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Sheng Wang,1– 3,* Wufei Ye,1,3,* Kui Yang,1,3 Xiongwen Lv,2 Jiajie Luan1,3 1Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, 241001, People’s Republic of China; 2The Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Institute for Liver Disease of Anhui Medical University, Hefei, Anhui, 230032, People’s Republic of China; 3School of Pharmacy, Wannan Medical College, Wuhu, Anhui, 241002, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiongwen Lv, The Key Laboratory of Anti-inflammatory and Immune medicines, Ministry of Education, Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Institute for Liver Disease of Anhui Medical University, Hefei, Anhui, 230032, People’s Republic of China, Email xiongwen_lv2019@163.com Jiajie Luan, Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, 241001, People’s Republic of China, Email luanjiajie775@163.comObjective: Hepatocellular carcinoma (HCC) is the predominant form of liver cancer. Hypoxia can be involved in HCC tumor growth, invasion and metastasis through inducing angiogenesis. Nevertheless, the assessment of the impact of hypoxia and angiogenesis on the prognosis of HCC remains inadequate.Methods: According to hypoxia-angiogenesis-related genes (HARGs) expression information and clinical data from patients within the Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort, we constructed a prognostic model (HARG-score) using bioinformatic tools. In addition to assessing the predictive ability of this prognostic model in both Liver Cancer-Riken-Japan (LIRI-JP) and GSE14520 cohorts, we analyzed the correlation between HARG-score and clinical characteristics, immune infiltration and immunotherapy efficacy. Moreover, we investigated the exact role and underlying mechanism of key HARGs through molecular experiments.Results: We constructed a 5-gene prognostic model HARG-score consisting of hypoxia-inducible lipid droplet-associated (HILPDA), erythropoietin (EPO), solute carrier family 2 member 1 (SLC2A1), proteasome subunit alpha type 7 (PSMA7) and cAMP responsive element-binding protein 1 (CREB1) through differentially expressed HARGs. The findings demonstrated that HARG-score was a good predictor of the prognosis of HCC patients from distinct cohorts and was correlated with clinical characteristics and immune infiltration. Furthermore, the HARG-score was identified as an independent prognostic factor. Lower HARG-score implied greater immunotherapy efficacy and better response. The expression and prognostic significance of these 5 genes were additionally validated in clinical data. In addition, experimental data revealed that the key gene HILPDA contributes to the progression of HCC through facilitating angiogenesis and affecting the expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA4).Conclusion: HARG-score has promising applications in prognosis prediction of HCC patients, in which HILPDA may be a latent prognostic biomarker and therapeutic target, providing a foundation for further research and treatment of HCC.Keywords: hepatocellular carcinoma, hypoxia-angiogenesis, HILPDA, prognosis, immunotherapy efficacy

Haijie Tan,1,* Yi Chen,2,* Yan Jiang,1 Xiaojing Sun,1 Wei Ye,1 Xuefang Zhu,1 Xiangsheng Xiong1 1Department of Anesthesiology, The Fifth People’s Hospital of Huaian, Huaian, People’s Republic of China; 2Department of Anesthesiology and Perioperative Medicine, General Hospital of Ningxia Medical University, Yinchuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiangsheng Xiong, Department of Anesthesiology, The Fifth People’s Hospital of Huaian, Huaian, People’s Republic of China, Email 158193942@qq.comBackground: Vasopressors remain an important strategy for managing spinal anesthesia-induced hypotension in women with preeclampsia. The aim of this study was to investigate the ED90s and efficacy ratio of phenylephrine and norepinephrine in managing spinal anesthesia-induced hypotension in women with preeclampsia during cesarean delivery.Methods: 60 women with preeclampsia, who underwent cesarean delivery, were randomly assigned to receive either a continuous intravenous infusion of phenylephrine or norepinephrine following spinal anesthesia. The initial dosage of phenylephrine or norepinephrine for the first women was 0.5 or 0.05 μg/kg/min, respectively, and subsequent infusion dosages were adjusted based on their efficacy in preventing spinal anesthesia-induced hypotension (defined as a systolic blood pressure less than 80% of the baseline level). The incremental or decremental doses of phenylephrine or norepinephrine were set at 0.1 or 0.01 μg/kg/min. The primary outcomes were the ED90s and efficacy ratio of phenylephrine and norepinephrine infusions for preventing spinal anesthesia-induced hypotension prior to delivery.Results: The results obtained from isotonic regression analysis revealed that the ED90 values of the phenylephrine and norepinephrine group for preventing spinal anesthesia-induced hypotension were 0.597 (95% CI: 0.582– 0.628) and 0.054 (95% CI: 0.053– 0.056) μg/kg/min, respectively, with an efficacy ratio of 11.1:1. The results of Probit regression analysis revealed that the ED90 values were determined to be 0.665 (95% CI: 0.576– 1.226) and 0.055 (95% CI: 0.047– 0.109) μg/kg/min, respectively, with an efficacy ratio of 12.1:1.Conclusion: The administration of 0.6 μg/kg/min phenylephrine and 0.05 μg/kg/min norepinephrine has been found to effectively manage a 90% incidence of spinal anesthesia-induced hypotension in women with preeclampsia.Keywords: ED90, phenylephrine, norepinephrine, spinal anesthesia-induced hypotension, preeclampsia, cesarean delivery

Xuefang Li,1 Zhijun Li,2 Jian Ye,2 Wu Ye2 1Department of Infectious Diseases, Zhejiang Hospital, Hangzhou, People’s Republic of China; 2Department of Respiratory Diseases, Zhejiang Hospital, Hangzhou, People’s Republic of ChinaCorrespondence: Wu Ye, Department of Respiratory Diseases, Zhejiang Hospital, 1229 Gudun Road, Xihu District, Hangzhou, Zhejiang Province, 310013, People’s Republic of China, Tel +86 15158100052, Email yewu55@126.comObjective: To determine the association of urinary phthalate metabolites with chronic obstructive pulmonary disease (COPD), airflow obstruction, lung function and respiratory symptoms.Methods: Our study included a total of 2023 individuals aged ≥ 40 years old in the National Health and Nutrition Examination Survey (NHANES). Multivariate logistic regression was conducted to explore the correlation of eleven urinary phthalate metabolites (MCNP, MCOP, MECPP, MnBP, MCPP, MEP, MEHHP, MEHP, MiBP, MEOHP, and MBzP) with COPD, airflow obstruction and respiratory symptoms. Linear regression analyses were used to evaluate the relationship between urinary phthalate metabolites and lung function.Results: When compared to the first tertile, the third tertile of MEHHP was associated with the risk of COPD [OR: 2.779; 95% confidence interval (CI): 1.129– 6.840; P = 0.026]. Stratified analysis showed that MEHHP increased the risk of COPD by 7.080 times in male participants. Both MCPP and MBzP were positively correlated with the risk of airflow obstruction. The third tertile of MBzP increased the risk of cough by 1.545 (95% CI: 1.030– 2.317; P = 0.035) times. Both FEV1 and FVC were negatively associated with MEHHP, MECPP, MnBP, MEP, MiBP and MEOHP.Conclusion: Higher levels of MEHHP are associated with increased risk of COPD, and lower measures of FEV1 and FVC. MBzP is positively related to airflow obstruction and cough.Keywords: chronic obstructive pulmonary disease, phthalate, airflow obstruction, lung function, national health and nutrition examination survey

Haisong Hou,1,2 Liu Liang,3 Lihong Deng,4 Wanping Ye,5 Yuanzhang Wen,6 Jun Liu1 1Laboratory of Pathogenic Biology, Guangdong Medical University, Zhanjiang, People’s Republic of China; 2Department of Blood Transfusion, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China; 3Department of Laboratory Medicine, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China; 4Department of Hepatology, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China; 5Department of Gastroenterology, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China; 6Department of Hepatobiliary Surgery, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of ChinaCorrespondence: Jun Liu, Laboratory of Pathogenic Biology, Guangdong Medical University, Zhanjiang, People’s Republic of China, Email liujungd6@163.comBackground: The aim of this study was to describe the demographic and clinical characteristics of hepatitis B virus (HBV) associated hepatocellular carcinoma (HCC), analyse the risk factors associated with HBV-associated HCC, and to provide some references to the diagnosis and treatment of HCC.Methods: This study retrospectively enrolled 730 patients, including 390 patients with chronic hepatitis B (CHB) as controls, and 340 patients with CHB complicated with HCC as patients. Relevant information and medical records of these participants were collected, including age, sex, cigarette smoking, alcoholism, diabetes mellitus (DM), hypertension, coronary heart disease (CHD), cirrhosis, occupation, ascites, HBV-DNA load, the qualitative analysis of HBsAg, HBsAb, HBeAg, HBeAb, and HBcAb serological markers, and levels of alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), gamma-glutamyltransferase (GGT), TNM stage, tumor size and tumor number. The T test, Chi-square test, non-parametric rank-sum test, logistic regression analyses were used to explore the influencing factors and their degree of association with HCC in patients with HBV.Results: The proportion of smoking, alcoholism, married status, DM, hypertension, and the rate of HBV-DNA with a viral load of ≥ 500 copies/mL were significantly higher in the HCC group than in the controls (all p< 0.05). Cirrhosis was more common among patients with CHB+HCC than in controls (p=0.013). The proportion of patients with HBsAg, HBeAb, and HBcAb positive was greater in CHB+HCC group than that in CHB group. Logistic regression analysis indicated that age ≥ 60 years (OR: 1.835, 95% CI: 1.020– 3.302, p=0.043), HBeAb positive (OR: 9.105, 95% CI: 4.796– 17.288, p< 0.001), antiviral treatment with entecavir (OR: 2.209, 95% CI: 1.106– 4.409, p=0.025), and GGT (OR: 1.004, 95% CI: 1.001– 1.007, p=0.002) were risk factors for HCC in patients with CHB.Conclusion: Advanced age, HBeAb positive, antiviral treatment with entecavir, and GGT were independent risk factors for HCC in HBV patients.Keywords: chronic hepatitis B, hepatocellular carcinoma, cirrhosis, hepatitis B virus

