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3D Microfluidic System for Evaluating Inhibitory Effect of Chinese Herbal Medicine Oldenlandia diffusa on Human Malignant glioma Invasion Combined with Network Pharmacology Analysis

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Chinese Journal of Integrative Medicine 2023年第1期29卷 52-60页

作者： HAN Chun-hui MA Jing-yun ZOU Wei QU Jia-lin DU Yang LI Na LIU Yong JIN Guo LENG Ai-jing LIU Jing Stem Cells Clinical Research Institution the First Affiliated Hospital of Dalian Medical UniversityDalian116011Liaoning ProvinceChina Dalian Innovation Institute of Stem Cell and Precision Medicine Dalian116023Liaoning ProvinceChina Integrated Chinese and Western Medicine Laboratory the First Affiliated Hospital of Dalian Medical UniversityDalian116011Liaoning ProvinceChina Department of Traditional Chinese Medicine the First Affiliated Hospital of Dalian Medical UniversityDalian116011Liaoning ProvinceChina

Objective:To investigate the anti-invasion efficacy of the ethanol extract of Oldenlandia diffusa Will.(EEOD) on a three-dimensional(3D) human Malignant glioma(MG) cell invasion and perfusion model based on microfluidic chip culture and the possible mechanism of action of Oldenlandia diffusa Will.(OD).Methods:The comprehensive pharmacodynamic analysis method in this study was based on microfluidic chip 3D cell perfusion culture technology,and the action mechanism of Chinese medicine(CM) on human MG cells was investigated through network pharmacology analysis.First,the components of EEOD were analyzed by ultraperformance liquid chromatography with quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF/MS).Then,cell viability and apoptosis were assessed to determine the optimum concentration of EEOD for invasion experiments,and two-dimensional(2D) migration and invasion abilities of U87 and U251 MG cells were evaluated using scratch wound and Transwell assays.The possible mechanism underlying the effects of EEOD on glioma was analyzed through a network pharmacology approach.Results:Thirty-five compounds of EEOD were detected by UPLC-Q-TOF/MS.EEOD suppressed the viability of MG cells,promoted their apoptosis,and inhibited their migratory and invasive potentials(all P<0.05).Network pharmacology analysis showed that OD inhibited the invasion of MG cells by directly regulating MAPK and Wnt pathways through MAPK,EGFR,MYC,GSK3B,and other targets.The anti-invasion effect of OD was also found to be related to the indirect regulation of microtubule cytoskeleton organization.Conclusion:EEOD could inhibit the invasion of human MG cells,and the anti-invasion mechanism of OD might be regulating MAPK and Wnt signaling pathways and microtubule cytoskeleton organization.

关键词： invasion Malignant glioma Oldenlandia diffusa microfluidic chip Chinese medicine

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Survival Analysis of Patients Undergoing Intraoperative Contrast-enhanced Ultrasound in the Surgical Treatment of Malignant glioma

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当代医学科学（英文） 2024年第2期44卷 399-405页

作者： Xu CHEN Ya-ni PENG Fang-ling CHENG Dan CAO An-yu TAO Jian CHEN Department of Neurosurgery Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Department of Urology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Department of Medical Ultrasound Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China

Objective:Complete resection of Malignant gliomas is often challenging.Our previous study indicated that intraoperative contrast-enhanced ultrasound(ICEUS)could aid in the detection of residual tumor remnants and the total removal of brain lesions.This study aimed to investigate the survival rates of patients undergoing resection with or without the use of ICEUS and to assess the impact of ICEUS on the prognosis of patients with Malignant glioma.Methods:A total of 64 patients diagnosed with Malignant glioma(WHO grade Ⅲ and Ⅳ)who underwent surgery between 2012 and 2018 were included.Among them,29 patients received ICEUS.The effects of ICEUS on overall survival(OS)and progression-free survival(PFS)of patients were evaluated.A quantitative analysis was performed to compare ICEUS parameters between gliomas and the surrounding tissues.Results:The ICEUS group showed better survival rates both in OS and PFS than the control group.The univariate analysis revealed that age,pathology and ICEUS were significant prognostic factors for PFS,with only age being a significant prognostic factor for OS.In multivariate analysis,age and ICEUS were significant prognostic factors for both OS and PFS.The quantitative analysis showed that the intensity and transit time of microbubbles reaching the tumors were significantly different from those of microbubbles reaching the surrounding tissue.Conclusion:ICEUS facilitates the identification of residual tumors.Age and ICEUS are prognostic factors for Malignant glioma surgery,and use of ICEUS offers a better prognosis for patients with Malignant glioma.

