Background:The dysregulation of Isocitrate dehydrogenase(IDH)and the subsequent production of 2-Hydroxyglutrate(2HG)may alter the expression of epigenetic proteins in Grade 4 astrocytoma.The interplay mechanism betwee...Background:The dysregulation of Isocitrate dehydrogenase(IDH)and the subsequent production of 2-Hydroxyglutrate(2HG)may alter the expression of epigenetic proteins in Grade 4 astrocytoma.The interplay mechanism between IDH,O-6-methylguanine-DNA methyltransferase(MGMT)-promoter methylation,and protein methyltransferase proteins-5(PRMT5)activity,with tumor progression has never been described.Methods:A retrospective cohort of 34 patients with G4 astrocytoma is classified into IDH-mutant and IDH-wildtype tumors.Both groups were tested for MGMT-promoter methylation and PRMT5 through methylation-specific and gene expression PCR analysis.Inter-cohort statistical significance was evaluated.Results:Both IDH-mutant WHO grade 4 astrocytomas(n=22,64.7%)and IDH-wildtype glioblastomas(n=12,35.3%)had upregulated PRMT5 gene expression except in one case.Out of the 22 IDH-mutant tumors,10(45.5%)tumors showed MGMT-promoter methylation and 12(54.5%)tumors had unmethylated MGMT.All IDH-wildtype tumors had unmethylated MGMT.There was a statistically significant relationship between MGMT-promoter methylation and IDH in G4 astrocytoma(p-value=0.006).Statistically significant differences in progression-free survival(PFS)were also observed among all G4 astrocytomas that expressed PRMT5 and received either temozolomide(TMZ)or TMZ plus other chemotherapies,regardless of their IDH or MGMT-methylation status(p-value=0.0014).Specifically,IDH-mutant tumors that had upregulated PRMT5 activity and MGMT-promoter methylation,who received only TMZ,have exhibited longer PFS.Conclusions:The relationship between PRMT5,MGMT-promoter,and IDH is not tridirectional.However,accumulation of D2-hydroxyglutarate(2-HG),which partially activates 2-OG-dependent deoxygenase,may not affect their activities.In IDH-wildtype glioblastomas,the 2HG-2OG pathway is typically inactive,leading to PRMT5 upregulation.TMZ alone,compared to TMZ-plus,can increase PFS in upregulated PRMT5 tumors.Thus,using a PRMT5 inhibitor in G4 astrocytomas may help in tumor regression.展开更多
Glioblastoma multiforme(GBM)is an aggressive primary brain tumor characterized by extensive heterogeneity and vascular proliferation.Hypoxic conditions in the tissue microenvironment are considered a pivotal player le...Glioblastoma multiforme(GBM)is an aggressive primary brain tumor characterized by extensive heterogeneity and vascular proliferation.Hypoxic conditions in the tissue microenvironment are considered a pivotal player leading tumor progression.Specifically,hypoxia is known to activate inducible factors,such as hypoxia-inducible factor 1alpha(HIF-1α),which in turn can stimulate tumor neo-angiogenesis through activation of various downward mediators,such as the vascular endothelial growth factor(VEGF).Here,we aimed to explore the role of HIF-1α/VEGF immunophenotypes alone and in combination with other prognostic markers or clinical and image analysis data,as potential biomarkers of GBM prognosis and treatment efficacy.We performed a systematic review(Medline/Embase,and Pubmed database search was completed by 16th of April 2024 by two independent teams;PRISMA 2020).We evaluated methods of immunoassays,cell viability,or animal or patient survival methods of the retrieved studies to assess unbiased data.We used inclusion criteria,such as the evaluation of GBM prognosis based on HIF-1α/VEGF expression,other biomarkers or clinical and imaging manifestations in GBM related to HIF-1α/VEGF expression,application of immunoassays for protein expression,and evaluation of the effectiveness of GBM therapeutic strategies based on HIF-1α/VEGF expression.We used exclusion criteria,such as data not reporting both HIF-1αand VEGF or prognosis.We included 50 studies investigating in total 1319 GBM human specimens,18 different cell lines or GBM-derived stem cells,and 6 different animal models,to identify the association of HIF-1α/VEGF immunophenotypes,and with other prognostic factors,clinical and macroscopic data in GBM prognosis and therapeutic approaches.We found that increased HIF-1α/VEGF expression in GBM correlates with oncogenic factors,such as miR-210-3p,Oct4,AKT,COX-2,PDGF-C,PLDO3,M2 polarization,or ALK,leading to unfavorable survival.Reduced HIF-1α/VEGF expression correlates with FIH-1,ADNP,or STAT1 upregulation,as well as with clinical manifestations,like epileptogenicity,and a favorable prognosis of GBM.Based on our data,HIF-1αor VEGF immunophenotypes may be a useful tool to clarify MRI-PET imaging data distinguishing between GBM tumor progression and pseudoprogression.Finally,HIF-1α/VEGF immunophenotypes can reflect GBM treatment efficacy,including combined first-line treatment with histone deacetylase inhibitors,thimerosal,or an active metabolite of irinotecan,as well as STAT3 inhibitors alone,and resulting in a favorable tumor prognosis and patient survival.These data were supported by a combination of variable methods used to evaluate HIF-1α/VEGF immunophenotypes.Data limitations may include the use of less sensitive detection methods in some cases.Overall,our data support HIF-1α/VEGF’s role as biomarkers of GBM prognosis and treatment efficacy.展开更多
