Publications by authors named "Ruifeng Shi"

30 Publications

  • Page 1 of 1

EML4-ALK-mediated activation of the JAK2-STAT pathway is critical for non-small cell lung cancer transformation.

BMC Pulm Med 2021 Jun 6;21(1):190. Epub 2021 Jun 6.

Department of Lung Cancer Surgery, Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.

Background: The echinoderm microtubule-associated protein-like-4 anaplastic lymphoma kinase (EML4-ALK) fusion gene was identified in a subset of non-small cell lung cancer (NSCLC) patients. They responded positively to ALK inhibitors. This study aimed to characterize the mechanisms triggered by EML4-ALK to induce NSCLC transformation.

Methods: HEK293 and NIH3T3 cells were transfected with EML4-ALK variant 3 or pcDNA3.1-NC. H2228 cells were transfected with siRNA-EML4-ALK or siRNA-NC. Cell viability and proliferation were measured by the CCK-8 and EdU methods, respectively. Flow cytometry revealed apoptosis. Gene expression profiles were generated from a signaling pathway screen in EML4-ALK-regulated lung cancer cells and verified by qPCR and Western blotting. The co-immunoprecipitation and immunohistochemistry/ immunofluorescence determined the interaction and colocalization of JAK2-STAT pathway components with EML4-ALK.

Results: Microarray identified several genes involved in the JAK2-STAT pathway. JAK2 and STAT6 were constitutively phosphorylated in H2228 cells. EML4-ALK silencing downregulated phosphorylation of STAT6. Expression of EML4-ALK in HEK293 and NIH3T3 cells activated JAK2, STAT1, STAT3, STAT5, and STAT6. In EML4-ALK-transfected HEK293 cells and EML4-ALK-positive H2228 cells, activated STAT6 and JAK2 colocalized with ALK. STAT3 and STAT6 were phosphorylated and translocated to the nucleus of H2228 cells following IL4 or IL6 treatment. Apoptosis increased, while cell proliferation and DNA replication decreased in H2228 cells following EML4-ALK knockdown. In contrast, HEK293 cell viability increased following EML4-ALK overexpression, while H2228 cell viability significantly decreased after treatment with ALK or JAK-STAT pathway inhibitors.

Conclusions: Our data suggest that the aberrant expression of EML4-ALK leads to JAK2-STAT signaling pathway activation, which is essential for the development of non-small cell lung cancer.
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http://dx.doi.org/10.1186/s12890-021-01553-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180148PMC
June 2021

Prognostic value of ferroptosis-related genes in patients with lung adenocarcinoma.

Thorac Cancer 2021 Jun 12;12(12):1890-1899. Epub 2021 May 12.

Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China.

Background: The prevalence of lung adenocarcinomas (LUADs) has dramatically increased in recent decades. Ferroptosis is a process of iron-dependent regulatory cell death. It is still unclear whether the expression of ferroptosis-related genes (FRGs) is involved in the pathogenesis and survival of patients with LUAD.

Methods: We retrieved LUAD data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and used LASSO Cox regression analysis to select the gene signature suitable for modeling. The risk score was calculated according to the model, and the patients were divided into high- and low-risk groups according to the median risk score. Functional enrichment analysis was carried out by this group, and a model for predicting clinical prognosis was established by combining this group with clinical factors.

Results: Gene set enrichment analysis (GSEA) and single-sample gene set enrichment analysis (ssGSEA) analysis showed that there were several immune-related pathways and immune infiltration differences between high- and low-risk groups. A prognostic model integrating 10 ferroptosis-related genes (FR-DEGs), and clinical factors were constructed and validated in an external cohort.

Conclusions: The FR-DEGs signature was related to immune infiltration, and a model based on FR-DEGs and clinical factors was established to predict the prognosis of patients with LUAD.
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http://dx.doi.org/10.1111/1759-7714.13998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201541PMC
June 2021

[Immune Microenvironment Comparation Study between EGFR Mutant and EGFR Wild Type Lung Adenocarcinoma Patients Based on TCGA Database].

Zhongguo Fei Ai Za Zhi 2021 Apr;24(4):236-244

Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China.

Background: Lung cancer is a malignant with high incidence and mortality and adenocarcinoma is among the most popular subtypes. Epidermal growth factor receptor (EGFR) mutation is one of the most important driver mutations for lung adenocarcinoma and EGFR-tyrosine kinase inhibitor (TKI) will benefit those patients with sensitive EGFR mutations. Recently, immune checkpoint inhibitor (ICI) therapy, provide a new breakthrough treatment for lung cancer patients. Whereas immunotherapy as an emerging treatment does not benefit patients with EGFR mutations, for which mechanistic studies are poorly defined and focused on the link of EGFR mutations and programmed cell death-ligand 1 (PD-L1) expression, we speculate that the different immune microenvironment associated with the two classes of patients.

Methods: Lung adenocarcinoma datasets were collected from the Cancer Genome Atlas (TCGA) database, and clinical information and gene expression profiles were downloaded. The immune related lymphocyte infiltration in TCGA database were generated through timer 2.0 GSEA was used to analyze the difference of pathway expression between EGFR mutant patients and wild type patients.

Results: EGFR mutation was more frequently among women and never smokers. Immunoinfiltration analysis showed that patients with EGFR mutation tends to have more tumor associated fibroblasts, common myeloid progenitor cells, hematopoietic stem cells, effector CD4⁺ T cells and natural killer T cells infiltration, and less memory B cells, naïve B cells, plasma B cells, plasmacytoid dendritic cells, memory CD4⁺ T cells, CD4⁺ helper T cells 2, naive CD8⁺ T cells, CD8⁺ T cells and central memory CD8⁺ T cells infiltration. Moreover, patients with more infiltration of CD8⁺ T cells, natural killer T cells, memory B cells and hematopoietic stem cells, tends have better prognosis (Log-rank test, P=0.017, 0.0093, 0.018, 0.016). However, the patients with more CD4⁺ T th2 infiltration in the tumor tends to have worse prognosis (Log-rank test, P=0.016). Furthermore, the results of gene set enrichment analysis showed that compared with the lung adenocarcinoma patients with EGFR wild type, the three pathways positive regulation of natural killer (NK) cell-mediated immune response to tumor cells, NK cell activation involved in immune response, and NK cell-mediated immune response to tumor cells related to natural killer cells in patients with EGFR mutation were down regulated, while the pathway the positive regulation of cytokine secretion involved in immune response was up-regulated in EGFR mutation patients.

Conclusions: The tumour microenvironment of patients with EGFR mutations lacks potent tumour killing effector cells and appears dysfunctional with effector cells. This may be a potential reason for the poor efficacy of immunotherapy in patients with EGFR mutations.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2021.102.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105612PMC
April 2021

Mutations Associated with No Durable Clinical Benefit to Immune Checkpoint Blockade in Non-S-Cell Lung Cancer.

