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Yuhua Wen,1,2,* Lianghe Lu,1,2,* Jie Mei,1,2 Yihong Ling,2,3 Renguo Guan,1,2 Wenping Lin,1,2 Wei Wei,1,2 Rongping Guo1,2 1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 2Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 3Department of Pathology of Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rongping Guo; Wei Wei, Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China, Email guorp@sysucc.org.cn; weiwei@sysucc.org.cnBackground: Microvascular invasion (MVI) is a significant pathological feature in hepatocellular carcinoma (HCC), adjuvant hepatic arterial infusion chemotherapy (a-HAIC) and adjuvant transcatheter arterial chemoembolization (a-TACE), are commonly used for HCC patients with MVI. This study aims to evaluate the efficacies of two adjuvant therapies after surgical treatment for HCC, compare them, and identify the significant factors.Methods: Clinical data from two randomized controlled trials involving HCC patients with MVI after surgical treatment were retrospectively reviewed. Propensity score matching (PSM) analysis was performed to balance baseline differences between patients who received a-HAIC or a-TACE, and control groups who underwent hepatectomy alone. Disease-free survival (DFS) and overall survival (OS) rates were compared.Results: In total of 549 patients were collected from two randomized controlled trials. Using the PSM and Kaplan-Meier method, the median DFS of the a-HAIC, a-TACE, and control groups was 63.2, 21.7, and 11.2 months (P

Jingwen Jiang,1– 3,* Na Kong,1– 3,* Qingqing Shi,1– 3,* Yuan Yan,1– 3 Xiaoyue Shen,1– 3 Jie Mei,1– 3 Haixiang Sun,1– 3 Chenyang Huang1– 3 1Center for Reproductive Medicine and Obstetrics and Gynecology, Drum Tower Clinic Medical College of Nanjing Medical University, Nanjing, 210008, People’s Republic of China; 2Reproductive Medicine Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, People’s Republic of China; 3Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, 210008, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haixiang Sun; Chenyang Huang, Center for Reproductive Medicine and Obstetrics and Gynecology, Drum Tower Clinic Medical College of Nanjing Medical University, Nanjing, 210008, People’s Republic of China, Tel +8625-8310-6666-70261, Fax +8625-8310-7188, Email stevensunz@163.com; dianshui19901562@126.comBackground: Previous studies suggested higher serum progesterone (P) levels were strongly associated with a lower clinical pregnancy rate (CPR) for in vitro fertilization-embryo transfer (IVF-ET). However, the effect of increased serum P levels on the day of human chorionic gonadotropin (hCG) administration on clinical outcomes in short-acting gonadotropin-releasing hormone agonist (GnRHa) downregulated IVF-ET cycles remains unclear.Methods: We conducted a retrospective cohort study from January 2017 to December 2021, which included a total of 1664 patients receiving their first short-acting GnRHa IVF-ET cycles at our reproductive medicine centre of Nanjing Drum Tower Hospital. The smooth curve fitting and interaction analysis were employed to analyse the association between the CPR and the serum P levels with different embryo types (cleavage-stage embryo or blastocyst). In addition, total cycles were grouped according to different P levels on the trigger day of hCG administration for further analysis.Results: The CPR of patients with increased serum P level (higher than 1.5 ng/mL) on the hCG day did not decrease. A smoothing curve fitting showed that the CPR did not change obviously with the increase in serum P levels. Subgroup analysis of different types of embryos transferred showed that no correlation was observed between the CPR and serum P levels on the day of hCG administration in cleavage-stage embryo transfer cycles. However, the CPR of patients receiving blastocyst transfer showed a downward trend with the increase in serum P levels. At the same time, an interaction analysis also confirmed that the CPR of blastocyst transfer was more likely to be affected by elevated serum P levels on the hCG day.Conclusion: In the luteal phase short-acting GnRHa downregulated IVF-ET cycles, the elevated serum P levels on the hCG day did not affect the CPR of cleavage-stage embryo transfer but reduced the CPR of blastocyst transfer.Keywords: short-acting GnRHa, elevated progesterone level, hCG trigger day, clinical pregnancy rate, blastocyst transfer

Bowen Chang,1,2,* Jiaming Mei,1,2,* Chen Ni,1,2 Chaoshi Niu1,2 1Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China; 2Anhui Province Key Laboratory of Brain Function and Brain Disease, Hefei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chaoshi Niu, Email niuchaoshi@ustc.edu.cnBackground: Anxiety is one of the most common and disturbing non-motor symptoms of Parkinson’s disease (PD). However, few studies have explored the relationship between functional connectivity (FC) and the rate of anxiety improvement after subthalamic nucleus deep brain stimulation (STN-DBS). Therefore, in this study, we aimed to explore the correlation between FC and the rate of anxiety improvement in patients with PD who underwent STN-DBS.Methods: The resting-state functional magnetic resonance imaging (rs-fMRI) data of 62 patients with anxious PD (aPD), 68 patients with PD without anxiety (naPD), and 64 healthy controls (HCs) were analyzed according to FC. Intergroup comparison and correlation analyses of anxiety improvement rates were performed.Results: The HC, aPD and naPD groups of zFCs were then used for the ANOVA test, and the results were FDR-corrected. There were 24 significant differences in FCs between the three groups. Post tests were conducted between groups found that 15 significantly different FCs were observed between the naPD and aPD groups. In addition, the two FCs in patients with aPD were significantly correlated with the rate of improvement in anxiety.Conclusion: We found that the two FCs in patients with aPD (olfactory cortex and inferior frontal gyrus [IFG] pars orbitalis; inferior temporal gyrus and posterior orbital gyrus) were significantly correlated with the rate of improvement in anxiety. Our study may help us understand the underlying mechanisms by which STN-DBS improves anxiety in PD patients and identify more effective treatment strategies.Keywords: Parkinson’s disease, deep brain stimulation, anxiety, functional connectivity, fMRI

Wei Huang,1,* Zhengtao Qian,2,* Yuxin Shi,1,3,* Zheming Zhang,3 Rui Hou,1,3 Jie Mei,1,3 Junying Xu,1 Junli Ding1 1Department of Oncology, the Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, 214023, People’s Republic of China; 2Department of Clinical Laboratory, Changshu Medicine Examination Institute, Changshu, 215500, People’s Republic of China; 3Wuxi School of Clinical Medicine, Nanjing Medical University, Wuxi, 214023, People’s Republic of China*These authors contributed equally to this workCorrespondence: Junli Ding; Junying Xu, Email dingjunliletters@163.com; doctorxjy123@163.com; xujunying@wuxiph.comBackground: Proteasome 26S subunit ATPase 2 (PSMC2) is a part of the 19S regulatory complex, which catalyzes the unfolding and transport of substrates into the 20S proteasome. Our previous research demonstrated that PSMC2 participates in the tumorigenesis and progression of pancreatic cancer (PC). However, no systematic analysis has been conducted to conclude its expression pattern and correlation with tumor immunity.Aim: To investigate the expression level of PSMC2 in PC, its prognostic value and its relationship with tumor immunity.Methods: In numerous public and internal cohorts, the expression, prognostic significance, and immunological connections of PSMC2 in PC were investigated. Additionally, using data from The Cancer Genome Atlas (TCGA), a pan-cancer analysis was carried out to examine PSMC2’s immunological assocaition, and the predictive power of PSMC2 for immunotherapy was also evaluated in numerous public cohorts.Results: PSMC2 was overexpressed in tumor tissues and linked to unfavorable prognosis in PC. PSMC2 was not only positively correlated with TIICs, also positively correlated with immune checkpoints in PC. In addition to PC, PSMC2 was expected to be an indicator of high immunogenicity in most cancer types. Importantly, PSMC2 could predict the immunotherapeutic responses in various cancer types, including urothelial carcinoma and breast cancer.Conclusion: From PC to pan-cancer analysis, we report that PSMC2 is a novel prognostic biomarker in multiple cancer types. PSMC2 is related to the immuno-hot phenotype and predicts the outcome of immunotherapy. Therefore, the current study emphasizes that cancer patients with high PMSC2 expression should actively receive immunotherapy to improve their prognosis.Keywords: PSMC2, tumor immunity, pancreatic cancer, biomarker, bioinformatics

