Enzhou Lu

First Affiliated Hospital of Harbin Medical University

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Jingxian Sun

University of Chinese Academy of Sciences

Guang Yang

Second Hospital of Shandong University

Qiuyi Jiang

Harbin Medical University

Boxian Zhao

Harbin Medical University

Shiguang Zhao

Anhui Polytechnic University

Penglei Yao

Harbin Medical University

Chunyang Liu

Harbin Medical University

Xun Xu

BGI Group (China)

Xiaoxiong Wang

Qilu Hospital of Shandong University

Junyi Ye

Ningbo University

Cooperative Institutions

Harbin Medical University

First Affiliated Hospital of Harbin Medical University

Chinese Academy of Sciences

Heilongjiang Institute of Technology

Sun Yat-sen University

Southern Medical University

Chinese Academy of Medical Sciences & Peking Union Medical College

Sichuan University

Heilongjiang University

Chongqing Medical University

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Total intracranial volume as a covariate for predicting prognosis in patients with primary intracerebral hemorrhage

Clinical Neurology and Neurosurgery (2022)

Lixiang Wang Chunyang Liu Enzhou Lu Daming Zhang Haopeng Zhang

Spontaneous intracerebral hemorrhage

Decompressive craniectomy

Midline shift

10.1016/j.clineuro.2022.107135

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Citations (4)

A Six-lncRNA Signature for Immunophenotype Prediction of Glioblastoma Multiforme

Frontiers in Genetics (2021)

Ming Gao Xinzhuang Wang Dayong Han Enzhou Lu Jian Zhang

Glioblastoma multiforme (GBM) is the most aggressive primary tumor of the central nervous system. As biomedicine advances, the researcher has found the development of GBM is closely related to immunity. In this study, we evaluated the GBM tumor immunoreactivity and defined the Immune-High (IH) and Immune-Low (IL) immunophenotypes using transcriptome data from 144 tumors profiled by The Cancer Genome Atlas (TCGA) project based on the single-sample gene set enrichment analysis (ssGSEA) of five immune expression signatures (IFN-γ response, macrophages, lymphocyte infiltration, TGF-β response, and wound healing). Next, we identified six immunophenotype-related long non-coding RNA biomarkers (im-lncRNAs, USP30-AS1, HCP5, PSMB8-AS1, AL133264.2, LINC01684, and LINC01506) by employing a machine learning computational framework combining minimum redundancy maximum relevance algorithm (mRMR) and random forest model. Moreover, the expression level of identified im-lncRNAs was converted into an im-lncScore using the normalized principal component analysis. The im-lncScore showed a promising performance for distinguishing the GBM immunophenotypes with an area under the curve (AUC) of 0.928. Furthermore, the im-lncRNAs were also closely associated with the levels of tumor immune cell infiltration in GBM. In summary, the im-lncRNA signature had important clinical implications for tumor immunophenotyping and guiding immunotherapy in glioblastoma patients in future.

Immunophenotyping

Tumor-infiltrating lymphocytes

10.3389/fgene.2020.604655

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Citations (22)

Impact of surface ultraviolet radiation intensity on hospital admissions for ischemic and hemorrhagic stroke: A large-scale database study using distributed lag nonlinear analysis, 2015-2022, in Harbin, China

Journal of Stroke and Cerebrovascular Diseases (2024)

Shouyue Wu Hongli Zhang Chunyang Liu Qiunan Yang J.X. Sun

Lag time

Intensity

Stroke

Time lag

10.1016/j.jstrokecerebrovasdis.2024.107908

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RRM2 Mediates the Anti-Tumor Effect of the Natural Product Pectolinarigenin on Glioblastoma Through Promoting CDK1 Protein Degradation by Increasing Autophagic Flux

Frontiers in Oncology (2022)

