Publications by authors named "Zhiguo Lin"

45 Publications

Automatic analysis of integrated magnetic resonance and positron emission tomography images improves the accuracy of detection of focal cortical dysplasia type IIb lesions.

Eur J Neurosci 2021 Mar 15. Epub 2021 Mar 15.

Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, China.

We aimed to develop an efficient and objective pre-evaluation method to identify the precise location of a focal cortical dysplasia lesion before surgical resection to reduce medication use and decrease the post-operative frequency of seizure attacks. We developed a novel machine learning-based approach using cortical surface-based features by integrating MRI and metabolic PET to identify focal cortical dysplasia lesions. Significant surface-based features of 22 patients with histopathologically proven FCD IIb lesions were extracted from PET and MRI images using FreeSurfer. We modified significant parameters, trained and tested the XGBoost model using these surface-based features, and made predictions. We detected lesions in all 20 patients using the XGBoost model, with an accuracy of 91%. We used one-way chi-squared test to test the null hypothesis that the population proportion was 50% (p = 0.0001), indicating that our classification of the algorithm was statistically significant. The sensitivity, specificity, and false-positive rates were 93%, 91%, and 9%, respectively. We developed an objective, quantitative XGBoost classifier that combined MRI and PET imaging features to locate focal cortical dysplasia. This automated method yielded better outcomes than conventional visual analysis and single modality quantitative analysis for surgical pre-evaluation, especially in subtle or visually unidentifiable FCD lesions. This time-efficient method would also help doctors identify otherwise overlooked details.
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http://dx.doi.org/10.1111/ejn.15185DOI Listing
March 2021

Expression Profile Analysis Identifies a Novel Seven Immune-Related Gene Signature to Improve Prognosis Prediction of Glioblastoma.

Front Genet 2021 23;12:638458. Epub 2021 Feb 23.

Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.

Glioblastoma multiform (GBM) is a malignant central nervous system cancer with dismal prognosis despite conventional therapies. Scientists have great interest in using immunotherapy for treating GBM because it has shown remarkable potential in many solid tumors, including melanoma, non-small cell lung cancer, and renal cell carcinoma. The gene expression patterns, clinical data of GBM individuals from the Cancer Genome Atlas database (TCGA), and immune-related genes (IRGs) from ImmPort were used to identify differentially expressed IRGs through the Wilcoxon rank-sum test. The association between each IRG and overall survival (OS) of patients was investigated by the univariate Cox regression analysis. LASSO Cox regression assessment was conducted to explore the prognostic potential of the IRGs of GBM and construct a risk score formula. A Kaplan-Meier curve was created to estimate the prognostic role of IRGs. The efficiency of the model was examined according to the area under the receiver operating characteristic (ROC) curve. The TCGA internal dataset and two GEO external datasets were used for model verification. We evaluated IRG expression in GBM and generated a risk model to estimate the prognosis of GBM individuals with seven optimal prognostic expressed IRGs. A landscape of 22 types of tumor-infiltrating immune cells (TIICs) in glioblastoma was identified, and we investigated the link between the seven IRGs and the immune checkpoints. Furthermore, there was a correlation between the IRGs and the infiltration level in GBM. Our data suggested that the seven IRGs identified in this study are not only significant prognostic predictors in GBM patients but can also be utilized to investigate the developmental mechanisms of GBM and in the design of personalized treatments for them.
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http://dx.doi.org/10.3389/fgene.2021.638458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940837PMC
February 2021

Differential DNA Methylation Profiles in Patients with Temporal Lobe Epilepsy and Hippocampal Sclerosis ILAE Type I.

J Mol Neurosci 2021 Jan 5. Epub 2021 Jan 5.

Department of Neurosurgery of the First Affiliate Hospital, Harbin Medical University, Harbin, China.

Hippocampal sclerosis (HS) is one of the most prevalent pathological types of temporal lobe epilepsy (TLE), and it significantly affects patient prognoses. The methylation of DNA plays an important role in the development of epilepsy. However, few studies have focused on HS subtypes to determine DNA methylation profiles in TLE. This study aimed to determine the pathogenesis of TLE from an epigenetic perspective in patients with TLE-HS type I (TLE-HSTI) and TLE without HS (TLE-nHS) using whole-genome bisulfite sequencing (WGBS). We defined 1171 hypermethylated and 2537 hypomethylated regions and found 632 differentially methylated genes (DMG) in the promoter region that were primarily involved in the regulation of various aspects of epilepsy development. Twelve DMG overlapped with differentially expressed genes (DEG) in the promoter region, and RT-qPCR findings revealed significant overexpression of the SBNO2, CBX3, RASAL3, and TMBIM4 genes in TLE-HSTI. We present the first systematic analysis of methylation profiles of TLE-HSTI and TLE-nHS from an epigenetic perspective using WGBS. Overall, our preliminary data highlight the underlying mechanism of TLE-HSTI, providing a new perspective for guiding treatment of TLE.
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http://dx.doi.org/10.1007/s12031-020-01780-9DOI Listing
January 2021

Magnetic FeO@MgAl-LDH@La(OH) composites with a hierarchical core-shell structure for phosphate removal from wastewater and inhibition of labile sedimentary phosphorus release.

Chemosphere 2021 Feb 7;264(Pt 2):128551. Epub 2020 Oct 7.

Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, China.

In order to facilitate recovery and enhance phosphate adsorption capacity of lanthanum (La)-based materials, magnetic FeO@MgAl-LDH@La(OH) (MMAL) composites with a hierarchical core-shell structure were synthesized. In the preparation process, citric acid played a vital role in the morphology control of La(OH), deciding the La content and phosphate adsorption capacity of materials. MMAL composites with a citric acid-to-La molar ratio of 0.375 (MMAL-0.375) exhibited a high adsorption capacity of 66.5 mg P/g, fast adsorption kinetics of 30 min, widely applicable pH range of 4.0-10.0, outstanding selective adsorption performance, and superior reusability in batch adsorption experiments. Moreover, the phosphate in the desorption solution could be concentrated by repeated use of desorption solution and recovered by using CaCl. When the obtained composites were used for the sedimentary phosphorus sequestration and recovery, the results showed that the addition of MMAL-0.375 effectively reduced the concentration of soluble reactive phosphorus (SRP) in the overlying water. Accompanied by an evident increase in HCl-extractable phosphorus (HCl-P), mobile phosphorus (P) in sediments was effectively reduced. This work indicates that the MMAL-0.375 composites can serve as an effective tool for the removal of phosphate from wastewater and the control of sedimentary phosphorus.
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http://dx.doi.org/10.1016/j.chemosphere.2020.128551DOI Listing
February 2021

Identification and Analysis of Genes Underlying Bone Mineral Density by Integrating Microarray Data of Osteoporosis.