Yin-Ting Yang,1,2,* Xi-Ya Jiang,1,2,* Hong-Liang Xu,3,* Guo Chen,1,2,* Sen-Lin Wang,4 He-Ping Zhang,3 Lin Hong,1,2 Qin-Qin Jin,1,2 Hui Yao,1,2 Wei-Yu Zhang,1,2 Yu-Ting Zhu,1,2 Jie Mei,1,2 Lu Tian,1,2 Jie Ying,1,2 Jing-Jing Hu,5 Shu-Guang Zhou1,2 1Department of Gynecology and Obstetrics, Maternity and Child Healthcare Hospital Affiliated to Anhui Medical University, Anhui Province Maternity and Child Healthcare Hospital, Hefei, Anhui, 230001, People’s Republic of China; 2Department of Gynecology and Obstetrics, The Fifth Clinical College of Anhui Medical University, Hefei, Anhui, 230032, People’s Republic of China; 3Department of Pathology, Anhui Province Maternity and Child Healthcare Hospital, Hefei, Anhui, 230001, People’s Republic of China; 4Department of Medical Genetics Center, Anhui Province Maternity and Child Healthcare Hospital, Hefei, Anhui, 230001, People’s Republic of China; 5Department of Gynecology and Obstetrics, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shu-Guang Zhou, Department of Gynecology, Anhui Medical University Affiliated Maternity and Child Healthcare Hospital, The Fifth Clinical College of Anhui Medical University, Anhui Province Maternity and Child Healthcare Hospital, No. 15, Yi-Min Street, Lu-Yang District, Hefei, Anhui, 230001, People’s Republic of China, Email zhoushuguang@ahmu.edu.cn Jing-Jing Hu, Department of Gynecology and Obstetrics, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China, Email janejj55@126.comBackground: Endometriosis, a common gynecological condition, can cause symptoms such as dysmenorrhea, infertility, and abnormal bleeding, which can negatively affect a woman’s quality of life. In the current study, the pathophysiological mechanisms of endometriosis are unknown, but this study suggests that endometriosis is associated with dysregulation of the autoimmune system. This study identify hub genes involved in the prevalence, identification and diagnostic value of endometriosis and autoimmune diseases, and explore the central genes and immune infiltrates, the diagnosis of endometriosis provides a new sight of thinking about diagnosis and treatment.Methods and Results: The relevant datasets for endometriosis GSE141549, GSE7305 and autoimmune disease-related genes (AIDGs) were downloaded from online database. Using the “limma” package and WGCNA to screen out the autoimmune disease related genes and endometriosis related genes, the autoimmune disease gene-related differential genes (AID-DEGs) progressive GO, KEGG enrichment analysis, and then using the protein interaction network and Cytoscape software to select hub genes (CXCL12, PECAM1, NGF, CTGF, WNT5A), using the “pROC” package to analyze the hub genes for the diagnostic value of endometriosis. The difference in the importance of hub genes for the diagnosis of endometriosis was analyzed by machine learning random forest, and the combined diagnostic value of hub genes was analyzed by using the Support Vector Machine (SVM) algorithm. The eutopic (EU) and ectopic endometrium (EC) immune microenvironment of endometriosis was evaluated using CIBERSORT, the correlation of hub genes to the immune microenvironment was analyzed.Conclusion: The hub genes associated with AIDGs are differentially expressed in EC and EU of endometriosis and possess important value for the diagnosis of endometriosis. The hub genes have a very important impact on the immune microenvironment of endometriosis, which is important for exploring the connection between endometriosis and autoimmune diseases and provides a new insight for the subsequent study of immunotherapy and diagnosis of endometriosis.Keywords: EMT, hub genes, diagnosis, immunotherapy, immune microenvironment

Junli Ding,1,* Hao Wang,1,* Rui Hou,1,* Yuxin Shi,1 Honghong Fan,1 Yuting Li,1 Jie Mei,1 Qinglin Zhang,2 Tingyan Ruan,1 Junying Xu1 1Department of Oncology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, 214023, People’s Republic of China; 2Department of Gastroenterology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, 214023, People’s Republic of China*These authors contributed equally to this workCorrespondence: Junying Xu; Tingyan Ruan, Department of Oncology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, No. 299 Qingyang Road, Wuxi, Jiangsu, 214023, People’s Republic of China, Tel/Fax +86-510-82700775, Email doctorxjy123@163.com; ruantingyan165@163.comBackground: Immune checkpoint inhibitors have achieved limited clinical effectiveness in colon cancer. Stem memory T cells (TSCMs) and in-situ cytotoxic T cells are dominant contributors to host immunity. Currently, data on the correlation between TSCM and T cell abundance and clinicopathological characteristics in colon cancer are largely unavailable.Methods: In-situ cytotoxic T cells are identified based on the quantification of CD3+ and CD8+ markers using immunohistochemistry (IHC) in the core of the tumor and the invasive margin of the tumor. The expression of representative markers of TSCMs, CD27 and CD95, was assayed using IHC in colon cancer tissues. Correlations between the levels of each marker and the clinicopathological characteristics as well as prognosis were evaluated.Results: High densities of CD3+ and CD8+ T cells correlated with stage I-II tumors, whereas a lower infiltration of cytotoxic T cells correlated with advanced-stage tumors. CD27 and CD95 were both expressed in the membrane of T cells present in the tumor stroma and their levels showed a negative correlation with the TNM stage. CD3, CD8, and CD27 were expressed at the same locations simultaneously, indicating their coordinated action against cancer. In addition, cytotoxic T cell densities and CD27 and CD95 expression remained independent prognostic factors for overall survival.Conclusion: In-situ cytotoxic T cells and TSCMs play important roles in colon cancer development. TSCMs marker CD27 and CD95 were both indicators of survival in patients with colon cancer. Thus, it is believed that TSCMs represent a desirable population for future use in combination immunotherapy.Keywords: T cell, CD27, CD95, prognosis, colon cancer

Ye Song,1 Jiangjun Mei,1 Dongwei Xu,2 Ying Ma1 1Department of Ultrasonography, Shanghai Pudong New Area Zhoupu Hospital, Shanghai University of Medicine & Health Sciences, Shanghai, 201318, People’s Republic of China; 2Department of Critical Care Medicine, Shanghai Pudong New Area Zhoupu Hospital, Shanghai University of Medicine & Health Sciences, Shanghai, People’s Republic of ChinaCorrespondence: Ye Song, Tel +86 13818086439, Email songye@tongji.edu.cnBackground: Ultrasound can assess renal perfusion, but its role in the evaluation of acute kidney injury (AKI) is still unclear. This prospective cohort study was to investigate the value of contrast-enhanced ultrasound (CEUS) in the evaluation of AKI in intensive care unit (ICU) patients.Methods: Fifty-eight patients were recruited from ICU between October 2019 and October 2020, and CEUS was used to monitor the renal microcirculation perfusion within 24h after admission. Parameters included rise time (RT), time to peak intensity (TTP), amplitude of peak intensity (PI), area under the curve (AUC), time from peak to one half (TP1/2) of renal cortex and medulla. Ultrasonographical findings, demographics, laboratory, etc were collected for further analysis.Results: There were 30 patients in the AKI group and 28 patients in the non-AKI group. The TTP, PI, TP1/2 of the cortex and the RT, TTP, TP1/2 of the medulla in the AKI group were significantly longer than in the non-AKI group (P < 0.05);. The TTP (OR = 1.261, 95% CI: 1.083– 1.468, P = 0.003) (AUCs 0.733, Sen% 83.3, Spe%57.1), TP1/2 (OR = 1.079, 95% CI: 1.009– 1.155, P = 0.027) (AUCs 0.658, Sen% 76.7, Spe%50.0) of the cortex and RT (OR = 1.453, 95% CI: 1.051– 2.011, P = 0.024) (AUCs 0.686, Sen% 43.3, Spe%92.9) of the medulla were related to the AKI. Eight new-onset AKI cases occurred in the non-AKI group within 7 days, the RT, TTP, TP1/2 of the cortex and medulla were significantly longer in the new-onset AKI group than in the non-AKI group (P < 0.05), but serum creatinine and blood urea nitrogen were no differences between groups (P > 0.05).Conclusion: This study indicates CEUS can assess the renal perfusion in AKI. TTP and TP1/2 of the cortex and RT of the medulla can aid the diagnosis of AKI in ICU patients.Keywords: contrast-enhanced ultrasound, acute kidney injury, intensive care unit