Siyu Fan,1,&ast; Yu Zhao,1,&ast; Shiyu Wang,1,&ast; Na Zhang,1,&ast; Zhi Li,1,&ast; Hongyuan Liu,1 Yaodi Wei,1 Yunhui Yu,1 Yifeng Gu,2 Qun Wei,3 Weijuan Ye,4 Ninghan Feng,5 Fengping Liu1 1Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, People’s Republic of China; 2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 3Department of Surgical Oncology, Institute of Clinical Medicine, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 4Lishui Maternal and Child Health center, Lishui, Zhejiang, People’s Republic of China; 5Department of Urology, Jiangnan University Medical Center, Wuxi, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ninghan Feng, Department of Urology, Jiangnan University Medical Center, Wuxi, Jiangsu, 214002, People’s Republic of China, Email n.feng@njmu.edu.cn Fengping Liu, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, 214122, People’s Republic of China, Email liulaoshiyc@jiangnan.edu.cnAim: This study aims to explore the psychological reactions of medical students during the pandemic.Design: A qualitative study.Methods: A purposive sampling technique was employed, and a qualitative approach was adopted. Semi-structured questionnaires were utilized, and online interviews were conducted. Forty medical students were selected as participants for the interviews. The interview data were analyzed using Colaizzi’s seven-step analysis method.Results: The study identified five themes related to the psychological reactions of medical students during the pandemic. Firstly, COVID-19’s influence on medical careers was characterized by increased interest and determination in pursuing medical professions, heightened admiration for frontline workers, reinforced commitment to a medical career due to the pandemic, and recognition of the significance of medical education. Secondly, challenges and concerns in medical career pursuit were identified, including negative sentiments towards medical careers during COVID-19 and hesitations and concerns about entering the medical field amidst the pandemic. Thirdly, the impact on mental well-being encompassed diverse anxieties expressed by participants regarding control, transmission, treatment, and intentional spreading of the virus. Participants experienced an emotional progression from calmness to fear and anxiety, with heightened anxiety when relatives or acquaintances contracted COVID-19. Academic delays also contributed to anxiety among medical students. Fourthly, changes in behaviors and mindset were observed, including altered behaviors and mindset in response to the pandemic, as well as increased attention to personal hygiene and disease prevention measures. Lastly, expectations of medical students from government, public, and parents were explored.Conclusion: Understanding the psychological reactions of medical students during public health emergencies is crucial for their well-being and professional development. The findings have implications for medical education and the development of strategies to enhance the psychological well-being of medical students during similar crises.Keywords: COVID-19, medical students, psychological reactions, pandemic, mental health

Hui Rao,1 Xianfang Wang,2 Yu Luo,3 Liu Liang,1 Wei Ye,1 Xuemin Guo1 1Department of Laboratory Medicine, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China; 2Center for Cardiovascular Diseases, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China; 3Department of Gynaecology, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of ChinaCorrespondence: Xuemin Guo, Department of Laboratory Medicine, Meizhou People’s Hospital, No. 63 Huangtang Road, Meijiang District, Meizhou, People’s Republic of China, Email Guoxm12@126.comBackground: The role of aldehyde dehydrogenase 2 (ALDH2) in cardiovascular diseases has been gradually studied. However, it is unclear whether ALDH2 polymorphism is associated with the risk of early onset (onset age ≤ 55 years old in men and ≤ 65 years old in women) coronary artery stenosis (CAS). The association between ALDH2 single nucleotide polymorphism (SNP) rs671 and risk in patients with early onset CAS was investigated in this study.Methods: The study included 213 early onset CAS patients and 352 individuals without CAS were set as controls. The ALDH2 rs671 polymorphism was genotyped by polymerase chain reaction (PCR) - microarray. Differences in ALDH2 rs671 genotypes and alleles between patients and controls were compared. Multiple logistic regression analysis was performed after adjusting for gender, body mass index (BMI), smoking history, drinking history, and diabetes mellitus to assess the relationship between ALDH2 rs671 genotypes and early onset CAS risk.Results: The frequency of the ALDH2 rs671 G/G genotype was lower in the early onset CAS patients (43.7% vs 55.3%, p=0.007) than that in the controls. The frequency of the ALDH2 rs671 A allele was higher (32.9% vs 25.0%) than that in the controls (p=0.005). After adjusting for other confounding factors, multivariate logistic regression showed that ALDH2 rs671 A/A genotype (A/A vs G/G: odds ratio (OR) 2.508, 95% confidence interval (CI): 1.130– 5.569, p=0.024), overweight (BMI≥ 24.0 vs 18.5– 23.9: OR 5.047, 95% CI: 3.275– 7.777, p< 0.001), history of smoking (yes vs no: OR 2.813, 95% CI: 1.595– 4.961, p< 0.001), and diabetes mellitus (yes vs no: OR 2.191, 95% CI: 1.397– 3.437, p=0.001) were the independent risk factors of early onset CAS.Conclusion: In men ≤ 55 years old and women ≤ 65 years old, individuals with ALDH2 rs671 A/A genotype, overweight (BMI ≥ 24.0 kg/m2), smoking history, and diabetes mellitus increased risk of developing CAS.Keywords: aldehyde dehydrogenase 2, gene polymorphism, coronary artery stenosis, early onset

Wei Ye,1,&ast; Junwen Lu,1,&ast; Zuxian Yang,2 Ben Yang,2 Guanya Zhu,2 Chunli Xue2 1Department of Burn Surgery, the First Clinical Medical College of Guangdong Medical University, Huizhou, 516001, People’s Republic of China; 2Department of Burn Surgery, Huizhou Municipal Central Hospital, Huizhou, 516001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chunli Xue, Department of Burn Surgery, Huizhou Municipal Central Hospital, No. 41, Eiling North Road, Huicheng District, Huizhou, 516001, People’s Republic of China, Email xuechunli2001@163.comBackground: lncRNA β‑1,3‑galactosyltransferase 5‑AS1 (B3GALT5-AS1) plays a vital regulatory role in colon and gastric cancers. However, the biological functions and regulatory mechanisms of B3GALT5-AS1 in keloid progression remain unknown. This study aims to investigate the molecular mechanisms in the B3GALT5-AS1-regulated keloid proliferation and invasion.Methods: Secondary mining of the lncRNA sequencing data from GSE158395 was conducted to screen differentially expressed lncRNAs between keloid and normal tissues. MTT, cell migration and invasion assays were performed to detect the effects of B3GALT5-AS1 on keloid fibroblasts (KFs) proliferation and metastasis. The extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were also determined to evaluate glycolysis in KFs. RNA pull-down and RNA-protein immunoprecipitation assays were used to confirm the interaction between B3GALT5-AS1 and Hu-Antigen R (HuR). Further ubiquitination and rescue experiments were performed to elucidate the regulatory relationship between B3GALT5-AS1 and HuR.Results: B3GALT5-AS1 was significantly down-regulated in keloid tissues and fibroblasts. B3GALT5-AS1 overexpression significantly inhibited KFs proliferation, glycolysis, invasion, and migration and promoted cell apoptosis, whereas silencing B3GALT5-AS1 inhibited these effects. Moreover, B3GALT5-AS1 binds to HuRand reduces its stability through β-Transducin repeats-containing protein 1 (β-Trcp1)-mediated ubiquitination. Overexpression of HuR reversed the inhibition of B3GALT5-AS1 on cell proliferation, migration, and invasion in KFs, where glycolysis pathway was involved.Conclusion: Our findings illustrate that B3GALT5-AS1 has great effect on inhibition of keloid formation, which provides a potential target for keloid therapy.Keywords: B3GALT5-AS1, keloid, fibroblast, HuR, β-Trcp1

Zhenhua Liu,1,&ast; Mingxi Cai,2,&ast; Haoteng Ke,2,&ast; Huazong Deng,2 Weijia Ye,2 Tao Wang,1 Qifan Chen,1 Shuizhong Cen1 1Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People’s Republic of China; 2The Second Clinical School, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shuizhong Cen, Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China, Tel +86 13480297160, Email censhzh3@mail2.sysu.edu.cnPurpose of the Review: Emerging evidence has shown that ankylosing spondylitis fibroblasts (ASFs) act as crucial participants in inflammation and abnormal ossification in ankylosing spondylitis (AS). This review examines the investigations into ASFs and their pathological behavior, which contributes to inflammatory microenvironments and abnormal bone formation. The review spans the period from 2000 to 2023, with a primary focus on the most recent decade. Additionally, the review provides an in-depth discussion on studies on ASF ossification at the cellular level.Recent Findings: ASFs organize immune functions by recruiting immune cells and influencing their differentiation and activation, thus mediate the inflammatory response in the early phase of disease. ASFs promote joint destruction at sites of cartilage and actively promote abnormal ossification by recruiting osteoblasts, differentiation into myofibroblasts or ossification directly. Many signaling pathways and cytokines such as Wnt signaling and BMP/TGF-β signaling are involved in ASF ossification.Summary: ASFs play a key role in AS inflammation and osteogenesis. Further studies are required to elucidate molecular mechanisms behind that and provide new targets and directions for AS diagnosis and treatment from a new perspective of fibroblasts.Keywords: ankylosing spondylitis, fibroblast, inflammation, ossification

Meiyan Sun,1,2,&ast; Xiaoyong Zhao,2,&ast; Xingyue Li,2 Chunling Wang,2 Lili Lin,3 Kaifang Wang,2 Yingui Sun,2 Wei Ye,3 Haiyan Li,3 Ye Zhang,1 Chaolu Huang2,4 1Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, People’s Republic of China; 2Department of Anesthesiology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, 261053, People’s Republic of China; 3The First Clinical Medical College, Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China; 4Department of Clinical Medicine, Qiandongnan Ethnic Vocational and Technical College, Kaili, 556000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ye Zhang, Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, People’s Republic of China, Email zhangy@ahmu.edu.cn Chaolu Huang, Department of Clinical Medicine, Qiandongnan Ethnic Vocational and Technical College, Kaili, 556000, People’s Republic of China, Email huangzhaolu2020@163.comObjective: Diabetes mellitus (DM) implicates oxidative stress, apoptosis, and inflammation, all of which may contribute liver injury. Aerobic exercise is assured to positively regulate metabolism in the liver. This project was designed to investigate whether and how aerobic exercise improves DM-induced liver injury.Methods: Seven-week-old male db/db mice and age-matched m/m mice were randomly divided into a rest control group or a group that received 12 weeks of aerobic exercise by treadmill training (10 m/min). Haematoxylin and eosin (HE) staining, electron microscopy, Oil Red O staining and TUNEL assays were used to evaluate the histopathological changes in mouse liver. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TRIG), cholesterol (CHOL) were analyzed by serum biochemical analysis. Interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), and tissue levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were analyzed via ELISA. Nuclear factor E2-associated factor-2 (Nrf2), nuclear factor κB (NF-κB) and JAK2/STAT3 pathway-related proteins were measured by immunofluorescence, Western blotting and q-PCR. F4/80 expression in liver tissues was assessed by immunohistochemistry.Results: In diabetic mice, exercise training significantly decreased the levels of serum TRIG, CHOL, IL-6, TNF-α, ALT and AST; prevented weight gain, hyperglycaemia, and impaired glucose and insulin tolerance. Morphologically, exercise mitigated the diabetes-induced increase in liver tissue microvesicles, inflammatory cells, F4/80 (macrophage marker) levels, and TUNEL-positive cells. In addition, exercise reduced the apoptosis index, which is consistent with the results for caspase-3 and Bax. Additionally, exercise significantly increased SOD activity, decreased MDA levels, activated Nrf2 and decreased the expression of NF-kB, phosphorylated JAK2 and STAT3 proteins in the livers of diabetic mice.Conclusion: This study demonstrated that aerobic exercise reversed liver dysfunction in db/db mice with T2DM by reducing oxidative stress, apoptosis and inflammation, possibly by enhancing Nrf2 expression and inhibiting the JAK2/STAT3 cascade response.Keywords: db/db mice, aerobic exercise, inflammation, apoptosis, Nrf2, JAK2/STAT3