关键词： intraoperative contrast-enhanced ultrasound Malignant glioma extent of resection survival prognosis

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Dendritic cell-based immunotherapy for Malignant glioma

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Neuroscience Bulletin 2008年第1期24卷 39-44页

作者： Jin-Hai GU Gang LI Department of Neurosurgery Qilu Hospital of Shandong University Jinan 250012 China

The immunotherapy for Malignant glioma faces unique difficult, due to some anatomical and immunological characteristics including the existence of blood brain barrier, the absence of lymphatic tissues and dendritic cells （DCs） in the central nervous system （CNS） parenchyma, and the presence of an immunosuppressive microenvironment. Therefore, immunothera-peutic approaches will not be beneficial unless the compromised immune status in Malignant glioma patients is overcome. DC-based immunotherapy, vaccinating cancer patients with DCs pulsed with various tumor antigens, is one of the most promising immunotherapeutic approaches for treatment of malignantglioma because it seems able to overcome, at least partially, the immunosuppressive state associated with primary malignancies. The preparation of DCs, choice of antigen, and route and schedule of administration are improving and optimizing with rapid development of molecular biology and gene engineering technology. DC vaccination in humans, after a number of pre-clinical models and clinical trials, would increase the clinical benefits for Malignant glioma immunotherapy.

关键词： dendritic cell immunotherapy Malignant glioma

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The process of life adjustment in patients at onset of glioma who are receiving continuous oral anticancer drug: A qualitative descriptive study

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International Journal of Nursing Sciences 2019年第2期6卷 134-140页

作者： Koji Amano Kumi Suzuki Faculty of Nursing Doshisha Women's College of Liberal ArtsKyotoJapan Faculty of Nursing Osaka Medical CollegeOsakaJapan

Objective: Patients with Malignant gliomas have to adjust their daily lives because of the threat of impending death and declining abilities.Thus,clarifying the process of life adjustment in such patients would help them lead a normal life.To clarify the process of life adjustment in patients at the onset of glioma,who continuously receive oral anticancer drug.Methods: The study institution consisted of two designated cancer centers.Semi-structured interviews were conducted with 10 patients,and the data were analyzed using the Modified Grounded Theory Approach of Kinoshita (M-GTA).Results: As a core category representing the process of life adjustment in patients at the onset of glioma,"trials and errors for self-fulfillment even in a limited lifespan" was extracted.Patients began "seeking information about the unfamiliar life-threatening disease," and "imaging their uncertain lives after the disease and the resulting disability" while "conducting repeated trials and errors to establish coping methods according to their abilities." When facing difficulties in such trials and errors,they reported "losing self-confidence due to unexpected limitations." However,they regulated their feelings by "resigning themselves to their unchangeable reality." Contrarily,as "functional improvement enhanced their motivation to recover," they attempted to promote functional recovery and organized their daily lives in "fulfilling their desires in their limited lifespan." Conclusion: The process of life adjustment in patients with Malignant gliomas involved identifying a way of living despite limited lifespan.To ensure appropriate nursing care for patients at the onset of glioma,it is important to help them establish coping methods in accordance with their abilities.