Front Cell Dev Biol 2020 27;8:798. Epub 2020 Aug 27.

Department of Rheumatology and Immunology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.

Osteoporosis is a kind of brittle bone disease, which is characterized by a reduction in bone mineral density (BMD). In recent years, a number of genes and pathophysiological mechanisms have been identified for osteoporosis. However, the genes associated with BMD remain to be explored. Toward this end, we integrated multiple osteoporosis microarray datasets to identify and systematically characterize BMD-related genes. By integrating the differentially expressed genes from three osteoporosis microarray datasets, 152 genes show differentially expressed between high and low BMD osteoporosis samples in at least two of the three datasets. Among them, 88 were up-regulated in high BMD samples and 64 were up-regulated in low BMD samples. The expression of ZFP36, JUNB and TMEM8A were increased at high BMD samples in all three datasets. Hub genes were further identified by co-expression network analysis. Functional enrichment analysis showed that the gene up-regulated in high BMD were enriched in immune-related functions, suggesting that the immune system plays an important role in osteoporosis. Our study explored BMD-related genes based on the integration of osteoporosis microarray data, providing guidance to other researchers from a new perspective.
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http://dx.doi.org/10.3389/fcell.2020.00798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481435PMC
August 2020

Effect of ferric chloride on phosphorus immobilization and speciation in Dianchi Lake sediments.

Ecotoxicol Environ Saf 2020 Jul 18;197:110637. Epub 2020 Apr 18.

Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, China. Electronic address:

Immobilization of phosphorus in lake sediments and control of internal-loading phosphorus release have become crucial aspects of eutrophication lake management. In this study, the immobilization efficiency of phosphorus by ferric chloride in Dianchi Lake sediments was investigated. In addition, effects of the dosage of ferric chloride and contact time on the release of phosphorus from sediments were investigated. Laboratory experiments revealed that ferric chloride can effectively inhibit the release of phosphorus from sediments. At a ferric chloride dosage of 10 mg/g, the total phosphorus concentration of the overlying water was reduced by ~87%. With the increase in the contact time, the amount of phosphorus immobilized by ferric chloride increased. To further evaluate the feasibility of ferric chloride for immobilising phosphorus in sediments, an amplification experiment with a water volume of 50 L was carried out. By the addition of 6 mg/g of ferric chloride, the total phosphorus concentration of the overlying water was still less than 0.01 mg/L after 100 days. At the same time, the phosphorus species in the sediment after treatment with ferric chloride were analyzed. Results revealed that ferric chloride mainly converts unstable exchangeable phosphorus (Ex-P), ferric phosphate (Fe-P) and organic phosphorus (Or-P) into more stable occluded phosphate (O-P), reducing the possible release of phosphorus from sediments. Practical applications of ferric chloride to control the release of phosphorus from Dianchi Lake sediments were discussed.
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http://dx.doi.org/10.1016/j.ecoenv.2020.110637DOI Listing
July 2020

Dysregulation of Glutamate Transport Enhances Treg Function That Promotes VEGF Blockade Resistance in Glioblastoma.

Cancer Res 2020 02 13;80(3):499-509. Epub 2019 Nov 13.

Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, Florida.

Anti-VEGF therapy prolongs recurrence-free survival in patients with glioblastoma but does not improve overall survival. To address this discrepancy, we investigated immunologic resistance mechanisms to anti-VEGF therapy in glioma models. A screening of immune-associated alterations in tumors after anti-VEGF treatment revealed a dose-dependent upregulation of regulatory T-cell (Treg) signature genes. Enhanced numbers of Tregs were observed in spleens of tumor-bearing mice and later in tumors after anti-VEGF treatment. Elimination of Tregs with CD25 blockade before anti-VEGF treatment restored IFNγ production from CD8 T cells and improved antitumor response from anti-VEGF therapy. The treated tumors overexpressed the glutamate/cystine antiporter SLC7A11/xCT that led to elevated extracellular glutamate in these tumors. Glutamate promoted Treg proliferation, activation, suppressive function, and metabotropic glutamate receptor 1 (mGlutR1) expression. We propose that VEGF blockade coupled with glioma-derived glutamate induces systemic and intratumoral immunosuppression by promoting Treg overrepresentation and function, which can be pre-emptively overcome through Treg depletion for enhanced antitumor effects. SIGNIFICANCE: Resistance to VEGF therapy in glioblastoma is driven by upregulation of Tregs, combined blockade of VEGF, and Tregs may provide an additive antitumor effect for treating glioblastoma.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-1577DOI Listing
February 2020

CXCR1- or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors.

Nat Commun 2019 09 5;10(1):4016. Epub 2019 Sep 5.

Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA.

Chimeric antigen receptor (CAR) T-cell therapy targeting solid tumors has stagnated as a result of tumor heterogeneity, immunosuppressive microenvironments, and inadequate intratumoral T cell trafficking and persistence. Early (≤3 days) intratumoral presentation of CAR T cells post-treatment is a superior predictor of survival than peripheral persistence. Therefore, we have co-opted IL-8 release from tumors to enhance intratumoral T-cell trafficking through a CAR design for maximal antitumor activity in solid tumors. Here, we demonstrate that IL-8 receptor, CXCR1 or CXCR2, modified CARs markedly enhance migration and persistence of T cells in the tumor, which induce complete tumor regression and long-lasting immunologic memory in pre-clinical models of aggressive tumors such as glioblastoma, ovarian and pancreatic cancer.
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http://dx.doi.org/10.1038/s41467-019-11869-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728370PMC
September 2019

Development and validation of an interferon signature predicting prognosis and treatment response for glioblastoma.

Oncoimmunology 2019;8(9):e1621677. Epub 2019 Jun 12.

Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China.