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

Diming Wang,1,&ast; Wei Ye,2,&ast; Dongmei Chen,1 Qingming Shi,1 Dongchun Ma3 1Department of Oncology, Anhui Chest Hospital, Hefei, 230022, People’s Republic of China; 2Department of Pathology, Anhui Chest Hospital, Hefei, 230022, People’s Republic of China; 3Department of Thoracic Surgery, Anhui Chest Hospital, Hefei, 230022, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongchun Ma, Department of Thoracic Surgery, Anhui Chest Hospital, Hefei, 230022, People’s Republic of China, Email madongchun126@126.com Qingming Shi, Department of Oncology, Anhui Chest Hospital, Hefei, 230022, People’s Republic of China, Email shqm0324@163.comAbstract: The transformation of lung adenocarcinoma to small cell lung cancer (SCLC) following treatment with epidermal growth factor (EGFR) receptor tyrosine kinase inhibitors (TKIs) is a relatively common phenomenon. However, transformation of non-small cell lung cancer (NSCLC) to SCLC following treatment with immunotherapy is very rare. Here, we report a case of a 56-year-old patient diagnosed with driver gene mutation-negative lung squamous cell carcinoma (SCC). He received four cycles of immunotherapy with sugemalimab and chemotherapy with albumin paclitaxel in combination with carboplatin, and a partial response was achieved. Subsequently, the patient received 5 cycles of immunotherapy with sugemalimab. However, he developed rapid progression of mediastinal lymph nodes, and biopsy results showed transformation to SCLC. His tumor did not respond to the next line of carboplatin combined with etoposide, and he died six months after the discovery of SCLC transformation. In conclusion, SCLC transformation is also an important resistance mechanism for lung SCC patients treated with immunotherapy and predicts a very poor outcome. Repeat biopsy is needed for advanced lung SCC that has progressed with immunotherapy.Keywords: lung squamous cell carcinoma, immunotherapy, small cell transformation

Zhuzhu Qin,1,&ast; Xinxin Ye,2,&ast; Huanju Liu,3 Yining Tao,4 Xutong Zheng,1 Yanxia Zhong,5 Danfeng Chen,1 Wan Ye,6 Chenju Zhan7 1School of Nursing, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China; 2Department of Sports and Exercise Science, College of Education, Zhejiang University, Hangzhou, Zhejiang, China; 3Women’s Hospital and Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, China; 4Department of Global Public Health, Karolinska Institute, Stockholm, Sweden; 5Department of Nursing, Shijiazhuang Medical College, Shijiazhuang, China; 6Department of Nursing, Xiamen Medical College, Xiamen, Fujian, China; 7Department of Nursing, Mindong Hospital Affiliated to Fujian Medical University, Ningde, China&ast;These authors contributed equally to this workCorrespondence: Wan Ye, Department of Nursing, Xiamen Medical College, Xiamen, Fujian, China, Tel +86 13806086169, Email 200600010142@xmmc.edu.cn Chenju Zhan, Department of Nursing, Mindong Hospital Affiliated to Fujian Medical University, No. 89 HeShan Road, Fuan City, Fujian Province, 355000, China, Tel +86 13809562183, Email zhanchenju@yeah.netObjective: This study investigated factors influencing the knowledge, attitudes, practice profiles, and vaccination intentions among Chinese nursing students and nursing interns toward the coronavirus disease (COVID-19) vaccination.Materials and Methods: The multicenter cross-sectional study was based on a self-reported questionnaire collecting information among nursing students and nursing interns from three major geographic regions of China, and the sample was selected by consecutive sampling. The questionnaire was developed by knowledge, attitudes, and practice (KAP) theory. Univariate and multivariate logistic regression were used for statistical analysis.Results: A total of 3180 nursing students and interns (effective rate: 99.8%) from six Chinese provinces were polled. The vaccine hesitation rate was 9.65% (307/3180), 2230 participants (70.1%) had gotten at least one dose of the vaccine, and 643 participants (67.7%) had indicated a readiness to be vaccinated. The results showed that older age, higher academic background, perfect vaccine management, others’ recommendations, influenza vaccination history, epidemic under control, knowledge of vaccines or intervals, and vaccine knowledge training were associated with higher vaccination rates. Conversely, vaccine hesitancy was caused by a perceived lack of physical need, uncertainty about vaccination requirements, and fear of vaccination.Conclusion: This study provided population-based estimates of COVID-19 vaccine uptake intention among mainland Chinese nursing students and interns. Factors such as age, education, vaccine knowledge, and attitudes influence COVID-19 vaccine behaviour. Relevant authorities should understand the barriers to COVID-19 vaccination from knowledge, attitude and practice, which is significant for formulating effective response strategies in future global public health crises.Graphical Abstract: Keywords: COVID-19, vaccine, knowledge, attitudes, practice, nursing students and interns

Wenhong Chen,1 Yunping Chen,2 Wenjuan Ye,3 Ting Wang1 1Department of Pediatric Neurology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3Department of Pediatric, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaCorrespondence: Ting Wang, Department of Pediatric Neurology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, 745 Wuluo Road, Hongshan District, Wuhan, Hubei, People’s Republic of China, Tel +86-27-87169308, Email 67722896@qq.comPurpose: The study aims to identify the characteristics of SSR in patients with AICVD and their correlation with clinical presentations.Methods: SSR of the upper limbs, the National Institute of Health stroke scale (NIHSS), the Barthel index (BI), the Essen stroke risk score (ESRS), and imaging examinations, was evaluated in 30 healthy subjects and 66 patients with AICVD. All results were recorded and analyzed via Statistical Package for the Social Sciences (SPSS 22.0) software. t-test and Spearman rank correlation were used.Results: Compared to the control group, SSR of upper limbs in patients with AICVD showed prolonged latency, reduced amplitude, and disappeared waveform (p=0.000, p=0.015, p=0.004), No statistically significant difference was observed between the affected side and the healthy side (p=0.068, p=0.661). In the case group, the higher the abnormal rate of SSR, the more severe the neurological impairment (NIHSS and ADL scores) and the worse the long-term prognosis. Specific results are as follows: Firstly, the total abnormality rate of SSR, prolonged SSR latency were positively related to the NIHSS, also the ESRS (r=0.347, p=0.004; r=0.437, p< 0.001), (r=0.371, p=0.005; r=0.433, p=0.001), the reduced amplitude was positively related to the NIHSS (r=0.341, p=0.012) while the disappeared waveform was positively related to the ESRS (r=0.299, p=0.015); Secondly, the total abnormality rate of SSR, prolonged SSR latency and reduced amplitude were negatively related to the BI (r=− 0.346, p=0.004) (r=− 0.426, p=0.001) (r=− 0.316, p=0.020).Conclusion: There may be inhibition of sympathetic reflex activity in patients with AICVD, SSR abnormality rate in patients with AICVD may be correlated with the degree of neurological impairment and long-term prognosis.Keywords: acute ischemic cerebrovascular disease, AICVD, sympathetic skin response, SSR, autonomic nervous system, ANS

Wuqing Huang,1,&ast; Ruimei Feng,1,&ast; Xin Xu,1,&ast; Mingyang Ma,1 Jun Chen,1 Junzhuo Wang,1 Zhijian Hu,1,2 Shanshan Du,1 Weimin Ye1– 3 1Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 2Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, People’s Republic of China; 3Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden&ast;These authors contributed equally to this workCorrespondence: Weimin Ye; Shanshan Du, Fujian Medical University, No. 1, Xue Yuan Road, University Town, Fuzhou City, Fujian Province, 350108, People’s Republic of China, Tel +86 591 2286 2023, Fax +86 591 2286 2510, Email ywm@fjmu.edu.cn; dushanshan1007@163.comBackground: Emerging data suggest that the interpretation of the association between obesity and lipids appears to be oversimplified. This study aimed to quantify the complex relationships between anthropometric indices and lipid profile.Methods: This is a cross-sectional study including 9620 participants in Southern China. Anthropometric indices included the indices of general obesity (ie, body mass index (BMI)) and central obesity (ie, waist circumference (WC) and waist-to-hip ratio (WHR)). Lipids included low-density lipoprotein cholesterol (LDLc) and atherogenic lipids (ie, high-density lipoprotein cholesterol (HDLc), triglycerides (TG) and TG/HDLc ratio). LOESS regression and general linear model were the main statistical methods.Results: Almost all associations between anthropometric indices and lipids were lost in obese adults. The loss of association occurred quicker with LDLc than that with atherogenic lipids; the break point for the association loss was at BMI of 24 kg/m2 with LDLc (Slope Below break-point = 1.81, P< 0.001; Slope Above break-point = 0.29, P=0.121), while at 28 kg/m2 with HDLC (Slope Below break-point = − 1.41, P< 0.001; Slope Above break-point = 0.07, P=0.666) or TG (Slope Below break-point = 4.96, P< 0.001; Slope Above break-point = 2.93, P=0.01), and at 30 kg/m2 with TG/HDLc ratio (Slope Below break-point = 0.15, P< 0.001; Slope Above break-point= 0.01, P=0.936), respectively. Similar relationships were found for WC and WHR. Besides, the presence of other metabolic disorders contributed to the loss of anthropometry-lipids relationships, for example, the BMI-LDLc association attenuated to null in both obese adults and non-obese population but with more than one other metabolic disorders.Conclusion: The relationships were lost between anthropometric indices and lipids in obese adults with different break points across different lipids, which appeared to be dependent on metabolic status.Keywords: anthropometry, lipid profile, epidemiology

Yan Li,1,&ast; Ensi Hong,1,2,&ast; Wenguo Ye,2 Jianyu You1 1Jiangxi University of Chinese Medicine, Nanchang, People’s Republic of China; 2The Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenguo Ye, The Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, Jiangxi Province, People’s Republic of China, Email 648957697@qq.com Jianyu You, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi Province, People’s Republic of China, Email youjytcm@163.comPurpose: Pain is one of the most common and feared symptoms among cancer patients. Unrelieved pain denies patients comfort and greatly affects their overall quality of life. Moxibustion is commonly used to manage chronic pain. However, its efficacy on cancer pain remains inconclusive. This study aimed to evaluate the efficacy of moxibustion for cancer pain.Methods: We searched seven databases to obtain articles about moxibustion combined with pharmacotherapy for cancer pain published before November 2022. All data extraction was carried out independently by two investigators. RevMan 5.4 software was used for data analysis.Results: A total of ten trials involving 999 cases were included. The results of the meta-analysis revealed that moxibustion combined with pharmacotherapy was significantly better than drug therapy alone in improving pain relief rate (RR =1.16, 95% CI = [1.04, 1.30], P = 0.01), reducing pain scores (SMD = − 1.43, 95% CI = [− 2.09, − 0.77], P < 0.0001), Shortening the onset of analgesia (MD = − 12.07, 95% CI = [− 12.91, − 11.22], P < 0.00001), prolonging the duration of analgesia (MD = 3.69, 95% CI = [3.21, 4.18], P < 0.00001), and improving quality of life (SMD = 2.48, 95% CI = [0.67, 4.29], P = 0.007). In addition, moxibustion combined with pharmacotherapy can effectively reduce adverse reactions of drugs (RR =0.35, 95% CI = [0.21, 0.57], P < 0.0001).Conclusion: The evidence in this review supports moxibustion as an effective adjuvant therapy for cancer pain management. However, high-quality RCTs are needed to further confirm these findings.Registration Number: PROSPERO CRD42022370942.Keywords: moxibustion, cancer pain, systematic review, meta-analysis