Cancers (Basel) 2021 Mar 19;13(6). Epub 2021 Mar 19.

Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300050, China.

(1) Background: The immune checkpoint blockade (ICB) has shown promising efficacy in non-small-cell lung cancer (NSCLC) patients with significant clinical benefits and durable responses, but the overall response rate to ICBs is only 20%. The lack of responsiveness to ICBs is currently a central problem in cancer immunotherapy. (2) Methods: Four public cohorts comprising 2986 patients with NSCLC were included in the study. We screened 158 patients with NSCLC with no durable clinical benefit (NDB) to ICBs in the Rizvi cohort and identified NDB-related gene mutations in these patients using univariate and multivariate Cox regression analyses. Programmed death-ligand 1 (PD-L1) expression, tumor mutation burden (TMB), neoantigen load, tumor-infiltrating lymphocytes, and immune-related gene expression were analyzed for identifying gene mutations. A comprehensive predictive classifier model was also built to evaluate the efficacy of ICB therapy. (3) Results: Mutations in FAT1 and KEAP1 were found to correlate with NDB in patients with NSCLC to ICBs; however, the analysis suggested that only mutation in FAT1 was valuable in predicting the efficacy of ICB therapy, and that mutation in KEAP1 acted as a prognostic but not a predictive biomarker for NSCLC. Mutations in FAT1 were associated with a higher TMB and lower multiple lymphocyte infiltration, including CD8 (T-Cell Surface Glycoprotein CD8)+ T cells. We established a prognostic model according to PD-L1 expression, TMB, smoking status, treatment regimen, treatment type, and FAT1 mutation, which indicated good accuracy by receiver operating characteristic (ROC) analysis (area under the curve (AUC) for 6-months survival: 0.763; AUC for 12-months survival: 0.871). (4) Conclusions: Mutation in FAT1 may be a predictive biomarker in patients with NSCLC who exhibit NDB to ICBs. We proposed an FAT1 mutation-based model for screening more suitable NSCLC patients to receive ICBs that may contribute to individualized immunotherapy.
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http://dx.doi.org/10.3390/cancers13061397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003499PMC
March 2021

Integrative Analyses of Genes Associated With Osteoporosis in CD16+ Monocyte.

Front Endocrinol (Lausanne) 2020 21;11:581878. Epub 2021 Jan 21.

Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.

Background: Osteoporosis is a metabolic bone disease characterized by decreased bone mineral density and abnormal bone quality. Monocytes can secret cytokines for bone resorption, resulting in bone mass loss. However, the mechanism by which monocytes subpopulations lead to osteoporosis remains unclear. The aim of this study was to identify genes associated with osteoporosis in monocytes subsets.

Methods: Three microarray datasets including GSE7158 (transcription of low/high-peak bone mass), GSE101489 (transcription of CD16+/CD16- monocyte) and GSE93883 (miRNA expression profile of primary osteoporosis) were derived from the Gene Expression Omnibus (GEO) database and analyzed with GEO2R tool to identify differentially expressed genes (DEGs). Functional enrichment was analyzed using Metascape database and GSEA software. STRING was utilized for the Protein-Protein Interaction Network construct. The hub genes were screened out using the Cytoscape software. Related miRNAs were predicted in miRWalk, miRDB, and TargetScan databases.

Results: Total 368 DEGs from GSE7158 were screened out, which were mostly enriched in signaling, positive regulation of biological process and immune system process. The hub genes were clustered into two modules by PPI network analysis. We identified 15 overlapping DGEs between GSE101489 and GSE7158 microarray datasets. Moreover, all of them were up-regulated genes in both datasets. Then, nine key genes were screened out from above 15 overlapping DEGs using Cytoscape software. It is a remarkable fact that the nine genes were all in one hub gene module of GSE7158. Additionally, 183 target miRNAs were predicted according to the above nine DEGs. After cross-verification with miRNA express profile dataset for osteoporosis (GSE93883), 12 DEmiRNAs were selected. Finally, a miRNA-mRNA network was constructed with the nine key genes and 12 miRNAs, which were involved in osteoporosis.

Conclusion: Our analysis results constructed a gene expression framework in monocyte subsets for osteoporosis. This approach could provide a novel insight into osteoporosis.
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http://dx.doi.org/10.3389/fendo.2020.581878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859337PMC
June 2021

Identification of small proline-rich protein 1B (SPRR1B) as a prognostically predictive biomarker for lung adenocarcinoma by integrative bioinformatic analysis.

Thorac Cancer 2021 03 26;12(6):796-806. Epub 2021 Jan 26.

Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China.

Background: With the ongoing development of targeted therapy and immunotherapy in recent years, the overall five-year survival rate of NSCLC patients has not improved, and the search for novel diagnostic and prognostic markers for lung adenocarcinoma continues.

Methods: Lung adenocarcinoma (LUAD) gene expression data and relevant clinical information were obtained from the TCGA. Hub genes were identified with weighted gene co-expression network analysis (WGCNA) and protein-protein interaction network (PPI). Survival analyses were also performed using GEPIA. The 536 LUAD patients were divided into two groups according to the SPRR1B expression level and analyzed by gene set enrichment analysis (GSEA) and verified by immunoblotting. The effects of SPRR1B on cell proliferation and cell metastasis and apoptosis were evaluated by 5-ethynyl-2'-deoxyuridine (EdU) staining, colony formation assay, transwell migration and invasion assay, and flow cytometry, respectively.

Results: A total of 2269 DEGs were analyzed by WGCNA and five hub genes (CCK, FETUB, PCSK9, SPRR1B, and SPRR2D) were identified. Among them, SPRR1B was selected as one of the most significant prognostic genes in LUAD. SPRR1B was found to be highly expressed in lung adenocarcinoma cells compared with that in normal bronchial epithelial cells. In addition, silencing of SPRR1B could inhibit the cell proliferation, invasion, and migration of lung adenocarcinoma cells, but induced cell apoptosis and G2/M phase arrest in vitro. The result of GSEA and immunoblotting revealed that SPRR1B activated the MAPK signaling pathway involved in the proliferation and metastasis of lung cancer.

Conclusions: Our findings demonstrate that SPRR1B may function as a prognosis predictor in lung adenocarcinoma.
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http://dx.doi.org/10.1111/1759-7714.13836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952803PMC
March 2021

EZH2 inhibitors reverse resistance to gefitinib in primary EGFR wild-type lung cancer cells.

BMC Cancer 2020 Dec 4;20(1):1189. Epub 2020 Dec 4.

Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, P.R. China.

