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Guoxia Zhou,1,2,&ast; Yuecheng Yang,1,2,&ast; Yunkui Zhang,1,2,&ast; Congxia Pan,1,2 Xing Wu,1,2 Jun Zhang1,2 1Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Fudan University Shanghai Medical College, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun Zhang, Department of Anesthesiology, Fudan University Shanghai Cancer Center, No. 270, Dong-An Road, Shanghai, 200032, People’s Republic of China, Tel +86-021-64175590, Fax +86-021-64174774, Email snapzhang@aliyun.comObjective: To investigate the efficacy of ultrasound-guided interscalene brachial plexus block in the treatment of shoulder pain following hepatectomy.Design: A randomized controlled trial.Methods: We conducted a single-center, randomized controlled trial. Forty-four patients with shoulder pain scores of at least 5 were randomly assigned to two groups: the treatment group, which received 0.5% ropivacaine (5mL) combined with dexamethasone (5 mg) (n=22), and the control group, which received normal saline (5mL) (n=22). The intervention was performed in the postanesthesia care unit after shoulder pain was identified by using the visual analogue scale. The shoulder pain was re-evaluated 15 minutes after intervention. The incidence of effective pain relief, defined as at least 75% reduction in pain intensity, was the primary outcome. Secondary outcomes included shoulder pain intensity within 2 days after surgery, the timing of the first rescue analgesia, total additional analgesic use, arterial oxygen saturation, intervention-related adverse reactions, and patient satisfaction regarding shoulder pain.Results: The incidence of effective pain relief was significantly higher in the treatment group compared to the control group (15 (68.2%) vs 2 (9.1%), P< 0.001). The interscalene brachial plexus block not only prolonged the time to first analgesic request (P < 0.001), but also reduced the number of analgesic requests (P < 0.001). In the comparison between groups, arterial oxygen saturation was lower in the control group than that in the treatment group, attributed to the use of sufentanil for remedial analgesia (92.4% vs 94.5%, P=0.014).Conclusion: Interscalene brachial plexus block can effectively relieve post-hepatectomy shoulder pain without clinically significant hypoxemia.Keywords: interscalene brachial plexus block, hepatectomy, referred pain, phrenic nerve

Chi Pan,1,&ast; Yawen Gu,2,&ast; Qingtao Ni2 1Department of General Surgery, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, 225300, People’s Republic of China; 2Department of Oncology, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, 225300, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qingtao Ni, Department of Oncology, Jiangsu Taizhou People’s Hospital, Taihu Road 366, Taizhou, 225300, People’s Republic of China, Tel +8618852656280, Email niqingtao@njmu.edu.cnObjective: This study examined the potential risk value of the serum albumin to globulin ratio (AGR) in patients with breast cancer (BC).Methods: This study employed a retrospective design, enrolling 332 patients with BC and 38 patients without BC treated at Taizhou People’s Hospital between September 2015 and May 2021. Multivariate Cox proportional hazard regression models were used to identify potential risk factors. A prognostic nomogram was developed based on the multivariate analyses. The receiver operating characteristic curve determined the optimal cutoff value for AGR.Results: The results indicated a statistically significant decrease in AGR among patients with BC. Significant disparities were observed in globulin and AGR levels between the two cohorts. AGR was significantly associated with tumor size and stage, with a marked decline in advanced stages of BC. Additionally, AGR and aspartate transaminase/Alanine aminotransferase (AST/ALT) emerged as significant diagnostic indicators for invasive carcinoma and advanced stages (II–IV) of BC. Specifically, AGR exhibited an area under the curve of 0.645 (P < 0.003), highlighting the discriminatory capacity of serum globulin levels in distinguishing between BC and non-BC cohorts.Conclusions: The AGR, routinely assessed due to its simplicity, objectivity, and cost-effectiveness, holds promise as a potential risk factor for BC and may have practical implications in clinical settings.Keywords: albumin to globulin ratio, risk factor, breast cancer, retrospective study

Zhenzhu Wu,1 Jie Li,1 Peipei Fang,1 Chenwei Pan,1 Yi Chen2 1Department of Infectious Disease, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, 325000, People’s Republic of China; 2Department of Gastroenterology, Wenzhou People’s Hospital, Wenzhou, Zhejiang, 325000, People’s Republic of ChinaCorrespondence: Yi Chen; Zhenzhu Wu, Email alivefish1993@qq.com; 15003890524@163.comBackground: The prevalence of pyogenic liver abscess (PLA) is increasing worldwide. However, evaluation on its economic burden is still lack.Methods: A retrospective study that included all patients identified PLA from 2017 to 2020 was conducted. Clinical information and hospital costs were collected through the electronic medical records. We evaluated the economic burden using disability-adjusted life years (DALYs). Differences in socioeconomic burdens between Klebsiella pneumoniae-caused liver abscesses (KPLA) and non-Klebsiella pneumoniae-caused liver abscesses (non-KPLA) were compared.Results: We found 327 patients identified PLA in the study, including 146 with KPLA and 181 with non-KPLA. The demographic characteristics, median hospital stay, severity, and in-hospital mortality were similar between the two groups. The median total in-hospital cost was higher in the non-KPLA than in the KPLA group, although no statistical difference was found (&dollar;3607.2 vs &dollar;3424.6; P = 0.446). The median DALY loss was significantly higher in the KPLA than in the non-KPLA group [1.49 (0.97– 2.30) vs 1.27 (0.87– 1.89); P = 0.033)], and male patients presented a higher average DALY loss than female patients. KPLA had a substantially greater median indirect economic loss than the non-KPLA group [&dollar;1442.8 (915.9– 17,221.5) vs &dollar;1232.5 (764.6– 15,473.0); P = 0.028], and indirect economic loss exhibited a significant increase from 2017 to 2020 in patients with PLA. No differences were found in the socioeconomic burden between the two groups [&dollar;8019.6 (4200.3– 21,832.1) vs &dollar;7436.4 (4023.2– 19,063.9); P = 0.172].Conclusion: The economic burden of PLA is significant, particularly in patients with KP. Patients with KPLA experienced increased DALY loss and indirect economic loss than non-KPLA. PLA must be prioritized as the indirect economic burden rises annually.Keywords: pyogenic liver abscess, Klebsiella pneumoniae, socioeconomic burden, disability-adjusted life years

Hu Y, Yan Z, Pan C. Diabetes Metab Syndr Obes. 2021;14:2683–2691. The authors have advised Figure 2 on page 2689 is incorrect. Due to an error at the time of figure assembly Figure 1B and Figure 2B were inadvertently duplicated. The correct Figure 2 is as follows. Figure 2 Prevalence ratio of macrovascular complications based on multivariate logistic regression on thyroid hormone levels within patients with abnormal HbA1c. (A) Adjusted for age and sex. (B) Adjusted for age, sex, duration of T2DM, SBP, DBP, BMI, HbA1c, TG, TC, HDL-C, LDL-C, and VLDL-C.

Mingxing Guo,1,&ast; Chen Pan,1,&ast; Ying Zhao,1 Wanyi Xu,1 Ye Xu,1 Dandan Li,1 Yichen Zhu,2 Xiangli Cui1 1Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiangli Cui, Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China, Email xianglicui@ccmu.edu.cn Yichen Zhu, Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China, Email yczhu@ccmu.edu.cnBackground: The risk of transplant recipient infection is unknown when the preservation solution culture is positive.Methods: We developed a prediction model to evaluate the infection in kidney transplant recipients within microbial contaminated preservation solution. Univariate logistic regression was utilized to identify risk factors for infection. Both stepwise selection with Akaike information criterion (AIC) was used to identify variables for multivariate logistic regression. Selected variables were incorporated in the nomograms to predict the probability of infection for kidney transplant recipients with microbial contaminated preservation solution.Results: Age, preoperative creatinine, ESKAPE, PCT, hemofiltration, and sirolimus had a strongest association with infection risk, and a nomogram was established with an AUC value of 0.72 (95% confidence interval, 0.64– 0.80) and Brier index 0.20 (95% confidence interval, 0.18– 0.23). Finally, we found that when the infection probability was between 20% and 80%, the model oriented antibiotic strategy should have higher net benefits than the default strategy using decision curve analysis.Conclusion: Our study developed and validated a risk prediction model for evaluating the infection of microbial contaminated preservation solutions in kidney transplant recipients and demonstrated good net benefits when the total infection probability was between 20% and 80%.Keywords: risk prediction model, kidney transplant, nomogram, risk factors

Pengwen Ouyang,1 Zhijie Zhou,2 Chanyuan Pan,3 Peijuan Tang,1 Sheng Long,1 Xiangjian Liao,1 Qiong Liu,1 Liangyi Xie1 1Department of Clinical Laboratory, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, People’s Republic of China; 2Department of Respiratory Medicine, The Affiliated Zhuzhou Hospital of Xiangya School of Medicine, Central South University, Zhuzhou, People’s Republic of China; 3Department of Respiratory Medicine, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, People’s Republic of ChinaCorrespondence: Liangyi Xie, Email lyxie78@hunnu.edu.cnPurpose: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is closely related to respiratory tract infection. The aim of this study was to investigate the clinical features and prognostic factors of CRKP-induced pneumonia in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients.Methods: A single-centre, retrospective case-control study on COPD patients hospitalized for acute exacerbation and CRKP-induced pneumonia was conducted from January 1, 2016, to December 31, 2022. The mortality rate of acute exacerbation due to CRKP-induced pneumonia was investigated. The patients were divided into the CRKP-induced pneumonic acute exacerbation (CRKPpAE) group and the non-CRKP-induced pneumonic acute exacerbation (non-CRKPpAE) group, and the clinical characteristics and prognostic factors were compared using univariate analysis and multivariate analysis.Results: A total of 65 AECOPD patients were included, composed of 26 patients with CRKPpAE and 39 patients with non-CRKPpAE. The mortality rate of CRKPpAE was 57.69%, while non-CRKPpAE was 7.69%. Compared with non-CRKPpAE, a history of acute exacerbation in the last year (OR=8.860, 95% CI: 1.360– 57.722, p=0.023), ICU admission (OR=11.736, 95% CI: 2.112– 65.207, p=0.005), higher NLR levels (OR=1.187, 95% CI: 1.037– 1.359, p=0.013) and higher D-dimer levels (OR=1.385, 95% CI: 1.006– 1.905, p=0.046) were independently related with CRKPpAE. CRKP isolates were all MDR strains (26/26, 100%), and MDR strains were also observed in non-CRKP isolates (5/39, 12.82%).Conclusion: Compared with non-CRKPpAE, CRKPpAE affects the COPD patient’s condition more seriously and significantly increases the risk of death.Keywords: chronic obstructive pulmonary disease, acute exacerbation, carbapenem-resistant K. pneumoniae, pneumonia

Qiankun Luo,1,&ast; Yifei Dong,1,&ast; Pan Liu,1,&ast; Chao He,2 Lei Chen,1 Kailun Zhang,1 Changjie Pan,1 Yahui Gao,1 Tao Qin1 1Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou, Henan, People’s Republic of China; 2Department of Hepatobiliary and Pancreatic Surgery, Henan University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou, Henan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tao Qin, Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, No. 7, Weiwu Road, Jinshui District, Zhengzhou, Henan, 450003, People’s Republic of China, Tel +86 13949116088, Email qtgoodfreecn@zzu.edu.cnIntroduction: Chemotherapy combined with immune checkpoint inhibitors (ChIM) is used to treat advanced pancreatic ductal adenocarcinoma (PDAC). However, the efficacy of ChIM is similar to that of chemotherapy alone.Methods: To assess potential factors affecting the effectiveness of ChIM, we analyzed the clinical data of 359 patients with PDAC who visited the hospital during June 2017 to December 2022.Results: Surgical resection, diabetes, and ChIM were risk factors for pancreatic exocrine insufficiency (PEI). The adjusted odds ratio of ChIM was 2.63 (95% confidence interval (CI) 1.492– 4.626) (P = 0.001). The incidence of PEI in the ChIM group (76.9%) was significantly higher than that of the chemotherapy group (60.2%) (P = 0.004). Survival analysis showed that ChIM did not improve the survival rate of patients with PDAC (hazard ratio (HR) 0.92, 0.707– 1.197) (P = 0.534) in comparison with that of the chemotherapy group. However, in patients without PEI, those receiving ChIM showed a higher 1-year overall survival (OS) rate of 70.8% (two-sided, P = 0.045) and a median OS of 22.0 months (95% CI 11.5– 32.5). Moreover, pancreatic enzyme replacement therapy significantly improved the OS of patients with PDAC (HR = 0.73, 95% CI = 0.561– 0.956) (P = 0.022).Conclusion: Immune checkpoint inhibitors (ICIs) increased the incidence of PEI in patients with PDAC. The OS was not different between patients receiving chemotherapy and ChIM due to irregular PERT treatment. The finding show that pancreatic enzyme replacement therapy may improve the response rate of patients with PDAC to ICIs.Keywords: pancreatic cancer, pancreatic exocrine insufficiency, immune checkpoint inhibitors, pancreatic enzyme replacement therapy