: Interferon treatment, as an important approach of anti-tumor immunotherapy, has been implemented in multiple clinical trials of glioma. However, only a small number of gliomas benefit from it. Therefore, it is necessary to investigate the clinical role of interferons and to establish robust biomarkers to facilitate its application. : This study reviewed 1,241 glioblastoma (GBM) and 1,068 lower grade glioma (LGG) patients from six glioma cohorts. The transcription matrix and clinical information were analyzed using R software, GraphPad Prism 7 and Medcalc, etc. Immunohistochemical (IHC) staining were performed for validation in protein level. : Interferon signaling was significantly enhanced in GBM. An interferon signature was developed based on five interferon genes with prognostic significance, which could reflect various interferon statuses. Survival analysis showed the signature could serve as an unfavorable prognostic factor independently. We also established a nomogram model integrating the risk signature into traditional prognostic factors, which increased the validity of survival prediction. Moreover, high-risk group conferred resistance to chemotherapy and high expression levels. Functional analysis showed that the high-risk group was associated with overloaded immune response. Microenvironment analysis and IHC staining found that high-risk group occupied a disorganized microenvironment which was characterized by an enrichment of M0 macrophages and neutrophils, but less infiltration of activated nature killing (NK) cells and M1 type macrophages. : This interferon signature was an independent indicator for unfavorable prognosis and showed great potential for screening out patients who will benefit from chemotherapy and interferon treatment.
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http://dx.doi.org/10.1080/2162402X.2019.1621677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685507PMC
February 2021

CD48 is a key molecule of immunomodulation affecting prognosis in glioma.

Onco Targets Ther 2019 28;12:4181-4193. Epub 2019 May 28.

Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, People's Republic of China.

Glioma is a refractory disease associated with immune cell infiltration, and the effectiveness of checkpoint blockade remains suboptimal. As an adhesion and costimulatory molecule, CD48 plays a significant role in immunomodulation. As such, studying CD48 may provide additional understanding of the immune and inflammation response of glioma. Using R language and GraphPad Prism 7, RNA sequencing data of 946 patients from Chinese Glioma Genome Atlas and The Cancer Genome Atlas cohorts were analyzed. CD48 was highly expressed in the malignant progression of glioma. As an independent risk factor, high-CD48 patients were associated with poor prognosis. CD48 influenced glioma purity and the local immune cell subpopulation. CD48 was closely related to immune function in glioma. Patients with an enhanced immune phenotype, high CD48, were associated with immune suppressive molecules and checkpoints. In addition, CD48 correlated with the immune and inflammatory response. A checkpoint risk score including CD48, SLAMF8 and PD-L1 was used to assess the role of checkpoints. Risk score was particularly high in a malignant subtype of glioma and was an independent predictive indicator of unfavorable outcome. Additionally, age, IDH subtype and MGMT promoter status influenced the predictive significance of checkpoint risk score. CD48 exhibits a crucial role in reduced survival and immunomodulation in glioma. In addition, we found that checkpoints play a greater role in patients older than 40 years old with IDH wild-type and MGMT methylated status. These findings suggest that combining CD48 blockade with PD-L1 may be a promising approach to glioma immunotherapy for specific subpopulations of patients.
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http://dx.doi.org/10.2147/OTT.S198762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549391PMC
May 2019

The MicroRNA Expression Profiles of Human Temporal Lobe Epilepsy in HS ILAE Type 1.

Cell Mol Neurobiol 2019 Apr 21;39(3):461-470. Epub 2019 Feb 21.

Department of Neurosurgery, The First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.

Temporal lobe epilepsy (TLE) is associated with neurodegeneration, often leading to hippocampal sclerosis (HS). Type 1 HS, which is characterized by severe neuronal loss and gliosis predominantly in regions CA1 and CA4, is the most common subtype and is associated with the best prognosis according to the ILAE classification system. MiRNAs participate in the biological processes underlying many nervous system diseases, including epilepsy. However, the miRNA expression profile of HS ILAE type 1 is not completely understood. A total of 14 patients were identified as having the ILAE subtype, as determined by NeuN immunohistochemistry (ILAE type 1 = 7; no-HS = 7). Next-generation sequencing and reverse transcription polymerase chain reaction technology were used to validate the dysregulated miRNAs. Bioinformatics analysis of the predicted target genes was conducted using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. In total, 1643 mature miRNAs were detected in this study, along with 5 miRNAs that were upregulated and 2 miRNAs that were downregulated in the type 1 group. Bioinformatics analysis showed that 1545 target genes were predicted using the miRDB and Targetscan databases and that these predicted genes showed enrichment in pathways associated with nucleic acid binding, intracellular and cellular macromolecule metabolic processes, and the PI3K-Akt signaling pathway. This study is the first to report the miRNA expression profile of HS ILAE type 1 compared with those of no-HS. These results provide new insights into the neuronal loss pathology of type 1 HS.
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http://dx.doi.org/10.1007/s10571-019-00662-yDOI Listing
April 2019

Checkpoint Blockade Reverses Anergy in IL-13Rα2 Humanized scFv-Based CAR T Cells to Treat Murine and Canine Gliomas.

Mol Ther Oncolytics 2018 Dec 28;11:20-38. Epub 2018 Aug 28.

Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

We generated two humanized interleukin-13 receptor α2 (IL-13Rα2) chimeric antigen receptors (CARs), Hu07BBz and Hu08BBz, that recognized human IL-13Rα2, but not IL-13Rα1. Hu08BBz also recognized canine IL-13Rα2. Both of these CAR T cell constructs demonstrated superior tumor inhibitory effects in a subcutaneous xenograft model of human glioma compared with a humanized EGFRvIII CAR T construct used in a recent phase 1 clinical trial (ClinicalTrials.gov: NCT02209376). The Hu08BBz demonstrated a 75% reduction in orthotopic tumor growth using low-dose CAR T cell infusion. Using combination therapy with immune checkpoint blockade, humanized IL-13Rα2 CAR T cells performed significantly better when combined with CTLA-4 blockade, and humanized EGFRvIII CAR T cells' efficacy was improved by PD-1 and TIM-3 blockade in the same mouse model, which was correlated with the levels of checkpoint molecule expression in co-cultures with the same tumor . Humanized IL-13Rα2 CAR T cells also demonstrated benefit from a self-secreted anti-CTLA-4 minibody in the same mouse model. In addition to a canine glioma cell line (J3T), canine osteosarcoma lung cancer and leukemia cell lines also express IL-13Rα2 and were recognized by Hu08BBz. Canine IL-13Rα2 CAR T cell was also generated and tested by co-culture with canine tumor cells and in an orthotopic model of canine glioma. Based on these results, we are designing a pre-clinical trial to evaluate the safety of canine IL-13Rα2 CAR T cells in dog with spontaneous IL-13Rα2-positive glioma, which will help to inform a human clinical trial design for glioblastoma using humanized scFv-based IL-13Rα2 targeting CAR T cells.
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http://dx.doi.org/10.1016/j.omto.2018.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174845PMC
December 2018

Targeting of microRNA-21-5p protects against seizure damage in a kainic acid-induced status epilepticus model via PTEN-mTOR.