Background: Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. In traditional anti-cancer therapy, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) have been proven to be beneficial for patients with EGFR mutations. However, patients with EGFR wild-type NSCLC were usually not respond to EGFR-TKIs. Enhancer of zeste homolog 2 (EZH2) is a key molecular in the PRC2 complex and plays an important role in epigenetic regulation and is overexpressed in variant tumors. EZH2 inhibitors have been reported to sensitize variant tumor cells to anticancer drugs. This study aimed to investigate whether the EZH2 inhibitors, GSK343 and DZNep when combined with gefitinib can reverse EGFR-TKIs resistance in EGFR wild-type NSCLC cells.

Methods: The RNA-sequencing data of patients with NSCLC [502 patients with lung squamous cell carcinoma, including 49 paracancerous lung tissues and 513 patients with lung adenocarcinoma (LUAD), including 59 paracancerous lung tissues] from the Cancer Genome Atlas (TCGA), were analyzed for EZH2 expression. EZH2 expression was verified in 40 NSCLC tissue cancer samples and their corresponding paracancerous tissues from our institute (TJMUGH) via RT-PCR. A549 and H1299 cells treated with siRNA or EZH2 inhibitors were subjected to cell viability and apoptosis analyses as well to EGFR pathway proteins expression analyses via western blotting.

Results: EZH2 was upregulated in human NSCLC tissues and correlated with poor prognosis in patients with LUAD based on data from both TCGA and TJMUGH. Both GSK343 and DZNep sensitized EGFR wild-type LUAD cells (A549 and H1299) to gefitinib and suppressed cell viability and proliferation in vitro by downregulating the phosphorylation of EGFR and AKT and by inducing cell apoptosis. Co-administration of EZH2 inhibitors (GSK343 or DZNep) with gefitinib exerted a stronger inhibitory effect on tumor activity, cell proliferation and cell migration than single drug administration in vitro and in vivo.

Conclusions: These data suggest that the combination of EZH2 inhibitors with EGFR-TKIs may be an effective method for treating NSCLC-patients with EGFR-wild type, who do not want to undergo traditional treatment with chemotherapy.
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http://dx.doi.org/10.1186/s12885-020-07667-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716470PMC
December 2020

Risk Factors and Clinical Significance of D-Dimer in the Development of Postoperative Venous Thrombosis in Patients with Lung Tumor.

Cancer Manag Res 2020 30;12:5169-5179. Epub 2020 Jun 30.

Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, People's Republic of China.

Background: The incidence of venous thromboembolism (VTE) is higher in patients with lung cancer. The aim of this study was to investigate the risk factors associated with postoperative VTE and explore the VTE predication capacity of D-dimer kinetics.

Patients And Methods: Six hundred patients who had lung tumor surgery were analyzed retrospectively between January 2018 and August 2019, and venous ultrasound imaging and D-dimer examination before and after surgery were recommended to all operative patients. Of these 600 patients, 523 patients had venous thromboembolism after surgery, and 77 patients had not found. The general clinical data, postoperative prophylactic anticoagulant therapy, early systemic thromboprophylaxis, 50% increment of D-dimer, 100% increment of D-dimer, and perioperative (preoperative and days 1, 3, and 5 after surgery) D-dimer levels were collected. Logistic regression analysis was used to analyze the independent risk factors of postoperative VTE.

Results: VTE developed in 77 (12.8%) patients. In a univariate analysis, age, surgical approach, tumor size, histology, postoperative preventive anticoagulation, postoperative limb compression therapy, postoperative hemostasis, duration of operation, early systemic thromboprophylaxis, 100% increment of D-dimer, preoperative and postoperative D-dimer level, intraoperative blood loss, and time spent in the hospital were significantly different between the thrombus group and nonthrombus group ( < 0.05). Multivariate analysis showed that age >60 years ( = 0.006) and D-dimer level on 5 days after surgery ( = 0.000) were significant independent risk factors for VTE. Postoperative D-dimer was significantly higher than the preoperative level ( < 0.001). Postoperative D-dimer level was significantly different between benign and malignant tumor groups ( < 0.05) and between the thrombus group and nonthrombus group ( < 0.001). Preventive anticoagulation and limb compression therapy starting from the first day after surgery was statistically significant between the thrombus group and the nonthrombus group ( < 0.05).

Conclusion: Continuous detection of D-dimer level after pulmonary tumor surgery combined with thrombotic-related risk factors can better evaluate the occurrence of VTE. Preventive anticoagulant therapy and limb compression therapy starting from the first day after surgery can effectively reduce the incidence of VTE.
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http://dx.doi.org/10.2147/CMAR.S256484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335272PMC
June 2020

[The Role of Plasma CDO1 Methylation in the Early Diagnosis of Lung Cancer].

Zhongguo Fei Ai Za Zhi 2020 May 22;23(5):314-320. Epub 2020 Apr 22.

Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China.

Background: The incidence and mortality of lung cancer often rank first in all malignant tumors. DNA methylation, as one of epigenetics, often participates in the development and progression of tumors. CDO1 as a tumor suppressor gene always undergoes methylation changes early in tumor development. Therefore, this study aims to discuss the value of CDO1 methylation in the early diagnosis of lung cancer.

Methods: Peripheral blood samples were collected from tumor patients and healthy people. Detection of the methylation level of CDO1 in plasma by sulfite modification and quantitative real-time PCR.

Results: The level of gene methylation in peripheral blood of lung cancer patients was significantly higher than that of benign lung disease patients and healthy people. The methylation level of CDO1 was significantly different in the stratified comparison of gender, lymph node metastasis and tumor-node-metastasis (TNM) stage (P<0.05). The sensitivity and specificity of CDO1 were 52.2% and 78.6%, respectively. The overall accuracy of the diagnosis was significantly higher than that of the clinical tumor markers, and the sensitivity of CDO1 to stage I and II patients was the highest (40.8%, 47.1%). In addition, CDO1 could effectively increase the sensitivity of diagnosis in multiple joint examinations.

Conclusions: Detecting the methylation level of CDO1 has a potentially huge advantage for the early diagnosis of lung cancer.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2020.102.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260387PMC
May 2020

[Apatinib Combined with CCI-779 Inhibits the Proliferation and Migration of Small Cell Lung Cancer NCI-H446 Cells In Vitro].

Zhongguo Fei Ai Za Zhi 2020 Apr 26;23(4):216-222. Epub 2020 Mar 26.

Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China.

Background: Lung cancer is the most common malignancy world-wide. Small cell lung cancer is the deadliest subtype of lung cancer, which features such as rapid growth, early metastasis, and high vascularization. Apatinib is a vascular endothelial growth factor receptor 2 inhibitor independently developed in China, which has a significant inhibition in a variety of solid tumors. The purpose of this study is to investigate the effects of Apatinib alone or Apatinib combined with mammalian target of rapamycin (mTOR) inhibitor, CCI-779, on small cell lung cancer cell line NCI-H446 in vitro.

Methods: The small cell lung cancer cell line NCI-H446 was grew in vitro. The effects of Apatinib alone or Apatinib combined with CCI-779 on proliferation, apoptosis, cell cycle and migration of NCI-H446 small cell lung cancer cells were detected by CCK8; FACS and transwell assays were also carried out; Western blot assays were used to detect vascular endothelial growth factor and cell cycle related protein expression.