Honghong Fan,&ast; Yuxin Shi,&ast; Huiyu Wang, Yuting Li, Jie Mei, Junying Xu, Chaoying Liu Department of Oncology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214023, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chaoying Liu; Junying Xu, Department of Oncology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, No. 299 Qingyang Road, Wuxi, Jiangsu, 214023, People’s Republic of China, Tel/Fax +86-510-82700775, Email liuchaoying666@163.com; doctorxjy123@163.comBackground: Immunotherapy drugs, immune checkpoint inhibitors (ICIs), have been approved for first- and second-line treatment of non-small cell lung cancer (NSCLC), but only a portion of patients respond to ICIs. It is crucial to screen the beneficiaries of immunotherapy through biomarkers accurately.Methods: Several datasets were used to explore the predictive value for immunotherapy and immune relevance of guanylate binding protein 5 (GBP5) in NSCLC, including the GSE126044 dataset, The Cancer Genome Atlas (TCGA) dataset, Clinical Proteomic Tumor Analysis Consortium (CPTAC) dataset, the Kaplan–Meier plotter dataset, the HLuA150CS02 cohort, and the HLugS120CS01 cohort.Results: GBP5 was upregulated in tumor tissues but associated with a good prognosis in NSCLC. Moreover, our findings demonstrated that GBP5 was strongly correlated with the expression of many immune-related genes, TIIC levels, and PD-L1 expression based on RNA-seq data onto online databases and validation of the NSCLC tissue microarray using IHC staining. Moreover, pan-cancer analysis has shown that GBP5 was a factor in identifying immuno-hot tumors, except for a few tumor types.Conclusion: In summary, our current research suggests that GBP5 expression is a potential biomarker for predicting the outcome of NSCLC patients treated with ICIs. More research with large-scale samples is needed to determine their value as biomarkers of ICIs benefit.Keywords: GBP5, biomarker, immunotherapy, NSCLC, bioinformatics

Wei Huang,1,2,&ast; Jia Mei,3,&ast; Yuan-Jie Liu,1,4 Jie-Pin Li,1,4,5 Xi Zou,1,6 Xiao-Ping Qian,2,7 Yu Zhang8 1Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China; 2Comprehensive Cancer Center, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210008, People’s Republic of China; 3Department of Pathology, Nanjing Jinling Hospital, Nanjing, Jiangsu, 210001, People’s Republic of China; 4No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, People’s Republic of China; 5Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, Jiangsu, 215600, People’s Republic of China; 6Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing, 210023, People’s Republic of China; 7The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, 210008, People’s Republic of China; 8Department of Oncology, Nanjing Jinling Hospital, Nanjing, Jiangsu, 210001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yu Zhang; Xiao-ping Qian, Email zyzyzhangyu1986@163.com; xiaopingqian@nju.edu.cnBackground: The Proteasome (PSM) is a large multi-catalytic protease complex consisting of a 20S core particle and a 19S regulatory particle whose main function is to accept and degrade ubiquitinated substrates, are now considered as one of the potential regulators of tumor proliferation, and stemness maintenance. However, to date, studies on the relationship between PSM and hepatocellular carcinoma (HCC) are limited.Methods: This study used a bioinformatics approach combining validation experiments to investigate the biological mechanisms that may be related with PSM. A series of experiments in vivo and in vitro were performed to explore the function of the 26S proteasome non-ATPase regulatory subunit 13 (PSMD13) in HCC.Results: HCC patients can be divided into two clusters. Cluster 1 (C1) patients having a significantly worse prognosis than Cluster (C2). Two subtypes had significant differences in proliferation-related signaling. In particular, the frequency of TP53 mutation was significantly higher in C1 than in C2. In addition, PSM-associated genes were highly consistent with the expression of DNA repair-related signatures, suggesting a potential link between PSM and genomic instability. We also found that downregulation of PSMD13 expression significantly inhibited stemness of tumor cells and impaired the Epithelial mesenchymal transition (EMT) process. Finally, the correlation between the PSMD13 and Ki67 was found to be strong.Conclusion: PSM is a valid predictor of prognosis and therapeutic response in patients with HCC disease. Furthermore, PSMD13 may be a potential therapeutic target.Keywords: hepatocellular carcinoma, proteasome, PSMD13, cell stemness, proliferation

Saiyue Deng,1 Quan Wang,2 Jingjing Fan,3 Xiaoyun Yang,3 Junhua Mei,4 Jiajia Lu,5 Guohua Chen,4 Yuan Yang,1 Wenhua Liu,6 Runsen Wang,7 Yujia Han,7 Rong Sheng,7 Wei Wang,1 Li Ba,1 Fengfei Ding1,8 1Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 2School of Nursing, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, People’s Republic of China; 3Cardiac Unit, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 4Department of Neurology, Wuhan No.1 Hospital, Wuhan, 430022, People’s Republic of China; 5Cardiac Unit, Wuhan No.1 Hospital, Wuhan, 430022, People’s Republic of China; 6Department of Clinical Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, People’s Republic of China; 7Huawei Technologies Co, Shenzhen, People’s Republic of China; 8Department of Pharmacology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of ChinaCorrespondence: Fengfei Ding, Department of Pharmacology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China, Tel +86 134 7625 5813, Email fengfei_ding@fudan.edu.cn Li Ba, Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China, Tel +86 136 0764 1809, Email bali2015@126.comPurpose: Heart rate variability (HRV) indices have been used as stress indicators. Rare studies investigated the associations of circadian rhythms of the HRV indices with the stress, mood, and sleep conditions in populations under stress.Methods: In total 257 female participants (203 shift workers and 54 non-shift workers) were included. All the participants completed a structured questionnaire to assess the stress, mood, and sleep conditions and performed 24-hour Holter electrocardiogram monitoring on the day away from shifts. Using epochs of 1-min or 5-min beat-to-beat intervals, the HRV indices (SDNN, RMSSD, LF, HF, LF/HF, and LFnu, SD1, SD2, SD1/SD2) were plotted as a function of time and fitted into cosine periodic curves, respectively. Three mathematical parameters based on the cosine periodic curves were extracted, MESOR (M, overall averages of the cosine curve), amplitude (A, amplitude of the peak of the cosine curve), and acrophase (θ, latency to the peak) to quantify the circadian rhythms of the HRV indices. Multivariable linear regression models were used to reveal the associations of these parameters with the clinical assessments of stress, mood, or sleep conditions, as well as with the 24-h averages of the HRV indices.Results: The parameters M and A of SDNN, RMSSD, LF, and HF, and θ of LF/HF and LFnu significantly differ between shift and non-shift workers. The parameter θ of LF/HF positively correlates with the severity of stress and anxiety. The parameter A of LF/HF and LFnu also positively correlates with daytime sleepiness and sleep fragmentation. In addition, the parameters M and A instead of θ of SDNN, RMSSD, LF, LF/HF, and LFnu significantly correlate with the 24-h averages of HRV indices.Conclusion: The circadian rhythms of the HRV indices over 24 hours can, to some extent, predict the severity of stress, emotion and sleep conditions in female populations under stress.Keywords: circadian rhythms, HRV indices, mental health, stress, sleepiness, fatigue, sleep fragmentation

