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Jianlong Zhou,1,2,* Dingxue Wang,3,* Dongxin Tang,3 Wenhua Huang1 1Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Oncology, The Affiliated Xinhui Hospital, Southern Medical University, Xinhui, People’s Republic of China; 3Department of Oncology, The First Affiliated Hospital, Guizhou University of Traditional Chinese Medicine, Guiyang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dongxin TangThe First Affiliated Hospital, Guizhou University of Traditional Chinese Medicine, No. 71 Baoshanbei Road, Guiyang 550000, People’s Republic of ChinaEmail tangdongxin@sina.comWenhua HuangDepartment of Oncology, Zhujiang Hospital, Southern Medical University, No.253 Gongye Middle Avenue, Guangzhou 510280, People’s Republic of ChinaEmail huangwenhua88888@outlook.comBackground: Lung tumors and normal lung tissues show large differences in epigenetic modification which can affect the chromosome structure and expression of genes. However, the epigenetic reprogramming in lung adenocarcinoma remains unclear.Methods and Results: With the bioinformatics analysis, we found that some activated super-enhancers (SEs) only appear in lung adenocarcinoma cells, and 781 abnormal activated super-enhancers (AASEs) were found. Not only are the traditional oncogenes found to be activated by AASEs, such as MET and SLC2A1, but also some new genes were activated by AASEs, which probably contributes to the carcinogenic process in lung cancer. The enrichment analysis of the genes activated by AASEs shows that the glycolysis process and cell proliferation were enhanced and the apoptotic process was negatively regulated. Two AASEs were separately knockout by CRISPR/Cas9 in A549, PC-9, and H1299 cell lines and the expression of target genes decreased. The motif of CTCF, SMARCA1, SOX4, FOXM1, IRF3, IRF7, and STAT2 was enriched in AASEs, supporting that the chromosome structure changed and these transcription factors would be the master regulators on the formation of AASEs.Conclusion: This study provided comprehensive insight into the mechanisms of SEs, as well as a potential therapeutic target for lung cancer.Keywords: lung adenocarcinoma, epigenetic, super-enhancer, transcription factors

Yulu Zhang,1,* Songyu Liu,1,* Jinyan Wan,1,* Qiyue Yang,2 Yan Xiang,1 Li Ni,1 Yu Long,1 Mingquan Cui,1 Zhimin Ci,1 Donglei Tang,1 Nan Li1 1College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, People’s Republic of China; 2Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Nan LiCollege of Pharmacy, Chengdu University of Traditional Chinese Medicine, No. 1166, Liutai Avenue, Chengdu 611137, People’s Republic of ChinaTel +86-28-61801001Email 55743198@qq.comPurpose: Baicalin (BA) has a good neuroprotective effect, but it is eliminated quickly in the body and does not easily reach the brain. In this experiment, borneol (BO) was used as an auxiliary drug to prepare borneol-baicalin-liposomes (BO-BA-LP) to prolong the efficacy time of BA, synergistically synergize, introduce drugs into the brain, and better exert the therapeutic effect on cerebral ischemia-reperfusion (I/R) injury.Methods: Through single-factor inspection and response surface optimization analysis, obtained the best preparation process of BO-BA-LP and characterized by various analytical techniques. Validated the long-term effectiveness of BA-BO-LP through pharmacokinetic studies and conducted pharmacodynamic studies on the middle cerebral artery occlusion (MCAO) rat model to verify the therapeutic effect of BO-BA-LP on cerebral I/R injury.Results: The optimum preparation conditions of BO-BA-LP were as follows: the dosage of BO was 9.55 mg, the ratio of phospholipid to drug was 4.02:1, the ratio of phospholipid to cholesterol was 7.25:1, the entrapment efficiency (EE) was 41.49%, and the drug loading (DL) was 4.29%. The particle size range of the liposomes was 167.1 nm, and the polydispersity index (PDI) range was 0.113. The results of pharmacokinetic experiments showed that the combination of BA and BO liposomes effectively improved the pharmacokinetic parameters of BA and prolonged the half-life of BA. Pharmacodynamic studies have found that, compared with BA-LP, BO-BA-LP can significantly improve neurological deficits, cerebral infarction volume, and brain pathological states on MCAO rats.Conclusion: These results demonstrated that BO-BA-LP can improve the circulation of drugs in the blood, and the addition of BO can enhance the therapeutic effect of BA and effectively improve cerebral I/R.Keywords: borneol-baicalin-liposome, pharmacokinetics, pharmacodynamics, MCAO