Chunran Pan,&ast; Wenjie Hou,&ast; Xiaofeng Deng, Jiawei Liu, Ruimin Chi, Xingru Shang, Tao Xu, Xiaoxia Hao Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoxia Hao, Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095&num;, Jie-Fang Avenue, Qiaokou District, Wuhan, 430030, People’s Republic of China, Tel +86 1-597-296-0593, Fax +86- 27-83662640, Email haoxiaoxia@hust.edu.cnAbstract: Intervertebral disc degeneration (IDD) is considered as a dominant contributor to low back pain (LBP), causing severe pain, limited range of lumbar motion, physical dysfunction, and restriction of social activity. However, the specific pathological mechanisms underlying IDD remain elusive, and effective strategies to delay the pathogenesis of IDD are still unclear and limited. In recent years, some studies have found that nuclear factor erythroid 2-related factor 2 (Nrf2), an important antioxidant transcription factor, may play crucial roles in the pathogenesis and progression of age-related diseases including IDD. Nrf2 can maintain redox homeostasis and protecting nucleus pulposus (NP) cells against oxidative stress, inflammatory response, extracellular matrix (ECM) catabolism, cell senescence and cell death involving in the progression of IDD. In this review, we aim to systematically describe the vital roles and pathological mechanism of Nrf2 signaling axis in the pathogenesis of IDD, which may put forward potential therapeutic strategies for the prevention and treatment of IDD by targeting Nrf2.Keywords: Nrf2, intervertebral disc degeneration, nucleus pulposus cells, oxidative stress

Nada Alsuhebany,1– 3 Congshan Pan,4 Eileen Holovac,5 Brian Do,6 Ali McBride7 1College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia; 2King Abdulaziz Medical City, National Guard Health Affairs, Riyadh, Kingdom of Saudi Arabia; 3King Abdullah International Medical Research Center, Riyadh, Kingdom of Saudi Arabia; 4Department of Oncology Pharmacy, University of Arizona Cancer Center, Tucson, AZ, USA; 5Department of Oncology Pharmacy, VA Loma Linda Healthcare System, Loma Linda, CA, USA; 6Department of Oncology Pharmacy, Southern Arizona VA Hlth Care, Tucson, AZ, USA; 7WW HEOR Markets, Bristol-Myers Squibb, New York City, NY, USACorrespondence: Nada Alsuhebany, Department of Clinical Pharmacy, College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, PO Box 3660, Riyadh, 11481, Kingdom of Saudi Arabia, Tel +966500828585, Email nalsuhebany@gmail.comPurpose: The pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of zanbrutinib are described.Summary: Mantle cell lymphoma (MCL) is a mature B-cell lymphoma that is typically associated with unfavorable outcomes, and virtually all patients with MCL have refractory or relapsed disease despite aggressive treatment. The treatment paradigm for MCL has transformed dramatically over the past decade owing to rapid advancements in immunotherapy and molecular-targeted therapies. Zanubrutinib, a second-generation Bruton’s tyrosine kinase inhibitor (BTKI) designated for mature B-cell non-Hodgkin’s lymphoma (NHL), has drastically improved the survival outcomes in relapsed/refractory (R/R) MCL patients. This selective BTKI is a small molecule that functions by forming a covalent bond in the active site of BTK. The inhibition of BTK activity is essential for the signaling of B-cell antigen receptor (BCR) and cytokine receptor pathways. In a preclinical study, zanubrutinib inhibited malignant B-cell proliferation and reduced tumor growth. Zanubrutinib was granted FDA-accelerated approval based on the results of Phase I and II trials. The investigator-assessed overall response rate was 83.7%, of which 78% of patients achieved complete response. The median duration of response was 19.5 months, and the median progression-free survival was 22.1 months. The most common (≥ 20%) all-grade adverse events were low neutrophil count (46.5%), upper respiratory tract infection (38.4%), rash (36.0%), low white blood cell count (33.7%), and low platelet count (32.6%).Conclusion: Zanubrutinib is a selective, next-generation, orally active, irreversible BTK inhibitor. The selectivity of zanubrutinib and its superior efficacy, with a well-tolerated safety profile, have proven to be attractive options for other malignancies.Keywords: zanubrutinib, mantle cell lymphoma, Bruton’s tyrosine kinase inhibitor

Mingshuang Wu,&ast; Chenxi Pan,&ast; Yi He, Bo Yang Department of Urology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yi He; Bo Yang, The Second Affiliated Hospital of Dalian Medical University, 467, Zhongshan Road, Shahekou District, Dalian, 116044, People’s Republic of China, Tel/Fax +86 411 84671291, Email heyi_gzr@163.com; yangbo20160101@163.comPurpose: The goal of this study was to assess the prognostic impact of the lower urinary tract symptoms (LUTS) in advanced prostate cancer (PCa) patients before progression to castration-resistant prostate cancer (CRPC).Methods: A retrospective analysis of the follow-up data for 152 CRPC patients was performed. Severe LUTS symptom was defined as an International Prostate Symptoms Score (IPSS) ≥ 20 at baseline. Cox regression analysis was conducted to assess CRPC prognostic factors. Nomogram model was created and assessed using the concordance index (C-index), calibration curves, receiver operating characteristic (ROC) curves, and decision curve analyses (DCA).Results: The median CRPC free survival of patients with severe LUTS was 20.5 months, significantly longer than that (7.5 months) of less symptomatic patients. Furthermore, severe LUTS, the hemoglobin, albumin, lymphocyte, and platelet (HALP) score, and Gleason sum were determined to be independent prognostic markers and combined to establish a nomogram, which performed well in the customized prediction of CRPC progression at 6th, 12th, 18th and 24th month. The C-index (0.794 and 0.816 for the training and validation cohorts, respectively), calibration curve, and ROC curve all validated the prediction accuracy. DCA curve showed that it could be effective in helping doctors make judgments. The Nomogram-related risk score separated the patients into two groups with notable progression differences.Conclusion: Severe LUTS was significantly associated with decreased risk for rapid progression to CRPC. The developed nomogram could help identify patients who are at a high risk of rapid CRPC progression and provide tailored follow-up and therapeutic advice.Keywords: LUTS, HALP, castration-resistant prostate cancer, nomogram

Mingshuang Wu,1 Yi He,1 Chenxi Pan2 1Department of Urology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China; 2Department of Breast Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of ChinaCorrespondence: Yi He; Chenxi Pan, The Second Affiliated Hospital of Dalian Medical University, 467, Zhongshan Road, Shahekou District, Dalian, 116044, People’s Republic of China, Tel/Fax +86 411 84671291, Email heyi_gzr@163.com; PCX980205@outlook.comPurpose: Serum lipids were reported to be the prognostic factors of various cancers, but their prognostic value in small cell lung cancer (SCLC) patients remains unclear. This study investigated the relationship between lipid profiles and clinical outcomes in extensive-stage (ES) SCLC by establishing a predictive risk classification model.Patients and Methods: We retrospectively analyzed the prognostic values of pretreatment serum lipids and their derivatives in patients with a confirmed diagnosis ES-SCLC. Independent factors of progression-free survival (PFS) were determined by univariate and multivariate cox analysis. Then, prognostic nomograms were established, of which predictive performance was evaluated by concordance index (C-index), calibration curves, receiver operating characteristic (ROC) curves, and decision curve analyses (DCA).Results: A total of 158 patients was included in this study. Four optimal PFS-related factors, total cholesterol (TC) ≥ 5.30, high-density lipoprotein cholesterol (HDL-C) > 1.30, triglycerides (TG)/HDL-C > 2.18, and ki67 expression > 70%, were included to construct the predictive nomogram. The C-indexes in training and validation sets were 0.758 and 0.792, respectively. ROC curves, calibration plots, and DCA all suggested favorable discrimination and predictive ability. Besides, the nomogram also performed better predictive ability than ki67 expression. Nomogram-related risk score divided the patients into two groups with significant progression disparities.Conclusion: The promising prognostic nomogram based on lipid parameters could help clinicians to conveniently and accurately evaluate the prognosis of ES-SCLC patients and identify high-risk groups, so as to formulate individualized therapeutic regimens and follow-up strategies in time.Keywords: small cell lung cancer, serum lipid, ki67, chemotherapy, nomogram

Gai Ge,1 Jingzhe Shang,2,3 Tian Gan,1 Zhiming Chen,1 Chun Pan,1 Youming Mei,1 Siyu Long,4 Aiping Wu,2,3 Hongsheng Wang1,5,6 1Laboratory of Mycobacteria, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, People’s Republic of China; 2Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 3Suzhou Institute of Systems Medicine, Suzhou, People’s Republic of China; 4Department of Dermatology, Beijing Chao-Yang Hospital & Capital Medical University, Beijing, People’s Republic of China; 5National Center for Sexually Transmitted Disease and Leprosy Control, China Centers for Disease Control and Prevention, Nanjing, People’s Republic of China; 6Centre for Global Health, School of Public Health, Nanjing Medical University, Nanjing, People’s Republic of ChinaCorrespondence: Hongsheng Wang, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 12 Jiang-wang-miao Street, Nanjing, Jiangsu Province, People’s Republic of China, Tel/Fax +86 258 5478953, Email whs33@vip.sina.comPurpose: Psoriasis (Ps) and leprosy are chronic inflammatory skin disorders, characterised by enhanced innate and adaptive immunity. Ps and leprosy rarely coexist. The molecular immune mechanism of the Ps and leprosy rarely coexistence is unclear.Patients and Methods: RNA-sequencing (RNA-seq) was performed on 20 patients with Ps, 5 adults with lepromatous leprosy (L-lep), and 5 patients with tuberculoid leprosy (T-lep) to analyse the differentially expressed genes (DEGs) between them. Moreover, the biological mechanism of Ps and leprosy was explored by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, Gene Ontology (GO) analysis, Gene Set Enrichment Analysis analysis, and protein–protein interaction (PPI) analyses. Finally, 13 DEGs of 10 skin biopsies of Ps patients, 6 samples of L-lep patients, 6 samples of T-lep patients and 5 healthy controls were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR).Results: The PPI network was constructed and primarily associated with immune response, IL-17 signalling, and Toll-like receptor pathway between Ps and leprosy. Th17 markers (interleukin (IL)- 19, IL-20, IL-36A, IL-36G, IL-22, IL-17A, and lipocalin-2 (LCN2) had higher expression in Ps than in L-lep and T-lep, whereas macrophage biomarkers (CLEC4E and TREM2), SPP1, and dendritic cell (DC)-related hallmarks (ITGAX) and TNF-a had significantly lower expression across Ps and T-lep than in L-lep.Conclusion: To put it simply, Ps patients with IL-17A, IL-19, IL-20, IL-36A, IL-36G, and IL-22 in conjunction with LCN2 with up-graduated expression might be not susceptible to L-lep. However, high levels of CLEC4E, TREM2, and SPP1 in L-lep patients indicated that they unlikely suffered from Ps.Keywords: psoriasis, leprosy, Th17 cell, macrophage, IL-17A, CLEC4E