Haiping Jiang Dongzhi Zhang Karpov Denis Aleksandrovich Junyi Ye Lixiang Wang

The natural product pectolinarigenin exerts anti-inflammatory activity and anti-tumor effects, and exhibits different biological functions, particularly in autophagy and cell cycle regulation. However, the antineoplastic effect of pectolinarigenin on glioblastoma (GBM) remains unclear. In the present study, we found that pectolinarigenin inhibits glioblastoma proliferation, increases autophagic flux, and induces cell cycle arrest by inhibiting ribonucleotide reductase subunit M2 (RRM2), which can be reversed by RRM2 overexpression plasmid. Additionally, pectolinarigenin promoted RRM2 protein degradation via autolysosome-dependent pathway by increasing autophagic flow. RRM2 knockdown promoted the degradation of CDK1 protein through autolysosome-dependent pathway by increasing autophagic flow, thereby inhibiting the proliferation of glioblastoma by inducing G2/M phase cell cycle arrest. Clinical data analysis revealed that RRM2 expression in glioma patients was inversely correlated with the overall survival. Collectively, pectolinarigenin promoted the degradation of CDK1 protein dependent on autolysosomal pathway through increasing autophagic flux by inhibiting RRM2, thereby inhibiting the proliferation of glioblastoma cells by inducing G2/M phase cell cycle arrest, and RRM2 may be a potential therapeutic target and a prognosis and predictive biomarker in GBM patients.

Protein Degradation

Temozolomide

10.3389/fonc.2022.887294

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Citations (11)

Extreme temperature increases the severity of intracerebral hemorrhage: An analysis based on the cold region of China

Frigid Zone Medicine (2022)

Xun Xu Chunyang Liu Rui Liu Qiuyi Jiang Enzhou Lu

Abstract Objective The purpose of this study was to find a suitable model to evaluate the relationship between temperature and intracerebral hemorrhage (ICH) and explore the effects of cold spells and heat waves on the clinicopathological parameters of ICH patients. Methods We conducted a retrospective study based on the ICH admission in the First Affiliated Hospital of Harbin Medical University from 2015 to 2020 ( N = 11 124). The relationship between different seasons and the number of patients with ICH was explored. Poisson Akaike information criterion (AIC) was used to select the optimal model for temperature and ICH. Binary logistic regression analysis was used to investigate the association between extreme temperatures and clinicopathological features. Results Hospital admissions for patients with ICH showed monthly changes. The optimal cold spell was defined as the daily average temperature < 3rd percentile, lasting for five days, while the optimal heat wave was defined as the daily average temperature >97th percentile, lasting for three days. Based on the generalized extreme weather model, cold climate significantly increased the risk of hematoma volume expansion ( OR 1.003; 95% CI : 1.000–1.005, P = 0.047). In the optimal model, the occurrence of cold spells and heat waves increased the risk of midline shift in both conditions ( OR 1.067; 95% CI : 1.021–1.115, P = 0.004; OR 1.077; 95% CI : 1.030–1.127, P = 0.001). Conclusion Our study shows that seasonal cold spells and heat waves are essential factors affecting ICH severity, and targeted preventive measures should be taken to minimize the pathological impacts.

Heat wave

Akaike information criterion

Maximum temperature

Extreme heat

10.2478/fzm-2022-0024

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Vision transformer-based weakly supervised histopathological image analysis of primary brain tumors

iScience (2022)

Zhongxiao Li Yuwei Cong Xin Chen Jiping Qi Jingxian Sun

Diagnosis of primary brain tumors relies heavily on histopathology. Although various computational pathology methods have been developed for automated diagnosis of primary brain tumors, they usually require neuropathologists' annotation of region of interests or selection of image patches on whole-slide images (WSI). We developed an end-to-end Vision Transformer (ViT) - based deep learning architecture for brain tumor WSI analysis, yielding a highly interpretable deep-learning model, ViT-WSI. Based on the principle of weakly supervised machine learning, ViT-WSI accomplishes the task of major primary brain tumor type and subtype classification. Using a systematic gradient-based attribution analysis procedure, ViT-WSI can discover diagnostic histopathological features for primary brain tumors. Furthermore, we demonstrated that ViT-WSI has high predictive power of inferring the status of three diagnostic glioma molecular markers, IDH1 mutation, p53 mutation, and MGMT methylation, directly from H&E-stained histopathological images, with patient level AUC scores of 0.960, 0.874, and 0.845, respectively.