Huiyu Wang,1,&ast; Dingyi Gu,1,&ast; Datian Chen,2,&ast; Jie Mei,1 Xuejing Yang,1 Junli Ding,1 Junying Xu,1 Meilin Wang,3 Chaoying Liu,1 Dong Hua1 1Comprehensive Cancer Center, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, 214023, People’s Republic of China; 2Department of Oncology, Haimen People’s Hospital Affiliated to Nantong University, Haimen, 226100, People’s Republic of China; 3The School of Public Health, Nanjing Medical University, Nanjing, 210000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Meilin Wang; Chaoying Liu, Email meilin_wang210@126.com; liuchaoying666@163.comPurpose: The aim of this study was to explore the clinical significance of deglycosylated PD-L1 level and its correlation with EGFR and ALK mutation in lung adenocarcinoma.Materials and Methods: We estimated the intensity of both native and deglycosylated PD-L1 signals using a 28– 8 antibody on lung adenocarcinoma tissue microarray sections. We analyzed the difference in the H-score between tumor and paratumor tissues, as well as that before and after deglycosylation. Correlations between EGFR or ALK status and PD-L1 expression were analyzed. We also evaluated the differences among survival curves.Results: The expression level of PD-L1 in lung adenocarcinoma tissues was significantly higher than that in paratumor tissues (P< 0.0001). Deglycosylation significantly enhanced the detection of PD-L1 in tumor tissues (P< 0.0001). There was no statistical significance between the signal intensity of deglycosylated PD-L1 and the survival of patients (P=0.9099). However, the response to deglycosylation of PD-L1 was significantly correlated with the survival of patients with stage N1-N3 (P=0.0435) and stage T3-T4 (P=0.0366) and male patients (P=0.0258). A statistical trend was found in the correlation between the response to deglycosylation of PD-L1 and the survival of patients with grade II–III plus grade III (P=0.0973). Correlation between EGFR or ALK status and the expression of PD-L1 was not found (P> 0.05).Conclusion: PD-L1 deglycosylation enhances the detection of PD-L1 when utilizing a 28– 8 antibody. Moreover, the response to deglycosylation of PD-L1 may predict the survival of certain patients with lung adenocarcinoma.Keywords: programmed death ligand 1, deglycosylation, lung adenocarcinoma, mutation, survival

Zili Hu,1,2,&ast; Xuqi Sun,3,&ast; Jie Mei,1,2,&ast; Zhiwen Hu,1,2 Ziliang Yang,1,2 Jingyu Hou,1,2 Yizhen Fu,1,2 Xiaohui Wang,4 Minshan Chen1,2 1Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 2Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, 510060, People’s Republic of China; 3Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, People’s Republic of China; 4Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, 410005, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Minshan Chen, Department of Liver Surgery, Sun Yat-sen University Cancer Center, Dongfeng Road East 651, Guangzhou, Guangdong, 510060, People’s Republic of China, Tel +86-20-87343117, Email chenmsh@sysucc.org.cn Xiaohui Wang, Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Jiefang Road West 61, Changsha, Hunan, 410005, People’s Republic of China, Tel +86-073183928052, Email xiaohuiwang21@163.comBackground: In consideration of no standard exclusion criteria for hepatitis B virus (HBV) loads in hepatocellular carcinoma (HCC)-related clinical trials, this study aimed to investigate the prevalence of HBV-related exclusion criteria among current clinical trials and evaluate whether antiviral treatments could eliminate the adverse effects from high HBV loads for HCC patients.Methods: This is a retrospective study including 772 HCC clinical trials on ClinicalTrials.gov and 1784 HCC patients receiving antiviral treatment. The Kaplan–Meier (K-M) method was used to compare the progression-free survival (PFS) and overall survival (OS) between different groups, and Cox regression analyses were performed to validate possible risk factors on PFS and overall survival OS.Results: Among 772 clinical trials, 58.3% did not adopt baseline HBV loads as exclusion criteria, 18.0% was 2000 IU/mL, and 10.5% was receiving antiviral therapy. We observed baseline HBV loads had no significant impact on PFS (p = 0.491, 0.155, 0.119, 0.788, 0.280, 0.683 respectively) and OS (p = 0.478, 0.741, 0.263, 0.039, 0.999, 0.581 respectively) in all patients or each treatment group including hepatectomy, radiofrequency ablation, interventional therapy, targeted drugs and anti-programmed cell death immunotherapy, except for the OS of interventional therapy group, where patients with high HBV loads had higher BCLC stage, serum AFP level and ALBI grade (p = 0.009, 0.015 and 0.003, respectively).Conclusion: Antiviral treatments could eliminate the adverse impacts of high HBV loads on the survival of HCC patients. Simplified eligibility criteria can be adopted for HCC patients with HBV infection where regular antiviral therapy should be enough.Keywords: hepatocellular carcinoma, hepatitis B virus loads, antiviral treatment, exclusion criteria, clinical trials

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

Jie Mei,1,2,&ast; Xu-Qi Sun,3,&ast; Wen-Ping Lin,1,2,&ast; Shao-Hua Li,1,2 Liang-He Lu,1,2 Jing-Wen Zou,1,2 Wei Wei,1,2 Rong-Ping Guo1,2 1Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China; 2State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 3Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Rong-Ping Guo; Wei Wei Email guorp@sysucc.org.cn; weiwei@sysucc.org.cnBackground: Inflammatory response is related to cancer progression and patient survival. However, the value in predicting survival in hepatocellular carcinoma (HCC) patients who received anti-PD-1 therapy has not been elucidated. This study aimed to compare the predictive ability of inflammation-based scores for the prognosis of HCC patients after anti-PD-1 therapy.Methods: A total of 442 patients who received anti-PD-1 therapy were included in the study. Representative inflammation-based prognostic scores, including the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-C-reactive protein (CRP) ratio (LCR), lymphocyte-to-monocyte ratio (LMR), systemic immune inflammation index (SII), CRP-to-albumin ratio (CAR), prognostic nutritional index (PNI), Glasgow Prognostic Score (GPS), modified Glasgow Prognostic Score (mGPS), and prognostic index (PI), were assessed for prediction accuracy using Kaplan–Meier survival curves, time-dependent receiver operating characteristic (ROC) and Harrell’s concordance index (C-index) analyses.Results: All the inflammation-based prognostic scores exhibited good discriminatory ability in overall survival (OS) (all P < 0.01), while the PNI score was a unique independent predictor for OS in multivariate analysis (hazard ratio, 1.770; confidence interval, 1.309– 2.393; P < 0.001). The areas under the ROC curves at 6, 12, 18 and 24 months and the C-index (0.65) demonstrated that the predictive accuracy of the PNI score was superior to that of the other inflammation-based scores.Conclusion: The PNI score is a discriminatory prognostic indicator for OS in HCC patients with anti-PD-1 therapy and is superior to the other inflammation-based prognostic scores in terms of predictive ability.Keywords: inflammation-based score, hepatocellular carcinoma, anti-PD-1 therapy, overall survival, prognostic nutritional index