Results: CCK8 assays showed that high concentration of Apatinib could inhibit the proliferation of NCI-H446 cells. Apoptosis assays showed that high concentration of Apatinib could induce NCI-H446 cell apoptosis. Transwell assays showed that high concentration of Apatinib could inhibit NCI-H446 cell migration. After combined with mTOR inhibitor CCI-779, low concentration of Apatinib could inhibit the proliferation and migration of NCI-H446 small cell lung cancer cells and induce apoptosis.

Conclusions: Apatinib has a concentration-dependent effect on the small cell lung cancer cell line NCI-H446. High concentration of Apatinib can inhibit the proliferation and migration of NCI-H446 small cell lung cancer cells, induce apoptosis. Apatinib combined with the mTOR inhibitor CCI-779 can sensitize the NCI-H446 cells to Apatinib.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2020.104.08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210093PMC
April 2020

[Research Progress of Epigenetics in Pathogenesis and Treatment of Malignant Tumors].

Zhongguo Fei Ai Za Zhi 2020 Feb;23(2):91-100

Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin Lung Cancer Institute, Tianjin Key Laboratory of lung Cancer Metastasis and Tumor Microenvironment, Tianjin 300052, China.

Epigenetic modification is closely related to the occurrence and development of tumors. It mainly regulates gene function and expression level through DNA methylation, histone modification, regulation of non-coding RNA and chromatin structure reconstruction. At present, epigenetic drugs have been gradually applied to the treatment of malignant tumors. Common drug types include: DNA methyltransferase inhibitors and histone deacetylase inhibitors. However, these drugs still have many shortcomings and a wide range of clinical applications need further research. Encouragingly, the epigenetic drugs in combination with various anti-tumor drugs have shown great application potential. In this paper, we summarized the development mechanism of epigenetics in malignant tumors and the progress of related drugs.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2020.02.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049791PMC
February 2020

Synthesis and cytotoxic activity of chalcone analogues containing a thieno[2,3-d]pyrimidin-2-yl group as the A-ring or B-ring.

Bioorg Chem 2020 01 10;94:103346. Epub 2019 Oct 10.

Guangdong Key Laboratory for Genome Stability & Disease Prevention and Carson International Cancer Center and Marshall Laboratory of Biomedical Engineering, Shenzhen University School of Medicine, Shenzhen, Guangdong, 518060, PR China. Electronic address:

Many natural or synthetic chalcones have potential anti-tumor activity. Here, we synthesized two series of chalcone analogues containing a thieno[2,3-d]pyrimidin-2-yl group and evaluated for their cytotoxic activity towards cultured human lung cancer A549 and colorectal HCT-116 cells. Among them, compound 8d was the most cytotoxic against HCT-116 cells, with an IC value of 2.65 μM. Analyses of the phenotypic changes induced by this compound found a dose-dependent accumulation of HCT-116 cells in sub-G1 phase, indicating that compound 8d might induce apoptosis. Furthermore, we found that 8d triggered mitochondrial membrane potential depolarization, promoted reactive oxygen species formation in HCT-116 cells, and increased the percentage of early and late apoptotic cells. Finally, immunoblotting indicated that 8d increased PARP-1 and caspases 3, 7 and 9 cleavage. These data suggest that compound 8d induces apoptosis via the mitochondrial death pathway.
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http://dx.doi.org/10.1016/j.bioorg.2019.103346DOI Listing
January 2020

Protective effects of Clec11a in islets against lipotoxicity via modulation of proliferation and lipid metabolism in mice.

Exp Cell Res 2019 11 5;384(1):111613. Epub 2019 Sep 5.

Department of Biochemistry and Molecular Biology, School of Medicine, Southeast University, Nanjing 210009, China. Electronic address:

The lipotoxicity is considered as one of the risk for diabetes. Here we report C-type lectin domain family 11, member A (Clec11a) as a new regulator in islet playing a protective role in lipotoxicity induced dysfunction. Islet transcriptome sequencing was performed using the high-fat diet induced obesity (DIO) mice model. We found a significant decrease of Clec11a expression in islets of DIO mice compared to normal control mice, which was further confirmed by real-time PCR. Immunostaining demonstrated the localization of the Clec11a protein in mouse islets. Administration of recombinant human Clec11a (rClec11a) protein promoted the proliferation of islet cells and rescued the inhibition of fatty acid on cell proliferation, which involved the activation of Erk signaling pathway. We also found that the rClec11a altered the expression of genes involved in lipid metabolism.
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http://dx.doi.org/10.1016/j.yexcr.2019.111613DOI Listing
November 2019

[Effect of Apatinib on Invasion and Migration of Lung Cancer Cells
and Its Mechanism].

Zhongguo Fei Ai Za Zhi 2019 May;22(5):264-270

Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China.

Background: Lung cancer is one of the most deadly cancers in the world for human. In recent years, the effect of targeted therapy has become increasingly significant. Apatinib is a multi-target anti-tumor drug that is currently under study. The purpose of this study is to investigate the effects of Apatinib on the biological characteristics of lung cancer cells and its possible mechanism.

Methods: Lung cancer cell lines H1299 and H3255 were cultured in vitro. The effects of Apatinib on proliferation, migration and invasion of H1299 and H3255 cells were detected by cell proliferation assays wound healing assays and Transwell assays. The protein expression related to cancer angiogenesis and invasion was detected by Western blot.

Results: Apatinib significantly inhibited the proliferation, migration and invasion of H1299 and H3255 in a concentration-dependent manner. Western blot showed that with the increasing of drug concentration, VEGF, VEGFR2, N-cadherin, MMP9, MMP2 and Vimentin were down-regulated, and E-cadherin were up-regulated.

Conclusions: Apatinib can inhibit the invasion and migration of lung adenocarcinoma cells H1299 and H3255. By regulation of epithelial-mesenchymal transition and the expression of matrix metalloproteinase-related proteins.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2019.05.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533190PMC
May 2019

[Role of EZH2 Inhibitor Combined with Gefitinib in EGFR-TKIs Resistant Lung Cancer Cells].

Zhongguo Fei Ai Za Zhi 2019 May;22(5):255-263

Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China.

Background: Lung cancer is one of the common malignant tumors that impair human health. With the development of epigenetics, the researchers found that enhancer of Zeste homolog 2 (EZH2) is highly expressed in lung cancer tissue and its expression is closely related to the prognosis. EZH2 inhibitor can also enhance the sensitivity of tumor cells to a variety of anti-tumor drugs. The purpose of this study is to investigate the effect of combination of EZH2 inhibitor and gefitinib on the proliferation, apoptosis and migration of Gefitinib-resistant lung cancer cells.