Hongru Zhao,1 Zheman Xiao,2 Lei Zhang,3 Janet Ford,4 Shiying Zhong,3 Wenyu Ye,4 Jinnan Li,3 Antje Tockhorn-Heidenreich,4 Sarah Cotton,5 Chunfu Chen6,7 1The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 3Eli Lilly China, Shanghai, People’s Republic of China; 4Eli Lilly and Company, Indianapolis, IN, USA; 5Adelphi Real World, Bollington, UK; 6Department of Neurology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University Jinan, Jinan, People’s Republic of China; 7Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of ChinaCorrespondence: Chunfu Chen, Department of Neurology, Shandong Provincial Hospital, &num; 324 Jingwuweiqi, Road, Shandong, 250021, People’s Republic of China, Tel +86 13853153248, Email chencf301@163.comObjective: This study assessed treatment patterns, disease burden, outcomes, and unmet needs among patients with episodic migraine (EM) in China using Adelphi Migraine Disease Specific Programme™ (DSP) real-world data.Background: Migraine is a prevalent and debilitating neurological disorder which presents a major public health burden globally. Research on characteristics, disease burden, and treatment patterns in EM patients in China is limited.Methods: Data were drawn from an existing data set Adelphi Migraine DSP, a point-in-time survey conducted in China (January-June 2014). Internists/neurologists completed patient record forms for the next 9 patients who consulted them in clinical practice; these same patients completed the ‘patient self-completion questionnaires’. Descriptive analyses were used to assess key variables: patient demographics, treatment patterns (current acute and preventive medication [AM/PM]), effectiveness, issues with existing treatment, Migraine Disability Assessment (MIDAS) scores, and Work Productivity and Activity Impairment scores.Results: Total of 125 internists/neurologists provided data on 1113 patients with EM (headache days/month < 15). Mean (standard deviation [SD]) age was 43.8 (13.1) years; mean (SD) number of migraine days/month was 3.2 (1.7). AM was prescribed in 86.1% of patients (non-steroid anti-inflammatory drugs [NSAIDs]: 62.7%; triptans: 7.7%), PM in 38.5%, and both in 24.9% of patients. Approximately 55% of patients experienced ≥ 1 issue with their current AM or PM. Migraine-related symptoms (including nausea, photophobia, and phonophobia) were fully controlled in < 50% of patients receiving NSAIDs (21.7– 38.4%) or triptans (32.4– 43.5%). Insufficient response to current AM (migraine headache fully resolved within 2 hours in ≤ 3/5 attacks) was reported by 42.5% of patients. Mild-to-severe disability was reported by 36.8% of patients with a mean (SD) MIDAS score of 5.8 (7.3). Overall, 58.0% of work time was impaired (including time missed and impairment while working).Conclusion: This analysis suggests, despite existing treatment options, disease burden and unmet medical needs remain substantial in Chinese patients with EM.Keywords: episodic migraine, clinical practice, patient-reported outcomes, real-world, disease burden

Oralee J Varnado,1 Janna Manjelievskaia,2 Wenyu Ye,1 Allison Perry,2 Kory Schuh,1 Richard Wenzel1 1Value, Evidence, and Outcomes, Eli Lilly and Company, Indianapolis, IN, USA; 2Watson Health Life Sciences, Research & Analytics, IBM Watson Health, Cambridge, MA, USACorrespondence: Oralee J Varnado, Value, Evidence, and Outcomes, Eli Lilly and Company, Lilly Corporate Center, 893 Delaware Street, Indianapolis, IN, 46285, USA, Tel +1 317 277 0599, Email varnado_oralee_johnson@lilly.comBackground: Most conventional, oral, preventive treatments for migraine are non-specific and ∼ 50% of patients discontinue them within six months. In 2018, the Food and Drug Administration approved three preventive migraine treatments: monoclonal antibodies (mAb) targeting the calcitonin gene-related peptide (CGRP) pathway implicated in migraine; galcanezumab and fremanezumab which target CGRP ligand; and erenumab which targets CGRP receptor. Real-world treatment patterns for CGRP mAb are limited.Purpose: To compare real-world treatment patterns for CGRP mAb, specifically galcanezumab versus standard-of-care (SOC) migraine preventive treatments.Patients and methods: This retrospective, observational study included 12-month baseline and 6- and 12-month follow-up analyses using IBM® MarketScan® databases. Patients identified were aged ≥ 18 years with ≥ 1 claim (first claim=index) for CGRP mAb (erenumab, fremanezumab, or galcanezumab) or SOC preventives (eg, antiepileptics, beta-blockers, antidepressants, or onabotulinumtoxinA) as index drugs between May/01/2018 and June/30/2019. Propensity score matching was used to address confounding by observed covariates. Outcomes analyzed included proportion of days covered (PDC), persistence (≤ 60-day gap), and first non-index drug switch. Descriptive, chi-square (categorical), and t-test (continuous) analyses were conducted.Results: The study included 3082 (CGRP mAb versus SOC) and 421 (galcanezumab versus SOC) matched patient pairs with 12-month follow-up. Mean age across cohorts ranged 43.2– 44.4 years (females: 85.7– 88.6%). Compared with SOC, the CGRP mAb cohort had higher mean persistence (212.5 vs 131.9 days), adherence (PDC: 55.1% vs 35.2%), and more patients were adherent with PDC ≥ 80% (32.7% vs 18.7%) (all p < 0.001). During 12-month follow-up, fewer patients discontinued CGRP mAb versus SOC (58.8% vs 77.6%, p < 0.001). Galcanezumab versus SOC comparisons yielded similar results. In the CGRP mAb cohort, most switchers (28.3%) used galcanezumab as subsequent treatment. Largely similar results were observed for 6-month follow-up cohorts.Conclusion: Patients on CGRP mAb and specifically galcanezumab showed higher adherence and persistence than patients on SOC migraine preventive treatments.Keywords: CGRP, persistence, adherence, discontinuation, switch

Zhou S, Cui Y, Yu D, Liang J, Zhang M, Ye W. Onco Targets Ther. 2017;10:2527–2538. The Editor and Publisher of OncoTargets and Therapy are retracting the published article. Concerns were raised regarding the duplication of western blot images and an investigation found duplicated images in Figures 3 and 6. Specifically, The image in Figure 3D, TE10, c-caspase-3, has been duplicated with the same image from Figure 6C, TE10, c-PARP. The image in Figure 3D, TE10, c-PARP has been duplicated with the same image from Figure 3D, TE11, c-PARP. The image in Figure 3D, TE10/miR-381(+), c-caspase-3, has been duplicated with the same image from Figure 3D, TE11/miR-NC(-), Total PARP. The image in Figure 3D, TE11, Total PARP, has been duplicated with the same image from Figure 6C, TE11, Total caspase-3. The image from Figure 6C, TE10/shXIAP(+), c-PARP has been duplicated with the same image from Figure 6C, TE11/shcontrol(-), Total caspase-3. The authors cooperated with the investigation but were unable to provide a satisfactory explanation regarding the duplicated images and were unable to verify the published work. Therefore, the Editor and Publisher are retracting the article and the authors have been notified. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Diming Wang,1 Wei Ye,2 Qingming Shi1 1Department of Oncology, Anhui Medical University Clinical College of Chest & Anhui Chest Hospital, Hefei, 230022, People’s Republic of China; 2Department of Pathology, Anhui Chest Hospital, Hefei, 230022, People’s Republic of ChinaCorrespondence: Qingming ShiDepartment of Oncology, Anhui Medical University Clinical College of Chest & Anhui Chest Hospital, Hefei, 230022, People’s Republic of ChinaEmail shqm0324@163.comBackground: The relationship between the Ki-67 expression level and chemotherapy response and survival prognosis in advanced lung squamous cell carcinoma (SCC) remains unclear.Methods: A total of 101 patients were included in the study. All patients received systemic first-line platinum-based chemotherapy. The Ki-67 expression level was determined by immunohistochemistry analysis.Results: The Ki-67 expression level was positively correlated with an increase in tumor T stage (P = 0.0140), N stage (P < 0.0001), and M stage (P < 0.0001) in advanced lung SCC. High Ki-67 expression could predict chemotherapy response (area under the curve = 0.7524, P < 0.0001). Patients with tumors that expressed high levels of Ki-67 had shorter overall survival (OS) (18.8 months vs 25.5 months, P = 0.0002) and progression-free survival (PFS) (4.8 months vs 6.7 months, P < 0.0001). Cox analysis found Ki-67 expression to be an independent prognostic biomarker of shortened OS (P = 0.009) and PFS (P = 0.008).Conclusion: Ki-67 expression may affect chemotherapy response and thus has prognostic value. Ki-67 expression may be a promising prognostic biomarker for advanced lung SCC.Keywords: Ki-67 expression, advanced lung squamous cell carcinoma, chemotherapy response, prognostic value

Janet Ford,1 Russell M Nichols,1 Wenyu Ye,1 Antje Tockhorn-Heidenreich,1 Sarah Cotton,2 James Jackson2 1Eli Lilly and Company, Indianapolis, IN, USA; 2Adelphi Real World, Bollington, UKCorrespondence: Janet FordEli Lilly and Company, Indianapolis, IN, 46285, USATel +1 317-903-8199Email ford_janet@lilly.comPurpose: To evaluate patient-reported outcomes (PROs) among patients with migraine, including those who were preventive-naïve and preventive-treated.Methods: This was a point-in-time, real-world study of patients with migraine in the US and EU5 (France, Germany, Spain, Italy, and UK) and their physicians using data from the Adelphi Migraine Disease Specific Programme (DSP™). Physicians completed patient record forms (PRFs) for the next nine consulting patients with migraine plus a tenth patient, who did not need to be consecutive, for whom prior preventive migraine treatments had failed at least once, in order to achieve oversampling of such patients. Patients were given self-completion (PSC) forms that included the Migraine-Specific Quality of Life Questionnaire v2.1 (MSQ), Migraine Disability Assessment Scale (MIDAS), and Work Productivity and Activity Impairment (WPAI) questionnaire. Populations of interest included preventive-naïve and preventive-treated patients defined by the number of treatment lines (1– 2 or 3+ preventive regimens). Continuous variables were compared using t-test or ANOVA if normally distributed and Mann–Whitney if not. Chi-squared was used for categorical variables.Results: During August–December 2017, 615 physicians (359 PCPs, 256 neurologists) completed PRFs for 5785 patients (71% female; mean age 40 (± 14) years; 65% in full- or part-time employment). Of these, 2798 completed a PSC (preventive-naïve/1– 2/3+ preventive lines, n=1707/1034/57). Preventive-treated patients had a greater patient-reported burden across multiple measures versus preventive-naïve patients. Preventive-treated patients had lower MSQ scores indicating greater functional impairment, higher MIDAS scores indicating greater migraine-associated disability, and higher WPAI scores indicating greater overall work and activity impairment than preventive-naïve patients. The magnitude of difference was greatest for the 3+ preventive-treatments cohort. Patterns were similar in the US and EU5.Conclusion: Among patients with migraine who are preventive-treated, including those with multiple lines of therapy, there remain considerable unmet needs in terms of restoring patient function.Keywords: migraine, preventive, patient-reported outcomes, real-world