Gliomas are primary brain tumors derived from glial cells of the central nervous system,afflicting both adults and children with distinct characteristics and therapeutic challenges.Recent developments have ushered in ...Gliomas are primary brain tumors derived from glial cells of the central nervous system,afflicting both adults and children with distinct characteristics and therapeutic challenges.Recent developments have ushered in novel clinical and molecular prognostic factors,reshaping treatment paradigms based on classi-fication and grading,determined by histological attributes and cellular lineage.This review article delves into the diverse treatment modalities tailored to the specific grades and molecular classifications of gliomas that are currently being discussed and used clinically in the year 2023.For adults,the therapeutic triad typically consists of surgical resection,chemotherapy,and radiotherapy.In contrast,pediatric gliomas,due to their diversity,require a more tailored approach.Although complete tumor excision can be curative based on the location and grade of the glioma,certain non-resectable cases demand a chemotherapy approach usually involving,vincristine and carboplatin.Addi-tionally,if surgery or chemotherapy strategies are unsuccessful,Vinblastine can be used.Despite recent advancements in treatment methodologies,there remains a need of exploration in the literature,particularly concerning the efficacy of treatment regimens for isocitrate dehydrogenase type mutant astrocytomas and fine-tuned therapeutic approaches tailored for pediatric cohorts.This review article explores into the therapeutic modalities employed for both adult and pediatric gliomas in the context of their molecular classification.展开更多
BACKGROUND: The detection of differential gene expression in brain is possible by cDNA microarray technology, and the screening of differentially expressed genes might provide a biological basis for gene-targeted the...BACKGROUND: The detection of differential gene expression in brain is possible by cDNA microarray technology, and the screening of differentially expressed genes might provide a biological basis for gene-targeted therapy for tumors. OBJECTIVE: To detect the differential expression of genes among astrocytoma SHG-44 (WHO grade Ⅳ), CHG-5 (WHO grade Ⅱ), and ATRA-treated SHG-44 cell lines by cDNA microarray. DESIGN: Laboratory experiments in vitro. SETTING: Department of Neurobiology, the Third Military Medical University. MATERIALS: The experiment was performed at the Department of Neurobiology in the Third Military Medical University of the Chinese PLA from January to October 2007. The SHG-44 cell line (WHO grade Ⅳ) was established by Prof. Ziwei Du, and the CHG-5 cell line (WHO grade Ⅱ) was set up by Prof. Xiuwu Bian from the Third Military Medical University of the Chinese PLA. The cDNA microarray containing 9182 known genes was prepared and provided by Dr. Yang Zhong at the City University of Hong Kong. METHODS: To screen differentially expressed genes from the gene expression profiles detected by cDNA microarray comparisons were made between CHG-5 and SHG-44 cells and between SHG-44 cells with or without treatment with 10 μmol/L ATRA. Some differentially expressed genes were selected randomly for Northern Blot analysis to confirm the results of the microarray. The determination criteria for differential gene expression were as follows. ① The ratio of Cy5 signal to Cy3 was greater than 2.0 or less than 0.5. ② The results of the triplicate microarray hybridizations showed the same trend in three experiments. ③ A gene appeared at least two times on the triplicate microarray hybridizations, and the 3^rd value did not show a contradictory trend. A normalized ratio of Cy5 intensity to Cy3 greater than 2.0 or less than 0.5 was considered to represent up-regulated or down-regulated gene expression, respectively. MAIN OUTCOME MEASURES: The identification of genes that were similarly regulated (overlapping) during tumor progression and differentiation, by comparison of gene expression profiles between CHG-5 and SHG-44 cells, and between SHG-44 cells with or without treatment with ATRA. RESULTS: Thirty-one overlapping genes were found to have similar regulatory effects on astrocytomas; among them, twenty genes were up-regulated and eleven were down-regulated in both comparisons between CHG-5 and SHG-44 cells, and between SHG-44 cells with or without treatment with ATRA. The four reported genes, SERPINFI, MAPKI 1, HIFIA and SOD2, were up-regulated in this study. CONCLUSION: The differentially expressed genes in different grade astrocytoma cell lines were revealed primarily by cDNA microarray; among them, five identified overlapping genes, SERPINF1, MAPK11, DCTN2, HIF1 A and SOD2, were related to the malignant progression of astrocytoma cells.展开更多
Some specially imaging of magnetic resonance imaging,the diffusion-weighted imaging(DWI),the diffusion tensor imaging and fractional anisotropy(FA),are useful to described,detect,and map the extent of spinal cord lesi...Some specially imaging of magnetic resonance imaging,the diffusion-weighted imaging(DWI),the diffusion tensor imaging and fractional anisotropy(FA),are useful to described,detect,and map the extent of spinal cord lesions.FA measurements may are used to predicting the outcome of patients who have spinal cord lesions.Fiber tracking enable to visualizing the integrity of white matter tracts surrounding some lesions,and this information could be used to formulating a differential diagnosis and planning biopsies or resection.In this article,we will describe the current uses for DWI and fiber tracking and speculate on others in which we believe these techniques will be useful in the future.展开更多
Pilomyxoid astrocytoma is a new identified variant type of pilocytic astrocytoma,and typically locates in the hypothalamic and chiasmatic region.Herein,we reported a nine-year-old boy with pilomyxoid astrocytoma in th...Pilomyxoid astrocytoma is a new identified variant type of pilocytic astrocytoma,and typically locates in the hypothalamic and chiasmatic region.Herein,we reported a nine-year-old boy with pilomyxoid astrocytoma in the cerebellum.MRI scanning showed a tumor involved the cerebellar vermis,tonsil,the forth ventricle and brainstem.It was homogeneous isointensity on T1WI,relative hyper-intensity on T2WI,hyper-intensity on fluid attenuated inversion recovery (FLAIR) images,and uniform enhancement on contrast T1WI.The tumor was sub-totally removed and was proved histologically to be pilomyxoid astrocytoma.Follow-up at the 5th month,MRI showed the residual tumor enlarged at the brainstem.The patient survived 10 months after the operation,and finally died of respiration failure resulting from brainstem dysfunction.展开更多