Guo-feng Xie,1,* Luo-dan Zhao,2,3,* Qiang Chen,4,* Dong-xiao Tang,4 Qiong-yu Chen,4 Hong-fei Lu,4 Jia-rong Cai,5 Zheng Chen4 1Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province 510095, People’s Republic of China; 2Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, People’s Republic of China; 3Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangzhou Higher Education Institutes, Sun Yat-sen University, Guangzhou, Guangdong Province, People’s Republic of China; 4Department of Stomatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, People’s Republic of China; 5Department of Urology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jia-rong CaiDepartment of Urology, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, Guangdong Province, People’s Republic of ChinaTel +86-20-82179727Fax +86-20-85253336Email caijiar@mail.sysu.edu.cnZheng ChenDepartment of Stomatology, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, Guangdong Province, People’s Republic of ChinaFax +86-20-85253336Email chenzh68@mail.sysu.edu.cnPurpose: Oral squamous cell carcinoma (OSCC) is a common malignancy of the oral cavity. As the survival rate of OSCC patients is low, it is crucial to explore new markers and therapeutic targets for early diagnosis of the disease. A high level of actinin alpha 1 (ACTN1) in patients could serve as an independent prognostic factor of acute myeloid leukemia. However, the role of ACTN1 in OSCC remains unclear. In the present study, we aimed to investigate the role of ACTN1 in OSCC.Methods: ACTN1 protein levels in tissues were determined by immunohistochemical (IHC) staining. The correlation of ACTN1 expression with clinicopathological features and prognosis was analyzed. Univariate and multivariate analyses were performed. The effect of ACTN1 knockdown on cell proliferation, migration, invasion, apoptosis, epithelial-mesenchymal transition (EMT), and the cell cycle was evaluated using Western blotting, Cell Counting Kit‑8 (CCK8) assays, flow cytometry analysis, transwell assays, wound-healing assays, and nude mouse models of subcutaneous xenograft and pulmonary metastasis.Results: Based on the total score of ACTN1 IHC staining analysis, ACTN1 expression was found to be low in 10 normal mucosal tissues, 48 normal mucosal tissues adjacent to OSCC, and 19 OSCC tissues, but high in 29 OSCC tissues. ACTN1 protein levels were significantly associated with the clinical stage and node metastasis, and a high ACTN1 protein level indicated poor prognosis. Moreover, ACTN1 expression was an independent predictor of poor prognosis of OSCC. Using in vitro assays, we found that ACTN1 knockdown could induce cell cycle arrest, promote apoptosis, and inhibit EMT and cell proliferation, migration, and invasion in the OSCC cell lines, SCC-15 and HSC-3. Moreover, ACTN1 knockdown inhibited subcutaneous tumor growth and pulmonary metastasis in vivo.Conclusion: ACTN1 levels were significantly associated with the clinical stage and node metastasis, and a high ACTN1 protein level indicated poor prognosis. Moreover, ACTN1 knockdown could suppress cell proliferation and metastasis of OSCC. Our results suggested that ACTN1 may serve as a diagnostic and prognostic marker of OSCC.Keywords: actinin alpha 1, poor prognosis, oral squamous cell carcinoma, knockdown, proliferation, metastasis

Genome-wide gene expression measurements have enabled comprehensive studies that integrate the changes of gene expression and phenotypic information to uncover their novel associations. Here we reported the association analysis between psychophysical phenotypes and genome-wide gene expression changes in human adaptation to one of the most extreme climates on Earth, the Antarctic Dome Argus. Dome A is the highest ice feature in Antarctica, and may be the coldest, driest and windiest location on earth. It is considered unapproachable due to its hostile environment. In 2007, a Chinese team of 17 male explorers made the expedition to Dome A for scientific investigation. Overall, 133 psychophysical phenotypes were recorded, and genome-wide gene expression profiles from the blood samples of the explorers were measured before their departure and upon their arrival at Dome A. We found that mood disturbances, including tension (anxiety), depression, anger and fatigue, had a strong, positive, linear relationship with the level of a male sex hormone, testosterone, using the Pearson correlation coefficient (PCC) analysis. We also demonstrated that significantly lowest-level Gene Ontology groups in changes of gene expression in blood cells with erythrocyte removal were consistent with the adaptation of the psychophysical characteristics. Interestingly, we discovered a list of genes that were strongly related to significant phenotypes using phenotype and gene expression PCC analysis. Importantly, among the 70 genes that were identified, most were significantly related to mood disturbances, where 42 genes have been reported in the literature mining, suggesting that the other 28 genes were likely novel genes involved in the mood disturbance mechanism. Taken together, our association analysis provides a reliable method to uncover novel genes and mechanisms related to phenotypes, although further studies are needed.