Guo Li,1 Ping Jing,2 Guohua Chen,3 Junhua Mei,3 Jinfeng Miao,1 Wenzhe Sun,1 Yan Lan,1 Xin Zhao,1 Xiuli Qiu,1 Zhou Zhu,1,&ast; Suiqiang Zhu1,&ast; 1Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China; 2Department of Neurology, Wuhan Central Hospital, Wuhan, Hubei, 430014, People’s Republic of China; 3Department of Neurology, Wuhan First Hospital, Wuhan, Hubei, 430022, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhou Zhu Tel +86-18171081029Email zhouzhu@hust.edu.cnSuiqiang Zhu Tel +86-13035101141Email zhusuiqiang@163.comPurpose: The early detection of major post-stroke depression (PSD) is essential to optimize patient care. A major PSD prediction tool needs to be developed and validated for early screening of major PSD patients.Patients and Methods: A total of 639 acute ischemic stroke (AIS) patients from three hospitals were consecutively recruited and completed a 3-month follow-up. Sociodemographic, clinical and laboratory test data were collected on admission. With major depression criteria being met in the DSM-V, 17-item Hamilton Rating Scale For Depression (HRSD) score ≥ 17 at 3 months after stroke onset was regarded as the primary endpoint. Multiple imputation was used to substitute the missing values and multivariable logistic regression model was fitted to determine associated factors with a bootstrap backward selection process. The nomogram was constructed based on the regression coefficients of the associated factors. Performance of the nomogram was assessed by discrimination (C-statistics) and calibration curve.Results: A total of 7.04% (45/639) of patients were diagnosed with major PSD at 3 months. The final logistic regression model included age, baseline NIHSS and mRS scores, educational level, calcium–phosphorus product, history of hypertension and atrial fibrillation. The model had acceptable discrimination, based on a C-statistic of 0.81 (95% CI, 0.791– 0.829), with 71.1% sensitivity and 78.6% specificity. We also transformed the model to a nomogram, an easy-to-use clinical tool which could be used to facilitate the early screening of major PSD patients at 3 months.Conclusion: We identified several associated factors of major PSD at 3 months and constructed a convenient nomogram to guide follow-up and aid accurate prognostic assessment.Keywords: major post-stroke depression, nomogram, calcium–phosphorus product, C-statistic

Jie Mei,1,2,* Shao-Hua Li,1,2,* Qi-Jiong Li,1,2,* Xu-Qi Sun,1,2 Liang-He Lu,1,2 Wen-Ping Lin,1,2 Lie Zheng,1,3 Min-Shan Chen,1,2 Ming Shi,1,2 Wei Wei,1,2 Rong-Ping Guo1,2 1Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, People’s Republic of China; 2Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 3Department of Medical Imaging, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rong-Ping Guo; Wei Wei Email guorp@sysucc.org.cn; weiwei@sysucc.org.cnBackground: Hepatic artery infusion chemotherapy (HAIC) and anti-programmed cell death protein-1 (PD-1) immunotherapy have shown promising outcomes in patients with advanced hepatocellular carcinoma (HCC), respectively. However, the combination of the two treatments has not been reported. In this study, we compared the efficacy of HAIC combined with anti-PD-1 immunotherapy (HAICAP) and HAIC in patients with advanced HCC.Methods: Between November 2018 and December 2019, advanced HCC patients that were treated with either HAICAP or HAIC were retrospectively recruited and reviewed for eligibility. Efficacy was evaluated according to tumor response and survival.Results: As a result, 229 patients were included in this study. Patients were divided into HAICAP group (n = 81) and HAIC group (n = 148) accordingly. The follow-up time ranged from 1.0 to 21.6 months, with a median of 11.0 months. The median overall survival was 18.0 months in the HAICAP group and 14.6 months in the HAIC group (p = 0.018; HR = 0.62; 95% CI 0.34– 0.91). The median progression-free survival was 10.0 months in the HAICAP group and 5.6 months in the HAIC group (p = 0.006; HR = 0.65; 95% CI 0.43– 0.87). The disease control rate in overall response (83% vs 66%; p = 0.006) and intrahepatic response (85% vs 74%, respectively; p = 0.045) were higher in the HAICAP group than in the HAIC group.Conclusion: In comparison to HAIC, HAICAP was associated with a better treatment response and survival benefits for patients with advanced HCC.Keywords: hepatocellular carcinoma, hepatic artery infusion chemotherapy, programmed cell death protein-1, FOLFOX, combination therapy

WeiGuo Gu,1,2 MingBin Hu,1,2 WeiJia Wang,1 Chao Shi,3 JinHong Mei1 1Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2First Clinical Medical College, Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 3Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of ChinaCorrespondence: JinHong MeiDepartment of Pathology, The First Affiliated Hospital of Nanchang University, No. 17 Yong Wai Street, Nanchang, Jiangxi 330006, People’s Republic of ChinaEmail mjhdoctor@126.comChao ShiDepartment of Oncology, The First Affiliated Hospital of Nanchang University, No. 17 Yong Wai Street, Nanchang, Jiangxi 330006, People’s Republic of ChinaEmail 43286143@qq.comBackground: Distant metastasis in early T1-2 (diameter≤ 5 cm) stage lung adenocarcinoma (ET-LUAD) patients largely affect treatment strategies in clinical practice. However, the associated mechanism remains unclear and related studies is less. This study aimed to establish and validate a novel nomogram to predict the risk of distant metastasis in ET-LUAD.Methods: A total of 258 patients diagnosed with ET-LUAD and not receiving any treatment were recruited into this study. The patients were randomly divided into a training cohort and validation cohort in a ratio of 1:2. Univariate and multivariate logistic regression analysis was used to select the most significant predictive risk factors associated with distant metastasis in the training cohort. The established nomogram was validated by the consistency index (C-index), calibration curve, and decision curve analysis (DCA).Results: There were 124 patients with confirmed distant metastasis and 134 patients with non-distant metastases ET-LUAD were enrolled in the study. Multivariate logistic hazards regression analysis identified independent risk factors associated with distant metastasis to include platelet-to-lymphocyte ratios (PLR), lactate dehydrogenase (LDH), neural-specific enolase (NSE), carcinoembryonic antigen (CEA) and cytokeratin 19 fragments (Cyfra211), which were included in the establishment of the nomogram. The nomogram achieved a high consistency (C-index=0.792), good calibration, and high clinical application value in the validation cohort.Conclusion: The established nomogram can be used to predict distant metastasis in high-risk ET-LUAD nonmetastasis patients and can also be used by doctors to guide preventive and individualized treatment for ET-LUAD patients.Keywords: lung adenocarcinoma, distant metastasis, nomogram

Kai Yuan,1,* Jingtian Mei,1,* Dandan Shao,2 Feng Zhou,1 Han Qiao,1 Yakun Liang,3 Kai Li,2 Tingting Tang1 1Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, People’s Republic of China; 2Key Laboratory of Inorganic Coating Materials, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, People’s Republic of China; 3Shanghai Institute of Precision Medicine, Shanghai 200125, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tingting TangShanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery,Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Room 701, No. 3 Building, 639 Zhizaoju Road, Shanghai 200011, People’s Republic of ChinaTel/Fax +86 21 6313 7020Email ttt@sjtu.edu.cnKai LiKey Laboratory of Inorganic Coating Materials, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Dingxi Road, Shanghai 200050, People’s Republic of ChinaTel/Fax +86 21-52413903Email likai@mail.sic.ac.cnBackground: Cerium oxide nanoparticles (CeO2NPs) are potent scavengers of cellular reactive oxygen species (ROS). Their antioxidant properties make CeO2NPs promising therapeutic agents for bone diseases and bone tissue engineering. However, the effects of CeO2NPs on intracellular ROS production in osteoclasts (OCs) are still unclear. Numerous studies have reported that intracellular ROS are essential for osteoclastogenesis. The aim of this study was to explore the effects of CeO2NPs on osteoclast differentiation and the potential underlying mechanisms.Methods: The bidirectional modulation of osteoclast differentiation by CeO2NPs was explored by different methods, such as fluorescence microscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting. The cytotoxic and proapoptotic effects of CeO2NPs were detected by cell counting kit (CCK-8) assay, TdT-mediated dUTP nick-end labeling (TUNEL) assay, and flow cytometry.Results: The results of this study demonstrated that although CeO2NPs were capable of scavenging ROS in acellular environments, they facilitated the production of ROS in the acidic cellular environment during receptor activator of nuclear factor kappa-&Bgr; ligand (RANKL)-dependent osteoclast differentiation of bone marrow-derived macrophages (BMMs). CeO2NPs at lower concentrations (4.0 μg/mL to 8.0 μg/mL) promoted osteoclast formation, as shown by increased expression of Nfatc1 and C-Fos, F-actin ring formation and bone resorption. However, at higher concentrations (greater than 16.0 μg/mL), CeO2NPs inhibited osteoclast differentiation and promoted apoptosis of BMMs by reducing Bcl2 expression and increasing the expression of cleaved caspase-3, which may be due to the overproduction of ROS.Conclusion: This study demonstrates that CeO2NPs facilitate osteoclast formation at lower concentrations while inhibiting osteoclastogenesis in vitro by inducing the apoptosis of BMMs at higher concentrations by modulating cellular ROS levels.Keywords: cerium oxide nanoparticles, osteoclast, osteoclastogenesis, ROS, apoptosis