Wei Sun,1,2,&ast; Songyi Xu,3,&ast; Tianlun Shen,1,3,&ast; Guangyao Li,1 Jingfeng Zhang,2 Chunshu Pan,1,2 Wei Lu,1,2 Xiangrui Liu,1 Jianjun Zheng,2 Jun Ling,1,3 Jihong Sun1 1Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Department of Radiology, Ningbo No. 2 Hospital, Ningbo, People’s Republic of China; 3MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jihong Sun, Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Tel +86 13857176538, Email sunjihong@zju.edu.cn Jianjun Zheng, President of Ningbo No. 2 Hospital, Ningbo, People’s Republic of China, Tel +86 574 83870280, Email zhjjnb2@163.comPurpose: Chemotherapy treatments for cancer are always accompanied by a low concentration of drug delivered in the tumor area and severe side effects including systemic toxicity. Improving the concentration, biocompatibility, and biodegradability of regional chemotherapy drugs is a pressing challenge in the field of materials.Methods: N-Phenyloxycarbonyl-amino acids (NPCs) which exhibit significant tolerance to nucleophiles, such as water and hydroxyl-containing compounds, are promising monomers for the synthesis of polypeptides and polypeptoids. Cell line and mouse models were used to comprehensively explore how to enhance the tumor MRI signal and evaluate the therapeutic effect of Fe@POS-DOX nanoparticles.Results: In this study, poly(3,4-dihydroxy-L-phenylalanine)-b-polysarcosine (PDOPA-b-PSar, simplified as POS) was synthesized by the block copolymerization of DOPA-NPC with Sar-NPC. Fe@POS-DOX nanoparticles were prepared in order to utilize the strong chelation of catechol ligands to iron (III) cations and the hydrophobic interaction between DOX and DOPA block to deliver chemotherapeutics to tumor tissue. The Fe@POS-DOX nanoparticles exhibit high longitudinal relaxivity (r1 = 7.06 mM− 1·s− 1) and act as T1-weighted magnetic resonance (MR) imaging contrast agents. Further, the main focus was improving tumor site-specific bioavailability and achieving therapeutic effects through the biocompatibility and biodegradability of Fe@POS-DOX NPs. The Fe@POS-DOX treatment exhibited excellent antitumor effects.Conclusion: Upon intravenous injection, Fe@POS-DOX delivers DOX specifically to the tumor tissues, as revealed by MR, and leads to the inhibition of tumor growth without overt toxicity to normal tissues, thus displaying considerable potential for use in clinical applications.Graphical Abstract: Keywords: poly (α-amino acid)s, polypeptides, polypeptoids, MRI, chemotherapy, nanoparticles

Yonghui Hu,1,2 Zhibo Hu,1,2 Wangna Tang,1,2 Wenjie Liu,1,2 Xiaoming Wu,1,2 Congqing Pan1,2 1NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, People’s Republic of China; 2Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, People’s Republic of ChinaCorrespondence: Congqing Pan; Xiaoming Wu, NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, People’s Republic of China, Email profpancq@163.com; xiaomingwu2014@126.comPurpose: To examine the prevalence of different microvascular complications and investigate the association between thyroid hormones (THs) and these complications in euthyroid patients with type 2 diabetes mellitus (T2DM).Methods: A total of 248 T2DM patients were analyzed retrospectively for the study. All patients received a detailed and standard assessment to identify diabetic peripheral neuropathy (DPN), diabetic nephropathy (DN), and diabetic retinopathy (DR). Multivariate logistic regression was carried out to analyze the association between THs and diabetic microvascular complications.Results: The study found the prevalence of any microangiopathy to be 72.18% (n = 179). At the same time, the prevalence of DPN was 54.84% (n=136), while that of DN was 31.85% (n=79). Likewise, the prevalence of DR was 35.48% (n=88). The odds ratios (ORs) for free triiodothyronine (FT3) developing any microangiopathy, DPN, DN and DR were 0.200, 0.361, 0.310, and 0.588 (P< 0.05), respectively. Also, the ORs for free thyroxine (FT4) developing any microangiopathy, DPN, DN and DR were 0.643, 0.800, 0.702 and 0.726 (P< 0.05), respectively. Lastly, the ORs for thyroid-stimulating hormone (TSH) developing DPN was 1.57 (95% CI: 1.148– 2.137, P=0.005).Conclusion: The study concludes that serum FT3 and FT4 levels are negatively associated with any microangiopathy, DPN, DN and DR in euthyroid patients with T2DM, independent of traditional risk factors. However, the TSH levels are positively associated with DPN. Future larger sample-size studies are needed to confirm the relationship between thyroid hormone levels and microvascular complications in euthyroid patients with T2DM.Keywords: microvascular complications, thyroid hormone, type 2 diabetes mellitus, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy

Xiuming Zhang,1,&ast; Wei Qiao,1,&ast; Zheng Kang,1 Chunhan Pan,1 Yan Chen,2 Kang Li,1 Wenrong Shen,1 Lei Zhang1 1Department of Radiology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2Department of Pathology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lei Zhang; Wenrong Shen, Email motozl163@163.com; jszlyyct@sohu.comObjective: To investigate computed tomography (CT) features of stage IA invasive mucinous adenocarcinoma (IMA) of the lung and establish a predictive model.Methods: Fifty-three lesions from 53 cases of stage IA IMA between January 2017 and December 2019 were examined, while 141 lesions from 141 cases of invasive non-mucinous lung adenocarcinoma (INMA) served as control cases. Univariate analysis was performed to compare differences in demographics and CT features between the two groups, and multivariate logistic regression analysis was performed to determine primary influencing factors of solitary nodular IMA. A risk score prediction model was established based on the regression coefficients of these factors, and receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive performance of the model.Results: Univariate analysis showed that age, nodule type, maximum nodule diameter, tumor lung interface, lobulation, spiculation, air bronchogram or vacuolar signs, and abnormal vascular changes differed significantly between the two groups (p < 0.05). Compared to INMA, spiculation of IMA was relatively longer and softer. Multivariate logistic regression analysis showed that nodule type, indistinct tumor lung interface, air bronchogram or vacuolar signs, and abnormal vascular changes were the primary influencing factors. A prediction model based on the regression coefficients of these factors was established. ROC curve analysis indicated that the area under the curve was 0.882 (p < 0.05).Conclusion: Compared to INMA, solitary peripheral stage IA nodular IMA were more common in older patients; they more frequently had indistinct tumor lung interface and air bronchogram or vacuolar signs on CT; spiculation was relatively longer and softer; our risk score prediction model based on nodule type, tumor lung interface, air bronchogram or vacuolar signs, and abnormal vascular changes was established with good predictive efficacy for solitary nodular IMA.Keywords: invasive mucinous adenocarcinoma of the lung, influencing factors, risk score modeling

Yonghui Hu,1,2,&ast; Wangna Tang,1,2,&ast; Wenjie Liu,1,2 Zhibo Hu,1,2 Congqing Pan1,2 1NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, People’s Republic of China; 2Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, 300134, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Congqing Pan, NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, People’s Republic of China, Email profpancq@163.comBackground: Epithelial–mesenchymal transition (EMT) plays an important role in interstitial matrix deposition and renal fibrosis in diabetic kidney disease (DKD). It has been verified that Astragaloside IV (AS-IV) is beneficial for ameliorating DKD. However, the underlying mechanisms of AS-IV on regulating EMT in DKD are yet to be established. Accumulated evidence has suggested that C-X3-C motif ligand 1 (CX3CL1) plays a significant role in the progression of EMT.Purpose: We aimed to investigate whether AS-IV could alleviate EMT by regulating CX3CL1 in DKD and reveal its underlying mechanisms.Methods: For the in vivo study, mice were divided into the following five groups (n=10): db/m+vehicle, db/db+vehicle, db/db+AS-IV-L (10mg/kg/d), db/db+AS-IV-M (20mg/kg/d), db/db+AS-IV-H (40mg/kg/d). After 12 weeks of treatment, the renal injuries were assessed based on the related parameters of urine, blood and histopathological examination. Immunohistochemistry and Western blotting were used to detect relative proteins levels. Then in HK-2 cells, the molecular mechanism of AS-IV attenuating the EMT in mice with DKD through the CX3CL1-RAF/MEK/ERK pathway was studied.Results: In the present study, we found that AS-IV reduced urinary protein levels and improved renal pathological damage in DKD mice. Moreover, AS-IV ameliorated the renal tubular EMT induced by hyperglycemia or high glucose (HG), and decreased the expression of CX3CL1 and inhibited the activation of the RAF/MEK/ERK pathway in vivo and in vitro. In HK-2 cells, downregulation of CX3CL1 suppressed the stimulation of the RAF/MEK/ERK pathway and EMT induced by HG. However, CX3CL1 overexpression eliminated the benefits of AS-IV on the RAF/MEK/ERK pathway and EMT.Conclusion: In summary, we indicated that AS-IV alleviates renal tubular EMT through the CX3CL1-RAF/MEK/ERK signaling pathway, indicating that CX3CL1 could be a potential therapeutic target of AS-IV in DKD.Keywords: Astragaloside IV, epithelial–mesenchymal transition, CX3CL1, diabetic kidney disease, renal fibrosis

Yan Lan, Chensheng Pan, Xiuli Qiu, Jinfeng Miao, Wenzhe Sun, Guo Li, Xin Zhao, Zhou Zhu, Suiqiang Zhu Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaCorrespondence: Zhou Zhu; Suiqiang Zhu, Tel +86-18171081029 ; +86-13035101141, Email zhouzhu@hust.edu.cn; zhusuiqiang@163.comPurpose: Previous studies have shown that persistent post-stroke depression (PSD) was associated with unfavorable prognosis. The aim of this multicenter prospective study was to investigate the predictors associated with persistent PSD, develop a nomogram and validate its clinical usefulness by decision curve analysis (DCA).Patients and Methods: A total of 875 acute ischemic stroke patients from four hospitals were consecutively recruited and completed 1-year follow-ups. Sociodemographic indicators, vascular risk factors, clinical information, serum biochemical indicators and cytokines were collected on admission. The functional outcome was assessed at 1 year after stroke. Persistent depression was defined as having a presentation of depression at each follow-up points and the depressive symptoms occurring persistently since the diagnosis of depression.Results: There were 513 patients who experienced PSD during the 1-year follow-up, the cumulative incidence of PSD within 1 year was 58.6%. Persistent PSD was recorded in 289 patients, of which 59 (20.4%) result in unfavorable outcomes. The risk factors of persistent PSD in 1 year after stroke were the Hamilton Depression Scale-17 items (HAMD-17) score at admission, serum direct bilirubin and free serum thyroxine (FT4) level and activated partial thromboplastin time (APTT). Nomogram conducted based on these factors has a C-index (± standard deviation) of 0.655 ± 0.039, and the DCA demonstrated that the nomogram had a favorable clinical utility.Conclusion: We found that persistent depression after stroke in the first-year time course after stroke was associated with HAMD-17 score at admission, lower serum direct bilirubin and FT4 level, and APTT. A nomogram was developed with advisable clinical usefulness in our study.Keywords: persistent post-stroke depression, nomogram, decision curve analysis

