hyperplasia at least partly by inhibiting the proliferation, adhesion and migration of vascular smooth muscle cells (VSMCs). However, whether zoledronate influences fibroblasts’ proliferation and activation, which also play a key role in neointimal hyperplasia and vascular remodeling, remains largely unknown. In the present study, the effect of zoledronate on fibroblasts was investigated and the underlying molecular mechanisms were examined.Methods: After treatment with zoledronate, changes in biological behaviors, including the morphology, proliferation, cell-cycle distribution and migration of fibroblasts (NIH3T3 cells), were observed. The expression of α-SMA, TGF-β1 and TGF-β2 and the level of Smad2/3 phosphorylation in cultured fibroblasts were examined by Western blot. In vivo expression of α-SMA and TGF-β1 was assessed by immunohistochemical staining.Results: It was shown that the typical fibroblast cell morphology was altered after zoledronate exposure. Cultured fibroblasts treated with zoledronate displayed dose-dependent inhibition of cell proliferation due to cell-cycle arrest in the S phase. Cell migration activities were also dose dependently suppressed by zoledronate treatment. Expression of α-SMA in cultured fibroblasts was significantly reduced by zoledronate treatment. Further analysis showed decreased expression of TGF-β1 and α-SMA by periadventitial delivery of zoledronate in the rat carotid balloon-injury model. The expression of TGF-β1 and TGF-β2 and the phosphorylation of Smad2/3 in cultured fibroblasts were significantly inhibited by zoledronate treatment.Conclusion: Our findings demonstrated that zoledronate can inhibit the proliferation, migration and activation of fibroblasts via the TGF-β signaling pathway and revealed a novel mechanism of zoledronate action against neointimal hyperplasia. Keywords: zoledronate, fibroblasts, neointimal hyperplasia, TGF-β pathway

Jianwei Dong,1,* Xiaofen Ma,2,* Wuhong Lin,1 Mengchen Liu,2 Shishun Fu,2 Lihua Yang,1 Guihua Jiang2 1School of Mathematics, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 2Department of Medical Imaging, Guangdong No. 2 Provincial People’s Hospital, Guangzhou, People’s Republic of China *These authors contributed equally to this work Purpose: The aim of this study is to investigate the morphology of cortical gray matter in patients with end-stage renal disease (ESRD) and the relationship between cortical thickness and kidney function. Patients and methods: Three-dimensional high-resolution brain structural magnetic resonance imaging data were collected from 35 patients with ESRD (28 men, 18–61 years old) and 40 age- and gender-matched healthy controls (HCs, 32 men, 22–58 years old). Vertex-wise analysis was then performed to compare the brains of the patients with ESRD with those of HCs to identify abnormalities in the brains of the former. Multiple biochemical measures of renal metabolin, vascular risk factors, general cognitive ability, and dialysis duration were correlated with brain morphometry alterations for the patients. Results: Patients with ESRD showed lesser cortical thickness than the HCs. The most significant cluster with decreased cortical thickness was found in the right prefrontal cortex (P

Yue Zhao,1 Kuiyuan Song,1 Yong Zhang,2 Hongtao Xu,1 Xiupeng Zhang,1 Liang Wang,1 Chuifeng Fan,1 Guiyang Jiang,1 Enhua Wang1 1Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China; 2Departments of Pathology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China Purpose: Current knowledge of TMEM17, a recently identified protein of the transmembrane (TMEM) family, is limited, especially with respect to its expression and biological functions in malignant tumors. This study analyzed TMEM17 expression in invasive breast cancer tissue and breast cell lines and its relevance to clinicopathological factors, and investigated the mechanisms underlying the biological effects of TMEM17 on breast cancer cells. Patients and methods: TMEM17 protein expression was determined in 20 freshly harvested specimens (tumor and paired normal tissues) by Western blotting. Immunohistochemical analysis was performed to determine the expression and subcellular localization of TMEM17 in samples from 167 patients (mean age, 49 years) diagnosed with invasive ductal carcinoma (38 with triple-negative breast cancer; 129 with non-triple-negative breast cancer) who underwent complete resection in the First Affiliated Hospital of China Medical University between 2011 and 2013. Furthermore, TMEM17 was knocked down by small interfering RNAs in breast cancer cell lines. Results: TMEM17 was found to be significantly upregulated in breast cancer tissues compared to the corresponding normal breast tissues by Western blotting (p=0.015). Immunohistochemical analysis revealed that TMEM was significantly upregulated in invasive breast cancer cells compared to adjacent normal breast duct glandular epithelial cells (10.78% vs 76.05%, p