Histopathology

Brain tumor

10.1016/j.isci.2022.105872

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Citations (35)

Interfering With Hyaluronic Acid Metabolism Suppresses Glioma Cell Proliferation by Regulating Autophagy

Research Square (Research Square) (2020)

Tao Yan Xin Chen Zhan Hua Penglei Yao Ning Wang

Abstract BackgroundThe tumor microenvironment plays an important role in tumor progression. Hyaluronic acid (HA), an important component of the extracellular matrix in the tumor microenvironment, abnormally accumulates in a variety of tumors. Whereas the role of abnormal HA metabolism in glioma remains unclear. MethodsThe expression level of hyaluronic acid (HA) was analyzed by ELISA assay and proteins such as HAS3, CD44, P62, LC3, CCND1 and CCNB1 were measured with Western blot analysis. The cell viability and proliferation were measured by MTT and KI67 immunofluorescence staining respectively. Autophagic vesicles and autophagosomes were quantified by transmission electron microscopy (TEM) and GFP-RFP-LC3 fluorescence analysis respectively. Cell cycle was analyzed by flowcytometry and Western blot analysis. Immunohistochemical (IHC) staining was used to detect expression levels of HA, Ki67, HAS3 and CD44 in human and mouse tumor tissues. Lentivirus constructed HAS3 and CD44 knockout stable glioma cells were transplanted to BALB/C nude mice for in vivo experiments. 4-Methylumbelliferone (4MU) was also used to treat glioma bearing mice for verifing its anti-tumor ability. The expression curve of HAS3, CD44 and the disease-free survival (DFS) curves for HAS3, CD44 in patients with LGG and GBM was performed based on TCGA database. ResultsAs shown in the present study, HA, hyaluronic acid synthase 3 (HAS3) and a receptor of HA named CD44 are expressed at high levels in human glioma tissues and negatively correlated with the prognosis of patients with glioma. Silencing HAS3 or blocking CD44 inhibited the proliferation of glioma cells in vitro and in vivo. The underlying mechanism was attributed to the inhibition of autophagy flux and further maintaining glioma cell cycle arrest in G1 phase. More importantly, 4-Methylumbelliferone (4-MU), a small competitive inhibitor of UDP with the ability to penetrate the blood-brain barrier (BBB), also inhibited the proliferation of glioma cells in vitro and in vivo. ConclusionApproaches that interfere with HA metabolism by altering the expression of HAS3 and CD44 and the administration of 4-MU potentially represent effective strategies for glioma treatment.

Hyaluronan synthase

Tumor progression

10.21203/rs.3.rs-88666/v1

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Citations (0)

The Mechanisms of Current Platinum Anticancer Drug Resistance in the Glioma

Current Pharmaceutical Design (2022)

Enzhou Lu Ilgiz Gareev Chao Yuan Yanchao Liang Jingxian Sun

Gliomas are the most common and malignant primary tumors of the central nervous system (CNS). Glioblastomas are the most malignant and aggressive form of primary brain tumors and account for the majority of brain tumor-related deaths. The current standard treatment for gliomas is surgical resection supplemented by postoperative chemotherapy. Platinum drugs are a class of chemotherapeutic drugs that affect the cell cycle, and the main site of action is the DNA of cells, which are common chemotherapeutic drugs in clinical practice. Chemotherapy with platinum drugs such as cisplatin, carboplatin, oxaliplatin, or a combination thereof is used to treat a variety of tumors. However, the results of gliomas chemotherapy are unsatisfactory, and resistance to platinum drugs is one of the important reasons. The resistance of gliomas to platinum drugs is the result of a combination of influencing factors. Decreased intracellular drug concentration, enhanced function of cell processing active products, enhanced repair ability of cellular DNA damage, and blockage of related apoptosis pathways play an important role in it. It is known that the pathogenic properties of glioma cells and the response of glioma towards platinum-based drugs are strongly influenced by non-coding RNAs, particularly, by microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). miRNAs and lncRNAs control drug sensitivity and the development of tumor resistance towards platinum drugs. This mini-review summarizes the resistance mechanisms of gliomas to platinum drugs, as well as molecules and therapies that can improve the sensitivity of gliomas to platinum drugs.