Yanyan Wang,1 He Wang,2 Wenzhe Sun,1 Jinfeng Miao,1 Wenwen Liang,1 Xiuli Qiu,1 Yan Lan,1 Chensheng Pan,1 Guo Li,1 Xin Zhao,1 Zhou Zhu,1 Suiqiang Zhu1 1Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China; 2Department of Medical Affairs, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of ChinaCorrespondence: Zhou Zhu; Suiqiang Zhu, Tel +86 18171081029 ; +86 13035101141, Fax +86 27-83663337, Email zhouzhu@hust.edu.cn; zhusuiqiang@163.comBackground: Post-stroke depression (PSD) is the most common neuropsychiatric complication after stroke, seriously affecting the quality of survivors’ life. As one of the important causes of PSD, neuroendocrine mechanism has been widely studied in recent years. The main objective of this study was to investigate the relationship between adrenocorticotropic hormone (ACTH) on admission and PSD at 3 months.Methods: This is a hospital-based prospective cohort study, which was conducted at three independent hospitals (Tongji Hospital, Wuhan First Hospital and Wuhan Central Hospital) between August 2018 and June 2019. A total of 768 ischemic stroke patients were finally eligible for analysis and categorized into equal tertiles according to the distribution of ACTH and the number of patients. The χ2-test, Mann–Whitney U-test and Kruskal–Wallis test were used to check for statistical significance. And restricted cubic spline (RCS) regression model was used to explore the non-linear relationship between continuous ACTH levels and PSD at 3 months.Results: The optimal cut-off points of ACTH were as follows: (T1) 0.32– 20.55 pg/mL, (T2) 20.56– 39.79 pg/mL, (T3) 39.80– 143.40 pg/mL. A total of 305 patients (39.7%) were diagnosed as PSD at 3 months follow-up. Significant differences were found between the PSD and non-PSD groups in ACTH concentration (P = 0.001). After adjustment for all conventional confounders, the odds ratios of PSD were 1.735 (95% CI = 1.176– 2.560, P = 0.005) for the highest tertile of ACTH and 1.496 (95% CI = 1.019– 2.194, P = 0.040) for the middle tertile of ACTH, as compared with the lowest tertile. In multiple-adjusted RCS regression, continuous ACTH showed saturation effect relation with PSD risk after 31.02 pg/mL (P for nonlinear = 0.0143).Conclusion: Higher ACTH level on admission is a significant and independent biomarker to predict the development of PSD at 3 months follow-up. Besides, saturation effect was revealed even if the underlying mechanism is unclear. For stroke patients, doctors should pay attention to the baseline ACTH for screening high-risk PSD in clinical practice.Keywords: neuroendocrinology, HPA axis, adrenocorticotropic hormone, post-stroke depression, restricted cubic spline, saturation effect

Chen Pan,1 Honghong Wang,2 Minzhen Chen,3 Yu Cai,1 Peihuan Li,4 Changgen Xiao,5 Qiuping Tang,1 Deborah Koniak-Griffin6 1Department of Clinical Psychology, The Third Xiangya Hospital of Central South University, Changsha, People’s Republic of China; 2Department of Fundamental Nursing, Xiangya School of Nursing, Central South University, Changsha, People’s Republic of China; 3Department of AIDS, The First Hospital of Changsha, Changsha, People’s Republic of China; 4College of Resources of Environment, Hunan Agricultural University, Changsha, People’s Republic of China; 5Department of Applied Psychology, Hunan University of Chinese Medicine, Changsha, People’s Republic of China; 6School of Nursing, University of California Los Angeles, Los Angeles, CA, USACorrespondence: Qiuping Tang, Department of Clinical Psychology, The Third Xiangya Hospital of Central South University, Changsha, People’s Republic of China, Tel +86 731 88618567, Email tt96@sina.comBackground/Purpose: Nurses engaged in the care of people living with HIV (PLWH) are commonly exposed to workplace stress. This study aimed to explore the stress experiences and coping strategies among nurses taking care of PLWH in China.Methods: Nurses were recruited from the AIDS department of a public, general, third-grade class-A hospital, which has the largest HIV care department in the Hunan Province of China. Thirty-three nurses working in the AIDS Department were recruited in this qualitative study. Eight nurses participated in a focus group and 25 nurses underwent in-depth individual interviews aimed at characterizing the nurse’s feelings and struggles with stress during caregiving for PLWH. The interviews were audio-recorded, transcribed verbatim, anonymized, and imported into NVivo 8.0 software. The data were coded and subjected to thematic analysis.Results: Concerns about occupational exposure, heavy workload, mental health problems and risk behaviors of patients, and discrimination towards nurses caring for PLWH were the four main sources of stress. The negative impact of stress included problems with emotion regulation, somatic health and sleep, and work performance. Some participants also reported a positive impact of work stress on their mental health. Using personality strengths, problem-solving, help-seeking, concealing and avoiding/suppression were common coping strategies employed by nurses caring for PLWH.Conclusion: Our findings help characterize the stress experienced by nurses caring for PLWH in the Chinese cultural context, and may inform specific interventions to help manage stress and promote mental health of nurses.Keywords: HIV, nurses, stress, job burnout, coping

Yao Yao,&ast; Yumeng Jia,&ast; Yan Wen, Bolun Cheng, Shiqiang Cheng, Li Liu, Xuena Yang, Peilin Meng, Yujing Chen, Chun’e Li, Jingxi Zhang, Zhen Zhang, Chuyu Pan, Huijie Zhang, Cuiyan Wu, Xi Wang, Yujie Ning, Sen Wang, Feng Zhang Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, School of Public Health, Health Science Center, Xi’an Jiaotong University, Xi’an, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Feng ZhangKey Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, School of Public Health, Health Science Center, Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of ChinaEmail fzhxjtu@mail.xjtu.edu.cnPurpose: Most previous genetic studies of sleep behaviors were conducted individually, without comprehensive consideration of the complexity of various sleep behaviors. Our aim is to identify the genetic architecture and potential biomarker of the sleep health score, which more powerfully represents overall sleep traits.Patients and Methods: We conducted a genome-wide association study (GWAS) of sleep health score (overall assessment of sleep duration, snoring, insomnia, chronotype, and daytime dozing) using 336,463 participants from the UK Biobank. Proteome-wide association study (PWAS) and transcriptome-wide association study (TWAS) were then performed to identify candidate genes at the protein and mRNA level, respectively. We finally used linkage disequilibrium score regression (LDSC) to estimate the genetic correlations between sleep health score and other functionally relevance traits.Results: GWAS identified multiple variants near known candidate genes associated with sleep health score, such as MEIS1, FBXL13, MED20 and SMAD5. HDHD2 (PPWAS = 0.0146) and GFAP (PPWAS = 0.0236) were identified associated with sleep health score by PWAS. TWAS identified ORC4 (PTWAS = 0.0212) and ZNF732 (PTWAS = 0.0349) considering mRNA expression level. LDSC found significant genetic correlations of sleep health score with 3 sleep behaviors (including insomnia, snoring, dozing), 4 psychiatry disorders (major depressive disorder, attention deficit/hyperactivity disorder, schizophrenia, autism spectrum disorder), and 9 plasma protein (such as Stabilin-1, Stromelysin-2, Cytochrome c) (all LDSC PLDSC < 0.05).Conclusion: Our results advance the comprehensive understanding of the aetiology and genetic architecture of the sleep health score, refine the understanding of the relationship of sleep health score with other traits and diseases, and may serve as potential targets for future mechanistic studies of sleep phenotype.Keywords: sleep, sleep health score, genome-wide association study, genetics, complex-traits

Guo Li,1 Jinfeng Miao,1 Chensheng Pan,1 Ping Jing,2 Guohua Chen,3 Junhua Mei,3 Wenzhe Sun,1 Yan Lan,1 Xin Zhao,1 Xiuli Qiu,1 Yanyan Wang,1 Zhou Zhu,1 Suiqiang Zhu,1 Lifei Lian1 1Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China; 2Department of Neurology, Wuhan Central Hospital, Wuhan, Hubei, 430014, People’s Republic of China; 3Department of Neurology, Wuhan First Hospital, Wuhan, Hubei, 430022, People’s Republic of ChinaCorrespondence: Lifei Lian Tel +86-151 7150 7263Email 47009189@qq.comPurpose: Post-stroke depression (PSD) is one of the most common and severe psychological sequelae after stroke, negatively affecting the patient’s functional outcome and quality of life. Rapidly measurable biomarkers to predict PSD are pivotal for the optimized care and allocation of healthcare resources. Lactic dehydrogenase (LDH) levels are increased in patients with central nervous system (CNS) disorders such as cerebral infarction and hypoxic–ischemic encephalopathy, which may be related to the occurrence of PSD in acute ischemic stroke (AIS) patients. This study aimed to investigate whether LDH levels on admission are associated with PSD at discharge.Patients and Methods: A multicenter prospective cohort study was conducted, including all consecutive AIS patients within 7 days after symptom onset from May 2018 to October 2019. According to the distribution of LDH and the number of patients, patients were divided into equal tertiles. PSD was evaluated by DSM-V criteria and the 17-item Hamilton Rating Scale for Depression (HRSD-17) at discharge.Results: A total of 518 AIS patients were included. The optimal cut-off points of LDH were: lowest tertile (T1) 102– 159/L, middle tertile (T2) 160– 189 U/L, and upper tertile (T3) 190– 520 U/L. A total of 249 patients (48.07%) were diagnosed with PSD at discharge. After adjusting for potential confounding factors, the odds ratio of T3 PSD was 1.698 (95% CI, 1.070– 2.694, P=0.025), compared with T1.Conclusion: In summary, LDH serum levels on admission are associated with PSD at discharge. Clinicians should pay more attention to the baseline LDH level in screening for PSD at discharge.Keywords: post-stroke depression, lactic dehydrogenase, screen, cohort study

Yihong Wang,&ast; Manyi Li,&ast; Chen Pan,&ast; Haiping Huang, Xiaoqing Hu, Jisheng Liu Department of Otolaryngology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jisheng LiuDepartment of Otolaryngology, The First Affiliated Hospital of Suzhou University, 188 Shizi Street, Suzhou, 215000, Jiangsu Province, People’s Republic of ChinaTel +86-13506216162Email ljswwq@sina.comPurpose: Hsa_circ_0007637 was discovered to be differentially expressed in nasopharyngeal carcinoma (NPC). However, the exact function and mechanism of Hsa_circ_0007637 on NPC have not been studied. This study firstly researched the function and mechanism of Hsa_circ_0007637 on NPC progression.Methods: Hsa_circ_0007637, miR-636 and TPD52 expressions in 80 NPC patients were detected by quantitative real-time polymerase chain reaction. Hsa_circ_0007637 effect on NPC cell proliferation, apopticosis, invasion and migration was investigated by cell counting kit-8 assay, flow cytometry, transwell experiment and wound healing assay accordingly. Dual-luciferase reporter gene assay, RNA immunoprecipitation experiment and RNA fluorescence in situ hybridization experiment were performed to identify the binding between Hsa_circ_0007637 and miR-636. Dual-luciferase reporter gene assay and RNA pull down assay were conducted to verify the binding between miR-636 and TPD52. TPD52 protein expression in NPC cells was determined by Western blot. In vivo study was performed using nude mice. Immunohistochemistry was performed to assess TPD52 and Ki67 expression in tissues.Results: Hsa_circ_0007637 was overexpressed in NPC tissues and cells. High Hsa_circ_0007637 expression predicted a poor outcome for NPC patients. Hsa_circ_0007637 knockdown decreased proliferation, invasion, migration and increased apoptosis of NPC cells (P < 0.01). Hsa_circ_0007637 could enhance TPD52 expression via sponging miR-636. miR-636 overexpression or TPD52 knockdown weakened the promoting effect of Hsa_circ_0007637 on NPC cells malignant phenotype (P < 0.01). Hsa_circ_0007637 knockdown suppressed NPC cells growth in vivo (P < 0.01).Conclusion: Hsa_circ_0007637 facilitates NPC progression by sponging miR-636/TPD52 axis.Keywords: NPC, Hsa_circ_0007637, miR-636/TPD52, proliferation, apoptosis

Lemeng Zhang, Yongzhong Luo, Tianli Cheng, Jianhua Chen, Hua Yang, Xiaoping Wen, Zhou Jiang, Haitao Li, Changqie Pan Thoracic Medicine Department 1, Hunan Cancer Hospital, Changsha, Hunan Province, 410013, People’s Republic of ChinaCorrespondence: Yongzhong Luo Tel/Fax +86-731-89762220Email luoyongzhong@hnca.org.cnPurpose: The prognostic value of an N6-methyladenosine (m6A) methylation-related immune gene signature for lung adenocarcinoma (LUAD) was investigated.Patients and Methods: Gene expression and clinical phenotype data of LUAD patients were downloaded from The Cancer Genome Atlas database. A list of immune-related genes was retrieved from the InnateDB database. Correlation analysis, survival analysis, and univariate and multivariate Cox regression analyses were performed. After allocating patients into a high-risk or a low-risk group, the corresponding survival rates, immune microenvironment, expression of immune checkpoint genes, and modulation of Kyoto Encyclopedia of Genes and Genomes pathways were examined. Finally, the expression levels of prognostic biomarkers were assessed in the GSE126044 dataset.Results: Seven m6A-related immune prognostic genes were identified. High expression of PSMD10P1, DIDO1, ABCA5, and CIITA was associated with high survival rates, while that of PRC1, ZWILCH, and ANLN was associated with low survival rates. The high- and low-risk groups showed significant differences in terms of the abundance of six tumor-infiltrating immune cell types and expression of 12 immune checkpoint genes. The risk group acted as an independent prognostic factor (hazard ratio = 0.398, 95% confidence interval = 0.217– 0.729, P = 0.003). Finally, the developed nomogram could predict most efficiently the 1-, 2-, and 3-year survival probability of LUAD patients with a C-index of 0.833.Conclusion: A seven-gene risk signature, associated with the immune microenvironment in LUAD, showed independent prognostic value.Keywords: lung adenocarcinoma, N6-methyladenosine methylation, immune-related genes, immune microenvironment, prognostic signature

