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Xiao-Hua Zhang,1,* Xin Zhang,1,* Xuan-Wei Liu,1 Peng-Hui Lai,1 Chang-Chun Cao,1 Yu-Long Wang,2 Li-Jie Ren2 1Department of Rehabilitation, Shenzhen Dapeng New District Nanao People’s Hospital, Shenzhen, 518121, People’s Republic of China; 2Department of Rehabilitation, The First Affiliated Hospital, Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, 518000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yu-Long Wang; Li-Jie Ren, Department of Rehabilitation, The First Affiliated Hospital, Shenzhen University, Shenzhen Second People’s Hospital, 3002 Sungang West Road, Futian District, Shenzhen, 518035, People’s Republic of China, Tel +86 13923448395 ; +86 13631605966, Email wangyulong6238@126.com; renlijiege2022@163.comObjective: This study aims to elucidate the potential links between the GLU/GABA to GLN metabolic cycle disruptions and the onset of depressive and insomnia disorders following a stroke. We particularly focus on understanding if these disorders share a common underlying pathogenic mechanism.Methods: We examined 63 patients with post-stroke insomnia, 62 patients with post-stroke depression, and 18 healthy individuals. The study involved assessing insomnia using the Acute Insomnia Scale (AIS) and depression using the Hamilton Depression Rating Scale. We measured serum concentrations of GLN, GLU, and GABA and analyzed their correlations with AIS and HAMD scores.Results: Our results indicate no significant difference in the serum levels of GLN, GLU, and GABA between the post-stroke insomnia and depression groups. However, these levels were notably lower in both patient groups compared to the healthy control group. A negative correlation between AIS scores and GABA levels was observed in the post-stroke insomnia group, suggesting a potential link between GABAergic disturbances and insomnia. Conversely, no significant correlation was found between Hamilton Depression Rating Scale scores and the levels of GABA, GLU, or GLN in the post-stroke depression group.Conclusion: The study highlights that abnormalities in the GLU/GABA to GLN metabolic cycle, particularly the levels of GLN, GABA, and GAD, might be intricately linked to the pathogenesis of post-stroke insomnia and depression. Our findings suggest that GABAergic imbalances could be indicative of post-stroke insomnia, serving as potential biological markers for differential diagnosis in clinical settings. Further research is warranted to explore these relationships in greater depth, potentially leading to new diagnostic and therapeutic approaches for post-stroke neuropsychiatric disorders.Keywords: glutamate, GLU, γ-aminobutyric acid, GABA, post-stroke depression, post-stroke insomnia

Shao-Li Huang,1– 3,* Hong-Yi Xin,4,5,* Xiao-Yan Wang,4,5,* Guang-Gui Feng,3 Fu-Qing Wu,3 Zhi-Peng Feng,6 Zhou Xing,2 Xi-He Zhang,4,5 Hong-Wu Xin,4,7,8 Wen-Ying Luo1 1Medical Laboratory Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524400, People’s Republic of China; 2First Clinical College, Guangdong Medical University, Guangdong, 524400, People’s Republic of China; 3Clinical laboratory, Lianjiang People’s Hospital, Guangdong, 524400, People’s Republic of China; 4Doctoral Scientific Research Center, Lianjiang People’s Hospital, Guangdong, 524400, People’s Republic of China; 5Guangdong Medical University Affiliated Lianjiang People’s Hospital, Guangdong, 524400, People’s Republic of China; 6Department of Gastroenterology, Yueyang Hospital Affiliated to Hunan Normal University, Yueyang, Hunan, 414000, People’s Republic of China; 7Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Faculty of Medicine, Yangtze University, Jingzhou, Hubei, 434023, People’s Republic of China; 8Research Centre of Molecular Medicine, Medical College of Chifeng University, Chifeng, Inner Mongolian Autonomous Region, 024000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wen-Ying Luo, Medical laboratory Center, Affiliated Hospital of Guangdong Medical University, 57th South Renmin Road, Zhanjiang, 524001, People’s Republic of China, Tel +86 18312728748, Email luo_wenying@126.com Xi-He Zhang, Doctoral Scientific Research Center, Lianjiang People’s Hospital, Guangdong, 524400, People’s Republic of China, Tel +86 19126491230, Email hljsnjx@163.comAbstract: Venous thromboembolism is a condition that includes deep vein thrombosis and pulmonary embolism. It is the third most common cardiovascular disease behind acute coronary heart disease and stroke. Over the past few years, growing research suggests that venous thrombosis is also related to the immune system and inflammatory factors have been confirmed to be involved in venous thrombosis. The role of inflammation and inflammation-related biomarkers in cerebrovascular thrombotic disease is the subject of ongoing debate. P-selectin leads to platelet-monocyte aggregation and stimulates vascular inflammation and thrombosis. The dysregulation of miRNAs has also been reported in venous thrombosis, suggesting the involvement of miRNAs in the progression of venous thrombosis. Plasminogen activator inhibitor-1 (PAI-1) is a crucial component of the plasminogen-plasmin system, and elevated levels of PAI-1 in conjunction with advanced age are significant risk factors for thrombosis. In addition, it has been showed that one of the ways that neutrophils promote venous thrombosis is the formation of neutrophil extracellular traps (NETs). In recent years, the role of extracellular vesicles (EVs) in the occurrence and development of VTE has been continuously revealed. With the advancement of research technology, the complex regulatory role of EVs on the coagulation process has been gradually discovered. However, our understanding of the causes and consequences of these changes in venous thrombosis is still limited. Therefore, we review our current understanding the molecular mechanisms of venous thrombosis and the related clinical trials, which is crucial for the future treatment of venous thrombosis.Keywords: venous thromboembolism, miRNA, neutrophil extracellular traps, plasminogen activator inhibitor-1, EVs, inflammatory factor

