Choroid Plexus as the Best Reference Region for Standardized Uptake Value Analysis on C11-Acetate PET/CT for Grading and Predicting Prognosis in Patients with Cerebral Gliomas

PurposeWe aimed to compare different reference regions and select one with the most clinical relevance on C11-acetate (ACE) positron emission tomography/computed tomography (PET/CT) in patients with cerebral glioma.MethodsWe retrospectively reviewed 51 patients with cerebral glioma who underwent baseline ACE PET/CT at diagnosis. Other than the standardized uptake value (SUV) of the primary tumor, SUVs of the reference regions including the normal gray matter, white matter, choroid plexus, and cerebellum were measured. Then, the SUV ratio (SUV_R = tumor SUV_max/reference region SUV_mean) was calculated. The effect of patient age on the SUV_mean of each reference was examined and the SUV_Rs of each reference region were compared between grades. age, sex, tumor size, histological grades, SUV_R, and the presence of isocitrate dehydrogenase (IDH) mutation were included for survival analyses.ResultsExcept for the cerebellum showing a mild negative correlation, we found no correlations between age and SUV_mean using the gray matter, white matter, and choroid plexus (r = − 0.280, P = 0.047). Only the SUV_R-choroid plexus was able to differentiate between the WHO grades (Grade II vs. III, P = 0.035; grade III vs. IV, P < 0.001; grade II vs. IV, P < 0.001). Multivariate Cox proportional hazards models found that the SUVR-choroid plexus and IDH mutation were statistically significant for predicting OS.ConclusionOf the different reference regions used for grading cerebral gliomas, the choroid plexus was found to be the most optimal. In addition, the SUV ratio is useful to predict the overall survival in the model with the choroid plexus as a reference region.     

Polyunsaturated fatty acids and gliomas: A critical review of experimental,clinical, and epidemiologic data

Certain polyunsaturated fatty acids (PUFAs) called essential fatty acids (EFAs) cannot be biosynthesized by the body and hence, need to be obtained from diet. These PUFAs and their metabolites have multiple physiological functions that are altered in tumor cells due to a decreased expression of Δdelta-6-desaturase, which is an essential step in their metabolism. As a result, tumor cells would be protected from the toxic effect caused by free radicals, one product of EFA metabolism. EFAs have been proposed to have therapeutic potential in the treatment of glioblastoma. Gliomas are the most common primary tumors of the central nervous system in children and adults. High-grade gliomas remain a therapeutic challenge in neuro-oncology because there is no treatment that achieves a significant improvement in survival. Novel therapeutic strategies that use PUFAs for the treatment of gliomas have been assessed in cell cultures, rodent glioma models, and humans, with encouraging results. Here we review the latest progress made in the field.     

The effects of selected inhibitors of histone modifying enzyme on C6 glioma cells

BackgroundAberrant epigenetic histone modifications are implicated in cancer pathobiology, therefore histone modifying enzymes are emerging targets for anti-cancer therapy. There is a few evidence for deregulation of the histone modifying enzymes in glioblastomas. Glioma treatment is a clinical challenge due to its resistance to current therapies.MethodsThe effect of selected inhibitors on epigenetic modifications and viability of glioma C6 cells were studied using immunofluorescence and MTT metabolism test.ResultsWe found that VPA and TSA increase histone H4 acetylation in glioma cells, while chaetocin and BIX01294 at low concentrations reduce H3K9me3, and 3DZNep decreases H3K27me3. Long-term treatment with some epigenetic inhibitors affects viability of glioma cells.ConclusionsWe established the concentrations of selected inhibitors which in C6 glioma cells inhibit the enzyme activity, but do not decrease cell viability, hence allow to study the role of histone modifications in C6 glioma biology.     