This study was designed to investigate whether the Notch pathway is involved in the develop-ment of diffuse spinal cord astrocytomas. BALB/c nude mice received injections of CD133+and CD133? cell suspensions prepare...This study was designed to investigate whether the Notch pathway is involved in the develop-ment of diffuse spinal cord astrocytomas. BALB/c nude mice received injections of CD133+and CD133? cell suspensions prepared using human recurrent diffuse spinal cord astrocytoma tissue through administration into the right parietal lobe. After 7–11 weeks, magnetic resonance imaging was performed weekly. Xenografts were observed on the surfaces of the brains of mice receiving the CD133+ cell suspension, and Notch-immunopositive expression was observed in the xenografts. By contrast, no xenografts appeared in the identical position on the surfaces of the brains of mice receiving the CD133? cell suspension, and Notch-immunopositive expres-sion was hardly detected either. Hematoxylin-eosin staining and immunohistochemical staining revealed xenografts on the convex surfaces of the brains of mice that underwent CD133+ astro-cytoma transplantation. Some sporadic astroglioma cells showed pseudopodium-like structures, which extended into the cerebral white matter. However,it should be emphasized that the sub-cortex xenograft with Notch-immunopositive expression was found in the fourth mouse received injection of CD133? astrocytoma cells. However, these ifndings suggest that the Notch pathway plays an important role in the formation of astrocytomas, and can be considered a novel treat-ment target for diffuse spinal cord astrocytoma.展开更多
Nonresectable Low-Grade Astrocytomas (LGA) can compromise function and threaten life. For the majority of patients, the most appropriate strategy is initial chemotherapy followed by Radiation Therapy (RT). Since curat...Nonresectable Low-Grade Astrocytomas (LGA) can compromise function and threaten life. For the majority of patients, the most appropriate strategy is initial chemotherapy followed by Radiation Therapy (RT). Since curative treatment is not available for most of these patients, it is reasonable to conduct clinical studies to evaluate new agents. This Phase II study evaluates efficacy and safety of Antineoplastons A10 and AS2-1 (ANP) in LGA. Sixteen children diagnosed with LGA were treated. They included 12 males and 4 females, ages 1.6 - 17.4 years (median 10.6). Efficacy was evaluated in 16 patients. The majority of patients were previously treated, but 1 patient had stereotactic biopsy only. Out of the remaining 15 patients, 6 patients received chemotherapy, and 7 patients had surgery, and 2 patients received RT and chemotherapy after surgery. The patients received treatment with ANP administered daily every 4 hours (median dose of A10 was 7.71 g/kg/d and AS2-1 was 0.26 g/kg/d) until objective response or stable disease was documented and for 8 months thereafter. The duration of ANP IV ranged from 1.4 to 286 weeks with a median of 83 weeks. A complete response was documented in 25.0%, partial response in 12.5%, and stable disease in 37.5%. Overall survival was 67.7% at 5 years, and 54.2% at 10 and 15 years. Progression-free survival was 48.1%, 34.4% and 34.4% at 5, 10, and 15 years respectively. The treatment was associated with grade 3 or grade 4 Adverse Drug Experiences (ADE) in 6 patients. There were two hypernatremias of grade 4 (12%). Grade 3 ADE included urinary frequency (6%), fatigue (6%) and hypernatremia (6%). There were no chronic toxicities, and there was a high quality of survival. ANP shows efficacy with a very good toxicity profile in this cohort of children with low-grade astrocytoma.展开更多
Pilocytic astrocytoma(PA)may be seen in both adults and children as a distinct histologic and biologic subset of low-grade glioma.Surgery is the principal treatment for the management of PAs;however,selected patients ...Pilocytic astrocytoma(PA)may be seen in both adults and children as a distinct histologic and biologic subset of low-grade glioma.Surgery is the principal treatment for the management of PAs;however,selected patients may benefit from irradiation particularly in the setting of inoperability,incomplete resection,or recurrent disease.While conventionally fractionated radiation therapy has been traditionally utilized for radiotherapeutic management,stereotactic irradiation strategies have been introduced more recently to improve the toxicity profile of radiation delivery without compromising tumor control.PAs may be suitable for radiosurgical management due to their typical appearance as well circumscribed lesions.Focused and precise targeting of these well-defined lesions under stereotactic immobilization and image guidance may offer great potential for achieving an improved therapeutic ratio by virtue of radiosurgical techniques.Given the high conformality along with steep dose gradients around the target volume allowing for reduced normal tissue exposure,radiosurgery may be considered a viable modality of radiotherapeutic management.Another advantage of radiosurgery may be the completion of therapy in a usually shorter overall treatment time,which may be particularly well suited for children with requirement of anesthesia during irradiation.Several studies have addressed the utility of radiosurgery particularly as an adjuvant or salvage treatment modality for PA.Nevertheless,despite the growing body of evidence supporting the use of radiosurgery,there is need for a high level of evidence to dictate treatment decisions and establish its optimal role in the management of PA.Herein,we provide a concise review of radiosurgery for PA in light of the literature.展开更多