Epilepsy Res 2018 08 4;144:34-42. Epub 2018 May 4.

Department of Neurosurgery, The First Affiliated Hospital, Harbin Medical University, Harbin, China. Electronic address:

Objective: Studies have shown that microRNAs play a role in the development of epilepsy by regulating downstream target messenger (m)RNA. The present study aims to determine the changes associated with microRNA-21-5p (miR-21-5p) during epileptogenesis in a kainic acid rat model, and to assess whether the PTEN-mTOR pathway is a target of miR-21-5p.

Method: Reverse transcription polymerase chain reaction (RT-PCR) was used to examine the quantitative expressions of miR-21-5p and PTEN, and Western blotting was used to test the activity of mTOR in the acute, latent, and chronic stages of epileptogenesis. The antagomir of miR-21-5p was injected into the intracerebroventricular space using a microsyringe. Neuronal death and epilepsy discharge were assessed by Nissl staining and electroencephalography (EEG), respectively. The Morris water maze (MWM) was used to assess the cognitive impairment in rats after status epilepticus (SE).

Results: Both miR-21-5p and mTOR were upregulated and PTEN was downregulated in rats during acute, latent, and chronic stages of epileptogenesis when compared with those of the control. After using antagomir miR-21-5p in vivo, miR-21-5p and mTOR decreased and the expression of PTEN increased compared with that in the SE model. The silencing of miR-21-5p diminished the number of abnormal spikes on EEG and decreased the number of neuron deletions on Nissl staining. The cognitive and memory impairment caused by epilepsy could also be improved after miR-21-5p knockdown in vivo.

Conclusion: The results of the present study demonstrate that PTEN-mTOR is the target of miR-21-5p in a kainic acid model of epilepsy. The knockout of miR-21-5p decreases the neuronal damage in stages of epileptogenesis. The miR-21-5p/PTEN/mTOR axis may be a potential target for preventing and treating seizures and epileptic damage.
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http://dx.doi.org/10.1016/j.eplepsyres.2018.05.001DOI Listing
August 2018

The IDH1 Mutation-Induced Oncometabolite, 2-Hydroxyglutarate, May Affect DNA Methylation and Expression of PD-L1 in Gliomas.

Front Mol Neurosci 2018 28;11:82. Epub 2018 Mar 28.

Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, United States.

Malignant gliomas are heterogeneous brain tumors with the potential for aggressive disease progression, as influenced by suppressive immunoediting. Given the success and enhanced potential of immune-checkpoint inhibitors in immunotherapy, we focused on the connections between genetic alterations affected by IDH1 mutations and immunological landscape changes and PDL-1 expression in gliomas. Paired surgically resected tumors from lower-grade gliomas (LGGs) and glioblastomas (GBM) were investigated, and a genetic analysis of patients' primary tumor samples culled from TCGA datasets was performed. The results demonstrate that when compared with IDH1-mutant tumors, IDH1 wildtype tumors represent an immunosuppression landscape and elevated levels of PD-L1 expression. DNA hypo-methylation of the PD-L1 gene, as well as high gene and protein expressions, were observed in the wildtype tumors. We also found that quantitative levels of IDH1 mutant proteins were positively associated with recurrence-free survival (RFS). A key product of the IDH1 mutation (2-hydroxyglutarate) was found to transiently increase DNA methylation and suppress PD-L1 expression. IDH1 mutations impact the immune landscape of gliomas by affecting immune infiltrations and manipulating checkpoint ligand PD-L1 expression. Applications of immune checkpoint inhibitors may be beneficial for chemoradiation-insensitive IDH1-wildtype gliomas.
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http://dx.doi.org/10.3389/fnmol.2018.00082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882817PMC
March 2018

CD4+ and Perivascular Foxp3+ T Cells in Glioma Correlate with Angiogenesis and Tumor Progression.

Front Immunol 2017 7;8:1451. Epub 2017 Nov 7.

Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, United States.

Background: Angiogenesis and immune cell infiltration are key features of gliomas and their manipulation of the microenvironment, but their prognostic significance remains indeterminate. We evaluate the interconnection between tumor-infiltrating lymphocyte (TIL) and tumor blood-vasculatures in the context of glioma progression.

Methods: Paired tumor tissues of 44 patients from three tumor-recurrent groups: diffuse astrocytomas (DA) recurred as DA, DA recurred as glioblastomas (GBM), and GBM recurred as GBM were evaluated by genetic analysis, immunohistochemistry for tumor blood vessel density, TIL subsets, and clinical outcomes. These cells were geographically divided into perivascular and intratumoral TILs. Associations were examined between these TILs, CD34+ tumor blood vessels, and clinical outcomes. To determine key changes in TIL subsets, microarray data of 15-paired tumors from patients who failed antiangiogenic therapy- bevacizumab, and 16-paired tumors from chemo-naïve recurrent GBM were also evaluated and compared.

Results: Upon recurrence in primary gliomas, similar kinetic changes were found between tumor blood vessels and each TIL subset in all groups, but only CD4+ including Foxp3+ TILs, positively correlated with the density of tumor blood vessels. CD4 was the predominant T cell population based on the expression of gene-transcripts in primary GBMs, and increased activated CD4+ T cells were revealed in Bevacizumab-resistant recurrent tumors (not in chemo-naïve recurrent tumors). Among these TILs, 2/3 of them were found in the perivascular niche; Foxp3+ T cells in these niches not only correlated with the tumor vessels but were also an independent predictor of shortened recurrence-free survival (RFS) (HR = 4.199, 95% CI 1.522-11.584,  = 0.006).