Jie Mei,1– 3,* Jing Ma,2,4,5,* Yuwei Xu,4 Yuanyuan Wang,6 Minghua Hu,6 Fangli Ma,6 Zhihai Qin,1,2,4 Rui Xue,1 Ning Tao2 1Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 2Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, People’s Republic of China; 3College of Life Science & Technology, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 4College of Life Science, University of the Chinese Academy of Sciences, Beijing, People’s Republic of China; 5School of Basic Medical Sciences of Southwest Medical University, Luzhou, People’s Republic of China; 6Infinitus Chinese Herbal Immunity Research Center, Infinitus China Company Ltd, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhihai Qin; Ning TaoKey Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, No. 15 Datun Road, Chaoyang Area, Beijing City, People’s Republic of ChinaEmail zhihai@ibp.ac.cn tao@ibp.ac.cnIntroduction: Cancer-associated fibroblasts (CAFs) promote tumor progression; thus, drugs that can modify CAFs need to be identified.Methods: To test the effect of cinnamaldehyde on prostate CAFs, the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-2H-tetrazolium bromide assay was used to determine their survival. When spleen cells were treated with CAF supernatant, the proliferation of T cells was inhibited as determined by flow cytometry. After cinnamaldehyde treatment, this immunosuppressive function of CAFs was partially reversed. To explore the molecular mechanism, Western blotting and the quantitative real-time polymerase chain reaction were applied, and TLR4-dependent signaling pathway-related protein and mRNA levels were quantified.Results: Cinnamaldehyde acted on the TLR4-dependent signaling pathway, altering the function of CAFs such that its supernatant no longer inhibited the proliferation of T cells.Conclusion: These data indicate that cinnamaldehyde can modify the functions of CAFs, which may be helpful for treating tumors. Cinnamaldehyde can suppress CAF T-cell inhibition.Keywords: cinnamaldehyde, cancer-associated fibroblasts, prostate cancer, TLR4

Jiang-jun Mei,1 Yun-xin Zhao,1 Yi Jiang,1 Jian Wang,2 Jia-shun Yu2 1Department of Ultrasound, Shanghai Punan Hospital of Pudong New District, Shanghai, People’s Republic of China; 2Department of Urology, Shanghai Punan Hospital of Pudong New District, Shanghai, People’s Republic of ChinaCorrespondence: Yun-xin ZhaoDepartment of Ultrasound, Shanghai Punan Hospital of Pudong New District, Room 1602, No. 15, Lane 910, Dingxiang Road, Pudong New District, Shanghai 200135, People’s Republic of ChinaTel +86-21-20302000Email 1153575759@qq.comBackground: Some patients with prostate cancer (PCa) will experience biochemical recurrence (BCR) after treatment. Current researches have identified the influencing factors of BCR, but these factors are difficult to quantify and hence unable to accurately predict the BCR in PCa patients.Objective: To explore the value of contrast-enhanced ultrasound (CEUS) indicators in predicting the BCR after treatment by evaluating the association between them.Patients and Methods: In a retrospective cohort study, 157 PCa patients were recruited and received prostate specific antigen (PSA) measurement, CEUS, pathological classification, and immunohistochemistry after puncture biopsy. PCa patients with BCR were included in the recurrence group, while the remaining patients were included in the non-recurrence group after a 5-year follow-up. The clinical characteristics and CEUS indicators were compared between the two groups, and the multivariable COX regression was used for screening the influencing factors of BCR. Receiver operating characteristic (ROC) curves were used to analyze the value of potential factors in predicting BCR. The effect of the combined prediction model was explored to improve the accuracy of the prediction.Results: Twelve patients are lost during the follow-up period and the final analysis included 145 patients. The 5-year BCR rate of PCa patients was 27%, with 43 patients in the recurrence group and 102 patients in the non-recurrence group. Multivariate analysis showed that lymph node metastasis (P< 0.001), distant metastasis (P< 0.001), Gleason score (P< 0.001), pretreatment PSA (P< 0.001), treatment method (P< 0.001), peak intensity (PI) (P=0.001), and time to peak (TTP) (P=0.003) were independent influencing factors for BCR after treatment. ROC analysis showed that the AUCs of all indicators in predicting BCR were not high (all < 0.9). The combination of lymph node metastasis, Gleason score, pretreatment PSA, and treatment method can improve the predictive accuracy (AUC = 0.85), but the AUC was still under 0.9. The combined prediction model including CEUS time-intensity curve (TIC) indicators (PI and TTP) could accurately predict the BCR after treatment (AUC=0.953). The sensitivity and specificity were 93.02% and 88.24%, respectively.Conclusion: The prediction model including TIC indicators and common influencing factors can more accurately predict the BCR in PCa patients.Keywords: contrast-enhanced ultrasound, time-intensity curve, prostate cancer, prostate specific antigen, Gleason score, biochemical recurrence

Qianqian Shi, Faying Zhou, Jing Mei, Haimei Yang, Huiyun Li Department of Neurology, Daping Hospital, Army Medical University, Chongqing 400042, People’s Republic of ChinaCorrespondence: Huiyun LiDepartment of Neurology, Daping Hospital, Army Medical University, Chongqing 400042, People’s Republic of ChinaTel +86 23 68757851Fax +86 23 68711956Email lihuiyun1359@163.comObjective: To explore the effect of Type 2 diabetes mellitus (T2DM) on the development of neuropsychiatric symptoms (NPS) in early Alzheimer’s disease (AD).Methods: From September 2017 to March 2019, a cross-sectional study was conducted on the clinical data of 158 early AD patients over 65 years old in the Department of Neurology of Daping Hospital. All early stage of AD patients were divided into early stage of AD with NPS group and early stage of AD without NPS group according to the presence or absence of NPS. Clinical data of age, sex, body mass index (BMI), smoking and alcohol consumption, history of hypertension, hyperlipidemia, white matter leisure (WML) and T2DM, MMSE, CDR and NPI-Q scores were collected. Multivariate logistic regression analyses were performed to examine the relationship between T2DM and NPS in early AD.Results: Compared with the early stage of AD group without NPS, the early stage of AD group with NPS was older, the proportion of women was higher, the proportion of T2DM, hypertension, hyperlipidemia and WML was higher, and the MMSE score was lower (P< 0.05). T2DM was an independent risk factor for NPS in early stage of AD patients (OR 3.48, 95% CI 2.91– 3.84). The incidence of T2DM in AD patients with depression, anxiety, nighttime behavioral disturbances, and appetite disturbances was significantly higher than in AD patients without these symptoms. T2DM was an independent risk factor of depression (OR 2.04, 95% CI 1.71– 2.38), anxiety (OR 1.69, 95% CI 1.38– 1.97), nighttime behavioral disturbances (OR 1.95, 95% CI 1.75– 2.13) and appetite disturbances (OR 1.62, 95% CI 1.33– 1.94) in early AD patients.Conclusion: T2DM was an important independent risk factor for NPS in early AD, which promotes the occurrence of depression, anxiety, nighttime behavioral disturbances and appetite disturbances in early AD.Keywords: Alzheimer’s disease, type 2 diabetes, neuropsychiatric symptoms