BACKGROUND: Although several genetic aberrations and gene expressional changes have been shown to exist in tumors and different grades of astrocytomas, as well as in normal tissues, the gene profiling and genetic pat...BACKGROUND: Although several genetic aberrations and gene expressional changes have been shown to exist in tumors and different grades of astrocytomas, as well as in normal tissues, the gene profiling and genetic pathways associated with malignant transformation and progression remain unclear. OBJECTIVE: To identify differentially expressed genes related to tumor invasion from various grades and all-trans retinoic acid (ATRA)-treated astrocytoma cell lines by cDNA microarray. DESIGN, TIME AND SETTING: In vitro gene experiment was performed at the Department of Neurobiology, Third Military Medical University of Chinese PLA from January to October 2007. MATERIALS: Two different grades of astrocytoma cell lines CHG-5 (WHO grade II ) and SHG-44 (WHO grade IV) were developed by our laboratory; a cell differentiation-inducing agent ATRA and a human cDNA microarray technology were used to determine differentially expressed genes (City University of Hong Kong). METHODS: Total RNA was extracted using the Trizol test kit. Reverse transcription was performed using Superscript 11 reverse transcriptase. The cDNA product (target DNA) was marked with fluorochromes Cy3 (normal SHG-44) and Cy5 (CHG-5 or ATRA-treated SHG-44), followed by chip hybridization. MAIN OUTCOME MEASURES: Gene expression profiles of CHG-5 vs. SHG-44 and ATRA-treated vs. normal SHG-44 were performed to identify differentially expressed genes. Several of these genes were randomly selected for Northern Blot analysis. The identification of genes that were similarly regulated (overlapping) was performed by comparing gene expression profiles between CHG-5 and SHG-44 cells, and between SHG-44 cells with or without treatment with ATRA. RESULTS: No significant differences were observed between CHG5 and SHG-44 cell line morphology. Under confocal microscopy, GFAP staining intensity of CHG5 cells was greater than SHG-44 cells (t = 6.078 P = 0.004). Growth curve analysis demonstrated that the speed of SHG-44 cell growth was greater than CHG5 cells. Flow cytometry analysis showed that the number of ATRA-treated SHG-44 cells at G0/G1 stage increased by 15%, compared with normal SHG-44 cells (P 〈 0.05). A total of 31 known genes with altered expression were identified in this study. Among them, 20 genes were upregulated and 11 were downregulated in CHG-5 compared with SHG-44 cells, and ATRA-treated SHG-44 compared with untreated SHG-44 ceils. Four of these reported genes (CD151, G3BP, UGB, and CSTB) were shown to be involved in tumor invasion. Validation of a selection of differentially expressed genes was perfonlaed by Northern blot. CONCLUSION: A total of 31 known genes were demonstrated by cDNA microarray to relate to the malignant progression of astrocytomas, and four differentially expressed genes (CD151, G3BP, UGB, and CSTB) were shown to relate to tumor invasion.展开更多
Differential protein expression between various pathological grades of glioma has been shown in studies of glioma proteomics. However, very little data is available regarding normal brain tissues and glioma differenti...Differential protein expression between various pathological grades of glioma has been shown in studies of glioma proteomics. However, very little data is available regarding normal brain tissues and glioma differential protein expression, because normal human brain tissues are difficult to harvest. The present study selected samples from low-grade astrocytomas and peritumoral brain tissues to analyze differential protein expression by two-dimensional (2D) electrophoresis and mass spectrometry techniques. Results revealing 36 protein spots by 2D electrophoresis, including 23 spots revealing increased expression and 13 spots revealing decreased expression. However, 25 differential proteins were identified by mass spectrometry, including 16 proteins with increased expression and 9 with decreased expression. Western blot analysis confirmed the mass spectrometry results, i.e., heat shock protein 70 (HSP70) and human transthyretin (TTR) expressions were increased, but glial fibrillary acidic protein (GFAP) was decreased, in astrocytomas. The present study constructed a 2D electrophoresis pattern between low-grade astrocytomas in the human brain and peritumoral tissues. Results demonstrated that a majority of differential proteins, such as HSP70, TTR, and GFAP, participate in malignant progression of gliomas.展开更多
A case of angioimmunoblastic T-cell lymphoma (AITL) which was misdiagnosed as adult Still's disease was presented. The clinical and laboratory characteristics of this case and related literatures were analyzed and ...A case of angioimmunoblastic T-cell lymphoma (AITL) which was misdiagnosed as adult Still's disease was presented. The clinical and laboratory characteristics of this case and related literatures were analyzed and reviewed. The patient was finally diagnosed as AITL (Ann Arbor classification: Stage IIIB) secondary to cranial astrocytoma (WHO classification: Stage III), complicated with severe pulmonary infection because of long time treatment of corticosteroid and misdiagnosis (about one and a half year). It is concluded that AITL is a rare disease which was easily misdiagnosed. The diagnosis of AITL should combine the clinical manifestation with pathological biopsy as well as corresponding immunohistochemical tests.展开更多
Objective: To study the relationship between deletion of P16 gene and occurrence and progression of astrocytomas Methods: The techniques of polymerase chain reaction (PCR) and immunohistochemistry were used to dete...Objective: To study the relationship between deletion of P16 gene and occurrence and progression of astrocytomas Methods: The techniques of polymerase chain reaction (PCR) and immunohistochemistry were used to detect the deletion of exon2 of P16 gene and expression of P16 gene in 52 cases of Brain astrocytoma Results: The deletion rate of exon2 of P16 gene in the tumors analyzed was 34 6% Most of them with deletion of exon2 of p16 gene were high grade astrocytomas (grade III 42%, grade IV 50%) 61 5% of the tumors were absent from expression of p16 and the deletion rate of p16 protein increased with the grade of astrocytoma (X 2=10 83, P <0 005) Conclusion: Deletion of p16 gene and protein may correlate with the malignant progression of astrocytoma展开更多