Conclusion: The minimal intratumoral T cell infiltration and low detection of CD8 transcripts expression in primary GBMs can potentially limit antitumor response. CD4+ and perivascular Foxp3+ TILs associate with tumor angiogenesis and tumor progression in glioma patients. Our results suggest that combining antiangiogenic agents with immunotherapeutic approaches may help improve the antitumor efficacy for patients with malignant gliomas.
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http://dx.doi.org/10.3389/fimmu.2017.01451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673996PMC
November 2017

Inhibition of angiogenesis by arsenic trioxide TSP-1-TGF-β1-CTGF-VEGF functional module in rheumatoid arthritis.

Oncotarget 2017 Sep 3;8(43):73529-73546. Epub 2017 Aug 3.

Department of Rheumatology, The First Affiliated Hospital, Harbin Medical University, Nan Gang, Harbin, China.

Angiogenesis is a critical factor for rheumatoid arthritis (RA). Although anti-TNF biologics work effectively on some RA patients, concerns have been raised about the possible increased development of malignancies alongside such treatments. Arsenic trioxide (AsO) has attracted worldwide attention and has been reported to treat some cancers. However, the effects of AsO on angiogenesis in the RA synovium remain unclear. Here, we report a systematic increased expression of TSP-1, TGF-β1, CTGF and VEGF in supernatants of a RA fibroblast-like synoviocytes (RA-FLS) and human dermal microvascular endothelial cells (HDMECs) co-culture compared with those from a normal human fibroblast-like synoviocytes (NH-FLS) and HDMECs co-culture. This increased expression may up-regulate endothelial tube formation and transwell migration, as well as microvessel sprouting in aortic ring assay. These networked angiogenic factors mainly form a functional module regulating angiogenesis in the RA synovium. We show that AsO inhibits angiogenesis in the collagen-induced arthritis (CIA) synovium and consequently arthritis severity via significant suppression of TSP-1, TGF-β1, CTGF and VEGF expression in the CIA synovium, plus in the RA-FLS and HDMECs co-culture as well as NH-FLS and HDMECs co-culture system along with the presence or absence of TNF-α treatment. Thus AsO has a significant anti-angiogenesis effect on the RA-FLS and CIA synovium via its inhibition of the RA angiogenic functional module of TSP-1, TGF-β1, CTGF and VEGF and may have a potential for treating RA beyond cancer therapy.
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http://dx.doi.org/10.18632/oncotarget.19867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650279PMC
September 2017

PARK2 negatively regulates the metastasis and epithelial-mesenchymal transition of glioblastoma cells via ZEB1.

Oncol Lett 2017 Sep 28;14(3):2933-2939. Epub 2017 Jun 28.

Department of Neurosurgery, The First Affiliated Clinical Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.

Glioblastoma multiforme (GBM), one of the most aggressive human malignant brain tumors, is induced by multiple complex pathological mechanisms. The main cause of mortality in patients with GBM is the invasion-metastasis cascade of tumor cells. The dysfunction of Parkinson protein 2 E3 ubiquitin protein ligase (PARK2) is closely linked with the development of certain human cancers. However, whether PARK2 is associated with metastasis in GBM remains unknown. The present study demonstrated that the metastasis and invasion of U87 cells were significantly repressed by PARK2 overexpression. Conversely, knockdown of PARK2 facilitated the metastasis and invasion of A172 cells. Furthermore, PARK2 downregulated zinc finger E-box-binding homeobox 1 (ZEB1) expression and mitigated epithelial-mesenchymal transition (EMT). Promoter effects of PARK2 knockdown on cell metastasis and EMT were antagonized by silencing ZEB1 expression. These results indicated that PARK2 participated in regulating the invasion-metastasis cascade of cancer cells by depressing ZEB1 expression and acting as a metastasis suppressor in GBM progression, providing a potential therapeutic approach for GBM treatment.
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http://dx.doi.org/10.3892/ol.2017.6488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5588166PMC
September 2017

Glutamine promotes Hsp70 and inhibits α-Synuclein accumulation in pheochromocytoma PC12 cells.

Exp Ther Med 2017 Aug 12;14(2):1253-1259. Epub 2017 Jun 12.

Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.

Hsp70 regulates α-Synuclein (α-Syn) degeneration in Parkinson's disease (PD), indicating that Hsp70 promotion may be able to prevent or reverse α-Syn-induced toxicity in PD. Additionally, it has been demonstrated that glutamine (Gln) enhances Hsp70 expression. In the present study, Gln-induced Hsp70 promotion in pheochromocytoma was investigated with reverse transcription- quantitative polymerase chain reaction and western blotting methods. Then it was observed whether heat shock factor (HSF)-1 was required for this phenomenon with an RNA interference strategy. The regulatory role of Gln on α-Syn degeneration was also determined in the α-Syn-overexpressed PC12 [PC12 (α-Syn+)] cells, which were treated with or without the proteasomal inhibitor lactacystin (Lac). The results demonstrated that treatment with ≥10 mM Gln significantly increased Hsp70 mRNA and protein levels (P<0.05) and that this promotion was HSF-1-dependent, as HSF-1 knockout with HSF-1-specific small interfering RNA abrogated Hsp70 promotion in PC12 (α-Syn+) cells. Furthermore, Gln treatment markedly upregulated α-Syn degeneration in PC12 (α-Syn+) cells, which was significantly reduced (P<0.05) in the presence of Lac. Therefore, the present study suggests that Gln is able to induce the promotion of Hsp70 expression in PC12 cells in an HSF-1-dependent manner and that Gln-mediated Hsp70 promotion may increase α-Syn degradation even in the presence of proteasomal inhibitor. Thus, glutamine may be a potential therapeutic agent to prevent α-Syn aggregation in PD.
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http://dx.doi.org/10.3892/etm.2017.4580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5525590PMC
August 2017

Cyclophilin A Maintains Glioma-Initiating Cell Stemness by Regulating Wnt/β-Catenin Signaling.

Clin Cancer Res 2017 Nov 8;23(21):6640-6649. Epub 2017 Aug 8.

Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.

Glioma-initiating cells (GIC) are glioma stem-like cells that contribute to glioblastoma (GBM) development, recurrence, and resistance to chemotherapy and radiotherapy. They have recently become the focus of novel treatment strategies. Cyclophilin A (CypA) is a cytosolic protein that belongs to the peptidyl-prolyl isomerase (PPIase) family and the major intracellular target of the immunosuppressive drug cyclosporin A (CsA). In this study, we investigate the functions of CypA and its mechanism of action in GICs' development. We analyzed differences in CypA expression between primary tumors and neurospheres from the GDS database, both before and after GIC differentiation. A series of experiments was conducted to investigate the role of CypA in GIC stemness, self-renewal, proliferation, radiotherapy resistance, and mechanism. We then designed glutathione S-transferase (GST) pulldown and coimmunoprecipitation assays to detect signaling activity. In this study, we demonstrated that CypA promotes GIC stemness, self-renewal, proliferation, and radiotherapy resistance. Mechanistically, we found that CypA binds β-catenin and is recruited to Wnt target gene promoters. By increasing the interaction between β-catenin and TCF4, CypA enhances transcriptional activity. Our results demonstrate that CypA enhances GIC stemness, self-renewal, and radioresistance through Wnt/β-catenin signaling. Due to its promotive effects on GICs, CypA is a potential target for future glioma therapy. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-0774DOI Listing
November 2017

CD70, a novel target of CAR T-cell therapy for gliomas.

Neuro Oncol 2018 01;20(1):55-65

UF Brain Tumor Immunotherapy Program, Preston A. Wells Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, Florida, USA.

Background: Cancer immunotherapy represents a promising treatment approach for malignant gliomas but is hampered by the limited number of ubiquitously expressed tumor antigens and the profoundly immunosuppressive tumor microenvironment. We identified cluster of differentiation (CD)70 as a novel immunosuppressive ligand and glioma target.

Methods: Normal tissues derived from 52 different organs and primary and recurrent low-grade gliomas (LGGs) and glioblastomas (GBMs) were thoroughly evaluated for CD70 gene and protein expression. The association between CD70 and patients' overall survival and its impact on T-cell death was also evaluated. Human and mouse CD70-specific chimeric antigen receptors (CARs) were tested respectively against human primary GBMs and murine glioma lines. The antitumor efficacies of these CARs were also examined in orthotopic xenograft and syngeneic models.

Results: CD70 was not detected in peripheral and brain normal tissues but was constitutively overexpressed by isocitrate dehydrogenase (IDH) wild-type primary LGGs and GBMs in the mesenchymal subgroup and recurrent tumors. CD70 was also associated with poor survival in these subgroups, which may link to its direct involvement in glioma chemokine productions and selective induction of CD8+ T-cell death. To explore the potential for therapeutic targeting of this newly identified immunosuppressive axis in GBM tumors, we demonstrate that both human and mouse CD70-specific CAR T cells recognize primary CD70+ GBM tumors in vitro and mediate the regression of established GBM in xenograft and syngeneic models without illicit effect.

Conclusion: These studies identify a previously uncharacterized and ubiquitously expressed immunosuppressive ligand CD70 in GBMs that also holds potential for serving as a novel CAR target for cancer immunotherapy in gliomas.
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http://dx.doi.org/10.1093/neuonc/nox116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761579PMC
January 2018

Tumor associated CD70 expression is involved in promoting tumor migration and macrophage infiltration in GBM.

Int J Cancer 2017 10 5;141(7):1434-1444. Epub 2017 Jul 5.

Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, Florida, USA.

Tumor migration/metastasis and immunosuppression are major obstacles in effective cancer therapy. Incidentally, these 2 hurdles usually coexist inside tumors, therefore making therapy significantly more complicated, as both oncogenic mechanisms must be addressed for successful therapeutic intervention. Our recent report highlights that the tumor expression of a TNF family member, CD70, is correlated with poor survival for primary gliomas. In this study, we investigated how CD70 expression by GBM affects the characteristics of tumor cells and the tumor microenvironment. We found that the ablation of CD70 in primary GBM decreased CD44 and SOX2 gene expression, and inhibited tumor migration, growth and the ability to attract monocyte-derived M2 macrophages in vitro. In the tumor microenvironment, CD70 was associated with immune cell infiltrates, such as T cells; myeloid-derived suppressor cells; and monocytes/macrophages based on the RNA-sequencing profile. The CD163+ macrophages were far more abundant than T cells were. This overwhelming level of macrophages was identified only in GBM and not in low-grade gliomas and normal brain specimens, implying their tumor association. CD70 was detected only on tumor cells, not on macrophages, and was highly correlated with CD163 gene expression in primary GBM. Additionally, the co-expression of the CD70 and CD163 genes was found to correlate with decreased survival for patients with primary GBM. Together, these data suggest that CD70 expression is involved in promoting tumor aggressiveness and immunosuppression via tumor-associated macrophage recruitment/activation. Our current efforts to target this molecule using chimeric antigen receptor T cells hold great potential for treating patients with GBM.
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http://dx.doi.org/10.1002/ijc.30830DOI Listing
October 2017

miR-422a Inhibits Glioma Proliferation and Invasion by Targeting IGF1 and IGF1R.

Oncol Res 2017 Jan;25(2):187-194

Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, P.R. China.

Glioma is a common type of malignant brain tumor characterized by aggressive metastasis capability. Recent evidence has suggested that noncoding RNAs, including microRNAs, have important functions in the pathophysiology of glioma development. In this study, we investigated the biological function of miR-422a in human glioma. We found that miR-422a was downregulated in glioma tissues. We also demonstrated that expression of miR-422a in glioma cells markedly suppressed cell proliferation, migration, and invasion. In addition, we identified insulin-like growth factor 1 (IGF1) and IGF1 receptor (IGF1R) as inhibitory targets of miR-422a in glioma cells. We established that the expression levels of miR-422a were negatively correlated with the expression levels of IGF1/IGF1R and the clinical parameters in glioma patients. An IGFR inhibitor, AG1024, completely blocked the activity of miR-442a on glioma cell proliferation and invasion, which further confirmed that miR-422a functions through IGF1 and IGF1R.
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http://dx.doi.org/10.3727/096504016X14732772150389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840806PMC
January 2017

miRNA-214 Inhibits Cellular Proliferation and Migration in Glioma Cells Targeting Caspase 1 Involved in Pyroptosis.