Zhenzhen Liu,1 Xiao Ma,2 Saif Ullah,1 Jitao Song,2 Lingjian Kong,1 Deliang Li,1 Chao Pan,2 Bingrong Liu1 1Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of ChinaCorrespondence: Bingrong LiuDepartment of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052, People’s Republic of ChinaTel/Fax +86-15713815559Email fccliubr@zzu.edu.cnPurpose: To evaluate the role of endoscopic retrograde appendicography for the diagnosis of acute appendicitis.Patients and Methods: We retrospectively analyzed 33 patients (20 men and 13 women, average age 44± 18 years) with suspected acute appendicitis between December 2016 and November 2018. Endoscopic direct-vision imaging or fluoroscopic endoscopic retrograde appendicography was performed to separate suspected acute appendicitis from actual acute appendicitis. The success rate, complications, and recurrence rate were recorded.Results: Acute appendicitis was ruled out by normal endoscopic retrograde appendicography in 8 (24%) and confirmed in 23 patients (70%). In 2 patients (6%), appendiceal orifice cannulation failed. Colonoscopic findings in acute appendicitis were mucosal hyperemia and edema of appendiceal orifice (83%), outpouring of pus from the appendiceal orifice (74%), and swollen cecal mucosa (61%). Appendicograpic findings were either normal or in acute disease showed diffuse luminal dilation (diameter: 0.8± 0.4 mm), partial stenosis (43%), stiffness or inflexibility (87%) and filling defects (22%). There were no complications during or after follow-up for a median of 13 months (IQR: 9– 24 months).Conclusion: Endoscopic retrograde appendicography appears to be a reliable and safe method to confirm or exclude the diagnosis of acute appendicitis and prevent unnecessary appendectomy.Keywords: acute appendicitis, endoscopic retrograde appendicography, diagnosis, appendicography

Mincong Wang,1,&ast; Yue Meng,1,&ast; Huifeng Zhu,1 Yong Hu,1 Chang-Peng Xu,2 Xiaomin Chao,1 Wenqiang Li,3 Chengguo Li,1 Chenglong Pan1 1Department of Joint Surgery, The Fifth Affiliated Hospital of Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Orthopaedics, Guangdong Second Provincial General Hospital, Guangzhou, People’s Republic of China; 3Engineering Technology Research Center for Sports Assistive Devices of Guangdong, Guangzhou Sport University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chenglong Pan; Chengguo Li Email pclgjwk@163.com; 356846516@qq.comIntroduction: Viola betonicifolia is a rich source of numerous secondary metabolites, such as alkaloids, flavonoids, tannins, phenolic compounds, saponins, triterpenoids, and so on, that are biologically active towards different potential biomedical applications. To broaden the potential use of Viola betonicifolia in the realm of bionanotechnology, we investigated the plant’s ability to synthesize gold nanoparticles (Au NPs) in a green and efficient manner for the very first time.Methods: The gold nanoparticles (VB-Au NPs) were synthesized using the leaves extract of Viola betonicifolia, in which plant’s secondary metabolites function as both reducing and capping agents. The VB-Au NPs were successfully characterized with spectroscopic techniques. The antimicrobial properties of the VB-Au NPs were further explored against bacterial and mycological species. Additionally, their antioxidant, cytotoxic, and cytobiocompatibility properties were examined in vitro against linoleic acid peroxidation, MCF-7 cancer cells, and human mesenchymal stem cells (hMSCs), respectively.Results: Results demonstrated that VB-Au NPs presented excellent antibacterial, antifungal, and biofilm inhibition performance against all the tested microbial species compared to plant leaves extract and commercially purchased chemically synthesized gold NPs (CH-Au NPs). Moreover, they also exhibited significant antioxidant potential, comparable to the external standard. The VB-Au NPs displayed good cytobiocompatibility with hMSCs and demonstrated excellent cytotoxic potential against MCF-7 cancer cells compared to CH-Au NPs. The current work presents a green method for synthesizing VB-Au NPs with enhanced antioxidant, antimicrobial, cytotoxic and biofilm inhibition efficacy compared to CH-Au NPs might be attributed to the synergistic effect of the nanoparticle’s physical properties and the adsorbed biologically active phytomolecules from the plant leaves extract on their surface.Conclusion: Thus, our study establishes a novel ecologically acceptable route for nanomaterials’ fabrication with increased and/or extra medicinal functions derived from their herbal origins.Keywords: Viola betonicifolia, gold NPs, antimicrobial, biofilm inhibition, antioxidant

Chunyang Pan, Yi Zhao, Haojie Xie, Yongyan Zhou, Ranran Duan, Yanfei Li, Yanjie Jia, Tao Peng Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of ChinaCorrespondence: Tao PengDepartment of Neurology, The First Affiliated Hospital of Zhengzhou University, Erqi District, Zhengzhou, Henan Province, People’s Republic of ChinaTel +861 367 366 5072Email zdyfy0420@163.comPurpose: To describe and compare the clinical features of patients with first-episode neuromyelitis optica spectrum disorder (NMOSD) in a normal complement C4 group and a low complement C4 group, and explore the mechanism by which low complement C4 affects the clinical features of patients with NMOSD.Patients and Methods: We retrospectively analyzed clinical data of 169 aquaporin-4 (AQP4) antibody positive patients with NMOSD from the First Affiliated Hospital of Zhengzhou University from December 2013 to March 2021. Prior to treatment, the blood was drawn for detection, and the patients underwent a 3.0 Tesla MRI examination. A low complement C4 level was defined as a serum complement C4 level < 0.14 g/L. Depending on whether the complement C4 level was reduced, it was divided into the normal complement C4 group and low complement C4 group. The basic demographics, clinical manifestations, laboratory examinations, and imaging findings of the two groups were compared.Results: Among the 169 AQP4 antibody positive patients, 54 were low-complement C4 patients and 115 were normal. There were no significant differences in the demographics, clinical manifestations, treatment options, or admission Expanded Disability Status Scale (EDSS) score between two groups (P > 0.05). The median of discharged EDSS was the same (4 vs 4), but the difference between the two was statistically significant (P = 0.019). Compared with the normal complement C4 group, the blood uric acid level (225 vs 179; P = 0.001) and the C3 level (1.06 vs 0.87, P = 0.000) of the low complement C4 group were significantly lower. The incidence of brainstem lesions in patients with low complement C4 was higher (53.7% vs 33%, P = 0.01).Conclusion: The treatment effect of the first-episode AQP4 antibody positive NMOSD low complement C4 group was poor, the blood-brain barrier was more severely damaged, and the disease changes were likely to involve the brainstem.Keywords: blood-brain barrier, brainstem, humoral immunity, optic neuritis

Yi Zhao, Haojie Xie, Chunyang Pan, Yaobing Yao, Zhe Gong, Yanfei Li, Yanjie Jia Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Yanjie JiaDepartment of Neurology, The First Affiliated Hospital of Zhengzhou University, 1st Jian She East Road, Zhengzhou, 450052, People’s Republic of ChinaTel +86-135 13802916Email jiayanjie1971@zzu.edu.cnPropose: To investigate the clinical characteristics and potential risk factors of the first onset of cerebral hemorrhage in patients with occult malignant tumors.Patients and methods: In this retrospective study, 23 patients with occult malignant tumors with the first onset of cerebral hemorrhage were enrolled in the tumor group, and 92 patients without occult tumors in the same period were enrolled in the control group. There were no statistical differences in age and sex between both groups by propensity score matching. Collected clinical data included age, sex, smoking history, drinking history, hypertension history, diabetes history, past medical history, routine blood tests, neutrophil-to-lymphocyte ratio (NLR), liver and kidney function, fasting blood glucose level, coagulation function, tumor markers, imaging examinations, National Institute of Health stroke scale (NIHSS) score on admission, modified Rankin Scale (mRS) score 90 days after intracerebral hemorrhage and final mRS score.Results: Compared with the control group, the tumor group had fewer patients with hypertension (52.2% vs 81.5%, P< 0.05), and the NLR was significantly decreased in the tumor group (2.74 vs 5.46, P< 0.05). The tumor group had a greater number of patients with the bleeding sites located in the lobar regions (43.5% vs.19.6%, P< 0.05) and a higher coagulation dysfunction (52.2% vs 29.3%, P< 0.05) than the control group. Multivariate logistic regression analysis revealed that no history of hypertension (OR: 3.141, 95% CI: 1.107– 8.916), lobar cerebral hemorrhage (OR: 3.465 95% CI:1.172– 10.243), and coagulation dysfunction (OR: 3.176, 95% CI: 1.131– 8.913) were independent predictors of occult tumors, and the receiver operating characteristic (ROC) curve showed that the area under the curve of the three-index combined diagnosis was 0.748, C-statistic analysis also showed the same result.Conclusion: No history of hypertension, lobar cerebral hemorrhage, and coagulation dysfunction may be predictors of the risk of occult malignancies in patients with cerebral hemorrhage.Keywords: cerebral hemorrhage, clinical features, malignant tumor, risk factors

Chun Pan,1 Jingzhe Shang,2,3 Haiqin Jiang,1 Ying Shi,1 Wenyue Zhang,1 Jingshu Xiong,1 Youming Mei,1 Siyu Long,1 Gai Ge,1 Zhenzhen Wang,1 Ziwei Wu,1 Hongsheng Wang,1 Aiping Wu2,3 1Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, 210046, People’s Republic of China; 2Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, People’s Republic of China; 3Suzhou Institute of Systems Medicine, Suzhou, 215123, People’s Republic of ChinaCorrespondence: Hongsheng WangInstitute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, 210046, People’s Republic of ChinaEmail whs33@vip.sina.comAiping WuInstitute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, People’s Republic of ChinaEmail wap@ism.cams.cnBackground: Given their similar appearance and histology, halo nevi (HN) were considered as a type of vitiligo. However, whether HN have stronger immune response than stable vitiligo (VL) remains unclear. In addition, the molecular alterations in HN compared with normal nevocytic nevi (NN) and primary cutaneous melanoma (MM) must be determined. This study aimed to systematically characterize the molecular immunological features of HN.Methods: Skin samples from patients with HN, VL, NN, and MM were obtained with informed consent. Each of the four groups underwent transcriptome sequencing and data analysis were for pairwise comparison. Quantitative real-time PCR (RT-qPCR) was conducted to confirm the transcriptional expression of some differentially expressed genes (DEGs) that were closely related to immunity.Results: A total of 441 and 1507 DEGs were found in the HN/NN and HN/MM groups, respectively. Compared with those of VL, HN lesions contained 162 up-regulated DEGs and 12 down-regulated DEGs. Bioinformatics analysis showed that the up-regulated genes in HN were substantially enriched in immune response, immune deficiency, and immune rejection; biological stimulation (virus, bacteria); and proliferation and activation of immune cells. Immune cell composition analysis also confirmed high expression levels of multiple immunocytes in HN.Conclusion: The molecular immune mechanisms of HN and VL were similar, but the immune activity of HN was stronger than that of VL. Innate and adaptive immunity were involved in the pathogenesis and progression of HN and VL.Keywords: vitiligo, halo nevi, transcriptome sequencing, differentially expressed genes