姜黄素对胶质瘤U87细胞增殖和迁移能力的影响

目的：探讨姜黄素对胶质瘤细胞系U87细胞增殖及迁移能力的影响。方法应用CCK-8比色法检测经正常培养液及含不同浓度（25、50、100μmol/L）姜黄素的培养液培养24、48、72 h后的U87细胞的存活率;应用细胞划痕实验检测100μmol/L姜黄素对U87细胞迁移能力的影响;将20只SD大鼠制备成胶质瘤模型,随机分成对照组及实验1、2、3组,每组5只,模型制备后第7天对照组给予生理盐水灌胃,实验1、2、3组分别给予姜黄素100、200、300 mg/kg灌胃,1/d,连续14 d,第15天用microPET-CT对载瘤大鼠肿瘤体积进行测定。结果 U87细胞存活率随着培养液中姜黄素浓度的升高和培养时间的延长而降低（ P〈0．05）;给予100μmol/L姜黄素的培养液培养24和48 h后U87细胞迁移度均低于空白对照组（P〈0．05）;实验2、3组肿瘤体积均小于实验1组和对照组（P〈0．05）。结论姜黄素可抑制胶质瘤U87细胞的增殖及迁移。     

Current advances of long non-coding RNAs mediated by wnt signaling in glioma

Glioma is the most common and aggressive brain tumor in the central nervous system (CNS), in which Wnt signaling pathway has been verified to play a pivotal role in regulating the initiation and progression. Currently, numerous studies have indicated that long non-coding RNAs (lncRNAs) have critical functions across biological processes including cell proliferation, colony formation, migration, invasion and apoptosis via Wnt signaling pathway in glioma. This review depicts canonical and non-canonical Wnt/β‐catenin signaling pathway properties and relative processing mechanisms in gliomas, and summarizes the function and regulation of lncRNAs mediated by Wnt signaling pathway in the development and progression of glioma. Ultimately, we hope to seek out promising biomarkers and reliable therapeutic targets for glioma.     

Decreased CDKL2 expression is correlated with the progression and poor prognosis of glioma

Glioma is the most common form of malignant intracranial tumors. Cyclin-dependent kinase-like 2 (CDKL2) was observed in various regions of the brain, but the specific role of CDKL2 in glioma has not been reported yet. In the present study, the expression of CDKL2 mRNA was detected by real-time QPCR in freshly collected glioma and para-carcinoma tissues, and we collected genomic and clinical data from The Cancer Genome Atlas to determine mRNA expression levels of CDKL2 in the normal brain and glioma samples. Moreover, western blot assay and immunohistochemistry experiments were implemented to identify CDKL2 protein expression, and clinical pathology characteristics from 151 glioma cases and thirty-four para-carcinoma tissues were also examined. The relationship between the levels of CDKL2 expression and clinical data was analyzed. Low mRNA and protein expression of CDKL2 was observed in glioma tissues compared to non-cancerous tissues. In addition, low levels of CDKL2 correlated with Astrocytic type, higher clinical WHO grade, and higher Ki-67 expression in glioma. Low mRNA and protein expression of CDKL2 in glioma predicted an observably shorter overall survival time than high expression. However, as revealed by multivariate analysis, CDKL2 protein expression was not an independent prognostic biomarker for the survival of patients with glioma. Our study firstly determined that low levels of CDKL2 expression are associated with poor clinical diagnosis. Thus, CDKL2 may serve as a prognostic factor of glioma.     

Paclitaxel loaded liposomes decorated with a multifunctional tandem peptide for glioma targeting

The treatment of glioma is a great challenge because of the existence of the blood-brain barrier (BBB). In order to reduce toxicity to the normal brain tissue and achieve efficient treatment, it is also important for drugs to specifically accumulate in the glioma foci and penetrate into the tumor core after entering into the brain. In this study, a specific ligand cyclic RGD peptide was conjugated to a cell penetrating peptide R8 to develop a multifunctional peptide R8-RGD. R8-RGD increased the cellular uptake of liposomes by 2-fold and nearly 30-fold compared to separate R8 and RGD respectively, and displayed effective penetration of three-dimensional glioma spheroids and BBB model in vitro. In vivo studies showed that R8-RGD-lipo could be efficiently delivered into the brain and selectively accumulated in the glioma foci after systemic administration in C6 glioma bearing mice. When paclitaxel (PTX) was loaded in liposomes, R8-RGD-lipo could induce the strongest inhibition and apoptosis against C6 cells and finally achieved the longest survival in intracranial C6 glioma bearing mice. In conclusion, all the results indicated that the tandem peptide R8-RGD was a promising ligand possessing multi functions including BBB transporting, glioma targeting and tumor penetrating. And R8-RGD-lipo was proved to be a potential anti-glioma drug delivery system.     