Having a survival rate to 5 years of only 3%,Glioblastoma’s(GBM)main treatment is surgical excision.Iron oxide nanoparticles have been proved to be a magnetic resonance imaging contrast agent and,if synthesized and t...Having a survival rate to 5 years of only 3%,Glioblastoma’s(GBM)main treatment is surgical excision.Iron oxide nanoparticles have been proved to be a magnetic resonance imaging contrast agent and,if synthesized and tuned correctly,could be used to improve complete GBM resection.In this work monodisperse iron oxide nanoparticles were synthesized using thermal decomposition method,then a ligand exchange reaction with 3-aminopropyl trimethoxysilane(APS)was performed,following Pegylation of the particles using dicarboxylic acid PEG(PEG-diacid)and finally aminating with 2,2’-(ethylenedioxy)bis(ethylamine),last two by amide reactions.STEM and DLS demonstrate monodispersity(log σ<0.2)and desired size range to penetrate the blood-brain barrier(BBB);FT-IR shows the reactions were executed correctly and finally stability in deionized water,0.07 M NaCl and PBS 1X,as a function of 0-30 days,was tested.Results revealed the importance that the oleic acid/iron oleate molar ratio and the growth stage time represents for determining iron oxide nanoparticles’ size;as well as APS concentration and nucleation time influence on silica coating when performing the ligand exchange reaction.The produced iron oxide nanoparticles exhibit stability and proper amine terminated groups which are needed to allow easy incorporation of Chlorotoxin,a 36-amino acid peptide that binds specifically to astrocytoma cells,and a fluorescent molecule,which enables real time visualization of the tumor during surgery.展开更多
文摘Background:The dysregulation of Isocitrate dehydrogenase(IDH)and the subsequent production of 2-Hydroxyglutrate(2HG)may alter the expression of epigenetic proteins in Grade 4 astrocytoma.The interplay mechanism between IDH,O-6-methylguanine-DNA methyltransferase(MGMT)-promoter methylation,and protein methyltransferase proteins-5(PRMT5)activity,with tumor progression has never been described.Methods:A retrospective cohort of 34 patients with G4 astrocytoma is classified into IDH-mutant and IDH-wildtype tumors.Both groups were tested for MGMT-promoter methylation and PRMT5 through methylation-specific and gene expression PCR analysis.Inter-cohort statistical significance was evaluated.Results:Both IDH-mutant WHO grade 4 astrocytomas(n=22,64.7%)and IDH-wildtype glioblastomas(n=12,35.3%)had upregulated PRMT5 gene expression except in one case.Out of the 22 IDH-mutant tumors,10(45.5%)tumors showed MGMT-promoter methylation and 12(54.5%)tumors had unmethylated MGMT.All IDH-wildtype tumors had unmethylated MGMT.There was a statistically significant relationship between MGMT-promoter methylation and IDH in G4 astrocytoma(p-value=0.006).Statistically significant differences in progression-free survival(PFS)were also observed among all G4 astrocytomas that expressed PRMT5 and received either temozolomide(TMZ)or TMZ plus other chemotherapies,regardless of their IDH or MGMT-methylation status(p-value=0.0014).Specifically,IDH-mutant tumors that had upregulated PRMT5 activity and MGMT-promoter methylation,who received only TMZ,have exhibited longer PFS.Conclusions:The relationship between PRMT5,MGMT-promoter,and IDH is not tridirectional.However,accumulation of D2-hydroxyglutarate(2-HG),which partially activates 2-OG-dependent deoxygenase,may not affect their activities.In IDH-wildtype glioblastomas,the 2HG-2OG pathway is typically inactive,leading to PRMT5 upregulation.TMZ alone,compared to TMZ-plus,can increase PFS in upregulated PRMT5 tumors.Thus,using a PRMT5 inhibitor in G4 astrocytomas may help in tumor regression.
文摘Glioblastoma multiforme(GBM)is an aggressive primary brain tumor characterized by extensive heterogeneity and vascular proliferation.Hypoxic conditions in the tissue microenvironment are considered a pivotal player leading tumor progression.Specifically,hypoxia is known to activate inducible factors,such as hypoxia-inducible factor 1alpha(HIF-1α),which in turn can stimulate tumor neo-angiogenesis through activation of various downward mediators,such as the vascular endothelial growth factor(VEGF).Here,we aimed to explore the role of HIF-1α/VEGF immunophenotypes alone and in combination with other prognostic markers or clinical and image analysis data,as potential biomarkers of GBM prognosis and treatment efficacy.We performed a systematic review(Medline/Embase,and Pubmed database search was completed by 16th of April 2024 by two independent teams;PRISMA 2020).We evaluated methods of immunoassays,cell viability,or animal or patient survival methods of the retrieved studies to assess unbiased data.We used inclusion criteria,such as the evaluation of GBM prognosis based on HIF-1α/VEGF expression,other biomarkers or clinical and imaging manifestations in GBM related to HIF-1α/VEGF expression,application of immunoassays for protein expression,and evaluation of the effectiveness of GBM therapeutic strategies based on HIF-1α/VEGF expression.We used exclusion criteria,such as data not reporting both HIF-1αand VEGF or prognosis.We included 50 studies investigating in total 1319 GBM human specimens,18 different cell lines or GBM-derived stem cells,and 6 different animal models,to identify the association of HIF-1α/VEGF immunophenotypes,and with other prognostic factors,clinical and macroscopic data in GBM prognosis and therapeutic approaches.We found that increased HIF-1α/VEGF expression in GBM correlates with oncogenic factors,such as miR-210-3p,Oct4,AKT,COX-2,PDGF-C,PLDO3,M2 polarization,or ALK,leading to unfavorable survival.Reduced HIF-1α/VEGF expression correlates with FIH-1,ADNP,or STAT1 upregulation,as well as with clinical manifestations,like epileptogenicity,and a favorable prognosis of GBM.Based on our data,HIF-1αor VEGF immunophenotypes may be a useful tool to clarify MRI-PET imaging data distinguishing between GBM tumor progression and pseudoprogression.Finally,HIF-1α/VEGF immunophenotypes can reflect GBM treatment efficacy,including combined first-line treatment with histone deacetylase inhibitors,thimerosal,or an active metabolite of irinotecan,as well as STAT3 inhibitors alone,and resulting in a favorable tumor prognosis and patient survival.These data were supported by a combination of variable methods used to evaluate HIF-1α/VEGF immunophenotypes.Data limitations may include the use of less sensitive detection methods in some cases.Overall,our data support HIF-1α/VEGF’s role as biomarkers of GBM prognosis and treatment efficacy.