Shi Zhou, Xing-Hu Zhang, Yuan Zhang, Ge Gong, Xiang Yang, Wen-Hui Wan Department of Geriatrics, Jinling Hospital, Medical School of Nanjing University, Nanjing, 21002, Jiangsu, People’s Republic of ChinaCorrespondence: Wen-Hui Wan, Department of Geriatrics, Jinling Hospital, Medical School of Nanjing University, Nanjing, 21002, Jiangsu, People’s Republic of China, Tel/Fax +86 25 80862433, Email wanwhnj@sina.comPurpose: The age-adjusted Charlson comorbidity index (ACCI) is a useful measure of comorbidity to standardize the evaluation of elderly patients and has been reported to predict mortality in various cancers. To our best knowledge, no studies have examined the relationship between the ACCI and survival of elderly patients with cancer. Therefore, the primary objective of this study was to investigate the relationship between the ACCI and survival of elderly patients with cancer.Patients and Methods: A total of 64 elderly patients (> 80 years) with cancer between 2011 and 2021 were enrolled in this study. According to the ACCI, the age-adjusted comorbidity index was calculated by weighting individual comorbidities; patients with ACCI< 11 were considered the low-ACCI group, whereas those with ACCI≥ 11 were considered the high-ACCI group. The correlations between the ACCI score and survival outcomes were statistically analyzed.Results: There was a significant difference in overall survival (OS) and progression-free survival (PFS) between the high-ACCI group and the low-ACCI group (P< 0.001). The median OS time of the high-ACCI group and the low-ACCI group were 13.9 (10.5– 22.0) months and 51.9 (34.1– 84.0) months, respectively. The 2-, 3-, and 5-year survival rates of the high-ACCI group were 28.1%, 18.8%, and 4.2%, respectively, whereas the 2-, 3-, and 5-year survival rates of the low-ACCI group were 77.3%, 66.4%, and 39.1%, respectively. Multivariate analysis showed that ACCI was independently associated with OS (HR=1.402, 95% CI: 1.226– 1.604, P < 0.05) and PFS (HR=1.353, 95% CI: 1.085– 1.688, P = 0.0073).Conclusion: The ACCI score is a significant independent predictor of prognosis in elderly patients with cancer.Keywords: age-adjusted Charlson comorbidity index, comorbidity, elderly cancer patients, prognosis

Yan Han,1,2 Yue-Ping Yin,1,2 Wen-Qi Xu,1,2 Xiao-Yu Zhu,1,2 Shao-Chun Chen,1,2 Xiu-Qin Dai,1,2 Li-Gang Yang,3,4 Bang-Yong Zhu,5 Na Zhong,6 Wen-Ling Cao,7 Xiao-Hui Zhang,3,4 Zhi-Zhou Wu,8 Liu-Feng Yuan,9 Zhong-Jie Zheng,10 Jun Liu,11 Xiang-Sheng Chen1,2 1Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, People’s Republic of China; 2National Center for STD Control, Chinese Center for Disease Control and Prevention, Nanjing, Jiangsu, People’s Republic of China; 3Dermatology Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 4Guangdong Provincial Dermatology Hospital, Guangzhou, Guangdong, People’s Republic of China; 5Institute of Dermatology, Nanning, Guangxi Autonomous Region, People’s Republic of China; 6Hainan Provincial Center for STD/Skin Disease Control and Prevention, Haikou, Hainan, People’s Republic of China; 7Guangzhou Institute of Dermatology, Guangzhou, Guangdong, People’s Republic of China; 8Jiangmen Dermatology Hospital, Jiangmen, Guangdong, People’s Republic of China; 9Beijing Ditan Hospital Capital Medical University, Beijing, People’s Republic of China; 10Tianjin Center for Disease Control and Prevention, Tianjin, People’s Republic of China; 11Harvard Medical School, Boston, MA, USACorrespondence: Yue-Ping YinInstitute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, 12 Jiangwangmiao Street, Nanjing 210042, People’s Republic of ChinaTel/ Fax +86 258 547 8024Email yinyp@ncstdlc.orgPurpose: Injectable ceftriaxone and oral cefixime are the last agents effective against Neisseria gonorrhoeae. In vitro antimicrobial-susceptibility testing (AST) is done to identify the most efficacious antibiotic needed to combat the infection in that particular individual. The objective of this study was to evaluate whether Kirby–Bauer (KB) disk-diffusion tests can detect N. gonorrhoeae isolates that have decreased susceptibility to ceftriaxone and cefixime for appropriate clinical management.Methods: A total of 1,633 consecutive clinical isolates of N. gonorrhoeae were collected from January 1, 2013 to December 31, 2017 from seven dermatology clinics located in five provinces in China. Consistency between KB disk-diffusion tests and the agar-dilution method, as well as sensitivity of the KB test for detecting N. gonorrhoeae isolates with decreased susceptibility to ceftriaxone and cefixime, were determined using 1,306 clinical isolates that had been recovered to complete agar-dilution AST.Results: The prevalence of isolates with decreased susceptibility to ceftriaxone and cefixime was 12.1% (198 of 1,633) and 12.7% (208 of 1,633), respectively, using KB disk-diffusion tests. The prevalence of isolates with decreased susceptibility was 9.9% (129 of 1,306) for ceftriaxone and 9.9% (129 of 1,305) for cefixime using agar-dilution AST. The categorical agreement of these two methods was 80.9% for both ceftriaxone and cefixime. Compared to agar-dilution AST, the sensitivity of the KB test for detecting N. gonorrhoeae isolates with decreased susceptibility was 22.5% (29 of 129) for ceftriaxone and 29.5% (38 of 129) for cefixime, and its specificity 87.3% (1,028 of 1,177) for ceftriaxone and 86.7% (1,018 of 1,176) for cefixime.Conclusion: Although KB tests are easy to carry out in clinical practice, their ability to detect cephalosporin-resistant gonorrhoea strains is limited. This method is not an appropriate selection for screening cephalosporin-resistant gonorrhoea strains in clinical practice in China.Keywords: Neisseria gonorrhoeae, Kirby–Bauer disk-diffusion tests, agar-dilution method, susceptibility, screen