Methods: PC9 and PC9/AB2 cells were used for this study. CCK-8 and EdU experiment were used to detect combined treatment on cell viability and proliferation activity; Wound healing assay and Transwell chamber experiment were used to determine the effects of combination therapy on cell migration ability; Flow cytometry was used to detect the effect of combination therapy on EZH2 and apoptosis; Western blot was used to observe the effect of combination therapy on epidermal growth factor receptor (EGFR) signaling pathway-related proteins expression.

Results: In gefitinib-resistant cell line PC9/AB2, gefitinib combined with EZH2 inhibitor GSK343 can significantly inhibit cell viability, reduce cell migration and increase cell apoptosis. At the same time, combination therapy can significantly inhibit the expression of EZH2 and phosphorylation EGFR proteins.

Conclusions: The combination of EZH2 inhibitor GSK343 and gefitinib sensitize PC9/AB2 cell to gefitinib response. This study also suggests that synergistic therapy plays a role in the reversal of EGFR-tyrosine kinase inhibitor (EGFR-TKIs) resistance in lung cancer.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2019.05.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533193PMC
May 2019

Efficacy of Co-administration of Liuwei Dihuang Pills and Ginkgo Biloba Tablets on Albuminuria in Type 2 Diabetes: A 24-Month, Multicenter, Double-Blind, Placebo-Controlled, Randomized Clinical Trial.

Front Endocrinol (Lausanne) 2019 22;10:100. Epub 2019 Feb 22.

Department of Endocrinology, Zhongda Hospital, School of Medicine, Institute of Diabetes, Southeast University, Nanjing, China.

We investigated the effects of Traditional Chinese Medicine (TCM) on the occurrence and progression of albuminuria in patients with type 2 diabetes. In this randomized, double-blind, multicenter, controlled trial, we enrolled 600 type 2 diabetes without diabetic nephropathy (DN) or with early-stage DN. Patients were randomly assigned (1:1) to receive Liuwei Dihuang Pills (LWDH) (1.5 g daily) and Ginkgo biloba Tablets (24 mg daily) orally or matching placebos for 24 months. The primary endpoint was the change in urinary albumin/creatinine ratio (UACR) from baseline to 24 months. There were 431 patients having UACR data at baseline and 24 months following-up in both groups. Changes of UACR from baseline to follow-up were not affected in both groups: -1.61(-10.24, 7.17) mg/g in the TCM group and -0.73(-7.47, 6.75) mg/g in the control group. For patients with UACR ≥30 mg/g at baseline, LWDH and Ginkgo biloba significantly reduced the UACR value at 24 months [46.21(34.96, 58.96) vs. 20.78(9.62, 38.85), < 0.05]. Moreover, the change of UACR from baseline to follow-up in the TCM group was significant higher than that in the control group [-25.50(-42.30, -9.56] vs. -20.61(-36.79, 4.31), < 0.05]. LWDH and Ginkgo biloba may attenuate deterioration of albuminuria in type 2 diabetes patients. These results suggest that TCM is a promising option of renoprotective agents for early stage of DN. The study was registered in the Chinese Clinical Trial Registry. (no. ChiCTR-TRC-07000037, chictr.org).
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http://dx.doi.org/10.3389/fendo.2019.00100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402447PMC
February 2019

MRE11 UFMylation promotes ATM activation.

Nucleic Acids Res 2019 05;47(8):4124-4135

Guangdong Key Laboratory for Genome Stability & Disease Prevention, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China.

A proper DNA damage response (DDR) is essential to maintain genome integrity and prevent tumorigenesis. DNA double-strand breaks (DSBs) are the most toxic DNA lesion and their repair is orchestrated by the ATM kinase. ATM is activated via the MRE11-RAD50-NBS1 (MRN) complex along with its autophosphorylation at S1981 and acetylation at K3106. Activated ATM rapidly phosphorylates a vast number of substrates in local chromatin, providing a scaffold for the assembly of higher-order complexes that can repair damaged DNA. While reversible ubiquitination has an important role in the DSB response, modification of the newly identified ubiquitin-like protein ubiquitin-fold modifier 1 and the function of UFMylation in the DDR is largely unknown. Here, we found that MRE11 is UFMylated on K282 and this UFMylation is required for the MRN complex formation under unperturbed conditions and DSB-induced optimal ATM activation, homologous recombination-mediated repair and genome integrity. A pathogenic mutation MRE11(G285C) identified in uterine endometrioid carcinoma exhibited a similar cellular phenotype as the UFMylation-defective mutant MRE11(K282R). Taken together, MRE11 UFMylation promotes ATM activation, DSB repair and genome stability, and potentially serves as a therapeutic target.
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http://dx.doi.org/10.1093/nar/gkz110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486557PMC
May 2019

RNF126 Quenches RNF168 Function in the DNA Damage Response.

Genomics Proteomics Bioinformatics 2018 12 4;16(6):428-438. Epub 2018 Dec 4.

College of Life Sciences, Capital Normal University, Beijing 100048, China; Guangdong Key Laboratory for Genome Stability & Disease Prevention, Shenzhen University Health Science Center, Shenzhen 518060, China. Electronic address:

DNA damage response (DDR) is essential for maintaining genome stability and protecting cells from tumorigenesis. Ubiquitin and ubiquitin-like modifications play an important role in DDR, from signaling DNA damage to mediating DNA repair. In this report, we found that the E3 ligase ring finger protein 126 (RNF126) was recruited to UV laser micro-irradiation-induced stripes in a RNF8-dependent manner. RNF126 directly interacted with and ubiquitinated another E3 ligase, RNF168. Overexpression of wild type RNF126, but not catalytically-inactive mutant RNF126 (CC229/232AA), diminished ubiquitination of H2A histone family member X (H2AX), and subsequent bleomycin-induced focus formation of total ubiquitin FK2, TP53-binding protein 1 (53BP1), and receptor-associated protein 80 (RAP80). Interestingly, both RNF126 overexpression and RNF126 downregulation compromised homologous recombination (HR)-mediated repair of DNA double-strand breaks (DSBs). Taken together, our findings demonstrate that RNF126 negatively regulates RNF168 function in DDR and its appropriate cellular expression levels are essential for HR-mediated DSB repair.
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http://dx.doi.org/10.1016/j.gpb.2018.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411902PMC
December 2018

Synthesis and evaluation of chalcone analogues containing a 4-oxoquinazolin-2-yl group as potential anti-tumor agents.

Eur J Med Chem 2019 Jan 16;162:586-601. Epub 2018 Nov 16.