Si-Yu Long,1 Le Wang,1,2 Hai-Qin Jiang,1 Ying Shi,1 Wen-Yue Zhang,1 Jing-Shu Xiong,1 Pei-Wen Sun,1,2 Yan-Qing Chen,1 You-Ming Mei,1 Chun Pan,1 Gai Ge,1 Zhen-Zhen Wang,1 Zi-Wei Wu,1 Mei-Wen Yu,1,2 Hong-Sheng Wang1– 3 1Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, 210042, People’s Republic of China; 2National Centre for Leprosy Control, China CDC, Nanjing, People’s Republic of China; 3Centre for Global Health, School of Public Health, Nanjing Medical University, Nanjing, People’s Republic of ChinaCorrespondence: Hong-Sheng Wang; Mei-Wen YuJiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, St 12 Jiangwangmiao, Nanjing, Jiangsu, 210042, People’s Republic of ChinaEmail whs33@vip.sina.com; yumeiwen@163.comBackground: Genome-wide association studies (GWASs) have identified some immune-related single-nucleotide polymorphisms (SNPs) to be associated with leprosy.Methods: This study investigated the association of 17 SNPs based on previously published GWAS studies with susceptibility to leprosy, different polar forms and immune states of leprosy in a case–control study from southwestern China, including 1344 leprosy patients and 2732 household contacts (HHCs) (1908 relatives and 824 genetically unrelated contact individuals). The differences of allele distributions were analyzed using chi-squared analysis and logistic regression.Results: After adjusting covariate factors, rs780668 and rs3764147 polymorphisms influenced susceptibilities to genetically related or unrelated leprosy contact individuals. rs142179458 was associated with onset early cases, rs73058713 A allele and rs3764147 A allele increased the risk of reversal reaction, while rs3764147 G allele had higher risk to present lepromatous leprosy and erythema nodosum leprosum.Conclusion: Our results demonstrated that genetic variants in the LACC1, HIF1A, SLC29A3 and CDH18 genes were positively correlated with the occurrence of leprosy and leprosy clinical phenotypes, providing new insights into the immunogenetics of the disease.Keywords: leprosy, association study, susceptibility gene, polymorphisms

Yifan Cai,1 Qiutang Zeng,1 Yuzhou Liu,2 Ruirui Zhu,1 Kunwu Yu,1 Wenbin Xu,1 Yue Wang,1 Yan Ding,1 Jian Yu,1 Chengliang Pan,1 Yudong Peng,1 Yi Mao,1 Peng Cheng,1 Lun Huang,1 Xiaobo Mao,1 Yucheng Zhong1 1Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 2Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of ChinaCorrespondence: Yucheng ZhongLaboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jie-Fang Avenue, Wuhan, 430022, People’s Republic of ChinaTel +86-27-85726423Fax +86-27-85726425Email zyc811029@126.comPurpose: This study aims to clarify the specific mechanism by which GARP affects the atherosclerotic plaques in ApoE−/- mice and the effect of GARP-tDC on atherosclerosis.Methods: The mice were randomly divided into three groups: the control group, the GARP-overexpressed group and the GARP-inhibited group. After 12 weeks, all the mice were euthanized, and the specimens were collected. In vitro, experiments were conducted to observe the effect of GARP on DC phenotype and the changes of the proportion of CD4+CD25+Foxp3+ Treg cells when GARP-tDCs were co-cultured with CD4+ T cells. Furthermore, adoptive transmission of GARP-tDCs was used to observe the effect on atherosclerotic plaque in mice.Results: The GARP-overexpressed group enhanced the biological activity of Foxp3+ CD4+CD25+ Tregs and resulted in increased expression of LAP in T cells. In addition, the GARP-overexpressed group significantly suppressed the function of Th1 and Th17, and decreased the secretion of INF-γ and IL-17A. Thus, GARP had a protective effect on atherosclerosis. In vitro, we found that GARP-tDC had a tolerance-inducing phenotype, and GARP-tDC also had the ability to induce tolerance when co-cultured with CD4+ T cells. More importantly, adoptive transmission of GARP-tDCs reduced the size of atherosclerotic plaques.Conclusion: GARP and the GARP-tDC play protective roles in atherosclerosis. The protective effect of GARP on atherosclerosis is achieved by increasing CD4+CD25+Foxp3+ Treg cells and inhibiting the production of IFN-γ and IL-17A.Keywords: GARP, Foxp3, GARP-tDC, atherosclerosis, LAP

Hang Guo,1 Zhiyue Yan,1 Yonghui Hu,1 Xitong Huang,2 Congqing Pan1 1NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, People’s Republic of China; 2Department of TCM, China Pharmaceutical University, Nanjing, Jiangsu, 211100, People’s Republic of ChinaCorrespondence: Congqing Pan Email cpan@tmu.edu.cnBackground: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, but it remains relatively underdiagnosed.Objective: In this study, we aimed to explore the key regulatory pathways and potential biomarkers related to DN using integrated bioinformatics analysis and validation.Methods: First, the microarray data of the GSE30528 and GSE96804 datasets were downloaded from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were screened. Then, weighted gene coexpression network analysis (WGCNA), gene ontology (GO) annotation, gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to identify key pathways and genes. qRT-PCR and receiver operating characteristic (ROC) curves were used to validate our results. Furthermore, single-cell RNA sequencing (scRNA-seq) data were reanalyzed to investigate the expression specificity of C7 in DN cells. An online database search and luciferase reporter assay identified the target relationship between miRNAs and C7.Results: The “complement and coagulation cascades” were significantly enriched, and complement C3 and C7 were candidate markers. The receiver operating characteristic (ROC) curve revealed that C7 had significant diagnostic value (AUC=0.865) in DN. Through scRNA-seq reanalysis, we found that C7 was specifically elevated in mesangial (MES) cells of DN. Moreover, we found that the expression of C7 was regulated by miR-494-3p and miR-574-5p.Conclusion: This is the first study to reveal that C7 is specifically expressed in mesangial cells, is a potential diagnostic biomarker for diabetic nephropathy, and is regulated by miR-494-3p and miR-574-5p.Keywords: diabetic nephropathy, mesangial (MES) cells, complement and coagulation cascades, complement C7, miR-494-3p, miR-574-5p, biomarker

Yan Gao,1,&ast; Ke Men,1,&ast; Congbin Pan,1 Jingmei Li,1 Jieping Wu,1 Xiaohua Chen,2 Sibei Lei,1 Xiang Gao,1 Xingmei Duan2 1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan Province, People’s Republic of China; 2Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ke MenState Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of ChinaEmail mendingbob@hotmail.comXingmei DuanDepartment of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, People’s Republic of ChinaEmail duanxingmei2003@163.comBackground: Gene therapy has emerged as a new strategy for cancer therapy. As an alternative nucleic acid material, messenger ribonucleic acid (mRNA) is being increasingly utilized in cancer gene therapy. However, unfulfilled requirements and a lack of ideal mRNA delivery vectors persist.Methods: We developed an advanced mRNA delivery system, DMP-039, by fusing a cell-penetrating peptide, cRGD-R9, and a cationic nano-sized DMP backbone together. The DMP gene vector backbone was synthesized by the self-assembly of DOTAP lipid and mPEG-PCL polymer. Introduction of the cRGD-R9 peptide onto the DMP backbone was performed to elevate the mRNA delivery capacity, which resulted in a peptide-functionalized hybrid delivery system.Results: The average size of the synthesized DMP-039 was 268.9 ± 12.4 nm (PDI = 0.382), with a potential of 17.4 ± 0.5 mV. The synthesized DMP-039 hybrid nanoparticles exhibited high mRNA delivery efficiency through multiple mechanisms during transmembrane transportation. By loading the encoding mRNA from the suicide gene Bim, a locally administered mBim/DMP-039 complex strongly inhibited growth in two colon cancer models. Moreover, intravenous administration of the mBim/DMP-039 complex efficiently suppressed C26 pulmonary metastatic tumor progression with high safety. The in vivo distribution, degradation, and excretion were also investigated in detail.Conclusion: Our results suggest that the DMP-039 peptide-functionalized hybrid nanoparticle is an advanced candidate for mRNA-based suicide gene therapy.Keywords: mRNA, Bim, cell-penetrating peptide, gene therapy

Yonghui Hu, Zhiyue Yan, Congqing Pan NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, People’s Republic of ChinaCorrespondence: Congqing PanNHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, People’s Republic of ChinaTel +86-13920423976Fax +86-22-59560475Email profpancq@163.comPurpose: The purpose of this study is to evaluate whether thyroid hormone in euthyroid patients with type 2 diabetes mellitus (T2DM) is associated with macrovascular complications.Patients and Methods: The authors examined 311 patients enrolled from February 2019 to December 2019 in Tianjin Medical University Chu Hsien-I Memorial Hospital. A medical record review enabled the collection of demographic and anthropometric information. We classified the patients into two groups based on the echocardiography and vascular ultrasonography results, namely, non-macrovascular complications (n=131) group and macrovascular complications (n=180) group. Odds ratios (OR) and 95% confidence intervals (CI) were calculated, adjusting for potential confounders, the prevalence of macrovascular complications was determined using multivariate logistic regression.Results: A significant association was observed for diabetic macrovascular complications with normal free triiodothyronine (FT3) (OR=0.534, 95% CI 0.358– 0.796, p = 0.002) and free thyroxine (FT4) (OR= 0.844, 95% CI 0.760– 0.937, p = 0.001). Nevertheless, there was no evidence of any association between thyroid-stimulating hormone (TSH) and the development of diabetic macrovascular complications. When stratified by the body mass index (BMI), a similar relationship existed with the overall results. The positive association remained in restricted analyses involving only patients with HbA1c abnormalities.Conclusion: Overweight or obese T2DM patients are at high risk due to the implicit association between low but clinically normal thyroid hormone levels and elevated risk of macrovascular complications. However, there were no statistically significant associations between TSH and diabetic macrovascular complications.Keywords: macrovascular complications, T2DM, thyroid hormone, type 2 diabetes mellitus

Chenwei Pan,1,* Tiaotiao Zhang,2,3,* Shaoxun Li,1,3,* Zhihua Xu,2,3 Binhui Pan,2,3 Sheng Xu,2,3 Shuanghong Jin,1,3 Guangrong Lu,2 Shouxing Yang,2 Zhanxiong Xue,2 Ping Chen,4 Xian Shen,5 Fangyan Wang,6 Changlong Xu2,7 1Department of Infectious Disease, Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China; 2Department of Gastroenterology, Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China; 3Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China; 4Department of Infectious Disease, Shulan Hospital, Hangzhou, Zhejiang, 310012, People’s Republic of China; 5Department of Gastrointestinal Surgery, Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China; 6Department of Pathophysiology, School of Basic Medicine Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China; 7Center for Diagnostics and Therapeutics, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30302, USA*These authors contributed equally to this workCorrespondence: Fangyan Wang; Changlong Xu Email wzyxywfy@126.com; xchlong@163.comBackground: As a therapeutic target for cancer treatment, HSP90 has been explored extensively. However, the significant side effects of the HSP90 inhibitor 17AAG have limited its clinical use.Methods: In this study, we used hyaluronic acid (HA)–decorated DOTAP–PLGA hybrid nanoparticles (HA-DOTAP-PLGA NPs) as 17AAG-delivery carriers for targeted colon cancer therapy.Results: Different methods were used to characterize the successful fabrication of these hybrid PLGA NPs. Our results demonstrated that internalization of HA-NPs in colon cancer cells was governed by CD44receptor–mediated endocytosis. Annexin V–propidium iodide staining experiments revealed that cell apoptosis induced by HA-NPs-17AAG in colon cancer cells was more efficient than free 17AAG. In two animal models used to screen anticancer efficacy (Luc-HT29 subcutaneous xenograft and AOM/DSS-induced orthotopic tumor model), HA-NPs-17AAG significantly inhibited xenograft and orthotopic tumor growth, demonstrating HA-NPs-17AAG had much better therapeutic efficiency than free 17AAG. It is worth noting that great biocompatibility of HA-DOTAP-PLGA NPs was observed both in vitro and in vivo.Conclusion: Our research offers a preclinical proof of concept for colon cancer therapy with DOTAP-PLGA NPs as a creative drug-delivery system.Keywords: cationic hybrid nanoparticles, hyaluronic acid, HA, HSP90 inhibitor, colon cancer, targeted delivery system

The mechanism governing the deoxidation of vanadium metal is regarded as fundamental knowledge; however, it has not been elucidated in existing literature. In this paper, the thermodynamic data of V-H-O systems were summarized, and the Gibbs free energies of the main compounds were calculated. Consequently, the deoxidation limits of different reductants in a V-O system were evaluated, namely: Si, Al, and Mg. It was observed that Si cannot remove an O content of less than 7.27 wt% from V. However, Al was the stronger reducing agent; it could remove O contents of up to 0.01 and 0.1 wt% at 800 and 1050 °C, respectively. Nevertheless, Mg exhibited the best reducing properties as it could remove less than 0.01 wt% of O at 1100 °C. The addition of H2 renders the V-O solid solution unstable to a certain extent, thereby indicating that H2 facilitates deoxygenation. Furthermore, the results obtained by analyzing the equilibrium conditions were in accordance with the results of the deoxidation limit in the V-O system. In other words, this study demonstrates that the oxygen in vanadium can be effectively controlled by changing the reductant dosage and temperature.