Xian Hu Zhang,1 Bing Feng Li,1 Jie Ding,2 Lei Shi,1 Huo Ming Ren,1 Kui Liu,1 Chuan Cai Huang,1 Fu Xiao Ma,1 Xin Yao Wu1 1Department of General Surgery, Suzhou First People’s Hospital, Suzhou, Anhui 234000, People’s Republic of China; 2Physical Examination Department, Suzhou Central Blood Station, Suzhou, Anhui 234000, People’s Republic of ChinaCorrespondence: Xian Hu ZhangDepartment of General Surgery, Suzhou First People’s Hospital, No. 26 Yinhe Road, Suzhou, Anhui 234000, People’s Republic of ChinaTel +86 18134605661Email zhang64332277735@126.comObjective: This study set out to probe into the effects of long non-coding RNA (LncRNA) differentiation antagonizing non-protein coding RNA (DANCR) on apoptosis and autophagy of breast cancer (BC) cells.Methods: The expression levels of DANCR, miR-758-3p and paired box 6 (PAX6) in BC tissues and cell lines were detected. The transcription and protein levels of PAX6, apoptosis-related factors (caspase-3, caspase-9, Bax/Bcl-2), and autophagy-related factors (LC3B, Atg5, Beclin-1) in BC cells were detected. The cell proliferation, apoptosis, autophagy and the regulatory relationship between genes and target genes were analyzed.Results: DANCR and PAX6 were up-regulated in BC tissues and cell lines, while miR-758-3p was opposite. Down-regulating DANCR inhibited the malignant proliferation of BC cells and also promoted apoptosis and autophagy, which showed that caspase-3, caspase-9, Bax/Bcl-2, LC3B, Atg5 transcription and protein levels increased, while Beclin-1 transcription and protein levels decreased. DANCR regulated miR-758-3p in a targeted manner, and its over-expression could weaken the anti-cancer effect of miR-758-3p on BC cells. In addition, miR-758-3p also directly targeted PAX6, and knocking down its expression could weaken the inhibitory effect of down-regulating PAK6 on BC cell apoptosis and autophagy. We also found that DANCR acted as a competitive endogenous RNA sponge miR-758-3p, thus regulating the PAX6 expression.Conclusion: DANCR-miR-758-3p-PAX6 molecular network plays a key regulatory role in BC cell apoptosis and autophagy, which may provide reference for treating patients.Keywords: DANCR, miR-758-3p, PAX6, breast cancer, BC, apoptosis and autophagy

Dian-Wei Liu,1,* Ling Ma,2,* Xu-Hua Zhang,2 Yun-Yan Wang31Department of Neurosurgery, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, People’s Republic of China; 2Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, Shandong 250033, People’s Republic of China; 3Department of Neurosurgery, QiLu Hospital of Shandong University, Jinan, Shandong 250012, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yun-Yan WangDepartment of Neurosurgery, QiLu Hospital of Shandong University, No. 44 Wen Hua Xi Road, Jinan, Shandong 250012, People’s Republic of ChinaTel +86 5 311 370 892 8040Fax +86 5 318 569 5463Email wyyqlh123@163.comBackground: Memory extinction has been reported to be related to psychiatric disorders, such as post-traumatic stress disorder (PTSD). Secretion and synthesis of brain-derived neurotrophic factor (BDNF) have been shown to temporally regulate various memory processes via activation of tropomyosin-related kinase B (TrkB) receptors. However, whether memory extinction induces the synthesis and secretion of BDNF on the basis of its localization is not understood. In this study, we aim to investigate activity-dependent BDNF secretion and synthesis in the insular cortex (IC) in the setting of conditioned taste aversion (CTA) memory extinction.Materials and methods: Rats were subjected to CTA memory extinction and BDNF antibody (or the equal volume of vehicle) was microinjected into the IC immediately after the extinction testing. Real-time polymerase chain reaction and in situ hybridization were used to detect the gene expression of BDNF, NGF and NT4. The protein levels of BDNF were determined through the enzyme-linked immunosorbent assay. In addition, the levels of phosphorylated TrkB normalized to total TrkB were evaluated using immunoprecipitation and immunoblotting. c-Fos, total extracellular signal-regulated kinase (Erk), phosphorylated Erk, and apoptosis-related protein (caspase-3), were detected by Western blotting.Results: We found that blocking BDNF signaling within the IC disrupts CTA extinction, suggesting that BDNF signaling in the IC is necessary for CTA extinction. Increased expression levels of c-Fos indicate the induced neuronal activity in the IC during CTA extinction. In addition, temporal changes in the gene expression and protein levels of BDNF in the IC were noted during extinction. Moreover, we found that phosphorylation of TrkB increased prior to the enhanced BDNF expression, suggesting that CTA extinction induces rapid activity-dependent BDNF secretion in the IC. Finally, we found decreased expression of caspase-3 in the IC after CTA extinction.Conclusion: These results demonstrate that CTA memory extinction temporally induces the release and synthesis of BDNF in the IC and inhibits neuronal apoptosis.Keywords: brain derived neurotrophic factor, insular cortex, conditioned taste aversion, secretion, apoptosis