Shenzhen University School of Medicine and Guangdong Key Laboratory for Genome Stability & Disease Prevention, Shenzhen, Guangdong, 518060, PR China. Electronic address:

The chalcone motif can be found in many molecules that contribute to essential biological processes, and many chalcone-containing compounds exhibit potent anti-cancer activity. Here, we synthesized two series of chalcone analogues (3a-s and 6a-s) based on substituting the chalcone B-ring or A-ring with a 4-oxoquinazolin-2-yl group, and then evaluated them for cytotoxic activity in human colorectal HCT-116 and breast cancer MCF-7 cell lines. Compounds 3a-s (in which a 4-oxoquinazolin-2-yl group functioned as the B-ring) were markedly more cytotoxic than compounds 6a-s (in which 4-oxoquinazolin-2-yl group functioned as the A-ring), based on their IC values to inhibit proliferation. Compound 3f was found as the most potent among 38 analogues and the mechanism of its cytotoxicity was investigated. Flow cytometry indicated that HCT-116 cells treated with compound 3f resulted in a dose-dependent accumulation of cells in the sub-G1 phase, which is representative of apoptotic cells. Subsequent assays (including Annexin V-FITC/PI, AO-EB, MitoSOX™ Red and JC-1 staining) confirmed that 3f exposure induced apoptosis in HCT-116 cells. Immunoblotting analysis indicated that cellular exposure to 3f increased the cleavage of PARP1 and caspases 3, 7, and 9. Taken together, this novel chalcone analogue has a cytotoxic effect on cultured cancer cell-lines that is likely mediated by inducing apoptosis via the mitochondrial death pathway.
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http://dx.doi.org/10.1016/j.ejmech.2018.11.034DOI Listing
January 2019

Score for lung adenocarcinoma in China with EGFR mutation of exon 19: Combination of clinical and radiological characteristics analysis.

Medicine (Baltimore) 2018 Sep;97(38):e12537

Department of Radiology Clinical Nutrition Department, Changhai Hospital, Second Military Medical University, Shanghai Department of Radiology, Yanan University Affiliated Hospital, Shanxi Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai, China.

Backgroud: The biopsy samples might be the only tumor material available for testing the EGFR mutation status in some cases, but these samples are often composed of variable ratios of tumor to normal cells. In this study, we sought to build a scoring system to predict Epidermal growth factor receptor (EGFR) exon 19 mutation in lung adenocarcinoma by clinical and radiological features.

Methods: Enrolled in this study were 601 patients with lung adenocarcinoma. Qualitative evaluation of the clinical and radiological features included 25 aspects. Statistical analysis was used to assess the association of these features between the EGFR wild type and exon 19 mutation, based on a clinical scoring system built by the statistical model and the experience of the radiologists.

Results: EGRF-exon-19-mutation was associated with the female gender [odds ratios (OR), 2.573; 95% confidence intervals (CI), 1.689-3.920], tumor maximum diameter (OR, 0.357; 95% CI, 0.235-0.542), the absence of emphysema (OR, 0.202; 95% CI, 0.110-0.368), the absence of fibrosis (OR, 0.168; 95% CI, 0.083-0.339), and pleural retraction (OR, 2.170; 95% CI, 1.434-3.285). The clinical scoring model assigned 3 points to the female gender, 2 points to small tumor maximum diameter (≤34.5 mm), 2 to the absence of emphysema, 2 to the absence of fibrosis, and 1 to the presence of pleural retraction.

Conclusions: The scoring system based on the statistical analysis of clinical and radiological features may be a new alternative to the prediction of EGFR mutation subtypes.
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http://dx.doi.org/10.1097/MD.0000000000012537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160170PMC
September 2018

A Transcriptional Sequencing Analysis of Islet Stellate Cell and Pancreatic Stellate Cell.

J Diabetes Res 2018 24;2018:7361684. Epub 2018 Jan 24.

Department of Endocrinology, Institute of Diabetes, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, China.

Background: Our previous studies have shown that islet stellate cell (ISC), similar to pancreatic stellate cell (PSC) in phenotype and biological characters, may be responsible for the islet fibrosis in type 2 diabetes. To further identify the differences between PSC and ISC and for better understanding of the physiological function of ISC, we employed genome-wide transcriptional analysis on the PSCs and ISCs of Wistar rats.

Method: PSCs and ISCs from each rat were primarily cultured at the same condition. Genome-wide transcriptional sequence of stellate cells was generated. The identified differentially expressed genes were validated using RT-PCR.

Results: 32 significant differentially expressed genes between PSCs and ISCs were identified. Moreover, collagen type 11a1 (), was found to be expressed 2.91-fold higher in ISCs compared with PSCs, indicating that COL11A1 might be a potential key gene modulating the differences between PSC and ISC.

Conclusions: Our study identified and validated the differences between PSC and ISC in genome-wide transcriptional scale, confirming the assumption that ISC and PSC are similar other than identical. Moreover, our data might be instrumental for further investigation of ISC and islet fibrosis, and some differential expressed genes may provide an insight into new therapeutic targets for type 2 diabetes.
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http://dx.doi.org/10.1155/2018/7361684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830286PMC
October 2018

Phosphorylation of LSD1 by PLK1 promotes its chromatin release during mitosis.

Cell Biosci 2017 23;7:15. Epub 2017 Mar 23.

Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing, 100048 China.

Background: Lysine-specific histone demethylase 1 (LSD1) modulates chromatin status through demethylation of H3K4 and H3K9. It has been demonstrated that LSD1 is hyperphosphorylated and dissociates from chromatin during mitosis. However, the molecular mechanism of LSD1 detachment is unknown.

Results: In this report, we found that polo-like kinase 1 (PLK1) directly interacted with LSD1 and phosphorylated LSD1 at Ser-126 . Nocodazole-induced metaphase arrest promoted release of LSD1 from chromatin, and the phosphorylation-defective mutant LSD1 (S126A) failed to dissociate from chromatin upon nocodazole treatment.

Conclusions: Taken together, our findings demonstrate that phosphorylation of LSD1 at Ser-126 by PLK1 promotes its release from chromatin during mitosis.
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http://dx.doi.org/10.1186/s13578-017-0142-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364692PMC
March 2017

Radiological and Clinical Features associated with Epidermal Growth Factor Receptor Mutation Status of Exon 19 and 21 in Lung Adenocarcinoma.

Sci Rep 2017 03 23;7(1):364. Epub 2017 Mar 23.

Department of Radiology, Changhai Hospital, Second Military Medical University, Shanghai, China.