Wen Ye,1 Yan Yan,2 Yunliang Tang,1 Xiaoyang Dong,1 Gengfa Chen,1 Junwei Kang,1 Lianghua Huang,1 Qi Xiong,1 Zhen Feng1 1Department of Rehabilitation, The First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of China; 2Department of Nephrology, The First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of ChinaCorrespondence: Zhen FengDepartment of Rehabilitation, The First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of ChinaEmail medstu@126.comBackground: Neuronal damage is the main cause of neurological diseases. Neural stem cells (NSCs) have the functions of cell repair and replacement of neurons, secretion of neurotrophic factors, and immune regulation of the neural microenvironment.Objective: Previous study found that Orexin-A had a protective effect on neurons in the central nervous system, but it is lacking in making great efforts on the function of Orexin-A on NSCs. This study aimed to investigate the anti-inflammatory responses and signaling mechanisms of Orexin-A on lipopolysaccharide (LPS)-induced NSCs.Methods: Quantitative real-time polymerase chain reaction was used to detect the mRNA level. Signaling pathway-related protein expression was detected by Western blot. The proliferation and migration of NSCs were investigated by Cell Counting Kit-8 (CCK-8) detection kit and transwell assay. Besides, the staining of hematoxylin and eosin (HE) was performed to study the morphology of cell.Results: Orexin-A decreased the pro-inflammatory cytokines of IL-1β, TNF-α, and IL-6 induced by LPS by regulating nuclear factor-k-gene binding (NF-kB) and phosphorylation of P38/Erk-mitogen-activated protein kinases (MAPKs) pathways, but not p-JNK signaling.Conclusion: Our findings indicate that Orexin-A can alleviate the inflammatory response of NSC. It can provide beneficial help in neural stem cell therapy applications.Keywords: NSCs, Orexin-A, NF-kB, MAPK

Siyao Deng,1 Wenjing Ye,1 Shichuan Zhang,2,3 Guiquan Zhu,4 Peng Zhang,2 Yanqiong Song,2 Fanglei Duan,3 Jinyi Lang,2,3 Shun Lu2,3 1School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 2Department of Radiation Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 3Radiation Oncology Key Laboratory of Sichuan Province, Chengdu, People’s Republic of China; 4State Key Laboratory of Oral Diseases, National Clinical Research Centre for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Shun LuDepartment of Radiation Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Renmin South Road 55#, Chengdu, 610041, People’s Republic of ChinaTel +86 28 85420897Fax +86 28 85420110Email lushun1982@live.cnPurpose: Fanconi anemia (FA) is a rare genetic disorder characterized by congenital anomalies, progressive bone marrow failure and high susceptibility to solid tumors, especially head and neck squamous cell carcinoma (HNSCC). Management of FA patients with head and neck cancer is a challenge due to increased risk of surgery, poor tolerance of chemotherapy, and severe myelotoxicity of radiotherapy.Patients and Methods: We present a case of a 33-year-old man with carcinoma of oral tongue (T1N2M0), who experienced prolonged and profound bone marrow failure as a consequence of concurrent cisplatin/radiation. The young patient who developed HNSCC without risk factors, the myelotoxicity after exposure to platinum-based agent cisplatin and the further evaluation of phenotypic characteristics raised suspicion of FA. Whole exome sequencing performed for the patient and parents ultimately established the diagnosis of FA.Results: Genetic testing in 23 FANC genes revealed two novel heterozygous mutations, c.367C>T and c.3971_3972delCGinsTT in FANCA gene of the patient, which were inherited from his father and mother, respectively. Radiotherapy with reduced dose has successfully alleviated the symptoms of tumor invasion and progression, and the radiation-related side effects were acceptable. Unfortunately, the patient eventually died of locoregional disease progression.Conclusion: This case highlights the importance of considering the diagnosis of FA in young patients who develop HNSCC in the absence of risk factors, thus permitting more effective oncological treatment strategies and improved outcomes. In conclusion, any decision on different modalities of management in such patients should be based on a balance between locoregional control and therapeutic toxicity.Keywords: fanconi anemia, radiotherapy, cisplatin, head and neck squamous cell carcinoma, toxicity

Zhipeng Zhu,1 Sihao Lin,1 Xiaofang Wu,2 Jiuhua Xu,2 Lulu Li,1 Weipeng Ye,2 Jiayi Li,3 Zhengjie Huang1,2 1Department of Gastrointestinal Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People’s Republic of China; 2Department of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian 350004, People’s Republic of China; 3Department of Medical Oncology, Xiamen Cancer center, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People’s Republic of ChinaCorrespondence: Zhengjie HuangDepartment of Gastrointestinal Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, 55 Zhen Hai Road, Si Ming District, Xiamen, Fujian 361003, People’s Republic of ChinaTel +86-592-2139280Fax +86-592-2137368Email huangzhengjie@xmu.edu.cnBackground: Cisplatin is a vital chemotherapy regimen for gastric cancer (GC), while partial response is observed (approximately 40%) because of drug resistance. Thus, it is urgent to improve drug sensitivity to improve the therapeutic effect of cisplatin on GC.Purpose: The study was performed to explore the synergistic effect of decitabine and cisplatin in GC.Materials and Methods: Cancer and matched adjacent tissues from patients with GC were obtained and quantitative real-time PCR (qRT-PCR), Western blot and immunohistochemistry were performed to evaluate Sox2 expression level. Methylation-specific PCR (MSP) was performed to assess the effect of 5-aza-2ʹ-deoxycytidine (5-Aza-CdR) on Sox2 promoter. Cell proliferation assay, scratch-wound migration assay and Transwell invasion ability were performed to assess the effect of 5-Aza-CdR on proliferation, migration and invasion ability. Meantime, the effect of 5-Aza-CdR was also investigated in gastric cell lines BGC-823 and nude mouse xenograft tumor model. Finally, the anti-cancer effect of decitabine, cisplatin and their combination treatment were investigated in a BGC-823 and nude mouse xenograft tumor model, Sox2 methylation level, Sox2 expression of BGC-823 and xenograft tumors were analyzed by MSP, qRT-PCR and Western blot.Results: Sox2 expression was significantly associated with different differentiated degrees, depth of invasion (0.0011), lymph node metastasis (0.0013), and TNM stage (0.0002). Next, methylation inhibitor 5-Aza-CdR restored Sox2 expression to promote proliferation, migration and invasion in vitro and in vivo. Finally, cisplatin and decitabine was found to be synergistic to inhibit proliferation of xenograft tumors. Likewise, cisplatin and decitabine were also synergistic to induce Sox2 DNA demethylation to promote Sox2 mRNA and protein expression in BGC-823 and xenograft tumors.Conclusion: Cisplatin and decitabine could be synergistic to induce Sox2 DNA demethylation to promote expression of the Sox2 gene, which exerted an anti-tumor effect on GC. It may suggest an insight for innovative therapeutics of GC.Keywords: Sox2, DNA demethylation, gastric cancer, decitabine, cisplatin, anti-tumor

Chuanben Chen,1,* Qinyan Chen,2,* Yuanji Xu,1 Wei Zheng,1 Zhizhong Lin,1 Zijie Wu,2 Wangzhong Ye,2 Xinyi Huang,2 Xiurong Lin,1 Penggang Bai1 1Department of Radiation Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou 350014, Fujian Province, People’s Republic of China; 2Graduate School, Fujian Medical University, Fuzhou 350000, Fujian Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chuanben Chen Tel +86 591-83660011Fax +86 591-83928767Email chenchuanben2010@126.comPurpose: To investigate whether juvenile patients with nasopharyngeal carcinoma (NPC) in China have better prognosis than their adult counterparts in the intensity-modulated radiation therapy (IMRT) era, after controlling for potential confounding variables.Methods: Data pertaining to 1139 patients with newly diagnosed NPC without metastasis, who were treated with IMRT at our hospital, were retrospectively analyzed. Of these, 60 patients were juvenile (age ≤ 18 years) diagnosed between January 2003 and December 2018, while 1079 patients were adults (≤ 65 years) diagnosed between January 2013 and December 2014. To minimize the influence of selection and confounding bias, 1:2 propensity score matching (PSM) was used. Overall survival (OS), disease-free survival (DFS), locoregional relapse-free survival (LRFS), and distant metastasis-free survival (DMFS) were estimated using the Kaplan–Meier method and between-group differences assessed using the Log rank test. The long-term toxicity of the juvenile patients was evaluated according to the criteria of the Radiation Therapy Oncology Group (RTOG) and the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.Results: Five-year OS of juvenile and adult patients were 88.07% and 85.08%, respectively. Before PSM, OS, PFS, DMFS, or LRFS were comparable in the two groups (all P > 0.05). After PSM, OS, DFS, and LRFS in the juvenile group were markedly longer than that in adults (P = 0.005, P = 0.027, and P = 0.024, respectively). With respect to long-term toxicity, the most common adverse effects in juvenile patients were cervix fibrosis, ototoxicity, and xerostomia. However, except for two patients who developed grade 3 ototoxicity, all adverse effects were within grade 2.Conclusion: In the IMRT era, juvenile Chinese patients with NPC had better 5-year OS, DFS, and LRFS than their adult counterparts. The adverse events in the juvenile cohort were relatively mild; however, the risk of severe ototoxicity should not be neglected.Keywords: juvenile nasopharyngeal carcinoma, intensity-modulated radiotherapy, prognosis