关键词： Adjustment Life Malignant glioma Patients Qualitative study

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Does Early Postsurgical Temozolomide Plus Concomitant Radiochemotherapy Regimen Have Any Benefit in Newly-diagnosed Glioblastoma Patients？ A Multi-center, Randomized, Parallel, Open-label, Phase II Clinical Trial

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Chinese Medical Journal 2015年第20期128卷 2751-2758页

作者： Ying Mao Yu Yao Li-Wei Zhang Yi-Cheng Lu Zhong-Ping Chen Jian-Min Zhang Song-Tao Qi Chao You Ren-Zhi Wang Shu-Yuan Yang Xiang Zhang Ji-Sheng Wang Ju-Xiang Chen Qun-Ying Yang Hong Shen Zhi-Yong Li Xiang Wang Wen-Bin Ma Xue-Jun Yang Hai-Ning Zhen Liang-Fu Zhou Department of Neurosurgery Huashan Hospital Fudan University Shanghai 200040 China Department of Neurosurgery Beijing Tiantan Hospital Capital Medical University Beijing 100050 China Department of Neurosurgery Changzheng Hospital Second Military Medical University Shanghai 200003 China Sun Yat-Sen University Cancer Center Guangzhou Guangdong 510060 China Department of Neurosurgery The Second Affiliated Hospital of Zhejiang University School of Medicine Hangzhou Zhejiang 310009 China Department of Neurosurgery Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 China Department of Neurosurgery West China Hospital of Sichuan University Chengdu Sichuan 610041 China Department of Neurosurgery Peking Union Medical College Hospital Beijing 100032 China Department of Neurosurgery General Hospital Tianjin Medical University Tianjin 300070 China Department of Neurosurgery Xijing Hospital The Fourth Military Medical University Xi'an Shaanxi 710032 China

Background： The radiochemotherapy regimen concomitantly employing temozolomide （TMZ） chemotherapy and radiotherapy （RT） 4 weeks after surgery, followed by 6 cycles of TMZ is a common treatment for glioblastoma （GBM）. However, its median overall survival （OS） is only 14.6 months. This study was to explore the effectiveness and safety of early TMZ chemotherapy between surgery and chemoradiotherapy plus the standard concomitant radiochemotherapy regimen. Methods： A randomized, parallel group, open-label study of 99 newly diagnosed GBM patients was conducted at 10 independent Chinese neurosurgical departments from June 2008 to June 2012. Patients were treated with concomitant radiochemotherapy regimen plus early postsurgical temozolomide （early TMZ group） or standard concomitant radiochemotherapy regimen （control group）. Overall response was assessed based on objective tumor assessments, administration ofcorticosteroid and neurological status test. Hematological, biochemical, laboratory, adverse event （AE）, and neurological condition were measured for 24 months of tbllow-up. The primary efficacy endpoint of this study was overall survival （OS）. The secondary endpoint was progression free survival （PFS）. Results： The median OS time in the early TMZ group was 17.6 months, compared with 13.2 months in the control group （log-rank test P 0.021 ）. In addition, the OS rate in the early TMZ group was higher at 6, 12, and 18 months than in the control group, respectively （P 〈 0.05）. The median PFS time was 8.7 months in the early TMZ group and 10.4 months in the control group （log-rank test P = 0.695）. AEs occurred in 29 （55.8%） and 31（73.8%） patients respectively in early and control groups, including nausea （15.4% vs. 33.3%）, vomiting （7.7% vs. 28.6%）, fever （7.7% vs. 11.9%）, and headache （3.8% vs. 23.8%）. Only 30.8% and 33.3% were drug-related, respectively. Conclusions： Addition of TMZ chemotherapy in the early break of the standard concomitant radiochemotherapy regimen was well tolerated and significantly improved the O

关键词： Chemoradiotherapy Chemotherapy： Glioblastoma Malignant glioma Temozolomide

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Progress on molecular biomarkers and classification of Malignant gliomas

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Frontiers of Medicine 2013年第2期7卷 150-156页