The exon 19 and 21 in Epidermal Growth Factor Receptor (EGFR) mutation are the most common subtype of lung adenocarcinoma, and the strongest predictive biomarker for progression-free survival and tumor response. Although some studies have shown differences in radiological features between cases with and without EFGR mutations, they lacked necessary stratification. This article is to evaluate the association of CT features between the wild type and the subtype (exon 19 and 21) of EGFR mutations in patients with lung adenocarcinoma. Of the 721 finally included patients, 132 were positive for EGFR mutation in exon 19, 140 were positive for EGFR mutation in exon 21, and 449 were EGFR wild type. EGFR mutation in exon 19 was associated with a small-maximum diameter (28.51 ± 14.07) (p < 0.0001); sex (p < 0.0001); pleural retraction (p = 0.0034); and the absence of fibrosis (p < 0.0001), while spiculated margins (p = 0.0095), subsolid density (p < 0.0001) and no smoking (p < 0.0001) were associated with EGFR mutation in exon 21. Receiver Operating Characteristic (ROC) curves suggested that the maximum Area Under the Curve (AUC) was related to the female gender (AUC = 0.636) and the absence of smoking (AUC = 0.681). This study demonstrated the radiological and clinical features could be used to prognosticate EGFR mutation subtypes in exon 19 and 21.
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http://dx.doi.org/10.1038/s41598-017-00511-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428650PMC
March 2017

Tissue Kallikrein Alleviates Cerebral Ischemia-Reperfusion Injury by Activating the B2R-ERK1/2-CREB-Bcl-2 Signaling Pathway in Diabetic Rats.

Oxid Med Cell Longev 2016;2016:1843201. Epub 2016 Jun 30.

Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.

Diabetes mellitus (DM) substantially increases the risk of ischemic stroke and reduces the tolerance to ischemic insults. Tissue kallikrein (TK) has been demonstrated to protect neurons from ischemia/reperfusion (I/R) injury in orthoglycemic model by activating the bradykinin B2 receptor (B2R). Considering the differential effects of B2R or bradykinin B1 receptor (B1R) on cardioprotection and neuroprotection in I/R with or without diabetes, this study was designed to investigate the role of TK during cerebral I/R injury in streptozotocin-induced diabetic rats. Intravenous injection of TK inhibited apoptosis in neurons, alleviated edema and inflammatory reactions after focal cerebral I/R, significantly reduced the infarct volume, and improved functional recovery. These beneficial effects were accompanied by activation of the extracellular signal-regulated kinase 1/2 (ERK1/2), cAMP response element-binding (CREB), and Bcl-2 signal proteins. Inhibition of the B2R or ERK1/2 pathway abated the effects of TK, whereas an antagonist of B1R enhanced the effects. These findings reveal that the neuroprotective effect of TK against cerebral I/R injury in streptozotocin-induced diabetic rats mainly involves the enhancement of B2R and ERK1/2-CREB-Bcl-2 signaling pathway activity.
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http://dx.doi.org/10.1155/2016/1843201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4944080PMC
June 2016

The impacts of premorbid hypertension treatment on functional outcomes of ischemic stroke.

J Neurol Sci 2016 Apr 10;363:1-4. Epub 2016 Feb 10.

Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China. Electronic address:

Background And Purpose: The low rate of hypertension control is a major cause for the high rate of stroke morbidity and mortality in China. This study aimed to evaluate the impacts of premorbid hypertension treatment on the functional outcomes in patients with acute ischemic stroke and hypertension.

Methods: Patients with first-ever ischemic stroke and hypertension were screened from Nanjing Stroke Registry Program for eligibility. Functional outcomes were followed at 3 months with modified Rankin Scale (mRS). A good functional outcome was defined as mRS≤2. Potential factors associated with good functional outcomes were analyzed with multivariate logistic regression.

Results: A total of 660 patients with both ischemic stroke and hypertension were included, of whom 284 (43.0%) were on antihypertensives before stroke. In univariate analysis, more patients with hypertension treatments had good outcomes than those without (47.7% vs 31.0%, P=0.0001). After adjusted for age, heart diseases, baseline stroke severity, systolic blood pressure at admission, pneumonia, intravenous thrombolysis, and hospital stay, multivariate logistic regression indicated that premorbid hypertension treatment was related to an increased likelihood of good functional outcomes (OR: 2.21, 95% CI: 1.30 to 3.74, P=0.003).

Conclusions: Less than half of the Chinese patients with hypertension were on drug treatment prior to stroke onset. Lack of premorbid hypertension treatment may have deteriorated functional outcomes of stroke. These findings emphasized the importance of improving hypertension treatment in Chinese, especially in whom at high risk of cerebrovascular diseases.
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http://dx.doi.org/10.1016/j.jns.2016.02.020DOI Listing
April 2016

Hypertension unawareness among Chinese patients with first-ever stroke.

BMC Public Health 2016 Feb 19;16:170. Epub 2016 Feb 19.

Department of Neurology, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, Jiangsu Province, China.

Background: The low rates of hypertension treatment and control, partly due to its unawareness, are the main causes of the high stroke incidence in China. The purpose of this study was to evaluate hypertension unawareness amongst patients with first-ever stroke and to detect factors associated with its unawareness.

Methods: We selected those diagnosed with hypertension from patients with first-ever stroke registered in the Nanjing Stroke Registry Program between 2004 and 2014. These hypertensives were divided as being aware or unaware of their hypertension by using a brief questionnaire conducted shortly after the stroke. Multivariate logistic regression analysis was performed to identify potential factors associated with hypertension unawareness.

Results: Of the 5309 patients with first-ever stroke, 3732 (70.3%) were diagnosed with hypertension. Among which, 593 (15.9%) were unaware of their hypertension at the time of stroke onset. Lower-level of education (primary school or illiteracy) and smoking were associated positively with hypertension unawareness; while advanced age, overweight, diabetes mellitus, heart diseases and family history of stroke were associated negatively with hypertension unawareness. Annual data analyzed indicated that the rate of hypertension awareness increased during the past 11 years (r = 0.613, P = 0.045 for trends).

Conclusions: A substantial proportion (15.9%) of Chinese patients with hypertension had not been aware of this covert risk until an overt stroke occurred. Hypertension unawareness was associated with lower educational levels and smoking, which address the importance of health education especially in these individuals.
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http://dx.doi.org/10.1186/s12889-016-2835-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759941PMC
February 2016

Tissue Kallikrein Prevents Restenosis After Stenting of Severe Atherosclerotic Stenosis of the Middle Cerebral Artery: A Randomized Controlled Trial.

Medicine (Baltimore) 2016 Feb;95(6):e2809

From the Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China (RS, RZ, FY, MLi, LL, QY, YX, WL, XF, QD, QC, XC, GX, XL); Department of Neurology, Fuzhou General Hospital of Nanjing Military Region, Fuzhou, Fujian, China (MLin, HL); State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Department of Biostatistics, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, China (LZ); and Department of Geriatric Neurology, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, China (WL).

