Amide proton transfer (APT) imaging is a novel molecular MRI technique to detect endogenous mobile proteins and peptides through chemical exchange saturation transfer. We prospectively assessed the usefulness of APT imaging in predicting the histological grade of adult diffuse gliomas. Thirty-six consecutive patients with histopathologically proven diffuse glioma (48.1 ± 14.7 y old, 16 males and 20 females) were included in the study. APT MRI was conducted on a 3T clinical scanner and was obtained with 2 s saturation at 25 saturation frequency offsets ω = −6 to +6 ppm (step 0.5 ppm). δB₀ maps were acquired separately for a point-by-point δB₀ correction. APT signal intensity (SI) was defined as magnetization transfer asymmetry at 3.5 ppm: magnetization transfer ratio (MTR)_asym = (S_{[−3.5 ppm]} − S_{[+3.5 ppm]})/S₀. Regions of interest were carefully placed by 2 neuroradiologists in solid parts within brain tumors. The APT SI was compared with World Health Organization grade, Ki-67 labeling index (LI), and cell density. The mean APT SI values were 2.1 ± 0.4% in grade II gliomas (n = 8), 3.2 ± 0.9% in grade III gliomas (n = 10), and 4.1 ± 1.0% in grade IV gliomas (n = 18). Significant differences in APT intensity were observed between grades II and III (P < .05) and grades III and IV (P < .05), as well as between grades II and IV (P < .001). There were positive correlations between APT SI and Ki-67 LI (P = .01, R = 0.43) and between APT SI and cell density (P < .05, R = 0.38). The gliomas with microscopic necrosis showed higher APT SI than those without necrosis (P < .001). APT imaging can predict the histopathological grades of adult diffuse gliomas.

Purpose: MicroRNAs (miRNA) are short noncoding RNAs that can play critical roles in diverse biological processes. They are implicated in tumorigenesis and function both as tumor suppressors and as oncogenes. The clinical significance of miRNA expression profiles in malignant gliomas remains unclear. Experimental Design: In this study, we examined the expression levels of 365 mature human miRNAs in 12 malignant gliomas, including 8 glioblastomas and 4 anaplastic astrocytomas, using TaqMan real-time quantitative PCR arrays. A validation study was done to corroborate a subset of the results, including expression levels of miR-196a, -196b, -21, and -15b, by analyzing 92 malignant gliomas by conventional real-time PCR. We modeled the relationship between the expression levels of these miRNAs and the survival rate of 39 glioblastoma patients by Kaplan-Meier method and multivariate analysis. Results: Expression profiles in glioblastomas and anaplastic astrocytomas suggested that 16 miRNAs were candidate markers associated with the malignant progression of gliomas. Among them, miR-196a showed the most significant difference (P = 0.0038), with miR-196b also having a high significance (P = 0.0371). Both miRNAs showed increased expression levels in glioblastomas relative to both anaplastic astrocytomas and normal brains in the validation study. Furthermore, patients with high miR-196 expression levels showed significantly poorer survival by the Kaplan-Meier method (P = 0.0073). Multivariate analysis showed that miR-196 expression levels were an independent predictor of overall survival in all 39 glioblastoma patients (P = 0.021; hazard ratio, 2.81). Conclusions: Our results suggest that miR-196 may play a role in the malignant progression of gliomas and may be a prognostic predictor in glioblastomas. Clin Cancer Res; 16(16); 4289–97. ©2010 AACR.

Many conventional chemotherapeutic drugs exert their cytotoxic function by inducing DNA damage in the tumor cell. Therefore, a cell-inherent DNA repair pathway, which reverses the DNA-damaging effect of the cytotoxic drugs, can mediate therapeutic resistance to chemotherapy. The monofunctional DNA-alkylating agent temozolomide (TMZ) is a commonly used chemotherapeutic drug and the gold standard treatment for glioblastoma (GBM). Although the activity of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) has been described as the main modulator to determine the sensitivity of GBM to TMZ, a subset of GBM does not respond despite MGMT inactivation, suggesting that another DNA repair mechanism may also modulate the tolerance to TMZ. Considerable interest has focused on MGMT, mismatch repair (MMR), and the base excision repair (BER) pathway in the mechanism of mediating TMZ resistance, but emerging roles for the DNA strand-break repair pathway have been demonstrated. In the first part of this review article, we briefly review the significant role of MGMT, MMR, and the BER pathway in the tolerance to TMZ; in the last part, we review the recent publications that demonstrate possible roles of DNA strand-break repair pathways, such as single-strand break repair and double-strand break repair, as well as the Fanconi anemia pathway in the repair process after alkylating agent-based therapy. It is possible that all of these repair pathways have a potential to modulate the sensitivity to TMZ and aid in overcoming the therapeutic resistance in the clinic.

OBJECTIVE. Bone marrow–derived human mesenchymal stem cells (hMSCs) are capable of localizing to gliomas after systemic delivery and can be used in gli

The subclassification of glioblastoma (GBM) into clinically relevant subtypes using microRNA (miRNA)– and messenger RNA (mRNA)–based integrated analysis has been attempted. Because miRNAs regulate multiple gene-signaling pathways, understanding miRNA-mRNA interactions is a prerequisite for understanding glioma biology. However, such associations have not been thoroughly examined using high-throughput integrated analysis. To identify significant miRNA-mRNA correlations, we selected and quantified signature miRNAs and mRNAs in 82 gliomas (grade II: 14, III: 16, IV: 52) using real-time reverse-transcriptase polymerase chain reaction. Quantitative expression data were integrated into a single analysis platform that evaluated the expression relationship between miRNAs and mRNAs. The 21 miRNAs include miR-15b, -21, -34a, -105, -124a, -128a, -135b, -184, -196a-b, -200a-c, -203, -302a-d, -363, -367, and -504. In addition, we examined 23 genes, including proneural markers (DLL3, BCAN, and OLIG2), mesenchymal markers (YKL-40, CD44, and Vimentin), cancer stem cell-related markers, and receptor tyrosine kinase genes. Primary GBM was characterized exclusively by upregulation of mesenchymal markers, whereas secondary GBM was characterized by significant downregulation of mesenchymal markers, miR-21, and -34a, and by upregulation of proneural markers and miR-504. Statistical analysis showed that expression of miR-128a, -504, -124a, and -184 each negatively correlated with the expression of mesenchymal markers in GBM. Our functional analysis of miR-128a and -504 as inhibitors demonstrated that suppression of miR-128a and -504 increased the expression of mesenchymal markers in glioblastoma cell lines. Mesenchymal signaling in GBM may be negatively regulated by miR-128a and -504.