Study and evaluation of mechanisms of dual targeting drug delivery system with tumor microenvironment assays compared with normal assays

A dual targeting delivery system was developed to completely conquer the two barriers that glioma treatment faces: the blood–brain barrier (BBB) and the brain–glioma barrier. Recently, a system comprising AS1411 aptamer (for glioma targeting) and TGN peptide (for BBB targeting) modified nanoparticles (AsTNPs) was developed, which can effectively target brain glioma and improve the survival of glioma-bearing mice. However, the in vitro models currently used are far too different from the in vivo tumor microenvironment that the glioma targeting delivery system actually faces. In this study, the pharmacology mechanisms of AsTNPs were explored in several models that imitated the tumor microenvironment. AsTNPs can be selectively taken up by endothelial and glioma cells, effectively penetrating the BBB and brain–glioma barriers to reach glioma cells and display their anti-glioma effect. The cell monolayers, tumor spheroids and coculture systems were more suitable in vitro models for the pharmacology evaluation of targeted drug delivery systems.     

Clinical value of CD133 and nestin in patients with glioma: a population-based study

Cancer stem cell-related (CSC) markers have been suggested to have promising potentials as novel types of prognostic and predictive markers in gliomas. However no single CSC-related marker is currently used in clinical decisions. The aim of this study was to investigate the prognostic value of CD133 and nestin separately and in combination using a novel quantitative approach in a well-characterized population-based cohort of glioma patients. The expression of CD133 and nestin was measured by systematic random sampling in stained paraffin sections from 239 glioma patients diagnosed between 2005 and 2009. We found that the expression of CD133 did not correlate with WHO grade, and there was no association with overall survival (OS). The level of nestin correlated positively with WHO grade. In patients with WHO grade II tumors, a high level of nestin was associated with short progression-free survival (PFS) in multivariate analysis. High levels of co-localization were associated with poor PFS in patients with WHO grade II tumors, but not with OS. We conclude that CD133 was not an independent prognostic factor, but a high level of nestin was associated with poor PFS in patients with WHO grade II tumors. The combination of double-immunofluorescence and automated analysis seems to be a feasible and reproducible approach for investigation of the prognostic potential of biomarkers.     

High expression and frequently humoral immune response of melanoma-associated antigen D4 in glioma

MAGE-D4 is a novel member of MAGE super-family. It has preliminarily been demonstrated that MAGE-D4 mRNA is not expressed in majority of normal tissues except for brain and ovary in which only trace amount of MAGE-D4 mRNA can be detected, but predominantly expressed in glioma. MAGE-D4 protein expression and its immunogenicity in glioma have not been elucidated well. This study was designed to analyze MAGE-D4 expression both at mRNA and protein level, characteristic of humoral immune response, and their relationships with glioma patients’ clinicopathological parameters. Recombinant MAGE-D4 protein and antiserum were generated. Quantitative RT-PCR analysis revealed that MAGE-D4 mRNA expression was overall up-regulated in 41 glioma specimens compared with that in 14 normal brain tissues. Immunohistochemistry analysis showed that 78% (21/27) glioma tissues expressed MAGE-D4 protein, which was predominantly located in the cytoplasm of tumor cells, but absent in any neuroglia cell of normal brain tissues. ELISA analysis demonstrated that humoral response against MAGE-D4 was detected in 17% (7/41) of glioma patients’ sera but not in 77 healthy donors. No apparent correlation was observed between the expression and immunogenicity of MAGE-D4 with clinicopathological parameters of glioma. In summary, these results indicate that MAGE-D4 is highly expressed in glioma and can develop specifically humoral response in glioma patients, which supports that it may be a promising biomarker for glioma diagnosis and immunotherapy.