Yun Feng, Jin-Ning Ye, Chuang-Qi Chen, Xin-Hua ZhangThe Center for Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, People’s Republic of ChinaAbstract: Gastric duplications are the least common gastrointestinal duplications, especially in adults. Duplication cyst with an accessory pancreatic lobe is extremely rare and is even more uncommon in the setting of polysplenia. No gastric duplication after partial gastrectomy has been reported. We present a 41-year-old male diagnosed with gastric duplications with an accessory pancreatic lobe and polysplenia. Another characteristic of this case is partial gastrectomy 20 years ago without the discovery of duplication cysts. The gastric duplications, accessory pancreatic lobe and accessory spleen were successfully resected.Keywords: gastric duplication, polysplenia, accessory pancreatic lobe, gastrectomy, adult

Ru-Tian Hao, Chen Zheng, Chen-Yong Wu, Er-Jie Xia, Xiao-Fen Zhou, Rui-Da Quan, Xiao-Hua ZhangDepartment of Thyroid and Breast Surgery, The First Affiliated Hospital of Wenzhou, Medical University, Wenzhou, Zhejiang, People’s Republic of ChinaAbstract: Papillary thyroid cancer (PTC) is the most frequent type of malignant thyroid cancer, but its molecular mechanisms remain unknown. To better understand the tumorigenesis and progression of PTC, we conducted a comprehensive analysis of the whole-transcriptome resequencing of paired PTC and normal thyroid tissues. Nectin cell adhesion molecule 4 (NECTIN4) was significantly overexpressed in thyroid carcinoma compared with that in matched normal tissue. We also assessed the relation between the expression level of NECTIN4 and the clinicopathological features of PTC in The Cancer Genome Atlas database, and results showed that upregulated NECTIN4 is associated with lymph node metastasis (P

Jiawang Wei,1–3,* Rong Huang,3,* Suping Guo,1,2,* Xuhui Zhang,1,2 Shaoyan Xi,1,4 Qiaoxuan Wang,1,2 Hui Chang,1,2 Xiaohao Wang,1,2 Weiwei Xiao,1,2 Zhifan Zeng,1,2 Yuanhong Gao1,2 1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China; 2Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China; 3Department of Oncology, Ganzhou People’s Hospital, Ganzhou, Jiangxi, People’s Republic of China; 4Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China *These authors contributed equally to this work Background: The purpose of this study was to investigate the value of the postsurgical pathological T and N (ypTN) category combined with the American Joint Committee on Cancer-tumor regression grade (AJCC-TRG) in evaluating the prognosis of neoadjuvant chemoradiation therapy (NeoCRT) for locally advanced rectal cancer (LARC) to screen for a subgroup of patients with the worst prognosis. Patients and methods: In total, 265 patients with LARC were enrolled in the trial. All patients received NeoCRT. Total mesorectal excision was performed 6–8 weeks after the completion of radiotherapy. The surgical specimens were re-evaluated based on the AJCC-TRG (seventh edition) and the AJCC-tumor-node-metastasis (TNM; seventh edition) systems. We followed up these patients and calculated their overall survival (OS), disease-free survival (DFS), local recurrence-free survival (RFS), and distant metastasis (DM)-free survival (MFS) rates through the Kaplan–Meier analysis. The logrank test was further applied to evaluate the predictive value of the ypTN stage combined with AJCC-TRG for several survival indexes. Results: The median follow-up period was 65.1 months. The 5-year OS, DFS, RFS, and MFS rates were 79.4%, 68.8%, 94.4%, and 76.5%, respectively. There were significant differences in OS, DFS, and MFS rates among different ypT+AJCC-TRG and ypN+AJCC-TRG subgroups. The 5-year OS, DFS, and MFS rates for ypT3–4+TRG 1 and ypT3–4+TRG2–3 subgroups were 73.9% vs 65.3%, 61.2% vs 52.9%, and 65.0% vs 61.5%, respectively. The 5-year OS, DFS, and MFS rates for ypN1–2+TRG 0–1 and ypN1–2+TRG2–3 subgroups were 64.8% vs 54.1%, 44.9% vs 41.7%, and 61.4% vs 46.3%, respectively. Conclusion: The ypTNM category combined with the AJCC-TRG can more accurately evaluate the prognosis of patients with LARC and identify the subgroup of patients with the worst prognosis and high risk of developing DM, thereby demonstrating clinical significance in guiding individualized postoperative adjuvant therapy and follow-up for LARC. Keywords: ypTNM, NeoCRT, rectal cancer, locally advanced rectal cancer, LARC, AJCC