Oncol Res 2017 Jul 15;25(6):1009-1019. Epub 2016 Dec 15.

Pyroptosis is a type of proinflammatory programmed cell death mediated by caspase 1 activity and occurs in several types of eukaryotic tumor cells, including gliomas. MicroRNAs (miRNAs), small endogenous noncoding RNAs, have been demonstrated to be advantageous in glioma therapy. However, the question of whether miRNAs regulate pyroptosis in glioma remains unknown. The current study found that caspase 1 expression was substantially increased in both glioma tissues and glioma cell lines, U87 and T98G, while miR-214 expression was significantly downregulated. Luciferase reporter assay recognized caspase 1 as a target gene of miR-214. These findings demonstrate that miR-214 could inhibit cell proliferation and migration through the regulation of pyroptosis intermediated by caspase 1 in glioma U87 and T98G cells and may suggest a novel therapeutic for the intervention of glioma.
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http://dx.doi.org/10.3727/096504016X14813859905646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840997PMC
July 2017

TUSC3 suppresses glioblastoma development by inhibiting Akt signaling.

Tumour Biol 2016 Sep 13;37(9):12039-12047. Epub 2016 May 13.

Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, Heilongjiang Province, 150001, China.

Glioblastoma multiform is one of the most common and most aggressive brain tumors in humans. The molecular and cellular mechanisms responsible for the onset and progression of GBM are elusive and controversial. The function of tumor suppressor candidate 3 (TUSC3) has not been previously characterized in GBM. TUSC3 was originally identified as part of an enzyme complex involved in N-glycosylation of proteins, but was recently implicated as a potential tumor suppressor gene in a variety of cancer types. In this study, we demonstrated that the expression levels of TUSC3 were downregulated in both GBM tissues and cells, and also found that overexpression of TUSC3 inhibits GBM cell proliferation and invasion. In addition, the effects of increased levels of methylation on the TUSC3 promoter were responsible for decreased expression of TUSC3 in GBM. Finally, we determined that TUSC3 regulates proliferation and invasion of GBM cells by inhibiting the activity of the Akt signaling pathway.
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http://dx.doi.org/10.1007/s13277-016-5072-4DOI Listing
September 2016

Centrosomal Protein of 55 Regulates Glucose Metabolism, Proliferation and Apoptosis of Glioma Cells via the Akt/mTOR Signaling Pathway.

J Cancer 2016 4;7(11):1431-40. Epub 2016 Jul 4.

1. Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China;

Introduction: Glioma is one of the most common and most aggressive brain tumors in humans. The molecular and cellular mechanisms responsible for the onset and the progression of glioma are elusive and controversial. Centrosomal protein of 55 (CEP55) was initially described as a highly coiled-coil protein that plays critical roles in cell division, but was recently identified as being overexpressed in many human cancers. The function of CEP55 has not previously been characterized in glioma. We aim to discover the effect and mechanism of CEP55 in glioma development.

Method: qRT-PCR and immunohistochemistry were used to analyze CEP55 expression. Glucose uptake, western blot, MTS, CCK-8, Caspase-3 activity and TUNEL staining assays were performed to investigate the role and mechanism of CEP55 on glioma cell process.

Results: We found that the levels of CEP55 expression were upregulated in glioma. In addition, CEP55 appeared to regulate glucose metabolism of glioma cells. Furthermore, knockdown of CEP55 inhibited cell proliferation and induced cell apoptosis in glioma. Finally, we provided preliminary evidence that knockdown of CEP55 inhibited glioma development via suppressing the activity of Akt/mTOR signaling.

Conclusions: Our results demonstrated that CEP55 regulates glucose metabolism, proliferation and apoptosis of glioma cells via the Akt/mTOR signaling pathway, and its promotive effect on glioma tumorigenesis can be a potential target for glioma therapy in the future.
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http://dx.doi.org/10.7150/jca.15497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4964127PMC
July 2016

Dual-Channel Minimally Invasive Endoscopic Port for Evacuation of Deep-Seated Spontaneous Intracerebral Hemorrhage with Obstructive Hydrocephalus.

World Neurosurg 2016 Jul 27;91:452-9. Epub 2016 Apr 27.

Fourth Department of Neurosurgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China. Electronic address:

Background: In minimally invasive endoscopic port surgery, the medium is air, and the image is clearer than in fluid. The most commonly used port is a single-channel port, which accommodates the rod lens of the endoscope and 2 microsurgical instruments. This setup decreases the freedom of movement of the 3 instruments, making the bimanual procedure difficult. We describe a novel "dual-channel" endoscopic port to facilitate a bimanual refinement procedure for removing deep-seated spontaneous intracerebral hematomas, and we demonstrate the feasibility of this method.

Methods: The small channel accommodates a 0° endoscope lens, and the large channel accommodates 2 microsurgical instruments. This method was used in 8 patients with deep-seated spontaneous intracerebral hematomas with obstructive hydrocephalus. It was necessary to evacuate the deep-seated hematomas in these patients as soon as possible to recover the circulation of cerebrospinal fluid.

Results: Dual-channel port surgery was performed in 8 patients with an average age of 55 years (range, 44-79 years). The time from ictus to surgery ranged from 4 hours to 12 days. The duration of drainage tube placement was 2-5 days. The hematomas in all patients, in the third ventricle or thalamus, were evacuated thoroughly. In each patient, improvements in Glasgow Coma Scale scores were observed from admission to discharge.

Conclusions: The dual-channel endoscopic port facilitated bimanual refinement microsurgery during the evacuation of deep-seated intracerebral hematomas, and it prevented the disturbance of the 3 instruments without restraining the scope of the operation during the microsurgical procedure.
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http://dx.doi.org/10.1016/j.wneu.2016.04.066DOI Listing
July 2016

Higher expression of monocyte chemoattractant protein 1 and its receptor in brain tissue of intractable epilepsy patients.

J Clin Neurosci 2016 Jun 22;28:134-40. Epub 2016 Jan 22.