Dianjun Tang,*,1,2 Yanshuo Han,*,3 Yu Lun,1 Han Jiang,1 Shijie Xin,1 Zhiquan Duan,1 Jian Zhang11Department of Vascular Surgery, The First Hospital of China Medical University, Key Laboratory of Pathogenesis, Prevention and Therapeutics of Aortic Aneurysm Liaoning Province, Shenyang, People’s Republic of China; 2Department of Vascular Surgery, The Second Hospital of Shandong University, Jinan, People’s Republic of China; 3Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China*These authors contributed equally to this workPurpose: Abdominal aortic aneurysm (AAA) demonstrates many features of autoimmune diseases. Y chromosome, sex-determining region of the Y chromosome (SRY) gene, androgen receptor (AR) gene, and androgen appear as potential candidates for influence of the male immune function. This study investigated Y chromosome numbers, SRY gene, AR gene, and androgen levels in male AAAs. We also investigated the correlation between Y chromosome loss (LOY) ratio, SRY expression, androgen levels, and age.Patients and methods: We investigated LOY by fluorescence in situ hybridization (FISH) in 37 AAAs and compared with 12 patients with abdominal aortic atherosclerotic occlusive disease (AOD) and 91 healthy controls (HC). We investigated SRY and AR expression at mRNA level by real-time PCR in peripheral T lymphocytes in AAA compared with AOD and HC, and AR protein levels by immunohistochemistry (IHC) in AAA. LOY, SRY expression, androgen levels, and age were examined for correlations using the Spearman’s rank correlation coefficient.Results: LOY ratio in peripheral T lymphocytes was significantly higher in the AAA group compared with the HC (9.11% vs 5.56%, P

Defeng Tang,1,2 Tianlong Lin,1 Yangyang Wang,1 Hui Cao11Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, People’s Republic of China; 2Department of General Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, People’s Republic of ChinaPurpose: The aim of this study was to elucidate the prognostic value of proenkephalin (PENK) in gastrointestinal stromal tumors (GISTs).Patients and methods: We collected data on 268 eligible postoperative patients diagnosed with GIST between January 1, 2002, and December 31, 2011. PENK expression was detected in GIST tissues classified using the United States National Institutes of Health (NIH) risk classification system. The associations between high PENK expression and the clinicopathological characteristics were assessed. Overall survival (OS) and recurrence-free survival (RFS) were estimated by Kaplan–Meier analysis, and the log-rank test was used to compare the differences between groups. Univariate and multivariate Cox regression analyses were conducted to assess the prognostic value of PENK in GIST patients.Results: High PENK expression was more common in the low- and intermediate-risk GIST groups compared with the high-risk group (P

Background: Apoptosis caused by endoplasmic reticulum (ER) stress contributes to atherothrombosis, the underlying cause of cardiovascular disease (CVD). T-cell death-associated gene 51 (TDAG51), a member of the pleckstrin homology-like domain gene family,