Wen-Xu Jin,1,2,* Dan-Rong Ye,2,* Yi-Han Sun,2,* Xiao-Fen Zhou,2 Ou-Chen Wang,2 Xiao-Hua Zhang,2 Ye-Feng Cai2 1Department of Vascular Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, 325000, China; 2Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, 325000, China *These authors contributed equally to this work Background: Preoperative diagnosis of central lymph node metastasis (CLNM) poses to be a challenge in clinical node-negative papillary thyroid microcarcinoma (PTMC). This research work aims at investigating the association existing between BRAF mutation, clinicopathological factors, ultrasound characteristics, and CLNM, in addition to establishing a predictive model for CLNM in PTMC.Materials and methods: The study included 673 PTMC patients, already undergone total thyroidectomy or lobectomy with prophylactic central lymph node dissection. The predictor factors were identified through univariate and multivariate analyses. The support vector machine was put to use to develop statistical models, which could predict CLNM on the basis of independent predictors.Results: Tumor size (>5 mm), lower location, no well-defined margin, contact of >25% with the adjacent capsule, display of enlarged lymph nodes, and BRAF mutation were independent predictors of CLNM. Through the use of the predictive model, 79.6% of the patients were classified accurately, the sensitivity and specificity amounted to be 85.1% and 75.8%, respectively, and the positive predictive value and negative predictive value stood at 71.6% and 87.6%, respectively.Conclusions: We established a predictive model in order to predict CLNM preoperatively in PTMC when preoperative diagnosis of CLNM was not clear. Keywords: papillary thyroid microcarcinoma, central lymph node, predictive factor, support vector machine

Jin-Xiu Li,1,2,* Wei-Ping Fu,3,* Jing Zhang,4 Xiao-Hua Zhang,1,2 Chang Sun,1,5 Lu-Ming Dai,3 Li Zhong,1,5,6 Li Yu,1,2 Ya-Ping Zhang1,7 1State Key Laboratory for Conservation and Utilization of Bio-Resource in Yunnan, 2Key Laboratory for Animal Genetic Diversity and Evolution of High Education in Yunnan Province, School of Life Sciences, Yunnan University, 3Department of Respiratory Critical Care Medicine, 4Department of Thoracic Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, 5College of Life Sciences, 6Provincial Demonstration Center for Experimental Biology Education, Shaanxi Normal University, Xi’an, 7State Key Laboratory of Genetic Resources and Evolution, and Yunnan Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China *These authors contributed equally to this work Background: Previous studies have suggested that β2-adrenergic receptor (ADRB2) is associated with COPD. However, the role of genetic polymorphisms in ADRB2 on COPD has not been evaluated yet. Methods: In this study, SNaPshot genotyping, luciferase assay, chromatin immunoprecipitation and real-time polymerase chain reaction were adopted to investigate the association between ADRB2 genetic polymorphisms and COPD, comprehensively. Results: One single nucleotide polymorphism (rs12654778), located upstream of ADRB2, showed a significant association with COPD by the logistic regression analysis after adjusting for age, sex and smoking history (p=0.04) in 200 COPD patients and 222 controls from southwest Chinese population. Furthermore, the luciferase assay indicated that rs12654778-A allele reduced the relative promoter activity by ~26% compared with rs12654778-G allele (p=0.0034). The chromatin immunoprecipitation analysis demonstrated that rs12654778 modulated the binding affinity of transcription factor neurofibromin 1. In addition, a significantly reduced expression of ADRB2 in COPD patients was observed, compared with normal controls (p=0.017). Conclusion: Our findings suggest a previously unknown mechanism linking allele-specific effects of rs12654778 on ADRB2 expression to COPD onset, for the first time. Keywords: β2-adrenergic receptor, ADRB2, FEV1, lung, polymorphism

Liang Qin,1,* Tianyuan Xu,1,* Leilei Xia,1 Xianjin Wang,1 Xiang Zhang,1 Xiaohua Zhang,1 Zhaowei Zhu,1 Shan Zhong,1 Chuandong Wang,2 Zhoujun Shen1 1Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 2Key Laboratory of Stem Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: It has been demonstrated that chloroquine (CQ) enhances the efficacy of chemotherapy. However, little is known about whether CQ could enhance the efficacy of cisplatin (DDP) in the treatment of adrenocortical carcinoma (ACC). In this study, we explore the efficacy and mechanism by which CQ affects DDP sensitivity in human ACC in vitro and in vivo.Methods: The autophagic gene Beclin-1 expression was detected by immunohistochemistry, and the protein levels were analyzed using immunoblotting assays of ACC tissues and normal adrenal cortex tissues. The ACC SW13 cells were treated with DDP and/or CQ. The cell viability assay was performed using the MTT method. Qualitative autophagy detection was performed by monodansylcadaverine staining of autophagic vacuoles. Annexin V-fluorescein isothiocyanate/propidium iodide double staining was used to count cell apoptosis by flow cytometry. The autophagy-related protein (Beclin-1, LC3, and p62) and apoptosis relative protein (Bax and Bcl-2) levels were evaluated with Western blot analysis. Furthermore, a murine model of nude BALB/c mice bearing SW13 cell xenografts was established to evaluate the efficacy of concomitant therapy.Results: The expression of the autophagic gene Beclin-1 was significantly downregulated in ACC tissues compared to normal adrenal cortex tissues. The Beclin-1 protein level in ACC tissues was lower than that in normal adrenal cortex tissues (P