文摘Gliomas are primary brain tumors derived from glial cells of the central nervous system,afflicting both adults and children with distinct characteristics and therapeutic challenges.Recent developments have ushered in novel clinical and molecular prognostic factors,reshaping treatment paradigms based on classi-fication and grading,determined by histological attributes and cellular lineage.This review article delves into the diverse treatment modalities tailored to the specific grades and molecular classifications of gliomas that are currently being discussed and used clinically in the year 2023.For adults,the therapeutic triad typically consists of surgical resection,chemotherapy,and radiotherapy.In contrast,pediatric gliomas,due to their diversity,require a more tailored approach.Although complete tumor excision can be curative based on the location and grade of the glioma,certain non-resectable cases demand a chemotherapy approach usually involving,vincristine and carboplatin.Addi-tionally,if surgery or chemotherapy strategies are unsuccessful,Vinblastine can be used.Despite recent advancements in treatment methodologies,there remains a need of exploration in the literature,particularly concerning the efficacy of treatment regimens for isocitrate dehydrogenase type mutant astrocytomas and fine-tuned therapeutic approaches tailored for pediatric cohorts.This review article explores into the therapeutic modalities employed for both adult and pediatric gliomas in the context of their molecular classification.
基金ScientificResearch Foundation from Health Bareau of Sichuan Province, No.050209
文摘BACKGROUND: The detection of differential gene expression in brain is possible by cDNA microarray technology, and the screening of differentially expressed genes might provide a biological basis for gene-targeted therapy for tumors. OBJECTIVE: To detect the differential expression of genes among astrocytoma SHG-44 (WHO grade Ⅳ), CHG-5 (WHO grade Ⅱ), and ATRA-treated SHG-44 cell lines by cDNA microarray. DESIGN: Laboratory experiments in vitro. SETTING: Department of Neurobiology, the Third Military Medical University. MATERIALS: The experiment was performed at the Department of Neurobiology in the Third Military Medical University of the Chinese PLA from January to October 2007. The SHG-44 cell line (WHO grade Ⅳ) was established by Prof. Ziwei Du, and the CHG-5 cell line (WHO grade Ⅱ) was set up by Prof. Xiuwu Bian from the Third Military Medical University of the Chinese PLA. The cDNA microarray containing 9182 known genes was prepared and provided by Dr. Yang Zhong at the City University of Hong Kong. METHODS: To screen differentially expressed genes from the gene expression profiles detected by cDNA microarray comparisons were made between CHG-5 and SHG-44 cells and between SHG-44 cells with or without treatment with 10 μmol/L ATRA. Some differentially expressed genes were selected randomly for Northern Blot analysis to confirm the results of the microarray. The determination criteria for differential gene expression were as follows. ① The ratio of Cy5 signal to Cy3 was greater than 2.0 or less than 0.5. ② The results of the triplicate microarray hybridizations showed the same trend in three experiments. ③ A gene appeared at least two times on the triplicate microarray hybridizations, and the 3^rd value did not show a contradictory trend. A normalized ratio of Cy5 intensity to Cy3 greater than 2.0 or less than 0.5 was considered to represent up-regulated or down-regulated gene expression, respectively. MAIN OUTCOME MEASURES: The identification of genes that were similarly regulated (overlapping) during tumor progression and differentiation, by comparison of gene expression profiles between CHG-5 and SHG-44 cells, and between SHG-44 cells with or without treatment with ATRA. RESULTS: Thirty-one overlapping genes were found to have similar regulatory effects on astrocytomas; among them, twenty genes were up-regulated and eleven were down-regulated in both comparisons between CHG-5 and SHG-44 cells, and between SHG-44 cells with or without treatment with ATRA. The four reported genes, SERPINFI, MAPKI 1, HIFIA and SOD2, were up-regulated in this study. CONCLUSION: The differentially expressed genes in different grade astrocytoma cell lines were revealed primarily by cDNA microarray; among them, five identified overlapping genes, SERPINF1, MAPK11, DCTN2, HIF1 A and SOD2, were related to the malignant progression of astrocytoma cells.
文摘Some specially imaging of magnetic resonance imaging,the diffusion-weighted imaging(DWI),the diffusion tensor imaging and fractional anisotropy(FA),are useful to described,detect,and map the extent of spinal cord lesions.FA measurements may are used to predicting the outcome of patients who have spinal cord lesions.Fiber tracking enable to visualizing the integrity of white matter tracts surrounding some lesions,and this information could be used to formulating a differential diagnosis and planning biopsies or resection.In this article,we will describe the current uses for DWI and fiber tracking and speculate on others in which we believe these techniques will be useful in the future.
文摘Pilomyxoid astrocytoma is a new identified variant type of pilocytic astrocytoma,and typically locates in the hypothalamic and chiasmatic region.Herein,we reported a nine-year-old boy with pilomyxoid astrocytoma in the cerebellum.MRI scanning showed a tumor involved the cerebellar vermis,tonsil,the forth ventricle and brainstem.It was homogeneous isointensity on T1WI,relative hyper-intensity on T2WI,hyper-intensity on fluid attenuated inversion recovery (FLAIR) images,and uniform enhancement on contrast T1WI.The tumor was sub-totally removed and was proved histologically to be pilomyxoid astrocytoma.Follow-up at the 5th month,MRI showed the residual tumor enlarged at the brainstem.The patient survived 10 months after the operation,and finally died of respiration failure resulting from brainstem dysfunction.