Hongjia Zhang,1,* Ke Men,1,* Congbin Pan,1 Yan Gao,1 Jingmei Li,1 Sibei Lei,1 Guonian Zhu,1 Rui Li,1 Yuquan Wei,1 Xingmei Duan2 1State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan Province, People’s Republic of China; 2Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ke Men StateKey Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, People’s Republic of ChinaEmail mendingbob@hotmail.comXingmei DuanDepartment of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, People’s Republic of ChinaEmail duanxingmei2003@163.comBackground: Drugs that work based on the mechanism of RNA interference have shown strong potential in cancer gene therapy. Although significant progress has been made in small interfering RNA (siRNA) design and manufacturing, ideal delivery system remains a limitation for the development of siRNA-based drugs. Particularly, it is necessary to focus on parameters including delivery efficiency, stability, and safety when developing siRNA formulations for cancer therapy.Methods: In this work, a novel degradable siRNA delivery system cRGD-R9-PEG-PEI-Cholesterol (rrPPC) was synthesized based on low molecular weight polyethyleneimine (PEI). Functional groups including cholesterol, cell penetrating peptides (CPPs), and poly(ethylene oxide) were introduced to PEI backbone to attain enhanced transfection efficiency and biocompatibility.Results: The synthesized rrPPC was dispersed as nanoparticles in water with an average size of 195 nm and 41.9 mV in potential. rrPPC nanoparticles could efficiently deliver siRNA into C26 clone cancer cells and trigger caveolae-mediated pathway during transmembrane transportation. By loading the signal transducer and activator of transcription 3 (STAT3) targeting siRNA, rrPPC/STAT3 siRNA (rrPPC/siSTAT3) complex demonstrated strong anti-cancer effects in multiple colon cancer models following local delivery. In addition, intravenous (IV) injection of rrPPC/siSTAT3 complex efficiently suppressed lung metastasis tumor progression with ideal in vivo safety.Conclusion: Our results provide evidence that rrPPC nanoparticles constitute a potential candidate vector for siRNA-based colon cancer gene therapy.Keywords: RNA interfering, nanoparticle, STAT3, colon cancer

Jingru Ren,1 Ping Hua,1 Chenxi Pan,1 Yuqian Li,1 Li Zhang,2 Wenbin Zhang,3 Pingyi Xu,4 Minming Zhang,5 Weiguo Liu1 1Department of Neurology, Affiliated Brain Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Geriatrics, Affiliated Brain Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 3Department of Neurosurgery, Affiliated Brain Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 4Department of Neurology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 5Department of Radiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Weiguo LiuDepartment of Neurology, Affiliated Brain Hospital of Nanjing Medical University, 264 Guangzhou Road, Gulou District, Nanjing 210029, People’s Republic of ChinaTel +86-25-82296569Email wgliunbh@sina.comBackground and Purpose: Little is known about non-motor symptoms (NMSs) associated with the postural instability and gait difficulty (PIGD) phenotype, especially in de novo Parkinson’s disease (PD) patients. The aims of this study were to compare NMSs between the tremor dominant (TD) and PIGD phenotypes in de novo PD patients and to determine factors that are associated with the PIGD subtype.Patients and Methods: In a cross-sectional study conducted at our single center, 226 de novo PD patients with a median disease duration of 2 years were recruited. Data, including comprehensive demographics, motor subtypes and NMSs were obtained. Motor subtypes were classified as PIGD and non-PIGD (TD and indeterminate) by Jankovic’s method. NMSs were evaluated by the non-motor symptoms questionnaire (NMSQuest).Results: We identified 73 (32.3%), 34 (15.0%) and 119 (52.7%) patients with TD, intermediate and PIGD subtypes, respectively. Patients with the PIGD subtype had poorer ADL, motor, depression, anxiety, sleep, and non-motor scores compared with those with the TD subtype. In the NMSQuest, the prevalence of cardiovascular, sleep, mood/cognitive and miscellaneous domains was increased in patients with the PIGD subtype compared with patients with the TD subtype. Multivariable forward stepwise logistic regression revealed that the Hamilton Depression Scale (HAMD) [odds ratio (OR), 1.059; 95% confidence interval (CI), 1.016– 1.104, p = 0.007] and pain (OR, 3.175; 95% CI, 1.695– 5.947, p < 0.001) exhibit significant discriminative power in differentiating PIGD and non-PIGD groups.Conclusion: The PIGD group had more severe cardiovascular symptoms, sleep impairments, mood disturbances and pain. We demonstrated for the first time that pain was associated with the PIGD phenotype. Prompt detection and early treatment of NMSs related to the PIGD phenotype may improve patient outcomes.Keywords: de novo Parkinson’s disease, motor subtypes, non-motor symptoms, tremor dominant, postural instability and gait difficulty

Min Lin, Chunyu Pan, Wenbin Xu, Jingwei Li, Xueqiong Zhu Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People’s Republic of ChinaCorrespondence: Xueqiong ZhuDepartment of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People’s Republic of ChinaTel +86 577 8800 2796Fax +86 577 88002796Email zjwzzxq@163.comBackground: Cisplatin-based neoadjuvant chemotherapy and concurrent radiotherapy and chemotherapy are the main treatment for advanced cervical cancer. However, the development of multidrug resistance (MDR) leads to chemotherapy failure, tumor recurrence and poor survival. In this research, we investigated the effect and corresponding mechanism of leonurine on cisplatin sensitivity of cervical cancer cells.Methods: Anti-cervical cancer efficacy of leonurine and leonurine combined with cisplatin was examined in C33A and Ms751 cells. The cell counting kit-8 assay and bromodeoxyuridine assay were applied for measuring cell proliferation. CompuSyn software was used to calculate the combination index and assess the synergistic effect of leonurine and cisplatin on cell proliferation. The cell cycle distribution and cell apoptosis were analyzed by flow cytometry. The expression of cleaved caspase-3, poly ADP-ribose polymerase (PARP), B-cell lymphoma-2 associated X (BAX), B-cell lymphoma-2 (BCL-2), P glycoprotein (P-Gp) protein and multiple drug resistance protein 1 (MRP1) was analyzed by Western blotting.Results: Leonurine had time- and dose-dependent anti-proliferative effects on C33A and MS751 cells. Leonurine and cisplatin combination was more efficacious in inhibiting the growth of cervical cancer cells than either of the two drugs. The combined application has shown that the cervical cancer cells were arrested at G1 phase after treatments. Moreover, flow cytometry analysis indicated that the combined treatment could cause more cell apoptosis than the single drug treatment. Consistently, combined treatment elevated BAX/BCL-2 ratio, and the expression of BAX, PARP and cleaved caspase-3 proteins. Mechanistic investigations uncovered that the tumor-inhibiting effects of the co-treatment were mediated by repressing MDR, including MRP1 and P-Gp protein, thereby enhancing the efficiency of cisplatin.Conclusion: Leonurine and cisplatin have synergistic antitumorigenic effects on cervical cancer. Combination with leonurine may serve as a novel strategy for enhancing cisplatin sensitivity via the inhibition of the expression of MRP1 and P-Gp.Keywords: cervical cancer, leonurine, cisplatin, multidrug resistance

Yanchun Wei, Sen Liu, Changjiang Pan, Zhongmei Yang, Ying Liu, Jianfang Yong, Li Quan Jiangsu Provincial Engineering Research Center for Biomedical Materials and Advanced Medical Devices, Huaiyin Institute of Technology, Huai’an, Jiangsu, People’s Republic of ChinaCorrespondence: Yanchun Wei; Li QuanJiangsu Provincial Engineering Research Center for Biomedical Materials and Advanced Medical Devices, Huaiyin Institute of Technology, Huai’an, Jiangsu, People’s Republic of ChinaTel +86-137 1691 3791Email weiyanchunha@hyit.edu.cn; quanli2016@hyit.edu.cnBackground: Photothermal therapy with accurate and real-time temperature detection is desired in clinic. Upconversion nanocrystals (UCNs) are candidate materials for simultaneous temperature detection and photothermal agents carrying. However, the weak luminescence and multiple laser excitations of UCNs limit their application in thermal therapy.Materials and Methods: NaYF4:Yb3+,Er3+,Nd3+, PL-PEG-NH2, IR-806 and folic acid are selected as structural components. A nanoprobe (NP) integrated with efficient photothermal conversion and sensitive temperature detection capabilities is synthesized for precise photothermal therapy. The probes are based on near-infrared upconversion nanocrystals doped with Yb, Er and Nd ions, which can be excited by 808 nm light. IR-806 dye molecules are modified on the surface as molecular antennas to strongly absorb near-infrared photons for energy transfer and conversion.Results: The results show that under an 808 nm laser irradiation upconversion luminescence of the nanocrystals is enhanced based on both the Nd ion absorption and the FRET energy transfer of IR-806. The luminescence ratio at 520 and 545 nm is calculated to accurately monitor the temperature of the nanoparticles. The temperature of the nanoprobes increases significantly through energy conversion of the molecular antennas. The nanoparticles are found successfully distributed to tumor cells and tumor tissue due to the modification of the biocompatible molecules on the surface. Tumor cells can be killed efficiently based on the photothermal effect of the NPs. Under the laser irradiation, temperature at mouse tumor site increases significantly, tissue necrosis and tumor cell death can be observed.Conclusion: Precision photothermal therapy can thus be achieved by highly efficient near-infrared light absorption and accurate temperature monitoring, making it promising for tumor treatment, as well as the biological microzone temperature detection.Keywords: temperature, photothermal therapy, molecule antennas, upconversion nanoparticle

Xue Wang, 1 Yizeng Jiang, 2 Yingzhe Bai, 3 Chao Pan, 2 Renzi Wang, 4 Miao He, 1 Jinghai Zhu 1 1Institute of Environmental and Health, School of Public Health China Medical University, Shenyang, People’s Republic of China; 2Department of Emergency, Horqin District First People’s Hospital of Tongliao, Tongliao, People’s Republic of China; 3Department of Air Detection Information Technology Support Center, Tongliao Meteorological Observation, Tongliao, People’s Republic of China; 4Department of Clinical Medicine, Air Force Medical University, Xian, People’s Republic of ChinaCorrespondence: Jinghai ZhuInstitute of Environmental and Health, School of Public Health China Medical University, Puhe Road 77, Shenyang, Shenbei 110122, People’s Republic of ChinaEmail zhujinghai2019@163.comAim: The aim of this study was to examine the association between air temperature and incidence of acute coronary heart disease in Northeast China.Methods: We obtained coronary heart disease (CHD) daily hospitalization data from January 2017 to June 2019, and collected meteorological data including average daily air temperature, air pressure, relative humidity, wind velocity, sunshine duration and water vapor pressure, for the same period. Totally, This study included data from 6775 patients with CHD.Results: After adjusting for confounding factors, low air temperature was inversely associated with CHD. Additionally, in the warm season (April–September), the number of daily hospital admissions for CHD was higher (≥ 24.2°C) if the average daily air temperature was low (≤ 15.4°C).Conclusion: Low air temperature might be a risk factor for CHD among the elderly, especially in the warm season.Keywords: air temperature, coronary heart disease, elderly, warm season, cold season