Xiang Gao,1,2,* Xiaohong Zhang,3,* Jinlin Song,1,2 Xiao Xu,4 Anxiu Xu,1 Mengke Wang,4 Bingwu Xie,1 Enyi Huang,2 Feng Deng,1,2 Shicheng Wei2–41College of Stomatology, 2Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Medical University, Chongqing, 3Center for Biomedical Materials and Tissue Engineering, Academy for Advanced Interdisciplinary Studies, Peking University, 4Department of Oral and Maxillofacial Surgery, Laboratory of Interdisciplinary Studies, Peking University School and Hospital of Stomatology, Beijing, People’s Republic of China*These authors contributed equally to this workAbstract: The construction of functional biomimetic scaffolds that recapitulate the topographical and biochemical features of bone tissue extracellular matrix is now of topical interest in bone tissue engineering. In this study, a novel surface-functionalized electrospun polycaprolactone (PCL) nanofiber scaffold with highly ordered structure was developed to simulate the critical features of native bone tissue via a single step of catechol chemistry. Specially, under slightly alkaline aqueous solution, polydopamine (pDA) was coated on the surface of aligned PCL nanofibers after electrospinning, followed by covalent immobilization of bone morphogenetic protein-7-derived peptides onto the pDA-coated nanofiber surface. Contact angle measurement, Raman spectroscopy, and X-ray photoelectron spectroscopy confirmed the presence of pDA and peptides on PCL nanofiber surface. Our results demonstrated that surface modification with osteoinductive peptides could improve cytocompatibility of nanofibers in terms of cell adhesion, spreading, and proliferation. Most importantly, Alizarin Red S staining, quantitative real-time polymerase chain reaction, immunostaining, and Western blot revealed that human mesenchymal stem cells cultured on aligned nanofibers with osteoinductive peptides exhibited enhanced osteogenic differentiation potential than cells on randomly oriented nanofibers. Furthermore, the aligned nanofibers with osteoinductive peptides could direct osteogenic differentiation of human mesenchymal stem cells even in the absence of osteoinducting factors, suggesting superior osteogenic efficacy of biomimetic design that combines the advantages of osteoinductive peptide signal and highly ordered nanofibers on cell fate decision. The presented peptide-decorated bone-mimic nanofiber scaffolds hold a promising potential in the context of bone tissue engineering.Keywords: biomimetic, nanofiber, peptide, bone tissue engineering

Shuo Liu,1 Yangang Ren,1 Deliang Wen,1 Yu Chen,2 Donghong Chen,1 Liyun Li,3 Xuhua Zhang,1 Yibing Zhang,4 Shuang Fu,5 Zhenhua Li,3 Shuyue Xia,6 Dongliang Wang,7 Hong Chen,8 Jian Zhao,9 Xiaoge Wang1 1The Fourth Affiliated Hospital, 2The Second Affiliated Hospital, 3The First Affiliated Hospital, China Medical University, 4The Shenyang Military General Hospital, Shenyang, 5The General Hospital of Fushun Mining Bureau, Fushun, 6Fengtian Hospital, Shenyang Medical College, 7202nd Hospital of People’s Liberation Army, Shenyang, 8The First People’s Hospital of Kazuo, Chaoyang, 9205th Hospital of People’s Liberation Army, Jinzhou, Liaoning, People’s Republic of China Background: COPD is one of the most common chronic diseases, and more and more farmers who were frequently exposed to greenhouse environments were diagnosed with COPD. However, little information is available on the prevalence of COPD among the greenhouse farmers. This study was conducted to assess the prevalence of COPD and investigate the potential risk factors for COPD among the Chinese greenhouse farmers.Methods: Cross-sectional studies involving a sample of greenhouse farmers living in northeast China were performed via stratified-cluster-random sampling. All subjects were interviewed using a uniform questionnaire and underwent pulmonary function tests between 2006 and 2009, based on the diagnostic criteria of the Global Initiative for Chronic Obstructive Lung Disease. Multiple logistic regression analysis was conducted to examine the risk factors for COPD.Results: Of the 5,880 greenhouse farmers from northeast China who were originally selected for this study, 5,420 questionnaires were completed. The overall prevalence of COPD in greenhouse farmers was 17.5%. The COPD prevalence was significantly higher in elderly subjects (≥50 years), current smokers, in those with lower body mass index (≤18.5 kg/m2) and less education, in those who were exposed to mushroom, flowers and poultry, and in those living in mountain and coastal region. Multiple logistic regression analysis revealed that age over 50 years old (odds ratio [OR]=298.69, 95% confidence interval [CI]=121.57–733.84), smoking (OR=2.18, 95% CI=1.84–2.59), planting mushroom and flowers (OR=1.46 and 1.53, 95% CI=1.13–1.87 and 1.24–1.95), and living in mountain and coastal region (OR=1.68 and 1.35, 95% CI=1.37–2.06 and 1.10–1.65) were associated with the development of COPD among greenhouse farmers.Conclusion: In northeast China, COPD is highly prevalent among greenhouse farmers, and advanced age, smoking, planting mushroom, and flowers, as well as living in mountain and coastal regions, are potential risk factors for this disease. Keywords: COPD, epidemiology, greenhouse farmers, prevalence, risk factor