基金supported by grants from Science Foundation of Ministry of Education of China for the Excellent Youth Scholars,No.200800011035the National Natural Science Foundation of China,No.81200969/H0912
文摘This study was designed to investigate whether the Notch pathway is involved in the develop-ment of diffuse spinal cord astrocytomas. BALB/c nude mice received injections of CD133+and CD133? cell suspensions prepared using human recurrent diffuse spinal cord astrocytoma tissue through administration into the right parietal lobe. After 7–11 weeks, magnetic resonance imaging was performed weekly. Xenografts were observed on the surfaces of the brains of mice receiving the CD133+ cell suspension, and Notch-immunopositive expression was observed in the xenografts. By contrast, no xenografts appeared in the identical position on the surfaces of the brains of mice receiving the CD133? cell suspension, and Notch-immunopositive expres-sion was hardly detected either. Hematoxylin-eosin staining and immunohistochemical staining revealed xenografts on the convex surfaces of the brains of mice that underwent CD133+ astro-cytoma transplantation. Some sporadic astroglioma cells showed pseudopodium-like structures, which extended into the cerebral white matter. However,it should be emphasized that the sub-cortex xenograft with Notch-immunopositive expression was found in the fourth mouse received injection of CD133? astrocytoma cells. However, these ifndings suggest that the Notch pathway plays an important role in the formation of astrocytomas, and can be considered a novel treat-ment target for diffuse spinal cord astrocytoma.
文摘Nonresectable Low-Grade Astrocytomas (LGA) can compromise function and threaten life. For the majority of patients, the most appropriate strategy is initial chemotherapy followed by Radiation Therapy (RT). Since curative treatment is not available for most of these patients, it is reasonable to conduct clinical studies to evaluate new agents. This Phase II study evaluates efficacy and safety of Antineoplastons A10 and AS2-1 (ANP) in LGA. Sixteen children diagnosed with LGA were treated. They included 12 males and 4 females, ages 1.6 - 17.4 years (median 10.6). Efficacy was evaluated in 16 patients. The majority of patients were previously treated, but 1 patient had stereotactic biopsy only. Out of the remaining 15 patients, 6 patients received chemotherapy, and 7 patients had surgery, and 2 patients received RT and chemotherapy after surgery. The patients received treatment with ANP administered daily every 4 hours (median dose of A10 was 7.71 g/kg/d and AS2-1 was 0.26 g/kg/d) until objective response or stable disease was documented and for 8 months thereafter. The duration of ANP IV ranged from 1.4 to 286 weeks with a median of 83 weeks. A complete response was documented in 25.0%, partial response in 12.5%, and stable disease in 37.5%. Overall survival was 67.7% at 5 years, and 54.2% at 10 and 15 years. Progression-free survival was 48.1%, 34.4% and 34.4% at 5, 10, and 15 years respectively. The treatment was associated with grade 3 or grade 4 Adverse Drug Experiences (ADE) in 6 patients. There were two hypernatremias of grade 4 (12%). Grade 3 ADE included urinary frequency (6%), fatigue (6%) and hypernatremia (6%). There were no chronic toxicities, and there was a high quality of survival. ANP shows efficacy with a very good toxicity profile in this cohort of children with low-grade astrocytoma.
文摘Pilocytic astrocytoma(PA)may be seen in both adults and children as a distinct histologic and biologic subset of low-grade glioma.Surgery is the principal treatment for the management of PAs;however,selected patients may benefit from irradiation particularly in the setting of inoperability,incomplete resection,or recurrent disease.While conventionally fractionated radiation therapy has been traditionally utilized for radiotherapeutic management,stereotactic irradiation strategies have been introduced more recently to improve the toxicity profile of radiation delivery without compromising tumor control.PAs may be suitable for radiosurgical management due to their typical appearance as well circumscribed lesions.Focused and precise targeting of these well-defined lesions under stereotactic immobilization and image guidance may offer great potential for achieving an improved therapeutic ratio by virtue of radiosurgical techniques.Given the high conformality along with steep dose gradients around the target volume allowing for reduced normal tissue exposure,radiosurgery may be considered a viable modality of radiotherapeutic management.Another advantage of radiosurgery may be the completion of therapy in a usually shorter overall treatment time,which may be particularly well suited for children with requirement of anesthesia during irradiation.Several studies have addressed the utility of radiosurgery particularly as an adjuvant or salvage treatment modality for PA.Nevertheless,despite the growing body of evidence supporting the use of radiosurgery,there is need for a high level of evidence to dictate treatment decisions and establish its optimal role in the management of PA.Herein,we provide a concise review of radiosurgery for PA in light of the literature.
