CXCR7, CXCR4, and Their Ligand Expression Profile in Traumatic Brain Injury.

OBJECTIVE: Traumatic brain injury (TBI) is a health problem worldwide, and therapeutic strategies to enhance brain tissue repair to lessen neurologic sequels are imperative. We aimed to analyze the impact of the inflammatory process in TBI through CXCR4 and CXCR7 chemokine receptors and their ligands' CXCL11 and CXCL12 expression profile in search for potential new druggable targets. METHODS: Twelve pericontusional tissues from severe TBI patients submitted to surgical treatment, and 20 control brain tissues from normal autopsy were analyzed for expression profile by real-time quantitative-polymerase chain reaction. CXCR7 and CXCR4 protein expressions were analyzed by immunohistochemistry. The findings were correlated with the clinical evolution. RESULTS: Increased gene expression of both receptors and their ligands was observed in TBI compared with controls, presenting high sensitivity and specificity to differentiate TBI from normal control (area under the curve ranging from 0.85 to 0.98, P < 0.001). In particular, CXCR7 expression highly correlated with CXCR4 and both ligands' expressions in TBI. Higher immunoreactions for CXCR7 and CXCR4 were identified in neurons and endothelial cells of TBI samples compared with controls. The patients presenting upregulated chemokine expression levels showed a trend toward favorable clinical evolution at up to 6 months of follow-up. CONCLUSIONS: The neuroprotective trend of CXCR4, CXCR7, CXCL11, and CXCL12 in TBI observed in this initial analysis warrants further studies with more patients, analyzing the involved signaling pathways for the development of new therapeutic strategies for TBI.

Multiple Intracranial Meningiomas: A Case Series and Review of the Literature.

OBJECTIVE: To review the published data to create a more comprehensive natural history of multiple meningiomas (MM). METHODS: A review of MM published until now was carried out through a Medline search up to August 2018. The use of the "multiple meningiomas" keyword returned 278 articles, and the characteristics analyzed in our present cohort were searched on those publications. Articles without detailed description of clinical findings, neuroimaging confirmation of tumor multiplicity, follow-up at least of 5 years, and clear description of clinical findings were excluded. We added series to this review. RESULTS: 293 patients with MM were analyzed: 220 women and 73 men, with a total of 932 tumors (3.1 tumors per patient). The majority of tumors were located in the convexity (653% to 74.5%). The total number of tumors treated was 429 (43.9%): 338 (78.8%) by surgical resection and 91 (21.2%) by radiotherapy. Histopathologic description was available in 303 of 429 cases, being grade I in 272 (90.3%) cases, with a predominance of the meningothelial subtype (30.7%). Tumor recurrence was described in 32 (8.07%) among 397 and only 10 deaths (3.4%) of 281 reported cases, where this characteristic was evaluated. CONCLUSIONS: World Health Organization grade I predominance was observed among multiple meningiomas in similarity to single meningiomas. Only a fraction of MM patients (43.89%) needed treatment. A benign tumor behavior was corroborated by the observed low frequency of recurrence and mortality.

Inhibition of Nuclear PTEN Tyrosine Phosphorylation Enhances Glioma Radiation Sensitivity through Attenuated DNA Repair.

Ionizing radiation (IR) and chemotherapy are standard-of-care treatments for glioblastoma (GBM) patients and both result in DNA damage, however, the clinical efficacy is limited due to therapeutic resistance. We identified a mechanism of such resistance mediated by phosphorylation of PTEN on tyrosine 240 (pY240-PTEN) by FGFR2. pY240-PTEN is rapidly elevated and bound to chromatin through interaction with Ki-67 in response to IR treatment and facilitates the recruitment of RAD51 to promote DNA repair. Blocking Y240 phosphorylation confers radiation sensitivity to tumors and extends survival in GBM preclinical models. Y240F-Pten knockin mice showed radiation sensitivity. These results suggest that FGFR-mediated pY240-PTEN is a key mechanism of radiation resistance and is an actionable target for improving radiotherapy efficacy.

Detection of somatic TP53 splice site mutations in diffuse astrocytomas.

Alteration in TP53 is the most common genetic event reported for many tumors, including astrocytomas. The majority of studies, on analyzing TP53 mutations, have not included all splice junctions. Consequently, splice site mutations are thought to be relatively infrequent. TP53 were examined for mutations by polymerase chain reaction, single strand conformation polymorphism and direct sequencing in cases of diffuse astrocytomas. We found TP53 mutations in 17.8% (8 out of 45) of the tumors tested: 3 splicing, 3 missense and 2 silent mutations. We have shown that splice site mutations of TP53 are more frequent than previously reported. These findings emphasize the importance of thorough screening of TP53 mutations in gliomas.