Department of Neurology, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin 150001, Heilongjiang, China. Electronic address:

We aimed to explore the pathogenesis of monocyte chemoattractant protein-1 (MCP1) and CC chemokine receptor 2 (CCR2) in brain tissue of patients with intractable epilepsy (IE). Hippocampi or temporal lobe tissues were obtained from 40 patients with IE and five patients without IE who had undergone surgical decompression and debridement. The levels of MCP1 and CCR2 were evaluated using immunohistochemistry. Pearson correlation analysis was employed to evaluate the correlation between levels of MCP1 and CCR2 in IE with or without hippocampal sclerosis (HS) and the disease duration, along with age. Higher levels of MCP1 (11.68±4.68% versus 1.72±1.54%) and CCR2 (11.54±4.65% versus 1.52±1.29%; P<0.05) were observed in IE patients compared to controls. Expression levels of MCP1 (R=0.867) and CCR2 (R=0.835) in IE patients with HS were correlated with the disease duration. However, no correlation was found in IE patients without HS. There was also no correlation between levels of MCP1 and CCR2 in IE patients with age, either with HS or without HS. These results suggest that MCP1 and its receptor may play a role in the pathogenesis and progression of IE.
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http://dx.doi.org/10.1016/j.jocn.2015.07.033DOI Listing
June 2016

High-Frequency Ultrasound in the Evaluation of Psoriatic Arthritis: A Clinical Study.

Am J Med Sci 2015 Jul;350(1):42-6

Department of Rheumatology, First Affiliated Hospital of Harbin Medical University, Harbin, China.

Background: This study aimed to compare high-frequency ultrasound (HFU) findings in the fingers with psoriatic arthritis (PsA) and rheumatoid arthritis (RA) and to explore the potential use of HFU in the early diagnosis of PsA.

Methods: Forty-four PsA patients with 123 fingers with symptoms, 39 RA patients with 122 fingers with symptoms and 20 healthy patients were recruited as controls. The ultrasound imaging manifestation and blood flow of fingers were recorded and compared. The results were analyzed by the χ test.

Results: Abnormal ultrasound findings in the fingers of RA and PsA patients were identified and compared. Among RA patients, 82 (67.21%) were diagnosed with joint effusion, 78 (63.93%) were synovial thickening and 59 (48.36%) were bone erosion, while no tenosynovitis, soft tissue inflammation or enthesitis was found. However, among the patients with PsA, 75 (60.97%) were diagnosed with joint effusion, 68 (55.28%) were synovial thickening, 71 (57.72%) were bone erosion, 71 (57.72%) were tenosynovitis, 44 (35.77%) were soft tissue inflammation and 39 (31.70%) were enthesitis.

Conclusions: HFU proved valuable in detecting soft tissue inflammation and enthesitis in the fingers of PsA patients. HFU may be an easy, safe and effective examination in the early diagnosis of PsA and observation of pathological changes of PsA.
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http://dx.doi.org/10.1097/MAJ.0000000000000504DOI Listing
July 2015

Tumor border sharpness correlates with HLA-G expression in low-grade gliomas.

J Neuroimmunol 2015 May 3;282:1-6. Epub 2015 Mar 3.

Beijing Neurosurgical Institute, Capital Medical University, Beijing, China; Beijing Tiantan Hospital, Capital Medical University, Beijing, China; Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing, China. Electronic address:

Human leukocyte antigen-G (HLA-G) is a tumor microenvironment molecule that is involved in the escape of cancerous tumors from host immune recognition and destruction. This study investigated the potential relationship between HLA-G expression levels and the sharpness of low-grade glioma tumor borders in magnetic resonance images. Preoperative T2-weighted images from 72 patients were retrospectively examined by manually segmenting the hyperintensive tumor areas and subsequently registering them to a standard brain template. Then, the intensity of the voxels inside the tumor border (tumor voxels) was compared with that of the voxels outside the tumor border (paratumor voxels). The radiologic sharpness of a tumor was defined as the mean ratio of the intensity of the tumor voxels to the intensity of the paratumor voxels. Tumors with high HLA-G expression were associated with larger tumors and lower mean hyperintensive contrast. These findings suggest that tumors with blurred boundaries may be those prone to diffuse invasion. Additionally, patients with tumors having high HLA-G expression were less likely to have undergone complete resections. Thus, this study is the first to identify an association between HLA-G expression and the radiologic morphology of the tumor border, and may further our understanding of the role of the HLA gene in immune escape in patients with low-grade gliomas.
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http://dx.doi.org/10.1016/j.jneuroim.2015.02.013DOI Listing
May 2015

Overexpression of N-myc downstream-regulated gene 1 inhibits human glioma proliferation and invasion via phosphoinositide 3-kinase/AKT pathways.

Mol Med Rep 2015 Jul 13;12(1):1050-8. Epub 2015 Mar 13.

Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.

N-myc downstream-regulated gene 1 (NDRG1) was previously shown to exhibit low expression in glioma tissue as compared with that in normal brain tissue; however, the role of NDRG1 in human glioma cells has remained to be elucidated. The present study used the U87 MG and SHG-44 human glioma cell lines as well as the normal human astrocyte cell line 1800, which are known to have differential NDRG1 expression. Small interfering (si)RNA targeting NDRG1, and NDRG1 overexpression vectors were transfected into the SHG-44 and U87 MG glioma cells, respectively. Cell proliferation, invasion, apoptosis and cell cycle arrest were subsequently examined by MTT assay, transwell chamber assay, flow cytometry and western blot analysis, respectively. Furthermore, a subcutaneous tumor mouse model was used to investigate the effects of NDRG1 on the growth of glioma cells in vivo. Overexpression of NDRG1 was shown to inhibit cell proliferation and invasion, and induce apoptosis in the U87 MG glioma cells, whereas NDRG1 downregulation increased proliferation, suppressed apoptosis and promoted invasion of the SHG‑44 glioma cells. In addition, in the subcutaneous tumor mouse model, overexpression of NDRG1 in U-87 MG cells suppressed tumorigenicity in vivo. The findings of the present study indicated that NDRG1 is required for the inhibition of gliomagenesis; therefore, targeting NDRG1 and its downstream targets may represent novel therapies for the treatment of glioma.
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http://dx.doi.org/10.3892/mmr.2015.3492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438970PMC
July 2015