Feng Chen,1 Xiao Hong Zhang,1 Xiao Dan Hu,1 Wei Zhang,1 Zhi Chao Lou,1 Li Hua Xie,1 Pei Dang Liu,2 Hai Qian Zhang1,21College of Materials Science and Technology, Nanjing University of Aeronautics and Astronautics, 2Jiangsu Laboratory for Biomaterials and Devices, Southeast University, Nanjing, People’s Republic of ChinaAbstract: Radiotherapy is one of the main strategies for cancer treatment but has significant challenges, such as cancer cell resistance and radiation damage to normal tissue. Radiosensitizers that selectively increase the susceptibility of cancer cells to radiation can enhance the effectiveness of radiotherapy. We report here the development of a novel radiosensitizer consisting of monodispersed ceria nanoparticles (CNPs) covered with the anticancer drug neogambogic acid (NGA-CNPs). These were used in conjunction with radiation in MCF-7 breast cancer cells, and the efficacy and mechanisms of action of this combined treatment approach were evaluated. NGA-CNPs potentiated the toxic effects of radiation, leading to a higher rate of cell death than either treatment used alone and inducing the activation of autophagy and cell cycle arrest at the G2/M phase, while pretreatment with NGA or CNPs did not improve the rate of radiation-induced cancer cells death. However, NGA-CNPs decreased both endogenous and radiation-induced reactive oxygen species formation, unlike other nanomaterials. These results suggest that the adjunctive use of NGA-CNPs can increase the effectiveness of radiotherapy in breast cancer treatment by lowering the radiation doses required to kill cancer cells and thereby minimizing collateral damage to healthy adjacent tissue.Keywords: ceria nanoparticles, radiotherapy, breast cancer cells, neogambogic acid, radiosensitization

Wenhua He,1,* Feng Shi,1,* Zhi-Wei Zhou,2,* Bimin Li,1 Kunhe Zhang,1 Xinhua Zhang,1 Canhui Ouyang,1 Shu-Feng Zhou,2 Xuan Zhu1 1Department of Gastroenterology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA*These authors contributed equally to this work Abstract: NADPH oxidases (NOXs) are a predominant mediator of redox homeostasis in hepatic stellate cells (HSCs), and oxidative stress plays an important role in the pathogenesis of liver fibrosis. Ursolic acid (UA) is a pentacyclic triterpenoid with various pharmacological activities, but the molecular targets and underlying mechanisms for its antifibrotic effect in the liver remain elusive. This study aimed to computationally predict the molecular interactome and mechanistically investigate the antifibrotic effect of UA on oxidative stress, with a focus on NOX4 activity and cross-linked signaling pathways in human HSCs and rat liver. Drug–drug interaction via chemical–protein interactome tool, a server that can predict drug–drug interaction via chemical–protein interactome, was used to predict the molecular targets of UA, and Database for Annotation, Visualization, and Integrated Discovery was employed to analyze the signaling pathways of the predicted targets of UA. The bioinformatic data showed that there were 611 molecular proteins possibly interacting with UA and that there were over 49 functional clusters responding to UA. The subsequential benchmarking data showed that UA significantly reduced the accumulation of type I collagen in HSCs in rat liver, increased the expression level of MMP-1, but decreased the expression level of TIMP-1 in HSC-T6 cells. UA also remarkably reduced the gene expression level of type I collagen in HSC-T6 cells. Furthermore, UA remarkably attenuated oxidative stress via negative regulation of NOX4 activity and expression in HSC-T6 cells. The employment of specific chemical inhibitors, SB203580, LY294002, PD98059, and AG490, demonstrated the involvement of ERK, PI3K/Akt, and p38 MAPK signaling pathways in the regulatory effect of UA on NOX4 activity and expression. Collectively, the antifibrotic effect of UA is partially due to the oxidative stress attenuating effect through manipulating NOX4 activity and expression. The results suggest that UA may act as a promising antifibrotic agent. More studies are warranted to evaluate the safety and efficacy of UA in the treatment of liver fibrosis. Keywords: ursolic acid, liver fibrosis, NADPH oxidase, ROS, DDI-CPI, DAVID

Heng Zhou, Xinghu Zhang Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China Aim: Our aim was to study the clinical features of postoperative meningitis after neurosurgery and identify the factors affecting the duration of treatment.Methods: This retrospective study assessed 283 patients with postoperative bacterial meningitis in the Neurosurgery Department of Beijing Tiantan Hospital, Beijing, People’s Republic of China, between January and December 2012. Patients’ clinical data were reviewed, and multivariate logistic regression analysis was used to identify the factors associated with a prolonged treatment course.Results: The mortality rate was 0.4% in these patients, of whom 12.4% were found with pathogens in the cerebrospinal fluid. Among the three most common pathogens detected were methicillin-resistant Staphylococcus aureus, Acinetobacter baumannii, and Pseudomonas aeruginosa. The mean treatment course was 13.5±2.1 days. Interestingly, the treatment duration for postoperative meningitis was significantly longer in patients with intracranial malignant tumors than in those with benign lesions. Single-factor analysis showed that male sex (P=0.042) and malignant (rather than benign) lesions (P