Xiaolan You,1,2 Yuanjie Wang,2 Jian Wu,2 Qinghong Liu,2 Dehu Chen,2 Dong Tang,3 Daorong Wang3 1Department of Integrated Traditional Chinese and Western Medicine, Medical College of Yangzhou University, Yangzhou, Jiangsu Province, People’s Republic of China; 2Department of Gastrointestinal Surgery, Taizhou People’s Hospital, Taizhou, Jiangsu Province, People’s Republic of China; 3Department of Gastrointestinal Surgery, Clinical Medical College of Yangzhou University (Subei People’s Hospital of Jiangsu Province), Yangzhou, Jiangsu Province, People’s Republic of China Introduction: We evaluated the expression of galectin-1 (Gal-1) and vasculogenic mimicry (VM) in gastric cancer (GC) and investigated their relationships with the clinicopathological factors and prognostic significance in GC.Materials and methods: Immunohistochemical (IHC) staining and CD34–periodic acid-Schiff double stain were used to investigate Gal-1 expression and VM in paraffin-embedded sections from 127 patients with GC of all tumor stages. The relationships between Gal-1 expression and VM, clinicopathological variables, and survival were analyzed. P < 0.05 was considered statistically significant.Results: Among the 127 cases, 86 (67.7%) were positive for Gal-1; VM was detected in 29 cases (22.8%). There was a significant association between VM and the Gal-1 IHC staining; all cases with VM were positive for Gal-1 staining. Gal-1 expression and VM in primary GC tissue were associated with tumor size, differentiation, depth of tumor invasion, stage, lymph node metastases, and tumor emboli in microvessels (all, P < 0.05). Kaplan–Meier analysis revealed that the overall survival time was 52.56 ± 2.44 months (95% confidence interval [CI]: 47.77–57.35) for patients with Gal-1-negative and VM-negative primary GC tissue, 43.83 ± 2.17 months (95% CI: 39.58–48.08) for patients with Gal-1-positive but VM-negative primary GC tissue, and 23.97 ± 2.44 months (95% CI: 19.18–28.76) for patients with Gal-1-positive and VM-positive primary GC tissue (χ2 = 60.21, P < 0.01). Gal-1 expression was positively associated with VM in primary GC tissue.Conclusion: Both Gal-1 expression and VM in primary GC tissue are indicators of poor prognosis for GC after gastrectomy, and Gal-1 may be a novel target for treating VM in GC. Keywords: galectin-1, vasculogenic mimicry, gastric cancer, prognosis

Qian Mu,1,2,* Miao Jiang,1,* Yuzhu Zhang,1 Fei Wu,1 Hui Li,1 Wen Zhang,1 Fang Wang,1 Jiang Liu,1 Liang Li,1 Dongshan Wang,3 Wenjuan Wang,1 Shiwu Li,1 Haibo Song,4 Dongqi Tang1 1Gene and Immunotherapy Center, The Second Hospital of Shandong University, Jinan, People’s Republic of China; 2Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Health Management Center, The Second Hospital of Shandong University, Jinan, People’s Republic of China; 4Central Research Laboratory, Zibo Maternal and Child Health Hospital, Affiliated to Shandong Academy of Medical Science, Zibo, People’s Republic of China *These authors contributed equally to this work Background: CD19-chimericantigen receptor (CAR) modified T cells (CD19-CAR T cells) have been well documented to possess potent anti-tumor properties against CD19-expressingleukemia cells. As a traditional medicine, metformin has been widely used to treat type II diabetes mellitus and more recently has become a candidate for the treatment of cancer. However, no report has revealed the direct effect of metformin on CD19-CAR T cell biological function and its underling mechanisms. Purpose: The purpose of this research was to explore the effect of metformin on CD19-CAR T cell biological function and the mechanisms involved. Methods: CD19-CAR T cells proliferation, apoptosis and cytotoxicity were mainly tested by CCK-8 assay, flow cytometry and ELISA. The detection of mechanism primarily used western blot. Bioluminescence imaging is the main application technology of animal studies. Results: In the current study, it was found that metformin inhibited CD19-CAR T cell proliferation and cytotoxicity and induced apoptosis. Furthermore, our study revealed that metformin activated AMPK and suppressed mTOR and HIF1α expression. By using an AMPK inhibitor, compound C, we demonstrated the crucial roles of AMPK in CD19-CAR T cells when they were treated with metformin. Finally, we verified that metformin suppressed the cytotoxicity of CD19-CAR T cell in vivo. Conclusion: Taken together, these results indicated that metformin may play an important role in modulating CD19-CAR T cell biological functions in an AMPK-dependent and mTOR/HIF1α-independent manner. Keywords: Chimeric antigen receptor, metformin, proliferation, apoptosis, cytotoxicity, AMPK