In-stent restenosis (ISR) following intracranial artery stenting affects long-term clinical outcome. This randomized controlled trial sought to identify the long-term efficacy of exogenous tissue kallikrein (TK) for preventing ISR after intracranial stenting of symptomatic middle cerebral artery (MCA) atherosclerotic stenosis.Sixty-one patients successfully treated with intracranial stenting for symptomatic MCA M1 segment stenosis (>70%) were enrolled and randomized into 2 groups: control group and TK group. Patients in the TK group received human urinary kallidinogenase for 7 days, followed by maintenance therapy of pancreatic kallikrein for 6 months. The primary end point was angiographically verified ISR at 6 months, and secondary end points included vascular events and death within 12 months. Endogenous TK plasma concentrations of patients were measured before stenting and at the 6-month follow-up time-point.Patients in the TK group had lower occurrence rates of ISR and vascular events than patients in the control group. There was no difference in endogenous TK levels in plasma at 6 months postoperatively between the TK and control groups. Further subgroup analysis revealed that patients without ISR had higher endogenous TK levels at baseline and lower concentrations at 6 months postoperatively compared with patients who underwent ISR.Exogenous TK is effective for the prevention of ISR after intracranial stenting.
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http://dx.doi.org/10.1097/MD.0000000000002809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753947PMC
February 2016

Neutrophil-to-Lymphocyte Ratio Predicts Length of Stay and Acute Hospital Cost in Patients with Acute Ischemic Stroke.

J Stroke Cerebrovasc Dis 2016 Apr 13;25(4):739-44. Epub 2016 Jan 13.

Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China. Electronic address:

Background: Although several risk factors for prolonged length of stay (LOS) and increased hospital cost have been identified, the association between LOS, hospital cost, and neutrophil-to-lymphocyte ratio (NLR) has not yet been investigated. We aimed to investigate the influence of NLR on LOS and hospital cost in patients with acute ischemic stroke.

Methods: Patients with acute ischemic stroke diagnosed within 24 hours of symptom onset were included. Univariate analysis and stepwise multiple regression analysis were used to identify independent predictors of LOS and hospital cost.

Results: A total of 346 patients were included in the final analysis. The median LOS was 11 days (range 8-13 days). The median acute hospital cost per patient was 19,030.6 RMB (U.S. $ 3065.8) (range 14,450.8 RMB-25,218.2 RMB). Neutrophil count to lymphocyte count (NLR) (P < .001), diabetes mellitus (P = .034), stroke subtype (P = .005), and initial stroke severity (P < .001) were significantly associated with prolonged LOS in the univariate analysis. NLR (P < .001), smoking (P = .04), stroke subtype (P < .001), initial stroke severity (P < .001), and LOS (P < .001) were significantly associated with increased hospital cost in the univariate analysis. Multivariate regression analysis showed that NLR was an independent predictor of both LOS and acute hospital cost. In addition, high NLR was significantly correlated with poor outcome at discharge, prolonged LOS, and increased hospital cost.

Conclusions: NLR is significantly associated with LOS and acute hospital cost in patients presenting with acute ischemic stroke. It is a simple, inexpensive, and readily available biomarker and may serve as a clinically practical indicator for assessing the economic burden of stroke.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.11.012DOI Listing
April 2016

Opposite roles of bradykinin B1 and B2 receptors during cerebral ischaemia-reperfusion injury in experimental diabetic rats.

Eur J Neurosci 2016 Jan;43(1):53-65

Department of Neurology, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, Jiangsu Province, China.

Bradykinin receptors play important roles in cerebral ischaemia-reperfusion (I/R) injury of non-diabetics. Their functions in diabetics, however, have not been studied. In this study, we hypothesized that bradykinin 1 receptor (B1R) and bradykinin 2 receptor (B2R) would be upregulated and participate in the regulation of diabetic ischaemic stroke. To investigate this, we first evaluated B1R and B2R expression at different time points after I/R in non-diabetic and diabetic rats (Sprague-Dawley) by using real-time quantitative reverse transcription polymerase chain reaction, western blotting, and immunofluorescence. Then, pharmacological inhibitors were separately administered via the tail vein to analyse their effects on cerebral ischaemia in diabetics. Both receptors were significantly upregulated after cerebral I/R in non-diabetic and diabetic rats. B1R expression in diabetic rats increased in a sharper manner than in non-diabetic rats, whereas B2R expression increased to the same level during the early stage of reperfusion but later became lower. Interestingly, the upregulated B1R was expressed in astrocytes, whereas B2R was mainly located in neurons in the ischaemic penumbra. Functional studies showed that inhibition of B1R significantly reduced infarct volume, neurological deficits, cell apoptosis, and neuron degeneration, probably by attenuating blood-brain barrier (BBB) disruption and post-ischaemic inflammation, at 24 h after reperfusion. In contrast, B2R antagonist had opposite effects, and exacerbated BBB penetrability and tissue inflammation. These findings suggest that B1R and B2R have detrimental and beneficial effects, respectively in diabetic cerebral ischaemia, which might open new avenues for the treatment of ischaemic stroke in diabetic patients through selective pharmacological blockade or activation.
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http://dx.doi.org/10.1111/ejn.13133DOI Listing
January 2016

Characterization and expression analysis of a fiber differentially expressed Fasciclin-like arabinogalactan protein gene in Sea Island cotton fibers.

PLoS One 2013 17;8(7):e70185. Epub 2013 Jul 17.

North China Key Laboratory for Crop Germplasm Resources of Education Ministry, Agricultural University of Hebei, Baoding, China.

Fasciclin-like arabinogalactan (FLA) protein is a cell-wall-associated protein playing crucial roles in regulating plant growth and development, and it was characterized in different plants including Upland cotton (Gossypium hirsutum L.). In cDNA-AFLP analysis of 25 DPA (days post anthesis) fiber mRNA, two FLA gene-related transcripts exhibit differential expression between Sea Island cotton (G. barbadense L.) and Upland cotton. Based on the transcript-derived fragment, RACE-PCR and realtime PCR technique, GbFLA5 full-length cDNA was isolated and its expression profiles were characterized in both cotton plant tissues and secondary cell wall (SCW) fibers in this study. The 1154 bp GbFLA5 cDNA contains an ORF of 720 bp, encoding GbFLA5 protein of 239 amino acids residues in length with an estimated molecular mass of 25.41 kDa and isoelectric point of 8.63. The deduced GbFLA5 protein contains an N-terminal signal sequence, two AGP-like domains, a single fasciclin-like domain, and a GPI anchor signal sequence. Phylogenetic analysis shows that GbFLA5 protein is homologous to some known SCW-specific expressed FLAs of plant developing xylem, tension wood and cotton fibers. In the SCW deposition stage from 15 to 45 DPA detected, FLA5 maintains a significantly higher expression level in Sea Island cotton fibers than in Upland cotton fibers. The increasing FLA5 transcript abundance coincided with the SCW deposition process and the expression intensity differences coincided with their fiber strength differences between Sea Island cotton and Upland cotton. These expression profile features of GbFLA5 in cotton fibers revealed its tissue-specific and SCW developmental stage-specific expression characters. Further analysis suggested that GbFLA5 is a crucial SCW-specific protein which may contribute to fiber strength by affecting cellulose synthesis and microfibril deposition orientation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0070185PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3714245PMC
March 2014