Jun Chang,1,2 Ling Hong,2 Yaozhong Liu,3 Yiwen Pan,2 Hao Yang,2 Wenrui Ye,3 Keli Xu,4 Zhijian Li,1 Shubing Zhang1,2,5,6 1Department of Anesthesiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, People’s Republic of China; 2Department of Cell Biology, School of Life Sciences, Central South University, Changsha, Hunan 410013, People’s Republic of China; 3Xiangya Medical School, Central South University, Changsha, Hunan 410013, People’s Republic of China; 4Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39216, USA; 5Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, Hunan 410013, People’s Republic of China; 6Breast Cancer Research Center, School of Life Sciences, Central South University, Changsha, Hunan 410013, People’s Republic of ChinaCorrespondence: Zhijian LiDepartment of Anesthesiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, People’s Republic of ChinaTel +8613787314214Email lizhijian@csu.edu.cnShubing ZhangDepartment of Cell Biology, School of Life Sciences, Central South University, Changsha, Hunan 410013, People’s Republic of ChinaTel +861397589680Email shubingzhang@csu.edu.cnPurpose: Molecular targeting is a powerful approach for aggressive claudin-low breast cancer (CLBC). Overexpression of PI3K catalytic subunit gamma (PIK3CG) in human CLBC is offering a promising opportunity for targeted therapies. We utilized a specific inhibitor of PIK3CG combined with paclitaxel (PTX) to treat CLBC cells in vitro and in vivo.Patients and Methods: The tumor cells growth and apoptosis in vitro were analyzed by CCK8, plate clone formation assay, tumorsphere assay, Hoechst staining and flow cytometry. The invasion and metastasis ability of tumor cells in vitro were investigated by wound healing and transwell experiments. Critical gene expression levels were checked by qRT-PCR and Western blot. Xenograft models with CLBC cell lines in SCID mice were established to investigate the effect of combined drugs in vivo.Results: We identified that PIK3CG was a potential therapeutic target for CLBC patients. Targeting PIK3CG potentiated CLBC cells growth inhibition in 2D and 3D cultures by PTX. Inhibition of PIK3CG activation could enhance CLBC cells apoptosis and migration suppression induced by PTX. Manipulating autophagy was a validated approach for the use of PIK3CG inhibitor. Using CLBC xenograft mice model, we found that CLBC tumors in vivo could be well treated by combined drugs of PIK3CG inhibitor and PTX.Conclusion: We demonstrated that PIK3CG was a potential target for the therapy of CLBC and inhibition of PIK3CG activation could reinforce the therapeutic effect of this aggressive disease by PTX. The combined use of PIK3CG inhibitor and PTX might be a potential regimen for treating this subtype of breast cancer.Keywords: PIK3CG, paclitaxel, claudin-low breast cancer, combined drugs, targeted therapy

Anna Karin Hedström,1 Rino Bellocco,2 Weimin Ye,3 Ylva Trolle Lagerros,4 Torbjörn Åkerstedt5 1Department of Clinical Neuroscience and Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 2Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden, and Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy; 3Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; 4Department of Medicine, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden, and Obesity Center, Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden; 5Stress Research, Stockholm University, Stockholm, Sweden, and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, SwedenCorrespondence: Anna Karin HedströmInstitute of Environmental Medicine, Karolinska Institutet Box 210, Stockholm 17177, SwedenTel +46762736426Email anna.hedstrom@ki.seBackground: Previous studies investigating the relationship between insomnia and mortality have been inconsistent.Purpose: We aimed to assess whether nocturnal insomnia symptoms and non-restorative sleep are associated with all-cause mortality and whether they modify the associations between short and long sleep duration and all-cause mortality.Patients and methods: The present report is based on a prospective cohort study of 39,139 participants with a mean follow-up time of 19.6 years. Cox proportional hazard models with attained age as timescale were used to estimate overall mortality hazard ratios (HRs) with 95% confidence intervals (CI) for different categories of sleep duration and insomnia symptoms.Results: Both difficulty initiating sleep and daytime sleepiness were independently associated with increased mortality among those with sleep duration of 9 hrs or more (HR 1.51, 95% CI 1.11–2.07 and HR 1.37, 95% CI 1.03–1.82). Mortality increased with increasing severity of difficulties initiating sleep (p for trend 0.04) and daytime sleepiness (p for trend 0.01) among the long sleepers. None of the insomnia symptoms were associated with mortality among those who reported sleep duration of 8 hrs or less.Conclusion: Long sleep in combination with difficulties initiating sleep and daytime sleepiness, possibly due to psychiatric or physical disorders, was thus associated with increased mortality, whereas long sleep without difficulties falling asleep or daytime sleepiness was not associated with mortality. Our study emphasizes the need to take nocturnal insomnia symptoms and daytime sleepiness into consideration when assessing the influence of sleep duration on mortality. Additional research is needed to elucidate the relationship between long sleep, insomnia and related psychiatric and physical disorders.Keywords: prospective cohort study, sleep quality, sleep duration

Zhihong Chai,1,* Yufei Yang,2,3,* ZhongYi Gu,4,* Xianli Cai,1 Wenwei Ye,1 Lin Kong,1 Xiaoxiao Qiu,1 Lingxiao Ying,1 Ziliang Wang,2,3 Linyou Wang1 1Department of Gynecology and Department of Radiology, Taizhou Municipal Hospital Affiliated to Taizhou University School of Medicine, Taizhou 318000, People’s Republic of China; 2Department of Obstetrics and Gynecology, Xihua Hospital Affiliated to Shanghai Jiaotong University School Medicine, Shanghai 200092, People’s Republic of China; 3Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, People’s Republic of China; 4Department of Nephrology, Children’s Hospital of Fudan University, Shanghai 201102, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ziliang WangDepartment of Obstetrics and Gynecology, Xihua Hospital Affiliated to Shanghai Jiaotong University School Medicine, 1665 Kongjiang Road, Shanghai 200092, People’s Republic of ChinaEmail huf_zlwang@126.comLinyou WangDepartment of Radiology, Taizhou Municipal Hospital, 381 East Zhongshan Road, Taizhou 318000, People’s Republic of ChinaEmail wanglinyou2007@163.comPurpose: Capsid protein L2 is the minor capsid protein of human papillomavirus 16 (HPV16). Although L2-based vaccines were developed, the therapeutic effect of recombinant viral capsid protein L2 (rVL2) was still to be illustrated.Methods: We used glucose uptake and lactate production assay to verify the inhibitory effect of rVL2 on the glucose metabolism in cervical cancer cells. Secondly, we performed gene-chip assay, RT-PCR, and Western blot to determine the role of ITGB7/C/EBPβ signaling pathway in rVL2-mediated glucose metabolism in vitro. Finally, we used an animal model to verify the function of rVL2 in cervical cancer.Results: We found that rVL2 reduced glucose uptake and lactate production levels in cervical cancer cells, which caused the inhibition of cell proliferation. rVL2 decreased the expression levels of key metabolic enzymes, including GLUT1, LDHA, and ALDOA, to affect cell metabolism in cervical cancer cells by inhibiting ITGB7/C/EBPβ signaling pathway in vitro and in vivo.Conclusion: These results demonstrated the vital role of rVL2 in the glycolysis-induced cell growth and proliferation via suppressing ITGB7/C/EBPβ signaling axis.Keywords: recombinant viral capsid protein L2, rVL2, C/EBPβ, glucose metabolism, cervical cancer

Xuefeng Gu,1,2,* Yuan Mao,3,* Chuanbing Shi,4 Wei Ye,2 Ning Hou,5 Li Xu,5 Yan Chen,5 Wei Zhao1,2 1Medical School, Southeast University, Nanjing, People’s Republic of China; 2Department of Liver Disease, The Second Hospital of Nanjing, Medical School, Southeast University, Nanjing, People’s Republic of China; 3Department of Hematology and Oncology, Geriatric Hospital of Nanjing Medical University, Jiangsu Province Geriatric Hospital, Nanjing, People’s Republic of China; 4Department of Pathology, Pukou District Central Hospital, Pukou Branch of Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 5Department of Pathology, Jiangsu Cancer Hospital, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei ZhaoMedical School, Southeast University, 87 Dingjiaqiao Street, 210000 Nanjing, Jiangsu, People’s Republic of ChinaTel +86 25 8362-6000Fax +86 25 8362-6060Email weizhaoseu@163.comPurpose: Although MAGEC2 was first cloned from a human hepatocellular carcinoma (HCC) cDNA library by serum screening, the detailed attributes of MAGEC2 in HCC have rarely been elucidated.Patients and methods: In this study, The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases were consulted to analyse the expression of MAGEC2 mRNA in liver cancer. Immunohistochemistry (IHC) analysis was performed to detect MAGEC2 expression in HCC, and the relationship between MAGEC2 expression and the clinicopathological characteristics of HCC patients was evaluated. Then, we employed the short hairpin (sh)RNA-mediated knockdown of MAGEC2 in HCC cell lines to explore the function of MAGEC2 in HCC development. Finally, the expression of epithelial-mesenchymal transition (EMT) markers in HCC xenografts and clinical samples was investigated.Results: The results showed a remarkably higher level of MAGEC2 expression in HCC tissues than in noncancerous tissues, and MAGEC2 expression could be used as an independent prognostic factor for overall survival in HCC. Moreover, sh-MAGEC2 inhibited a series of HCC malignant behaviours both in vitro and in vivo. Finally, decreased MAGEC2 expression and low levels of EMT markers were detected in sh-MAGEC2 xenografts, while increased MAGEC2 expression and high levels of EMT markers were observed in invasive and metastatic HCC samples.Conclusion: Taken together, our data imply that MAGEC2 is a novel prognostic marker for HCC and that MAGEC2 significantly promotes HCC tumourigenesis by inducing EMT. Targeting MAGEC2 may provide a promising therapeutic strategy for HCC treatment.Keywords: MAGEC2, hepatocellular carcinoma, prognosis, tumourigenesis, EMT

Yanyan Wei,1,2,* Yongxiang Yi,3,* Chen Tao,1,3 Wei Ye,1,3 Wei Zhao1,3 1Department of Infectious Diseases, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 2Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 3Department of Hepatobiliary Surgeon, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Ye; Wei ZhaoDepartment of Infectious Diseases, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, No. 1-1 Zhongfu Road, Nanjing, Jiangsu, People’s Republic of ChinaEmail yeweiseu@163.com; zhaoweiseu@126.comBackground: Hepatocellular carcinoma (HCC) is the second leading causes of cancer-related death. HCC is usually based on chronic liver disease, mainly including chronic hepatitis C virus infection or chronic hepatitis B virus (HBV) infection.Objective: The objective of the study was to evaluate the impact of the nucleos(t)ide analog (NA) use on the prognosis of patients with HBV-related small hepatocellular carcinomas (HBV-SHCC).Methods: In this retrospective study, there were 134 patients who had been treated with long-term NA before SHCC diagnosis as NA-experienced group, 43 patients received NA-naïve treatment after SHCC diagnosis as NA-naïve group, and 15 patients who did not receive NA treatment as untreated group. Among these patients, some patients underwent surgical resection and others with local recurrence were treated with transarterial chemoembolization (TACE), TACE-percutaneous microwave coagulation therapy or TACE alone. The Kaplan–Meier and Cox-proportional hazard model were used to calculate the survival analysis.Results: The data showed that 1-year, 3-year, 5-year overall survival rate of HBV-SHCC patients in NA-experienced group were 90.27%, 90.69%, 65%, NA-naïve group were 70.81%, 73.95%, 47.39%, and untreated group were 54.96%, 40.44%, 47.39%, respectively (Log-rank, P=0.031). The median survival time of HBV-SHCC patients treated with adefovir dipivoxil (ADV) or LAM+ADV has the longest survival time. Patients who have received rescue treatment after viral breakthrough or gotten maintained viral response had longer survival times than those who have not received rescue treatment after viral breakthrough or non-response. Compared with timely rescue treatment, viral breakthrough (hazard ratio=3.624, 95% CI, 1.035–12.687, P=0.044) was an independent risk factor for HBV-SHCC patients with Cox-proportional hazard model. For these patients conforming to NA-treatment indications, commencement of NA treatment should be given even after HBV-SHCC diagnosis. Moreover, HBV-SHCC patients who were suffering from virus break through should be treated timely rescue therapy even if their liver function was normal.Conclusion: SHCC patients treated with low drug resistance barrier drugs may not change the treatment regimen if they have gotten virological response.Keywords: chronic hepatitis B, hepatocellular carcinoma, liver cirrhosis, nucleos(t)ide analog, virus breakthrough, timely rescue therapy