Cheng Wang,1 Jun-Xiong Li,1 Dang Tang,2 Jian-Qing Zhang,1 Li-Zhou Fang,1 Wei-Ping Fu,1 Ling Liu,1 Lu-Ming Dai1 1Second Department of Respiratory Medicine, 2First Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China Background: Metabolomics is the global unbiased analysis of all the small-molecule metabolites within a biological system. Metabolic profiling of different high-resolution computed tomography (HRCT) phenotypes of COPD patients before and after treatment may identify discriminatory metabolites that can serve as biomarkers and therapeutic agents. Patients and methods: 1H nuclear magnetic resonance spectroscopy (1H-NMR)-based metabolomics was performed on a discovery set of plasma samples from 50 patients with stable COPD. Patients were assigned into two groups on the basis of HRCT findings including phenotype E (n=22) and phenotype M (n=28). After budesonide–formoterol treatment (160/4.5 µg ×2 inhalations twice daily for 3 months), clinical characteristics and metabolites were then compared between phenotype E pretreatment and posttreatment, phenotype M pretreatment and posttreatment, phenotype E pretreatment and phenotype M pretreatment, and phenotype E posttreatment and phenotype M posttreatment. Results: Inhaled budesonide–formoterol therapy for both phenotype E (emphysema without bronchial wall thickening) and phenotype M (emphysema with bronchial wall thickening) was effective. However, phenotype E and phenotype M were different in response to therapy. Patients with phenotype M in response to therapeutic effects were significantly greater compared with phenotype E. Certain metabolites were identified, which were closely related to the treatment and phenotype. Metabolic changes in phenotype E or phenotype M after treatment may be involved with adenosine diphosphate (ADP), guanosine, choline, malonate, tyrosine, glycine, proline, l-alanine, l-valine, l-threonine leucine, uridine, pyruvic acid, acetone and metabolism disturbance. Metabolic differences between phenotype E and phenotype M in pretreatment and posttreatment covered glycine, D-glucose, pyruvic acid, succinate, lactate, proline, l-valine and leucine. Conclusion: Bronchial wall thickening in COPD may be an indicator for predicting the better response to the treatment with bronchodilator and corticosteroid. The identification of metabolic alterations provides new insights into different HRCT phenotypes and therapeutic assessment of COPD. Keywords: COPD, metabolomics, budesonide–formoterol, HRCT

Eggs are suitable for the processing of set yoghurt as milk replacements, but there is no yoghurt mainly made from eggs. In the present work, production formula was designed and optimised for high-quality egg-based yoghurt processing by improving water holding capacity, aroma, texture, and taste using single factor experiment and D-optimal mixture design. Results showed that with optimised formula (whole liquid egg, 100 g; water, 180 g; sucrose, 30.89 g; diacetyl tartaric acid ester of mono(di)glycerides, 0.28 g; gelatine, 0.112 g; gellan gum, 0.14 g; and ß-cyclodextrin, 0.56 g), the product showed high sensory evaluation score, fine viscosity, as well as preferable hardness and suitable fracturability. SDS-PAGE electrophoretogram indicated that the proteins in egg-based yoghurt was degraded during fermentation, which might have contributed to the improvement of gel structure and taste. Based on the SEM images, the prepared egg-based yoghurt had smoother, stronger, and more compact gel network microstructure when compared with milk-based yoghurt. [ABSTRACT FROM AUTHOR]

The frequency of the Robertonian (ROB) translocation in newborn babies is approximately one in 1000. Robertsonian translocation is an unusual type of chromosome rearrangement caused by two particular chromosomes joining together. The aim of the study was to analyze the segregation of the ROB translocations in 13 male carriers, and to verify a possible inter-chromosomal effect (ICE) of the ROB translocation on chromosomes 18, X, and Y. Thirteen male patients were included in the study. Multicolor fluorescent in situ hybridization (FISH) was used to analyze chromosomes 13, 14, 15, 21, 22, 18, X and Y in sperm. Among the heterozygous ROB translocation carriers, the frequency of normal/balanced spermatozoa resulting from alternate segregation varied between 70.4 and 85.2%. The frequency of unbalanced spermatozoa resulting from adjacent segregation varied between 14.8 and 29.6%. Increased frequencies of aneuploidy for a sex chromosome were found in 10 ROB translocation carriers (P2-P8, P10-P12). Increased frequencies of aneuploidy for chromosome 18 were found in10 ROB translocation carriers (P3-P9, P11-P13). In addition, increased frequencies of diploid were found in 11 ROB translocation carriers (P2-P9, P11-P13). Among the homozygous ROB translocation carriers, the rate of balanced spermatozoa was 99.7% and the frequency of unbalanced spermatozoa was 0.3%. However, the frequencies of aneuploidy for a sex chromosome and chromosome 18 were normal. Despite the high number of normal/balanced frequencies, there remained many unbalanced spermatozoa resulting from alternate segregation. The ROB translocation carriers may be at an increased risk for ICE. Robertsonian translocation homozygosity could be seen as a potential speciation in humans with 44 chromosomes.