CoGA: An R Package to Identify Differentially Co-Expressed Gene Sets by Analyzing the Graph Spectra.

Gene set analysis aims to identify predefined sets of functionally related genes that are differentially expressed between two conditions. Although gene set analysis has been very successful, by incorporating biological knowledge about the gene sets and enhancing statistical power over gene-by-gene analyses, it does not take into account the correlation (association) structure among the genes. In this work, we present CoGA (Co-expression Graph Analyzer), an R package for the identification of groups of differentially associated genes between two phenotypes. The analysis is based on concepts of Information Theory applied to the spectral distributions of the gene co-expression graphs, such as the spectral entropy to measure the randomness of a graph structure and the Jensen-Shannon divergence to discriminate classes of graphs. The package also includes common measures to compare gene co-expression networks in terms of their structural properties, such as centrality, degree distribution, shortest path length, and clustering coefficient. Besides the structural analyses, CoGA also includes graphical interfaces for visual inspection of the networks, ranking of genes according to their "importance" in the network, and the standard differential expression analysis. We show by both simulation experiments and analyses of real data that the statistical tests performed by CoGA indeed control the rate of false positives and is able to identify differentially co-expressed genes that other methods failed.

CXCR7 and CXCR4 Expressions in Infiltrative Astrocytomas and Their Interactions with HIF1α Expression and IDH1 Mutation.

The CXCR7, a new receptor for CXCL12 with higher affinity than CXCR4 has raised key issues on glioma cell migration. The aim of this study is to investigate the CXCR7 mRNA expression in diffuse astrocytomas tissues and to evaluate its interactions with CXCR4 and HIF1α expression and IDH1 mutation. CXCR7, CXCR4 and HIF1α mRNA expression were evaluated in 129 frozen samples of astrocytomas. IDH1 mutation status was analyzed with gene expressions, matched with clinicopathological parameters and overall survival time. Protein expression was analyzed by immunohistochemistry in different grades of astrocytoma and in glioma cell line (U87MG) by confocal microscopy. There was significant difference in the expression levels of the genes studied between astrocytomas and non-neoplasic (NN) controls (p < 0.001). AGII showed no significant correlation between CXCR7/HIF1α (p = 0.548); there was significant correlation between CXCR7/CXCR4 (p = 0.042) and CXCR7/IDH1 (p = 0.008). GBM showed significant correlations between CXCR7/CXCR4 (p = 0.002), CXCR7/IDH1 (p < 0.001) and CXCR7/HIF1α (p = 0.008). HIF1α overexpression was associated with higher expressions of CXCR7 (p = 0.01) and CXCR4 (p < 0.0001), while IDH1 mutation was associated with lower CXCR7 (p = 0.009) and CXCR4 (p = 0.0005) mRNA expressions. Protein expression increased with malignancy and in U87MG cell line was mainly localized in the cellular membrane. CXCR7 was overexpressed in astrocytoma and correlates with CXCR4 and IDH1 in AGII and CXCR4, IDH1 and HIF1α in GBM. Overexpression HIF1α was related with higher expressions of CXCR7 and CXCR4, otherwise IDH1 mutation related with lower expression of both genes. No association between CXCR7 and CXCR4 expression and survival data was related.

Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas.

Mutations in the critical chromatin modifier ATRX and mutations in CIC and FUBP1, which are potent regulators of cell growth, have been discovered in specific subtypes of gliomas, the most common type of primary malignant brain tumors. However, the frequency of these mutations in many subtypes of gliomas, and their association with clinical features of the patients, is poorly understood. Here we analyzed these loci in 363 brain tumors. ATRX is frequently mutated in grade II-III astrocytomas (71%), oligoastrocytomas (68%), and secondary glioblastomas (57%), and ATRX mutations are associated with IDH1 mutations and with an alternative lengthening of telomeres phenotype. CIC and FUBP1 mutations occurred frequently in oligodendrogliomas (46% and 24%, respectively) but rarely in astrocytomas or oligoastrocytomas ( more than 10%). This analysis allowed us to define two highly recurrent genetic signatures in gliomas: IDH1/ATRX (I-A) and IDH1/CIC/FUBP1 (I-CF). Patients with I-CF gliomas had a significantly longer median overall survival (96 months) than patients with I-A gliomas (51 months) and patients with gliomas that did not harbor either signature (13 months). The genetic signatures distinguished clinically distinct groups of oligoastrocytoma patients, which usually present a diagnostic challenge, and were associated with differences in clinical outcome even among individual tumor types. In addition to providing new clues about the genetic alterations underlying gliomas, the results have immediate clinical implications, providing a tripartite genetic signature that can serve as a useful adjunct to conventional glioma classification that may aid in prognosis, treatment selection, and therapeutic trial design.