Yongping Yang,1,* Chenxi Pan,2,* Lingyun Yu,1 Hongxia Ruan,2 Ling Chang,2,3 Jingbo Yang,4 Zihan Zheng,2 Feng Zheng,2,3 Tongjun Liu1,4 1First Bethune Hospital, Jilin University, Changchun, Jilin, People’s Republic of China; 2Dalian Key Laboratory of Immune and Metabolic Kidney Diseases, Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, Liaoning, People’s Republic of China; 3Department of Nephrology, Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China; 4Second Bethune Hospital, Jilin University, Changchun, Jilin, People’s Republic of China*These authors contributed equally to this manuscriptCorrespondence: Tongjun LiuDepartment of Gastrointestinal Surgery, First Bethune Hospital of Jilin University, No.828 Xinmin Street, Changchun, Jilin 130021, People’s Republic of ChinaEmail tongjunliu@163.comFeng ZhengAdvanced Institute for Medical Sciences, Dalian Medical University, 9 West Section, South Road, Lushunkou District, Dalian, Liaoning 116044, People’s Republic of ChinaEmail fzheng63@163.comBackground: Colorectal cancers (CRC) are one of the most common forms of cancer seen worldwide, and also remain difficult to treat despite recent advances in chemotherapy. Although significant progress has been made in recent years towards precision medicine and mutation-guided therapy, common mechanisms that underlie tumor growth and progression remain incompletely understood.Methods: Tumor tissue and nearby unaffected tissue were collected from >15 patients at each stage of CRC, from which we generated representative proteomics profiles of three stages. Bioinformatics analysis was performed to discover common differences that may be shared between the representative profiles and across larger cohorts. Flow cytometry was then used to identify functional consequences of SSBP1 depletion in cell lines, since its expression level was consistently increased in tumor cells across all of the datasets analyzed.Results: Direct comparison of CRC tumor and unaffected tissue at each stage demonstrated that a number of proteins involved in mitochondrial function displayed significantly altered expression patterns. Depletion of SSBP1 in colon cancer cell lines was able to trigger loss of mitochondrial mass and an increase in tumor cell death, and this effect that was further accentuated in the presence of the common chemotherapy drug cisplatin.Conclusion: Mitochondrial biogenesis and maintenance may play an important part in tumor cell survival during CRC progression, and may be a useful target for directed inhibition or adjuvant targeting in the cases of cisplatin resistance.Keywords: SSBP1, colorectal cancer, proteomics

Chen Pan,1,2 Qi Liu,2 Xiaoling Wu1 1Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Gastroenterology, The Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of ChinaCorrespondence: Xiaoling WuDepartment of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People’s Republic of ChinaTel +86 189 8511 5661Email gzykdxwxl123456@sina.comPurpose: Various microRNAs are involved in the development of gastric cancer (GC). This study investigated the role and mechanism of miR-520a-3p in GC.Method: Quantitative real-time fluorescence PCR (qRT-PCR) was applied to measure the expression level of miR-520a-3p in GC tissues and cell lines. The chi-squared test was employed to evaluate the relationship between the expression level of miR-520a-30p and clinical traits. The cell count kit-8 assay was used to detect the effect of miR-520a-3p on GC cell proliferation, while its effect on glycolysis was determined using the glucose assumption, lactate, and ATP production assay. The effect of miR-520a-3p on tumor growth in vivo was examined using a xenograft model. The relationship between miR-520a-30p and AKT1/mTOR/HIF1α pathway in normoxia and hypoxia was investigated using bioinformatics analysis, dual-luciferase reporter assay, qRT-PCR and Western blotting.Results: The expression of miR-520a-3p was decreased in GC tissues and cell lines. The expression level of miR-520a-3p was negatively associated with various malignant biological properties in patients. Overexpression/inhibition of miR-520a-3p decreased/promoted cell proliferation and glycolysis in vitro. Overexpression of miR-520a-3p inhibited tumor growth in vivo. AKT1 is the functional target of MiR-520a-3p, which was decreased in miR-520a-3p-overexpressing cells. In addition, overexpression of miR-520a-3p decreased the protein level of AKT1, mTOR, HIF1α, and target genes of HIF1α such as Glut1 and VEGF. Restoration of the expression of AKT1 can decrease the inhibitory effect of miR-520a-3p on the AKT1/mTOR/HIF1α pathway, as well as cell proliferation and glycolysis. Furthermore, the level of miR-520a-3p was decreased, while that of AKT1 was increased under hypoxia. Notably, inhibition of HIF1α or overexpression of miR-520a-3p suppressed these effects.Conclusion: Our study provided the first evidence for the existence of HIF1α/miR-520a-3p/AKT1/mTOR feedback, which promotes the proliferation and glycolysis of GC cells, highlighting a potential novel target for treatment.Keywords: gastric cancer, miR-520a-3p, AKT/mTOR/HIF1α pathway, glycolysis

Chen Pan,1 Honghong Wang,2 Minzhen Chen,3 Yu Cai,1 Changgen Xiao,4 Qiuping Tang,1 Deborah Koniak-Griffin5 1Department of Clinical Psychology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, People’s Republic of China; 2Department of Fundamental Nursing, Xiangya School of Nursing, Central South University, Changsha, Hunan 410013, People’s Republic of China; 3AIDS Department of the First Hospital of Changsha, Hunan 410005, People’s Republic of China; 4Department of Applied Psychology, School of Humanities and Management, Hunan University of Chinese Medicine, Changsha, Hunan 410208, People’s Republic of China; 5School of Nursing of University of California Los Angeles, Los Angeles, CA 90095-1702, USACorrespondence: Qiuping TangDepartment of Clinical Psychology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, People’s Republic of ChinaTel +86 13787256418Fax +86 731 88618487Email tt96@sina.comBackground/purpose: Workplace stress among nurses providing care for people living with human immunodeficiency virus is a serious problem in China that may increase rates of job burnout and affect quality of care. Mindfulness-based intervention has been shown to be effective in relieving stress and burnout in nurses. Therefore, we designed a mixed-method pilot study to evaluate a mindfulness-based intervention for nurses providing care for people living with human immunodeficiency virus.Methods: Twenty nurses caring for people living with human immunodeficiency virus in the First Hospital of Changsha, China participated in a mindfulness-based intervention for 2 hr sessions weekly for 6 weeks. The Perceived Stress Scale, Maslach Burnout Inventory, Five Facets Mindfulness Questionnaire, State-Trait Anxiety Inventory, and the Beck Depression Inventory were used to collect data before and after the mindfulness-based intervention. Participants were invited to attend an in-depth interview 1 week after the end of the mindfulness-based intervention to give feedback.Results: The quantitative analyses revealed a significant change in Five Facets Mindfulness Questionnaire scores. There were no significant differences between pre- and post-intervention measures of any other variables. Qualitative results showed nurses experienced a decrease in work and daily life pressures; improvements in communications with patients, colleagues and families, with better regulation of negative emotions, and acceptance of other people and attention.Conclusion: This study supports the acceptability and potential benefits of the mindfulness-based intervention in helping nurses caring for people living with human immunodeficiency virus to manage stress and emotions, and improve their acceptance of others and attention. A larger study with a randomized controlled trial design is warranted to confirm the effectiveness of this mindfulness-based intervention.Keywords: human immunodeficiency virus, stress, emotions, job burnout, mindfulness-based intervention

Qingwen Wang,1 Xiankai Zhang,1 Tingting Xiao,2 Chenhua Pan,1 Xing Liu,3,4 Yulan Zhao1 1Department of Physiology, School of Life Sciences, East China Normal University, Shanghai, People’s Republic of China; 2Department of Botany, School of Life Sciences, Shanghai Normal University, Shanghai, People’s Republic of China; 3Department of Central Laboratory Medicine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 4Shanghai Biochip Corporation Ltd./National Engineering Center for Biochip at Shanghai, Shanghai, People’s Republic of China Background: Recent studies have shown that Toll-like receptors (TLRs) may be associated with cancers. The aim of this meta-analysis is to summarize the predicting role of TLRs for survival in patients with a variety of carcinomas. Materials and methods: Eligible studies were identified and assessed for quality through multiple search strategies. We collected data from studies investigating the relationship between the expression level of TLRs and survival in cancer patients. Studies were pooled and combined hazard ratios (HRs) of TLRs for survival were analyzed. Results: A total of 24 studies, including 2,812 patients with various cancers, were identified for the meta-analysis. Importantly, this meta-analysis showed that higher expression levels of TLR4 or TLR7 in tumor tissues could predict poorer survival, with the pooled HR being 1.29 (95% CI: 1.17, 1.42) and 1.71 (95% CI: 1.38, 2.12), respectively. However, higher expression of TLR9 had no significant association with outcome as HR was 0.84 (95% CI: 0.62, 1.115). Heterogeneity existed in TLR4 and TLR9 studies (P-value 0.05). Conclusion: The expression level of TLR4 or TLR7 in cancerous tissue may have a prognosis value in patients with various cancers. Keywords: Toll-like receptors, cancers, prognosis

Changqie Pan,1–3,* Yuqing Liu,2,3,* Minyu Zhou,1 Wensheng Wang,4 Min Shi,1 Malcolm Xing,2,3,5 Wangjun Liao11Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China; 2Department of Mechanical Engineering, 3Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada; 4The Imaging Center, 999 Brain Hospital, Guangzhou, China; 5Children’s Hospital Research Institute of Manitoba, Winnipeg, MB, Canada*These authors contributed equally to this work Abstract: A multifunctional theranostic nanoplatform integrated with environmental responses has been developed rapidly over the past few years as a novel treatment strategy for several solid tumors. We synthesized pH-sensitive poly(β-thiopropionate) nanoparticles with a supermagnetic core and folic acid (FA) conjugation (FA-doxorubicin-iron oxide nanoparticles [FA-DOX@IONPs]) to deliver an antineoplastic drug, DOX, for the treatment of folate receptor (FR)-overexpressed breast cancer. In addition to an imaging function, the nanoparticles can release their payloads in response to an environment of pH 5, such as the acidic environment found in tumors. After chemical (1H nuclear magnetic resonance) and physical (morphology and supermagnetic) characterization, FA-DOX@IONPs were shown to demonstrate pH-dependent drug release profiles. Western blotting analysis revealed the expression of FRs in three breast cancer cell lines, MCF-7, BT549, and MD-MBA-231. The cell counting kit-8 assay and transmission electron microscopy showed that FA-DOX@IONPs had the strongest cytotoxicity against breast cancer cells, compared with free DOX and non-FR targeted nanoparticles (DOX@IONPs), and caused cellular apoptosis. The FA-DOX@IONP-mediated cellular uptake and intracellular internalization were clarified by fluorescence microscopy. FA-DOX@IONPs plus magnetic field treatment suppressed in vivo tumor growth in mice to a greater extent than either treatment alone; furthermore, the nanoparticles exerted no toxicity against healthy organs. Magnetic resonance imaging was successfully applied to monitor the nanoparticle accumulation. Our results suggest that theranostic pH-sensitive nanoparticles with dual targeting could enhance the available therapies for cancer. Keywords: theranostics, magnetic nanoparticle, pH sensitivity, folate receptor targeting, breast cancer

Ye Zhang, Hong Deng, Chao Pan, Yang Hu, Qian Wu, Na Liu, Zhouping Tang Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China Abstract: Stroke is a clinical disease with high incidence, high disability rate, and high mortality. But effective and safe therapy for stroke remains limited. Adult mesenchymal stromal cells (MSCs) perform a variety of therapeutic functions. MSC delivery improves neurological outcomes in ischemic stroke models via neurorestorative and neuroprotective effects such as angiogenic effects, promoting endogenous proliferation, and reducing apoptosis and inflammation. MSC secretome also showed powerful therapeutic effects as a cell-based therapy in animal experiments. Several clinical trials on MSC implantation via different routes have now been completed in patients with stroke. Although challenges such as immunogenicity of allo-MSCs and large-scale production strategies need to be overcome, MSCs can be considered as a promising potential therapy for ischemic stroke. Keywords: mesenchymal stromal cell, stroke, therapy, transplantation, exosomes