Zhenghui Wang,1 Xiaoli Li,2 Xi-Jing He,3 Xianghong Zhang,1 Zhuangqun Yang,4 Min Xu,1 Baojun Wu,1 Junbo Tu,5 Huanan Luo,1 Jing Yan11Department of Otolaryngology – Head and Neck Surgery, 2Department of Dermatology, 3Department of Orthopedics, The Second Hospital, Xi’an Jiaotong University, 4Department of Plastic and Burns Surgery, The First Hospital, Xi’an Jiaotong University, 5Department of Oral and Maxillofacial Plastic Surgery, The Stomatological Hospital, Xi’an Jiaotong University, Xi’an, People’s Republic of ChinaPurpose: To determine the effects of RNA interference (RNAi) on chondrocyte proliferation, function, and immunological rejection after allogenic tissue-engineered cartilage transplantation within bone matrix gelatin scaffolds.Methods: Seven million rat normal and RNAi chondrocytes were harvested and separately composited with fibrin glue to make the cell suspension, and then transplanted subcutaneously into the back of Sprague Dawley rats after being cultured for 10 days in vitro. Untransplanted animals served as the control group. The allograft and immunological response were examined at 1, 2, 4, 8, and 12 months postoperatively with hematoxylin and eosin histochemical staining, immunohistochemical staining (aggrecan, type II collagen, class I and II major histocompatibility complex), and flow cytometry for peripheral blood cluster of differentiation 4+ (CD4+) and CD8+ T-cells.Results: There was no infection or death in the rats except one, which died in the first week. Compared to the control group, the RNAi group had fewer eukomonocytes infiltrated, which were only distributed around the graft. The ratio of CD4+/CD8+ T-cells in the RNAi group was significantly lower than the normal one (P

Zhong Q Wang,1,2 Yongmei Yu,1,2 Xian H Zhang,1,2 Z Elizabeth Floyd,3 Anik Boudreau,2 Kun Lian,4 William T Cefalu1,21Nutrition and Diabetes Research Laboratory, 2Botanical Research Center, 3Ubiquitin Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA; 4The Center for Energy and Environmental Studies, Southern University, Baton Rouge, LA, USAAim: To compare the effects of dietary fibers on hepatic cellular signaling in mice.Methods: Mice were randomly divided into four groups (n = 9/group): high-fat diet (HFD) control, cellulose, psyllium, and sugarcane fiber (SCF) groups. All mice were fed a HFD with or without 10% dietary fiber (w/w) for 12 weeks. Body weight, food intake, fasting glucose, and fasting insulin levels were measured. At the end of the study, hepatic fibroblast growth factor (FGF) 21, AMP-activated protein kinase (AMPK) and insulin signaling protein content were determined.Results: Hepatic FGF21 content was significantly lowered, but βKlotho, fibroblast growth factor receptor 1, fibroblast growth factor receptor 3, and peroxisome proliferator-activated receptor alpha proteins were significantly increased in the SCF group compared with those in the HFD group (P < 0.01). SCF supplementation also significantly enhanced insulin and AMPK signaling, as well as decreased hepatic triglyceride and cholesterol in comparison with the HFD mice. The study has shown that dietary fiber, especially SCF, significantly attenuates lipid accumulation in the liver by enhancing hepatic FGF21, insulin, and AMPK signaling in mice fed a HFD.Conclusion: This study suggests that the modulation of gastrointestinal factors by dietary fibers may play a key role in both enhancing hepatic multiple cellular signaling and reducing lipid accumulation.Keywords: dietary fiber, FGF21, insulin signaling, AMPK, GLP-1, PI 3K

The exchange coupling between a hard magnetic layer MnBi and a soft magnetic layer Co-Fe has been found to significantly improve the maximum energy product. In this work, the spin structure of exchange-coupled MnBi:Co-Fe bilayers is experimentally investigated by X-ray magnetic circular dichroism (XMCD) and polarized neutron reflectometry (PNR). We find that the out-of-plane magnetization reversal process of the MnBi:Co-Fe bilayer structure involves formation of a curling-type twisting of the magnetization in the film plane at low or intermediate reversal fields. Micromagnetic simulations are further performed to provide a detailed view of the spins at the curling center. Reminiscent of chiral spin structures known as spin bobbers, this curling in the exchange-coupled hard-soft magnetic bilayers is a new type of skyrmionic spin structure and worth further investigation.

We demonstrate substantial enhancement in the energy product of MnBi-based magnets by forming robust ferromagnetic exchange coupling between a MnBi layer and a thin CoFe layer in a unique perpendicular coupling configuration, which provides increased resistance to magnetization reversal. The measured nominal energy product of 172kJ/m3 at room temperature is the largest value experimentally attained for permanent magnets free of expensive raw materials. Our finding shows that exchange-coupled MnBi/CoFe magnets are a viable option for pursuing rare-earth-free magnets with energy products approaching those containing rare-earth elements.