Borong Chen,1* Zhipeng Zhu,1* Lulu Li,1* Weipeng Ye,2 Junjie Zeng,1 Jin Gao,1 Shengjie Wang,1 Liang Zhang,1 Zhengjie Huang1,21Department of Gastrointestinal Surgery, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People’s Republic of China; 2Department of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian 350004, People’s Republic of China*These authors contributed equally to this work Objective: Using the gastric cancer cell line SGC7901, we constructed a cell line that overexpressed octamer-binding protein 4 (Oct4) and SRY-box 2 (Sox2) to explore the stem cell oncological and biological characteristics of these cells and to elucidate the mechanisms of Oct4 and Sox2 in cancer.Methods: A lentiviral vector containing the Sox2 gene was constructed and transfected into a gastric cancer cell line overexpressing Oct4 (SGC7901-Oct4) to obtain a stably transfected cell line (SGC7901-Oct4-Sox2). Oct4 and Sox2 expression was detected by RT-PCR and Western blotting. The proliferation, drug resistance, migration, and invasion abilities of the cells were assessed using in vitro (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium), drug resistance, scratch-wound migration, transwell migration, transwell invasion, and spherical clone formation assays, and their tumorigenic ability was assessed using a tumor formation experiment in mice.Results: Compared with the control group, the expression of Oct4, Sox2, CD44, and E-cadherin was significantly higher in the group that overexpressed Oct4 and Sox2, while the expression of c-Myc and Klf4 did not significantly change. The proliferation, drug resistance, migration, and invasion abilities were significantly enhanced in the overexpression group, and the tumorigenic ability in mice was also significantly enhanced, with significantly increased tumor size and weight.Conclusion: The proliferation, drug resistance, migration, invasion, and tumorigenic abilities of SGC7901 cells overexpressing Oct4 and Sox2 were significantly improved. Oct4 and Sox2 play important roles in the proliferation, migration, invasion, and tumorigenicity of gastric cancer cells, and the two genes may be synergistic to a certain degree.Keywords: stomach cancer SGC7901, Oct4, Sox2, stem cells

Lei Lei,1,2,* Wei-Wu Ye,2,* Lin-Feng Zheng,3 Ping Huang,2 Lei Shi,2 Jian Huang,2 Ya-Bing Zheng,2 Zhan-Hong Chen,2 Xiao-Jia Wang,2 Xian Wang1 1Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China; 2Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province, China; 3Department of Pathology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province, China *These authors contributed equally to this work Abstract: Metastatic breast cancer (MBC) is the most life-threatening disease in women worldwide. HER2-mutated breast carcinoma has been reported to benefit from HER2-targeted tyrosine kinase inhibitors recently. Here, we presented a heavy pretreated and harbored HER2 V777L mutation de novo stage IV Luminal B (HER2 unamplified) breast cancer patient who achieved an unexpected good response to trastuzumab combined with vinorelbine therapy. Although HER2-unamplified MBC patients do not regularly benefit from anti-HER2 target therapy, HER2 V777L mutation detected by next-generation sequencing from ctDNA may present as a predictive biomarker for anti-HER2-based strategy therapy in HER2-negative MBC patients. Keywords: metastatic breast cancer, HER2 gene mutation, trastuzumab

Yanyan Wei,* Feng Dai,* Tianhui Zhao, Chen Tao, Lili Wang, Wei Ye, Wei Zhao Liver Disease Department, The Second Hospital of Nanjing, Medical School of Southeast University, Nanjing, China *These authors contributed equally to this work Background: The prognosis of massive hepatocellular carcinomas (MHCCs; ≥10 cm) remains worse. Purpose: The aim of this study was to evaluate the clinical benefits of transcatheter arterial chemoembolization (TACE) or TACE combined with percutaneous microwave coagulation therapy (PMCT) and the long-term survival rate of MHCC patients treated with these techniques. Patients and methods: A retrospective study was performed using data involving 102 MHCC patients admitted to the Second Hospital of Nanjing from September 2010 to August 2015. The median interval between treatments and overall survival (OS) was hierarchically analyzed using log-rank tests. Multivariate analysis was done using Cox regression model analysis. Results: The median survival time of MHCC patients was 3 months (range, 1–10 months) in the palliative group, 3 months (range, 1–39 months) in the TACE group, and 7.5 months (range, 3–30 months) in the TACE–PMCT group (P=0.038). The 6-, 12-, and 18-month OS rates for MHCC patients were 15%, 0%, and 0% in the palliative group, 30%, 25.63%, and 17.97% in the TACE group, and 50%, 41.67%, and 16.67% in the TACE–PMCT group, respectively (P=0.0467). In addition, TACE sessions had positive correlation with the survival time of MHCC patients (rho = 0.462, P

Jiayu Zhou,1,* Shizhen Zhang,2,* Guoxiang Fu,3 Zhengfu He,1 Yong Xu,1 Weiwen Ye,1 Zhoumiao Chen1 1Department of Thoracic Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China; 2Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, Zhejiang Province, China; 3Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China *These authors contributed equally to this work Background: Anaphase-promoting complex subunit 11 (APC11) plays an important role in gathering E2 and catalyzing ubiquitin-chain formation to support ubiquitination of substrates by acting as a catalytic core subunit of anaphase-promoting complex (APC/C). However, whether APC11 is implicated in the tumorigenesis of lung cancer is never known. Materials and methods: In this study, we used an online survival analysis software to estimate the prognostic value of APC11 mRNA expression level for lung cancer. Cell Counting Kit-8 assay, colony-forming assay, and transwell assay were used to assess the biological functions of APC11 in lung cancer cells. Then, 107 lung cancer patient tissues were collected to examine the expression level of APC11 by immunohistochemistry staining. Kaplan–Meier method and univariate Cox regression analysis were performed to reveal the prognostic value of APC11 protein expression in lung cancer. Results: Higher mRNA level of APC11 was significantly associated with worse survival for lung adenocarcinoma, but not for lung squamous cell carcinoma. Knockdown of APC11 by siRNA apparently inhibited cell proliferation and colon formation in both H1299 and H358 cells. In addition, silencing of APC11 decreased cell migrative and invasive abilities. Moreover, immunohistochemical analysis showed that APC11 was highly expressed in lung cancer tissues, and multivariate analysis suggested that APC11 overexpression was an independent prognostic factor in lung adenocarcinoma. Conclusion: We suggest that APC11 could serve as a prognostic biomarker and a novel target in treating lung adenocarcinoma. Keywords: APC11, lung cancer, cell proliferation, migration, invasion

Yongxin Chen, Xiaofei Li, Shuang Wu, Weiwei Ye, Lianqing Lou Department of Infectious Diseases, Yiwu Central Hospital, Yiwu, China Background: Patients with metabolic syndrome (MetS) were suggested to have a higher risk of hepatocellular carcinoma (HCC), although the results of previous cohort studies are not consistent. Aim: To perform an updated meta-analysis to evaluate the association between MetS and subsequent incidence of HCC. Methods: Relevant cohort studies were identified by searching PubMed and Embase databases. Cochrane’s Q-test and I2 statistic were used to analyze the heterogeneity. Random effects model was used for the meta-analysis. Results: Six cohort studies with 127,198 participants and 1,293 HCC cases during follow-up were included. Patients with MetS had a significantly higher incidence of HCC in studies with MetS defined by the revised National Cholesterol Education Program’s Adults Treatment Panel III (risk ratio [RR]: 1.43, 95% CI: 1.19–1.72, p

Fen Pan,1 Hong Zhang,1 Xiaoyan Dong,2 Weixing Ye,3 Ping He,4 Shulin Zhang,4 Jeff Xianchao Zhu,5 Nanbert Zhong1,2,6 1Department of Clinical Laboratory, Shanghai Children’s Hospital, Shanghai Jiaotong University, Shanghai, China; 2Department of Respiratory, Shanghai Children’s Hospital, Shanghai Jiaotong University, Shanghai, China; 3Shanghai Personal Biotechnology Co., Ltd, Shanghai, China; 4Department of Medical Microbiology and Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; 5Zhejiang Bioruida Biotechnology co. Ltd, Zhejiang, China; 6New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA Introduction: Multidrug resistance in Streptococcus pneumoniae has emerged as a serious problem to public health. A further understanding of the genetic diversity in antibiotic-resistant S. pneumoniae isolates is needed. Methods: We conducted whole-genome resequencing for 25 pneumococcal strains isolated from children with different antimicrobial resistance profiles. Comparative analysis focus on detection of single-nucleotide polymorphisms (SNPs) and insertions and deletions (indels) was conducted. Moreover, phylogenetic analysis was applied to investigate the genetic relationship among these strains. Results: The genome size of the isolates was ~2.1 Mbp, covering >90% of the total estimated size of the reference genome. The overall G+C% content was ~39.5%, and there were 2,200–2,400 open reading frames. All isolates with different drug resistance profiles harbored many indels (range 131–171) and SNPs (range 16,103–28,128). Genetic diversity analysis showed that the variation of different genes were associated with specific antibiotic resistance. Known antibiotic resistance genes (pbps, murMN, ciaH, rplD, sulA, and dpr) were identified, and new genes (regR, argH, trkH, and PTS-EII) closely related with antibiotic resistance were found, although these genes were primarily annotated with functions in virulence as well as carbohydrate and amino acid transport and metabolism. Phylogenetic analysis unambiguously indicated that isolates with different antibiotic resistance profiles harbored similar genetic backgrounds. One isolate, 14-LC.ER1025, showed a much weaker phylogenetic relationship with the other isolates, possibly caused by genomic variation. Conclusion: In this study, although pneumococcal isolates had similar genetic backgrounds, strains were diverse at the genomic level. These strains exhibited distinct variations in their indel and SNP compositions associated with drug resistance. Keywords: Streptococcus pneumoniae, antimicrobial resistance, whole-genome sequencing, insertions/deletions, SNPs, phylogenetic analysis