Carboplatin

10.2174/1381612828666220607105746

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Citations (15)

Novel cancer-fighting role of ticagrelor inhibits GTSE1-induced EMT by regulating PI3K/Akt/NF-κB signaling pathway in malignant glioma

Heliyon (2024)

Enzhou Lu Boxian Zhao Chao Yuan Yan-Chao Liang Xiaoxiong Wang

BackgroundGlioma is the most common malignant brain tumor of the central nervous system. Despite of the improvement of therapeutic strategy, the prognosis of malignant glioma patients underwent by STUPP strategy is still unexpected. Previous studies have suggested that ticagrelor exerted chemotherapeutic effects by inhibition of epithelial-mesenchymal transition (EMT) in various diseases including tumors. However, whether ticagrelor can exhibit the antitumor efficiency in glioma by affecting the EMT process is still unclear. In this study, we investigated the cancer-fighting role of ticagrelor and demonstrated its chemotherapeutic mechanism in glioma.Materials and methodsThe MTT assay was performed to detect the cytotoxicity of ticagrelor in glioma cells. We evaluated the expression of Ki67 in glioma cells by immunofluorescence assay after ticagrelor treatment. We conducted wound healing assay and transwell assay to determine the effects of ticagrelor on the migration and invasion of glioma cells. RNA-seq analysis was conducted to examine potential target genes and alternative signaling pathways for ticagrelor treatment. The expression levels of key EMT -related proteins were examined by western blot experiment.ResultsTicagrelor inhibited the proliferation, migration and invasion of glioma cells with a favorable toxicity profile in vitro. Ticagrelor downregulated the expression of GTSE1 in glioma cells. RNA-seq analysis explored that GTSE1 acted as the potential target gene for ticagrelor treatment. Upregulation of GTSE1 antagonized the inhibitory effect of ticagrelor on the invasion of glioma and EMT progression by regulation of PI3K/Akt/NF-κB signaling pathway. And ticagrelor also exhibited the similar chemotherapeutic effect of glioma in vivo.ConclusionsTicagrelor as a potential chemotherapeutic option induced the inhibition of the GTSE1-induced EMT progression by regulation of PI3K/AKT/NF-κB signaling pathway.

10.1016/j.heliyon.2024.e30833

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Citations (1)

Interfering with hyaluronic acid metabolism suppresses glioma cell proliferation by regulating autophagy

Cell Death and Disease (2021)

Tao Yan Xin Chen Hua Zhan Penglei Yao Ning Wang

Abstract The tumor microenvironment plays an important role in tumor progression. Hyaluronic acid (HA), an important component of the extracellular matrix in the tumor microenvironment, abnormally accumulates in a variety of tumors. However, the role of abnormal HA accumulation in glioma remains unclear. The present study indicated that HA, hyaluronic acid synthase 3 (HAS3), and a receptor of HA named CD44 were expressed at high levels in human glioma tissues and negatively correlated with the prognosis of patients with glioma. Silencing HAS3 expression or blocking CD44 inhibited glioma cell proliferation in vitro and in vivo. The underlying mechanism was attributed to the inhibition of autophagy flux and maintaining glioma cell cycle arrest in G1 phase. More importantly, 4-methylumbelliferone (4-MU), a small competitive inhibitor of Uridine diphosphate (UDP) with the ability to penetrate the blood-brain barrier (BBB), also inhibited glioma cell proliferation in vitro and in vivo. Thus, approaches that interfere with HA metabolism by altering the expression of HAS3 and CD44 and the administration of 4-MU potentially represent effective strategies for glioma treatment.

Hyaluronan synthase

Tumor progression

10.1038/s41419-021-03747-z

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Citations (26)