Xiaoxia Guo, 1,* Jie Mei, 1,* Chunping Zhang 2 1Department of Obstetrics and Gynecology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu 610041, Sichuan, People’s Republic of China; 2The Center of Clinical Laboratory, Sichuan Great Master Diagnostics Co. Ltd, Chengdu 611731, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chunping ZhangThe Center of Clinical Laboratory, Sichuan Great Master Diagnostics Co. Ltd, No. 8, Anhe the Second Road, Hi-Tech Industrial Development Zone, Chengdu 611731, Sichuan, People’s Republic of ChinaTel +86-189 8008 6040Email zcpcn7894@163.comPurpose: Multifunctional drug delivery systems (DDS) are emerging as a new strategy to highly treat malignant tumors. The aim of this study is to develop a drug dual-carriers delivery system (DDDS) using the natural protein ferritin (FRT) and a nanoscale graphene oxide (NGO) as dual-carriers.Methods: The FRT is a pH-sensitive hollow cage protein with disassembly and reassembly properties and the NGO has a large surface area and a photothermal effect by which it can load and release drugs under near-infrared irradiation (NIR). Due to these unique features, the NGO loaded the anticancer drug resveratrol (RSV) and the conjugated mitochondrion targeted molecule IR780 as IR780-NGO-RSV (INR), the first drug delivery platform. Next, the INR was capsulated by FRT to form the DDDS INR@FRT which was applied for synergistic photothermal-chemotherapy of ovarian cancer.Results: Through a series of characterizations, INR@FRT showed a uniform nanosphere structure and remarkable stability in physiological condition. Heat/pH 5.0 was confirmed to trigger RSV release from the INR@FRT. After taken up by cells, INR@FRT located to the lysosomes where the acidic environment triggered INR release. INR targeted the mitochondrion and released RSV to directly react with organelles, which in turn decreased the mitochondrion membrane potential and caused cell apoptosis. In-vivo experiments showed that INR@FRT combined with NIR irradiation displayed remarkable tumor suppression with a high survival rate after 60 days of treatment. Finally, the biocompatibility of INR@FRT was demonstrated in vitro and in vivo.Conclusion: These results highlight the immense potential of INR@FRT as a type of DDDS for the treatment of tumors.Keywords: resveratrol, apoptosis, drug dual-carriers delivery system, mitochondrion targeting, pH/heat-triggered tumor therapy

Hongfei Liu,1 Jiaao Mei,1 Ying Xu,1 Lei Tang,1 Daquan Chen,2 Yating Zhu,1 Shuguang Huang,1 Thomas J Webster,3 Hui Ding4 1College of Pharmacy, Jiangsu University, Zhenjiang 212013, People’s Republic of China; 2School of Pharmacy, Yantai University, Yantai 264005, People’s Republic of China; 3Department of Chemical Engineering, Northeastern University, Boston, MA 02115, USA; 4Department of Respiratory and Critical Care Medicine, The Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu 214200, People’s Republic of ChinaCorrespondence: Hui DingDepartment of Respiratory and Critical Care Medicine, The Affiliated Yixing Hospital Of Jiangsu University, Yixing, Jiangsu 214200, People’s Republic of ChinaTel +8601370656506Email dh1350519@163.comThomas J WebsterDepartment Of Chemical Engineering, Northeastern University, Boston, MA 02115, USA, Tel +1 617 373 6585Email th.webster@neu.eduObjective: Nintedanib (NDNB) is a triple receptor tyrosine kinase inhibitor with poor solubility in neutral conditions and low bioavailability. A self-microemulsifying drug delivery system (SMEDDS) of NDNB was developed to improve drug solubility in physical conditions and absorption in vivo.Methods: The NDNB-SMEDDS formulation was optimized via pseudo-ternary phase diagrams. The physicochemical properties of NDNB-SMEDDS, viz., morphological observation, droplet size, stability, compatibility and in vitro release were investigated. The permeability of NDNB-SMEDDS was detected using both a Caco-2 cell monolayer in vitro and an intestinal perfusion study in vivo. Furthermore, the pharmacokinetic characteristics of NDNB-SMEDDS were evaluated.Results: The optimal formulation was composed of MCT as an oil phase, RH 40 as a surfactant and ethylene glycol as a co-surfactant. The average droplet size of the microemulsion was about 23 nm with good stability within 30 days. The formulation did not exhibit any obvious cytotoxic effect on Caco-2 cells. Permeability of nintedanib in a Caco-2 cell monolayer was enhanced by 2.8-fold upon incorporation in SMEDDS compared with the drug solution. The intestinal perfusion study demonstrated that the Papp of NDNB-SMEDDS increased by 3.0-fold in the entire intestine and 3.2-fold in the colon in comparison with the drug solution. The pharmacokinetics study showed that the AUC of the NDNB-SMEDDS increased significantly.Conclusion: This study showed that the self-microemulsion formulations could improve the absorption of nintedanib, and can thus serve as a promising carrier for the oral delivery of nintedanib.Keywords: nintedanib, self-microemulsion drug delivery system, solubility, permeability, Caco-2 cell, intestinal perfusion, pharmacokinetics, bioavailability

Mengping Zhang,1,* Yong Bao,2,* Wei Chen,3,* Mengchao Wei,4 Hui Pang,5 Yu Feng Ren,2 Jie Mei,6 Sheng Ye,1 Shunjun Fu,7 Zhen Wei Peng1,61Department of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; 2Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; 3Department of Pancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; 4Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; 5Department of Medical Records Management, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; 6Clinical Trials Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; 7Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China*These authors contributed equally to this workPurpose: To explore a quantitative predictive model for the risk of chemotherapy-induced severe liver damage (CISLD).Materials and methods: In total, 3870 consecutive cancer patients initially treated with chemotherapy were retrospectively collected and randomly assigned to a training (n=2580) or internal validation (n=1290) set in a 2:1 ratio to construct and validate the model. Additional external validation was performed using another data set (n=413). A total of 486 patients were prospectively enrolled to assess the clinical significance of the model. CISLD was defined as grade ≥3 hepatotoxicity.Results: CISLD was found in 255 (9.9%), 128 (9.9%) and 36 (8.7%) patients in the training, internal and external validation sets, respectively. Serum triglyceride, body mass index and history of hypertension formed the basis of the score model. Patients could be stratified into low, intermediate and high-risk groups with 30% CISLD occurrence, respectively. This model displayed a concordance index (C-index) of 0.834 and was validated in both the internal (C-index, 0.830) and external (C-index, 0.817) sets. The incidence of CISLD was significantly reduced in those who received preventive hepatoprotective drugs compared to those who did not among patients assessed as the intermediate risk group (8.9% vs 17.5%, p=0.042) and the high risk group (15.6% vs 55.8%, p=0.043).Conclusions: The new score model can be used to accurately predict the risk of CISLD in cancer patients undergoing chemotherapy. Clinically, this can be translated into a reference tool for oncologists in the clinical decision-making process before chemotherapy to provide appropriate prevention and interventions for patients with a high risk of CISLD.Keywords: chemotherapy, liver damage, predictive model