Yuemei Shan,1,2 Wei Cao,1 Tao Wang,1 Guiyang Jiang,3 Yong Zhang,4 Xianghong Yang1 1Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, China; 2Department of Applied Technology, Institute of Technology of China Medical University, Shenyang, China; 3Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China; 4Department of Pathology, Cancer Hospital of China Medical University, Shenyang, China Background: Zinc finger protein 259 (ZNF259) is known to play essential roles in embryonic development and cell cycle regulation. However, its expression pattern and clinicopathological relevance remain unclear. Materials and methods: A total of 114 lung cancer specimens were collected. The ZNF259 expression was measured between the lung cancer tissues and the adjacent normal lung tissues by immunohistochemical staining and Western blotting. Moreover, the correlation of ZNF259 expression with clinicopathological features was analyzed in 114 cases of lung cancer. Additionally, ZNF259 was depleted in the lung cancer cells in order to analyze its effect in the lung cancer. Results: Immunohistochemical staining of 114 lung cancer specimens revealed significantly lower ZNF259 expression in lung cancer tissues than in adjacent normal lung tissues (53.5% vs 71.4%, P

Likun Xia,1 Shumei Li,2 Tianyue Wang,2 Yaping Guo,3 Lihong Meng,3 Yunping Feng,3 Yu Cui,1 Fan Wang,1 Jian Ma,1 Guihua Jiang2 1Department of Magnetic Resonance Imaging, People’s Hospital of Yuxi City, Yuxi, 2Department of Medical Imaging, Guangdong No 2 Provincial People’s Hospital, Guangzhou, 3Department of Rehabilitation Medicine, People’s Hospital of Yuxi City, Yuxi, People’s Republic of China Objective: We aimed to examine how spontaneous brain activity might be related to the pathophysiology of generalized anxiety disorder (GAD).Patients and methods: Using resting-state functional MRI, we examined spontaneous regional brain activity in 31 GAD patients (mean age, 36.87±9.16 years) and 36 healthy control participants (mean age, 39.53±8.83 years) matched for age, education, and sex from December 2014 to October 2015. We performed a two-sample t-test on the voxel-based analysis of the regional homogeneity (ReHo) maps. We used Pearson correlation analysis to compare scores from the Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, State–Trait Anxiety Scale-Trait Scale, and mean ReHo values.Results: We found abnormal spontaneous activity in multiple regions of brain in GAD patients, especially in the sensorimotor cortex and emotional regions. GAD patients showed decreased ReHo values in the right orbital middle frontal gyrus, left anterior cingulate cortex, right middle frontal gyrus, and bilateral supplementary motor areas, with increased ReHo values in the left middle temporal gyrus, left superior temporal gyrus, and right superior occipital gyrus. The ReHo value of the left middle temporal gyrus correlated positively with the Hamilton Anxiety Rating Scale scores.Conclusion: These results suggest that altered local synchronization of spontaneous brain activity may be related to the pathophysiology of GAD. Keywords: generalized anxiety disorder, functional magnetic resonance imaging, resting state, regional homogeneity

Yan-Min Long,1,2 Li-Gang Hu,1,3 Xue-Ting Yan,1,3 Xing-Chen Zhao,1,3 Qun-Fang Zhou,1,3 Yong Cai,2,4 Gui-Bin Jiang1,3 1State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Beijing, China; 2Institute of Environment and Health, Jianghan University, Wuhan, Hubei, China; 3College of Resources and Environment, University of Chinese Academy of Sciences, Beijing, China; 4Department of Chemistry and Biochemistry, Southeast Environmental Research Center, Florida International University, Miami, FL, USA Abstract: Understanding the mechanism of nanosilver-dependent antibacterial activity against microorganisms helps optimize the design and usage of the related nanomaterials. In this study, we prepared four kinds of 10 nm-sized silver nanoparticles (AgNPs) with dictated surface chemistry by capping different ligands, including citrate, mercaptopropionic acid, mercaptohexanoic acid, and mercaptopropionic sulfonic acid. Their surface-dependent chemistry and antibacterial activities were investigated. Owing to the weak bond to surface Ag, short carbon chain, and low silver ion attraction, citrate-coated AgNPs caused the highest silver ion release and the strongest antibacterial activity against Escherichia coli, when compared to the other tested AgNPs. The study on the underlying antibacterial mechanisms indicated that cellular membrane uptake of Ag, NAD+/NADH ratio increase, and intracellular reactive oxygen species (ROS) generation were significantly induced in both AgNP and silver ion exposure groups. The released silver ions from AgNPs inside cells through a Trojan-horse-type mechanism were suggested to interact with respiratory chain proteins on the membrane, interrupt intracellular O2 reduction, and induce ROS production. The further oxidative damages of lipid peroxidation and membrane breakdown caused the lethal effect on E. coli. Altogether, this study demonstrated that AgNPs exerted antibacterial activity through the release of silver ions and the subsequent induction of intracellular ROS generation by interacting with the cell membrane. The findings are helpful in guiding the controllable synthesis through the regulation of surface coating for medical care purpose. Keywords: silver nanoparticles, surface chemistry, silver ion release, Trojan-horse-type mechanism, respiratory chain, oxidative stress