Fengjun Liu1,* Wen Ye1,* Jun Wang2 Fengxiang Song1 Yingsheng Cheng3 Bingbo Zhang21Department of Radiology, Shanghai Public Health Clinical Center, 2Institute of Photomedicine, Shanghai Skin Disease Hospital, The Institute for Biomedical Engineering & Nano Science, Tongji University School of Medicine, 3Department of Radiology, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, China *These authors contributed equally to this work Abstract: Quantum dots (QDs) have been considered to be promising probes for biosensing, bioimaging, and diagnosis. However, their toxicity issues caused by heavy metals in QDs remain to be addressed, in particular for their in vivo biomedical applications. In this study, a parallel comparative investigation in vitro and in vivo is presented to disclose the impact of synthetic methods and their following surface modifications on the toxicity of QDs. Cellular assays after exposure to QDs were conducted including cell viability assessment, DNA breakage study in a single cellular level, intracellular reactive oxygen species (ROS) receptor measurement, and transmission electron microscopy to evaluate their toxicity in vitro. Mice experiments after QD administration, including analysis of hemobiological indices, pharmacokinetics, histological examination, and body weight, were further carried out to evaluate their systematic toxicity in vivo. Results show that QDs fabricated by the thermal decomposition approach in organic phase and encapsulated by an amphiphilic polymer (denoted as QDs-1) present the least toxicity in acute damage, compared with those of QDs surface engineered by glutathione-mediated ligand exchange (denoted as QDs-2), and the ones prepared by coprecipitation approach in aqueous phase with mercaptopropionic acid capped (denoted as QDs-3). With the extension of the investigation time of mice respectively injected with QDs, we found that the damage caused by QDs to the organs can be gradually recovered. This parallel comparative investigation suggests that synthetic methods and their resulting surface microenvironment play vital roles in the acute toxicity profiles of QDs. The present study provides updated insights into the fabrication and surface engineering of QDs for their translational applications in theranostics.Keywords: comparative investigation, amphiphilic polymer, glutathione, mercaptopropionic acid, DNA breakage, surface microenvironment

Suna Zhou,1,* Yaoyou Cui,1,* Dequan Yu,1 Jun Liang,1 Mingxin Zhang,2 Wenguang Ye2 1Department of Radiotherapy, 2Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi’an, China *These authors contributed equally to this work Background: Increasing evidence indicates that radioresistance remains a major problem in the treatment of patients with esophageal squamous cell carcinoma (ESCC). This study was designed to investigate the expression of microRNA-381 (miR-381) and its function in the radioresistance of ESCC.Methods: In this study, miR-381 expression was first detected in ESCC cell lines and tissue samples by quantitative real-time polymerase chain reaction (qRT-PCR). Then, the effects of miR-381 expression on growth, apoptosis, and radiosensitivity of ESCC cells were analyzed by MTT, colony formation, and flow cytometry, respectively. Dual-luciferase reporter assays were performed to validate the regulation of a putative target of miR-381, in corroboration with qRT-PCR and Western blotting assays.Results: ESCC cell lines or tissues were found to express significantly lower miR-381 than normal esophageal epithelial cells or adjacent normal tissues, respectively. Ectopic expression of miR-381 in ESCC cell lines blocked proliferation, reduced colony formation, enhanced apoptosis, and increased radiosensitivity by enhancing irradiation-induced apoptosis. In addition, dual-luciferase reporter assays showed that miR-381 binds to the 3'-untranslated region of X-linked inhibitor of apoptosis protein (XIAP), suggesting that XIAP should be a direct target of miR-381. Re-expression of miR-381 suppressed XIAP protein expression in ESCC cells, and the effects of miR-381 upregulation on ESCC cells were found to be similar with silencing of XIAP. In addition, XIAP mRNA expression significantly increased in ESCC tissues and was inversely correlated with miR-381 expression.Conclusion: The results of this study suggest that miR-381/XIAP pathway contributed to the growth inhibition, increase in apoptosis, and enhancement of radiosensitivity in ESCC cells Therefore, miR-381 may be a potential therapeutic target in human ESCC. Keywords: miR-381, esophageal squamous cell carcinoma, XIAP, growth, apoptosis

During a nematode biodiversity survey from 2012 to 2014 in Shenzhen, China, ten nematode populations (SZX1301–SZX1310) of Xiphinema were recovered from rhizosphere of different plants, namely Acacia mangium (SZX1306), A. confuse (SZX1309), Blechnum orientale (SZX1301, SZX1302, SZX1307, SZX1308), Litchi chinensis (SZX1304, SZX1310) in Tianxinshan and Gleichenia linearis (SZX1303, SZX1305) in Yangmeikeng environmental monitoring sites. Morphological and molecular profiles of these populations were determined. Three species of Xiphinema, i.e., X. hunanienseWang & Wu, 1992, X. brasilienseLordello, 1951 and X. americanum Cobb, 1913 sensu lato were identified using morphological characters and molecular data of partial 18S and 28S D2–D3 rDNA expansion segments. Four populations (SZX1301–SZX1304) were X. hunaniense, one population (SZX1305) X. brasiliense, and five populations (SZX1306–SZX1310) X. americanum s.l.. Phylogenetic analysis based on sequences of the 28S rDNA D2–D3 expansion segment revealed these three species are all distinct species and supported a close relationship with their corresponding species. This is the first report of X. hunaniense, X. brasiliense and X. americanum s.l. in their hosts except for L. chinensis.

Zhou J, Zhang S, Fu G, et al. Onco Targets Ther. 2018;11:7125–7132. Author intended to show unrepresentative images of cell migration and invasion, that the number of migration cells was similar with invasion cells in Figure 4, page 7129. The published image for Figure 4B was not consistent with the author’s expectation. Author repeated the assay test and received better and reasonable images for replacement. These replacement of images to Figure 4B and C have not changed the overall results to the study. The author apologizes for this error.Read the original article.

Xiaoling Xu,1 Ruifeng Zhang,1 Huihui Hu,1 Wu Ye,1 Jin Wang,2 Liying Chen,3 Lijun Qiu,4 Kejing Ying1 1Department of Respiratory Medicine, 2Department of Pathology, 3Department of Family Medicine, 4Endoscopy Center, Sir Run Run Shaw Hospital, Medicine School of Zhejiang University, Hangzhou, People’s Republic of China Abstract: Pulmonary artery intimal sarcoma (PAIS) is a rare malignant tumor that presents with nonspecific symptoms and may be misdiagnosed as thromboembolic disease. We report a case of a 40-year-old female who presented with diarrhea as the initial symptom, was misdiagnosed and received thrombolytic therapy for presumed pulmonary embolism. Progressive symptoms and subsequent surgery led to the diagnosis of PAIS, and early relapse after pulmonary endarterectomy. Her survival time was 17 months after pulmonary endarterectomy. To our knowledge, diarrhea as initial manifestation of PAIS has not been described. Keywords: pulmonary artery intimal sarcoma, chronic diarrhea, soft tissue sarcoma, pulmonary embolism, paraneoplastic syndromes

Jing Wu,1 Xiaoning He,1 Li Liu,2 Wenyu Ye,2 William Montgomery,3 Haibo Xue,2 Jeffery S McCombs41School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, People’s Republic of China; 2Lilly Suzhou Pharmaceutical Company, Ltd, Shanghai, People’s Republic of China; 3Eli Lilly and Company, Sydney, Australia; 4Departments of Clinical Pharmacy and Pharmaceutical Economics and Policy, School of Pharmacy, University of Southern California, Los Angeles, CA, USAObjective: Information concerning the treatment costs of schizophrenia is scarce in People’s Republic of China. The aims of this study were to quantify health care resource utilization and to estimate the direct medical costs for patients with schizophrenia in Tianjin, People’s Republic of China.Methods: Data were obtained from the Tianjin Urban Employee Basic Medical Insurance (UEBMI) database. Adult patients with ≥1 diagnosis of schizophrenia and 12-month continuous enrollment after the first schizophrenia diagnosis between 2008 and 2009 were included. Both schizophrenia-related, psychiatric-related, and all-cause related resource utilization and direct medical costs were estimated.Results: A total of 2,125 patients were included with a mean age of 52.3 years, and 50.7% of the patients were female. The annual mean all-cause costs were $2,863 per patient with psychiatric-related and schizophrenia-related costs accounting for 84.1% and 62.0% respectively. The schizophrenia-related costs for hospitalized patients were eleven times greater than that of patients who were not hospitalized. For schizophrenia-related health services, 60.8% of patients experienced at least one hospitalization with a mean (median) length of stay of 112.1 (71) days and a mean cost of $1,904 per admission; 59.0% of patients experienced at least one outpatient visit with a mean (median) number of visits of 6.2 (4) and a mean cost of $42 per visit during the 12-month follow-up period. Non-medication treatment costs were the most important element (45.7%) of schizophrenia-related costs, followed by laboratory and diagnostic costs (19.9%), medication costs (15.4%), and bed fees (13.3%).Conclusion: The costs related to the treatment of patients with schizophrenia were considerable in Tianjin, People’s Republic of China, driven mainly by schizophrenia-related hospitalizations. Efforts focusing on community-based treatment programs and appropriate choice of drug treatment have the potential to reduce the use of inpatient services and may lead to better clinical and economic outcomes in the management of patients with schizophrenia in People’s Republic of China.Keywords: schizophrenia, health care resource use, direct medical costs, People’s Republic of China

William Montgomery,1 Zbigniew Kadziola,2 Wenye Ye,3 Hai Bo Xue,4 Li Liu,4 Tamás Treuer5 1Global Patient Outcomes and Real World Evidence, Eli Lilly Australia Pty Ltd, West Ryde, NSW, Australia; 2Real World Analytics Capabilities, Eli Lilly GmbH, Vienna, Austria; 3Real World Analytics, Eli Lilly and Company, Indianapolis, IN, USA; 4Lilly Suzhou Pharmaceutical Company, Ltd, Shanghai, People’s Republic of China; 5Neuroscience Research, Eli Lilly and Company, Budapest, HungaryPurpose: The aim of this study was to investigate the correlation between changes in symptoms and changes in self-reported quality of life among Chinese patients with schizophrenia who were switched from a typical antipsychotic to olanzapine during usual outpatient care. Patients and methods: This post hoc analysis was conducted using data from the Chinese subgroup (n=475) of a multicountry, 12-month, prospective, noninterventional, observational study. The primary publication previously reported the efficacy, safety, and quality of life among patients who switched from a typical antipsychotic to olanzapine. Patients with schizophrenia were included if their symptoms were inadequately controlled with a typical antipsychotic and they were switched to olanzapine. Symptom severity was measured using the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impressions-Severity scale (CGI-S). Health-Related Quality of Life (HRQOL) was assessed using the World Health Organization Quality of Life–Abbreviated (WHOQOL-BREF). Paired t-tests were performed to assess changes from baseline to endpoint. Pearson’s correlation coefficients (r) were used to assess the correlations between change in symptoms (BPRS and CGI-S scores) and change in HRQOL (WHOQOL-BREF scores). Results: Symptoms and HRQOL both improved significantly over the 12 months of treatment (P