作者： Chuanbao Zhang Zhaoshi Bao Wei Zhang Tao Jiang Department of Neurosurgery Beijing Tiantan HospitalCapital Medical UniversityBeijing 100050China Beijing Neurosurgical Institute Beijing 100050China

gliomas are the most common primary intracranial tumors in adults.Anaplastic gliomas(WHO gradeⅢ)and glioblastomas(WHO gradeⅣ)represent the major groups of Malignant gliomas in the brain.Several diagnostic,predictive,and prognostic biomarkers for Malignant gliomas have been reported over the last few decades,and these markers have made great contributions to the accuracy of diagnosis,therapeutic decision making,and prognosis of patients.However,heterogeneity in patient outcomes may still be observed,which highlights the insufficiency of a classification system based purely on histopathology.Great efforts have been made to incorporate new information about the molecular landscape of gliomas into novel classifications that may potentially guide treatment.In this review,we summarize three distinctive biomarkers,three most commonly altered pathways,and three classifications based on microarray data in Malignant gliomas.

关键词： Malignant glioma molecular biomarker IDH1 MGMT molecular classification

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Commentary:Evaluating potential glioma serum biomarkers,with future applications

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World Journal of Clinical Oncology 2022年第5期13卷 412-416页

作者： Michael Goutnik Brandon Lucke-Wold Department of Neurosurgery University of FloridaGainesvilleFL 32608United States

Systemic inflammation within Malignant glioma is a topic of ongoing significance.In this commentary,we highlight recent findings from Gandhi et al and discuss alternative approaches.We present a counter argument with findings that IL-6 markers are controversial.We highlight the potential benefit of looking at microRNAs and other biomarkers.Finally,we present ideas for future application involving differentiation between radiation necrosis and recurrence.The commentary is intended to serve as a catalyst for further scientific discovery.

关键词： Systemic inflammation Malignant glioma Neutrophil-lymphocyte ratio Interleukin-6

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SLIT2 inhibits glioma invasion in the brain

SLIT2 inhibits glioma invasion in the brain

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中国抗癌协会神经肿瘤专业委员会第八届学术会议

作者： JJ Yiin B Hu J Wu Y Rao HI Ma SY Cheng Veteran General Hospital University of Pittsburgh Cancer Institute & Department of Pathology Northwestern University Feinberg Medical School Robert H Lurie Comprehensive Cancer CenterCenter for Genetic Medicine Department of Neurology Northwestern UniversityFeinberg Medical School

Malignant gliomas are the most common primary brain tumors in the central nervous system.Their infiltrative nature and heterogeneity represent a significant impediment to achieve a curative intervention by conventional therapies.Inhibition of migration involves multiple pathway alteration.SLIT2,a secreted protein with roles in axonal guidance and migration by binding to Robo receptors,has been shown to inhibit the migration of dendritic cells,vascular smooth muscle cell and leukocyte.However,SLIT2 was found to stimulate migration of breast cancer cells.In glioma,down regulation of SLIT2 and hypermethylation of promoter region CpG island comparing to normal astrocyte were found.The role of SLIT2 in vitro seems equivocal and the biological significance of SLIT2 in metastasis ＆ invasion of cancer cells in vivo has not yet been investigated.We recently report that engineer human glioma cells become lethally invasive in the brain of mice.cDNA array analysis of gene express profile followed by real-time PCR identifies a down regulation of SLIT2 expression.In the present study,the effects of SLIT2 on the migration and invasion of glioma cells in vitro and in vivo were further characterized.The expression of Robo and SLIT2 in glioma cell lines was found by RT PCR.Inhibition of migration and invasion by SLIT2 in glioma cell lines in vitro was found by wound healing,migration and invasion assay.Transfection of SLIT2 into glioma cell lines was performed.The cell clones with exogenous Over expression of SLIT2 were selected and confirmed by Western Blotting.Stereotactic injection of parental/or over expression of SLIT2 glioma cells was performed,which inhibition of invasion by SLIT2 was found followed by H＆E staining of brain sections.We first demonstrate here that SLIT2 play a role in inhibition of migration and invasion in vitro.The mechanism causing inhibition of migration and invasion by decrease of N-cadherin or Cdc42 was further studied.Studies of the SLIT2-Robo complex may foster new anti-chemorepellent approaches to t