Yue Hu,1,2,* Jingsi Mei,1,2,* Xiaofang Jiang,1,2 Ran Gu,1,2 Fengtao Liu,1,2 Yaping Yang,1,2 Hongli Wang,1,2 Shiyu Shen,1,2 Haixia Jia,3 Qiang Liu,1,2 Chang Gong1,21Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation; 2Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University; 3Department of Breast Surgery, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China*These authors contributed equally to this workPurpose: To assess whether radiologist needs to rescan the breast lesion to validate the final American College of Radiology (ACR) Breast Imaging Reporting and Data System (BI-RADS) ultrasonography (US) assessment made on the static images in the diagnostic setting.Patients and methods: Image data on 1,070 patients with 1,070 category 3–5 breast lesions with a pathological diagnosis scanned between January and June 2016 were included. Both real-time and static image assessments were acquired for each lesion. The diagnostic performance was evaluated by receiver operating characteristic (ROC) curves. The positive predictive values (PPVs) of each category in the two groups were calculated according to the ACR BI-RADS manual and compared. Kappas were determined for agreement on two assessment approaches.Results: The sensitivity, specificity, PPV, and negative predictive value for real-time US were 98.9%, 58.2%, 44.8% and 99.4%, and for static images were 98.9%, 57.1%, 44.1% and 99.3%, respectively. The performance of the two groups was not significantly different (areas under ROCs: 0.786 vs 0.780, P=0.566) if the final assessment was only dichotomized as negative (category 3) and positive (categories 4 and 5). All PPVs of each category for each assessment were within the reference range provided by the ACR in 2013 except subcategory 4B (reference range: >10% and ≤50%) of static image evaluation, which was also significantly higher than that of real-time assessment (54.8% vs 40.7%, P=0.037). The overall agreement of the two approaches was moderate (κ=0.43–0.56 according to different detailed assessment).Conclusion: Both static image and real-time assessment had similar diagnostic performance if only the treatment recommendations were considered, that is, follow-up or biopsy. However, as for subcategory 4B lesions without obviously benign or malignant US features, real-time scanning by the interpreter is recommended to obtain a more accurate BI-RADS assessment after assessing static images.Keywords: Breast Imaging Reporting and Data System, ultrasonography, diagnosis, real-time scanning

Qinglin Shen,1,2,* Haitao Yang,3,* Caixia Peng,4,5,* Han Zhu,6 Jia Mei,1 Shan Huang,1 Bin Chen,7 Jue Liu,8 Wenbo Wu,3 Shaokui Cao3 1Department of Oncology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 2Cancer Center, Renmin Hospital, Wuhan University, Wuhan, China; 3School of Materials Science and Engineering, Zhengzhou University, Zhengzhou, China; 4Key Laboratory for Molecular Diagnosis of Hubei Province, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 5Central Laboratory, The Central Hospital of Wuhanper, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 6Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering, Jiangnan University, Wuxi, China; 7Central Laboratory, Renmin Hospital, Wuhan University, Wuhan, China; 8Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China *These authors contributed equally to this work Background: Efficient and precise circulating tumor cells’ (CTCs) capture and release with minimal effect on cell viability for CTCs’ analysis are general requirements of CTCs’ detection device in clinical application. However, these two essential factors are difficult to be achieved simultaneously. Methods: In order to reach the aforementioned goal, we integrated multiple strategies and technologies of staggered herringbone structure, nanowires’ substrate, peptides, enzymatic release, specific cell staining, and gene sequencing into microfluidic device and the sandwich structure peptide-silicon nanowires’ substrate was termed as Pe-SiNWS. Results: The Pe-SiNWS demonstrated excellent capture efficiency (95.6%) and high release efficiency (92.6%). The good purity (28.5%) and cell viability (93.5%) of CTCs could be obtained through specific capture and biological release by using Pe-SiNWS. The good purity of CTCs facilitated precise and quick biological analysis, and five types of KRAS mutation were detected in 16 pancreatic cancer patients but not in healthy donors. Conclusion: The results proved that the effective capture, minor damage release, and precise analysis of CTCs could be realized simultaneously by our novel strategy. The successful clinical application indicated that our work was anticipated to open up new opportunities for the design of CTC microfluidic device. Keywords: circulating tumor cells, Pe-SiNWS, biological release, pancreatic cancers

Background and Objectives. Several anesthesia techniques were applied to hemorrhoidectomy, but postoperative pain and urinary retention were still two unsolved problems. The aim of this prospective randomized study was to evaluate the effect of ultrasound-guided pudendal nerve block (PNB) combined with deep sedation compared to spinal anesthesia for hemorrhoidectomy. Methods. One hundred and twenty patients undergoing Milligan–Morgan hemorrhoidectomy were randomized to receive PNB combined with deep sedation using propofol (Group PNB, n = 60) or spinal anesthesia (Group SA, n = 60). Pain intensity was assessed using the visual analogue scale (0: no pain to 10: worst possible pain). The primary outcome was pain scores recorded at rest at 3, 6, 12, 24, 36, and 48 h and on walking at 12, 24, 36, and 48 h postoperatively. Secondary outcomes were analgesic consumption, side effects, and patient satisfaction after surgery. Results. Ultrasound-guided bilateral PNB combined with deep sedation using propofol could successfully be applied to Milligan–Morgan hemorrhoidectomy. Postoperative pain intensity was significantly lower in Group PNB compared to Group SA at rest at 3, 6, 12, 24, 36, and 48 h (p

Fuqiang Ren,1,2,* Mingyu Fan,1,2,* Jiandong Mei,1,2 Yongqiang Wu,3 Chengwu Liu,1,2 Qiang Pu,1,2 Zongbing You,4–9 Lunxu Liu1,2 1Department of Thoracic Surgery, West China Hospital, 2Western China Collaborative Innovation Center for Early Diagnosis and Multidisciplinary Therapy of Lung Cancer, 3Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 4Department of Structural and Cellular Biology, 5Department of Orthopaedic Surgery, 6Tulane Cancer Center, 7Louisiana Cancer Research Consortium, 8Tulane Center for Stem Cell Research and Regenerative Medicine, 9Tulane Center for Aging, Tulane University Health Sciences Center, New Orleans, LA, USA *These two authors contributed equally to this study Abstract: Tumor-associated macrophages play an important role in tumor growth and progression. These macrophages are heterogeneous with diverse functions, eg, M1 macrophages inhibit tumor growth, whereas M2 macrophages promote tumor growth. In this study, we found that IFNγ and/or celecoxib (cyclooxygenase-2 inhibitor) treatment consistently inhibited tumor growth in a mouse lung cancer model. IFNγ alone and celecoxib alone increased the percentage of M1 macrophages but decreased the percentage of M2 macrophages in the tumors, and thus the M2/M1 macrophage ratio was reduced to 1.1 and 1.7 by IFNγ alone and celecoxib alone, respectively, compared to the M2/M1 macrophage ratio of 4.4 in the control group. A combination of IFNγ and celecoxib treatment reduced the M2/M1 macrophage ratio to 0.8. Furthermore, IFNγ and/or celecoxib treatment decreased expression of matrix metalloproteinase (MMP)-2, MMP-9, and VEGF, as well as the density of microvessels in the tumors, compared to the control group. This study provides the proof of principle that IFNγ and/or celecoxib treatment may inhibit lung-tumor growth through modulating the M2/M1 macrophage ratio in the tumor microenvironment, suggesting that IFNγ and celecoxib have potential to be further optimized into a new anticancer therapy. Keywords: tumor-associated macrophages, M1 macrophages, M2 macrophages, lung cancer, interferon-γ, celecoxib

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

The Qweak experiment, which took data at Jefferson Lab in the period 2010 - 2012, will precisely determine the weak charge of the proton by measuring the parity-violating asymmetry in elastic e-p scattering at 1.1 GeV using a longitudinally polarized electron beam and a liquid hydrogen target at a low momentum transfer of Q2 = 0.025 (GeV/c)2. The weak charge of the proton is predicted by the Standard Model and any significant deviation would indicate physics beyond the Standard Model. The technical challenges and experimental apparatus for measuring the weak charge of the proton will be discussed, as well as the method of extracting the weak charge of the proton. The results from a small subset of the data, that has been published, will also be presented. Furthermore an update will be given of the current status of the data analysis.