基金the Sichuan Provincial Bureau of Health,No.050209
文摘BACKGROUND: Although several genetic aberrations and gene expressional changes have been shown to exist in tumors and different grades of astrocytomas, as well as in normal tissues, the gene profiling and genetic pathways associated with malignant transformation and progression remain unclear. OBJECTIVE: To identify differentially expressed genes related to tumor invasion from various grades and all-trans retinoic acid (ATRA)-treated astrocytoma cell lines by cDNA microarray. DESIGN, TIME AND SETTING: In vitro gene experiment was performed at the Department of Neurobiology, Third Military Medical University of Chinese PLA from January to October 2007. MATERIALS: Two different grades of astrocytoma cell lines CHG-5 (WHO grade II ) and SHG-44 (WHO grade IV) were developed by our laboratory; a cell differentiation-inducing agent ATRA and a human cDNA microarray technology were used to determine differentially expressed genes (City University of Hong Kong). METHODS: Total RNA was extracted using the Trizol test kit. Reverse transcription was performed using Superscript 11 reverse transcriptase. The cDNA product (target DNA) was marked with fluorochromes Cy3 (normal SHG-44) and Cy5 (CHG-5 or ATRA-treated SHG-44), followed by chip hybridization. MAIN OUTCOME MEASURES: Gene expression profiles of CHG-5 vs. SHG-44 and ATRA-treated vs. normal SHG-44 were performed to identify differentially expressed genes. Several of these genes were randomly selected for Northern Blot analysis. The identification of genes that were similarly regulated (overlapping) was performed by comparing gene expression profiles between CHG-5 and SHG-44 cells, and between SHG-44 cells with or without treatment with ATRA. RESULTS: No significant differences were observed between CHG5 and SHG-44 cell line morphology. Under confocal microscopy, GFAP staining intensity of CHG5 cells was greater than SHG-44 cells (t = 6.078 P = 0.004). Growth curve analysis demonstrated that the speed of SHG-44 cell growth was greater than CHG5 cells. Flow cytometry analysis showed that the number of ATRA-treated SHG-44 cells at G0/G1 stage increased by 15%, compared with normal SHG-44 cells (P 〈 0.05). A total of 31 known genes with altered expression were identified in this study. Among them, 20 genes were upregulated and 11 were downregulated in CHG-5 compared with SHG-44 cells, and ATRA-treated SHG-44 compared with untreated SHG-44 ceils. Four of these reported genes (CD151, G3BP, UGB, and CSTB) were shown to be involved in tumor invasion. Validation of a selection of differentially expressed genes was perfonlaed by Northern blot. CONCLUSION: A total of 31 known genes were demonstrated by cDNA microarray to relate to the malignant progression of astrocytomas, and four differentially expressed genes (CD151, G3BP, UGB, and CSTB) were shown to relate to tumor invasion.
基金the National Basic Research Program of China (subtask of 973 Program),No.2007CB516809,2007CB914203
文摘Differential protein expression between various pathological grades of glioma has been shown in studies of glioma proteomics. However, very little data is available regarding normal brain tissues and glioma differential protein expression, because normal human brain tissues are difficult to harvest. The present study selected samples from low-grade astrocytomas and peritumoral brain tissues to analyze differential protein expression by two-dimensional (2D) electrophoresis and mass spectrometry techniques. Results revealing 36 protein spots by 2D electrophoresis, including 23 spots revealing increased expression and 13 spots revealing decreased expression. However, 25 differential proteins were identified by mass spectrometry, including 16 proteins with increased expression and 9 with decreased expression. Western blot analysis confirmed the mass spectrometry results, i.e., heat shock protein 70 (HSP70) and human transthyretin (TTR) expressions were increased, but glial fibrillary acidic protein (GFAP) was decreased, in astrocytomas. The present study constructed a 2D electrophoresis pattern between low-grade astrocytomas in the human brain and peritumoral tissues. Results demonstrated that a majority of differential proteins, such as HSP70, TTR, and GFAP, participate in malignant progression of gliomas.
文摘A case of angioimmunoblastic T-cell lymphoma (AITL) which was misdiagnosed as adult Still's disease was presented. The clinical and laboratory characteristics of this case and related literatures were analyzed and reviewed. The patient was finally diagnosed as AITL (Ann Arbor classification: Stage IIIB) secondary to cranial astrocytoma (WHO classification: Stage III), complicated with severe pulmonary infection because of long time treatment of corticosteroid and misdiagnosis (about one and a half year). It is concluded that AITL is a rare disease which was easily misdiagnosed. The diagnosis of AITL should combine the clinical manifestation with pathological biopsy as well as corresponding immunohistochemical tests.
文摘Objective: To study the relationship between deletion of P16 gene and occurrence and progression of astrocytomas Methods: The techniques of polymerase chain reaction (PCR) and immunohistochemistry were used to detect the deletion of exon2 of P16 gene and expression of P16 gene in 52 cases of Brain astrocytoma Results: The deletion rate of exon2 of P16 gene in the tumors analyzed was 34 6% Most of them with deletion of exon2 of p16 gene were high grade astrocytomas (grade III 42%, grade IV 50%) 61 5% of the tumors were absent from expression of p16 and the deletion rate of p16 protein increased with the grade of astrocytoma (X 2=10 83, P <0 005) Conclusion: Deletion of p16 gene and protein may correlate with the malignant progression of astrocytoma
文摘Having a survival rate to 5 years of only 3%,Glioblastoma’s(GBM)main treatment is surgical excision.Iron oxide nanoparticles have been proved to be a magnetic resonance imaging contrast agent and,if synthesized and tuned correctly,could be used to improve complete GBM resection.In this work monodisperse iron oxide nanoparticles were synthesized using thermal decomposition method,then a ligand exchange reaction with 3-aminopropyl trimethoxysilane(APS)was performed,following Pegylation of the particles using dicarboxylic acid PEG(PEG-diacid)and finally aminating with 2,2’-(ethylenedioxy)bis(ethylamine),last two by amide reactions.STEM and DLS demonstrate monodispersity(log σ<0.2)and desired size range to penetrate the blood-brain barrier(BBB);FT-IR shows the reactions were executed correctly and finally stability in deionized water,0.07 M NaCl and PBS 1X,as a function of 0-30 days,was tested.Results revealed the importance that the oleic acid/iron oleate molar ratio and the growth stage time represents for determining iron oxide nanoparticles’ size;as well as APS concentration and nucleation time influence on silica coating when performing the ligand exchange reaction.The produced iron oxide nanoparticles exhibit stability and proper amine terminated groups which are needed to allow easy incorporation of Chlorotoxin,a 36-amino acid peptide that binds specifically to astrocytoma cells,and a fluorescent molecule,which enables real time visualization of the tumor during surgery.