Chao Li, Mengshi Dong, Yi Yin, Kelei Hua, Shishun Fu, Guihua Jiang Department of Medical Imaging, The Affiliated Guangdong No 2 Provincial People’s Hospital of Southern Medical University, The Third Clinical Medical College of Southern Medical University, Guangzhou, People’s Republic of China Abstract: The investigation of the mechanism of insomnia could provide the basis for improved understanding and treatment of insomnia. The aim of this study is to investigate the abnormal functional connectivity throughout the entire brain of insomnia patients, and analyze the global distribution of these abnormalities. Whole brains of 50 patients with insomnia and 40 healthy controls were divided into 116 regions and abnormal connectivities were identified by comparing the Pearson’s correlation coefficients of each pair using general linear model analyses with covariates of age, sex, and duration of education. In patients with insomnia, regions that relate to wakefulness, emotion, worry/rumination, saliency/attention, and sensory-motor showed increased positive connectivity with each other; however, regions that often restrain each other, such as regions in salience network with regions in default mode network, showed decreased positive connectivity. Correlation analysis indicated that some increased positive functional connectivity was associated with the Self-Rating Depression Scale, Insomnia Severity Index, and Pittsburgh Sleep Quality Index scores. According to our findings, increased and decreased positive connectivities suggest function strengthening and function disinhibition, respectively, which offers a parsimonious explanation for the hyperarousal hypothesis in the level of the whole-brain functional connectivity in patients with insomnia. Keywords: primary insomnia, hyperarousal hypothesis, resting-state functional magnetic resonance imaging, functional connectivity, whole brain

Jin-Zhong Sun,1,* Chuang Chen,1,* Guan Jiang,2 Wei-Qun Tian,3 Yan Li,4 Sheng-Rong Sun1 1Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China; 2Department of Dermatology, Renmin Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China; 3Department of Biomedical Engineering, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei, People's Republic of China; 4Department of Oncology, Zhongnan Hospital of Wuhan University and Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuchang District, Wuhan, Hubei, People's Republic of China *These authors contributed equally to this work Background: The immunohistochemical assessment of Ki67 antigen (Ki67) is the most widely practiced measurement of breast cancer cell proliferation; however, it has some disadvantages and thus the prognostic value of Ki67 in breast cancer remains controversial. Our previous studies confirmed the advantages of quantum dots-based nanotechnology for quantitative analysis of biomarkers compared with conventional immunohistochemistry (IHC). This study was designed to assess Ki67 by quantum dot-immunohistochemistry (QD-IHC) and investigate the prognostic value of the Ki67 score in human epidermal growth factor receptor 2 (HER2)-positive (non-luminal) breast cancer. Methods: Ki67 expression in 108 HER2-positive (non-luminal) breast cancer specimens was detected by IHC and QD-IHC. Two observers assessed the Ki67 score independently and comparisons between the two methods were made. The prognostic value of the Ki67 score for five-year disease-free survival was estimated. Results: The same antigen localization, high correlation of staining rates (r=0.993), and high agreement of measurements (Κ=0.874) of Ki67 expression (cutoff: 30%) in breast cancer were found by QD-IHC and conventional IHC. The QD-IHC had a better interobserver agreement for the Ki67 score than conventional IHC (t=-7.280, P

We report on the fabrication of single-mode channel waveguide structures produced by the vacuum assisted microfluidic soft lithography technique. The soft lithographic technique in conjunction with a specially designed photomask pattern and a synthesized UV curable epoxy resin can result in a high yield, cost-effective method for fabrication of channel waveguides. In particular, the use of the microfluidic technique allows for the production of freestanding high quality single-mode channel waveguides on various substrates. Notably, the introduction of sectional flow tapers allows for proper uniform filling of long length small cross-sectional waveguide structures that would ordinarily succumb to clogging at shorter distances during channel filling. The fabricated polymer waveguide was 30 mm in length with a cross section dimension of 7 × 7 µm. The single-mode waveguide propagation was confirmed with beam profiler measurement, and the measured propagation loss for this polymer waveguide was about 0.55 dB/cm.

The ecological threshold concept describes how changes in one or more factors at thresholds can result in a large shift in the state of an ecosystem. This concept focuses attention on limiting factors that affect the tolerance of systems or organisms and changes in them. Accumulating empirical evidence for the existence of ecological thresholds has created favorable conditions for practical application to wildlife conservation. Applying the concept has the potential to enhance conservation of two large carnivores, Amur tiger and leopard, and the knowledge gained could guide the construction of a proposed national park. In this review, ecological thresholds that result from considering a paradigm of bottom-up control were evaluated for their potential to contribute to the conservation of Amur tiger and leopard. Our review highlights that large carnivores, as top predators, are potentially affected by ecological thresholds arising from changes in climate (or weather), habitat, vegetation, prey, competitors, and anthropogenic disturbances. What's more, interactions between factors and context dependence need to be considered in threshold research and conservation practice, because they may amplify the response of ecosystems or organisms to changes in specific drivers. Application of the threshold concept leads to a more thorough evaluation of conservation needs, and could be used to guide future Amur tiger and leopard research and conservation in China. Such application may inform the conservation of other large carnivores worldwide.