关键词： Invasion Malignant glioma Migration Robo receptors SLIT2

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Extracellular control of chromosomal instability and maintenance of intra-tumoral heterogeneity

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Journal of Cancer Metastasis and Treatment 2018年第1期4卷 468-482页

作者： Yi-Hong Zhou Kambiz Afrasiabi Mark E.Linskey UC Irvine Brain Tumor Laboratory in Department of Surgery University of CaliforniaIrvineIrvineCA 92697USA

Aim:Current cancer treatments are challenged by the plasticity of cancer cells,largely influenced by chromosomal instability(CIN)leading to variations in karyotype known as tumor-specific aneuploidy,which in turn,leads to intra-tumor cellular heterogeneity(TH).Cells with certain chromosomal defects often survive treatment and the growth-associated states of TH persist in recurrent tumors.Modulation of the CIN rate seems to reside within the tumor itself.In an attempt to develop a therapy targeting cancer plasticity,we studied the possible extracellular control of CIN rate in Chr7-defined TH in gliomas.Methods:Chr7-fluorescence in situ hybridization was applied on various grades of gliomas,in vitro cultures and intracranial xenografts of two syngeneic glioma lines(U251 and U251-NS)derived from various cell-inoculating densities,with or without EFEMP1 overexpression.Results:A grade-dependent increase of trisomy-7 population and Chr7-defined cell diversity was shown in gliomas.A negative association between Chr7-MS rate and initial cell-inoculating density was observed which was prevented by EFEMP1 overexpression.Conclusion:Our data demonstrate that CIN is a major driver for cancer cell plasticity and suggest that CIN can be controlled by extracellular factors derived from normal and tumor cells,and EFEMP1 is one of these factors.

关键词： Malignant glioma intra-tumoral heterogeneity functional tumor subpopulations chromosome 7 chromosome

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Semireplication-competent vesicular stomatitis virus as a novel platform for oncolytic virotherapy

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世界最新医学信息文摘 2015年第5期 245-245页

作者： Alexander Muik Catherine Dold Yvonne Gei Andreas Volk Marina Werbizki Ursula Dietrich Dorothee von Laer

Among oncolytic viruses, the vesicular stomatitis virus(VSV) is especially potent and a highly promising agent for the treatment of cancer. But, even though effective against multiple tumor entities in preclinical animal models, replicationcompetent VSV exhibits inherent neurovirulence, which has so far hindered clinical development. To overcome this limitation,replication-defective VSV vectors for cancer gene therapy have been tested and proven to be safe. However, gene delivery was inefficient and only minor antitumor efficacy was observed. Here, we present semireplicationcompetent vector systems for VSV(sr VSV), composed of two trans-complementing, propagation-deficient VSV vectors. The de novo generated deletion mutants of the two VSV polymerase proteins P(phosphoprotein) and L(large catalytic subunit), VSVΔP and VSVΔL respectively, were used mutually or in combination with VSVΔG vectors. These sr VSV systems copropagated in vitro and in vivo without recombinatory reversion to replication-competent virus. The sr VSV systems were highly lytic for human glioblastoma cell lines,spheroids, and subcutaneous xenografts. Especially the combination of VSVΔG/VSVΔL vectors was as potent as wild-type VSV(VSV-WT) in vitro and induced long-term tumor regression in vivo without any associated adverse effects. In contrast, 90% of VSV-WT-treated animals succumbed to neurological disease shortly after tumor clearance. Most importantly, even when injected into the brain, VSVΔG/VSVΔL did not show any neurotoxicity. In conclusion, sr VSVis a promising platform for virotherapeutic approaches and also for VSV-based vector vaccines, combining improved safety with an increased coding capacity for therapeutic transgenes, potentially allowing for multipronged approaches.

关键词： Vesicular stomatitis virus Oncolytic virus Virotherapy Malignant glioma

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