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Glioblastoma multiforme (GBM) is considered the most malignant form of primary brain tumor. Despite multimodal treatment, prognosis remains poor. Ketogenic diet (KD) has been suggested for the treatment of GBM. In this study, the syngenic, orthotopic GL261 mouse glioma model was used to evaluate the effects of KD on the metabolic responses of the tumor using 7T magnetic resonance imaging/spectroscopy. GL261 cells were injected into the caudate nucleus of mice. Following implantation, animals were fed with standard chow or underwent a KD. 18 days after initiating the diet, mice fed with KD displayed significantly higher plasmatic levels of ketone bodies and survived longer than those fed with the standard diet. Decreased concentrations of gamma-aminobutyric acid, N-Acetyl-Aspartate and N-acetylaspartylglutamate were found in tumor tissue after 9 days into the KD, while a huge increase in beta-hydroxybutyrate (bHB) was detected in tumor tissue as compared to normal brain. The accumulation of bHB in the tumor tissue in mice undergoing the KD, may suggest either elevated uptake/release of bHB by tumor cells, or the inability of tumor cells in this context to use it for mitochondrial metabolism.

The presence of redundant copy number variants (CNVs) in groups of patients with neurological diseases suggests that these variants could have pathogenic effect. We have collected array comparative genomic hybridization (CGH) data of about 2,500 patients affected by neurocognitive disorders and we observed that CNVs in 2p16.3 locus were as frequent as those in 15q11.2, being both the most frequent unbalances in our cohort of patients. Focusing to 2p16.3 region, unbalances involving NRXN1 coding region have been already associated with neuropsychiatric disorders, although with incomplete penetrance, but little is known about CNVs located proximal to the gene, in the long noncoding RNA AK127244. We found that, in our cohort of patients with neuropsychiatric disorders, the frequency of CNVs involving AK127244 was comparable to that of NRXN1 gene. Patients carrying 2p16.3 unbalances shared some common clinical characteristics regardless NRXN1 and AK127244 CNVs localization, suggesting that the AK127244 long noncoding RNA could be involved in neurocognitive disease with the same effect of NRXN1 unbalances. AK127244 as well as NRXN1 unbalances seem to have a particular influence on language development, behavior or mood, according with the topographic correlation between NRXN1 expression and prefrontal cortex functions.

BACKGROUND Meningioma is the most common primary tumor of CNS, usually a benign tumor (grade I) successfully treated by surgical resection, while in the 25–30% of cases is a more aggressive neoplasm with high recurrence rate and poor prognosis (grade II-III). In the last years some studies tried to investigate the genomic profile of meningioma to find additional prognostic factors and potential therapeutic targets. Aim of our study was to use the array-CGH (aCGH) to investigate possible indicators of recurrence risk in meningiomas. MATERIAL AND METHODS We retrospectively selected two group of patients: 34 with meningioma WHO grade I (24 F, 10 M, median age at diagnosis 56 yrs) and 19 with meningioma WHO grade II (9 F, 10 M, median age 59 yrs), in order to compare cases recurrent and non-recurrent in each group. We also analyzed 5/18 recurrences WHO grade I and 10/11 WHO grade II. Genomic profiles were investigated by aCGH. RESULTS We observed an increase in number of genomic imbalances related to grading and in non-recurrent versus recurrent tumors. 9 WHO I meningiomas were without alterations. The mainly alterations observed were deletions and duplications, moreover we also identified chromothripsis of a single chromosome in 2/18 WHO I recurrent and 2/8 WHO II non recurrent meningiomas, and chromothripsis of multiple chromosomes in 5/11 WHO II recurrent meningiomas. As well we detected the presence of mosaicism, mainly in WHO I recurrent and in grade II meningiomas. In 7/14 WHO I meningiomas we found differences in genomic profile analyzing two samples obtained from two distinct areas. 6/15 recurrences showed the same alterations of the primary tumor. We didn’t detected an association between alteration of 1p and 22q and recurrence risk, as previously suggested, as those were the most diffused imbalances in all meningiomas. CONCLUSION In our patients we found a difference in genomic imbalances between grade I and grade II meningiomas, but we also identified additional details of the complexity of alterations in meningioma with the detection of chromothripsis and mosaicism. This latter aspect is a new issue and suggests the presence of more aggressive cell clones that could be predictive of recurrence in grade I meningioma. Moreover, we observed a spatial heterogeneity in half of grade I meningioma analyzed. Our preliminary results suggest that the aCGH, a technique routinely used in many laboratories, could be used to better stratify meningioma patients.

We developed anin vitrocontact through-feet blood brain barrier (BBB) model built using type IV collagen, rat astrocytes, and human umbilical vein endothelial cells (HUVECs) cocultured through Transwell porous polycarbonate membrane. The contact between astrocytes and HUVECs was demonstrated by electron microscopy: astrocytes endfeet pass through the 8.0 μm pores inducing HUVECs to assume a cerebral phenotype. Using this model we evaluated transmigration of melanoma cells from two different patients (M1 and M2) selected among seven melanoma primary cultures. M2 cells showed a statistically significant higher capability to pass across thein vitroBBB model, compared to M1. Expression of adhesion molecules was evaluated by flow cytometry: a statistically significant increased expression of MCAM,αvβ3, and CD49b was detected in M1. PCR array data showed that M2 had a higher expression of several matrix metalloproteinase proteins (MMPs) compared to M1. Specifically, data suggest that MMP2 and MMP9 could be directly involved in BBB permeability and that brain invasion by melanoma cells could be related to the overexpression of many MMPs. Future studies will be necessary to deepen the mechanisms of central nervous system invasion.

Background Epilepsy is a frequent symptom in patients with glioma. Although treatment with antiepileptic drugs is generally effective in controlling seizures, drug-resistant patients are not uncommon. Multidrug resistance proteins (MRPs) and P-gp are over-represented in brain tissue of patients with drug-resistant epilepsy, suggesting their involvement in the clearance of antiepileptic medications. In addition to their anticonvulsant action, some drugs have been documented for cytotoxic effects. Aim of this study was to evaluate possible in vitro cytotoxic effects of two new-generation antiepileptic drugs on a human glioma cell line U87MG. Methods Cytotoxicity of brivaracetam and lacosamide was tested on U87MG, SW1783 and T98G by MTS assay. Expression of chemoresistance molecules was evaluated using flow cytometry in U87MG and human umbilical vein endothelial cells (HUVECs). To investigate the putative anti-proliferative effect, apoptosis assay, microRNA expression profile and study of cell cycle were performed. Results Brivaracetam and lacosamide showed a dose-dependent cytotoxic and anti-migratory effects. Cytotoxicity was not related to apoptosis. The exposure of glioma cells to brivaracetam and lacosamide resulted in the modulation of several microRNAs; particularly, the effect of miR-195-5p modulation seemed to affect cell cycle, while miR-107 seemed to be implicated in the inhibition of cells migration. Moreover, brivaracetam and lacosamide treatment did not modulate the expression of chemoresistance-related molecules MRPs1-3-5, GSTπ, P-gp on U87MG and HUVECs. Conclusion Based on antineoplastic effect of brivaracetam and lacosamide on glioma cells, we assume that patients with glioma could benefit by the treatment with these two molecules, in addition to standard therapeutic options. Electronic supplementary material The online version of this article (doi:10.1186/s13046-017-0546-9) contains supplementary material, which is available to authorized users.

Interferon inducible protein 16 (IFI-16) is a member of the p200 human family proteins, having two domains: C-terminus binding dsDNA and N-terminus as a typical protein-protein interaction domain. IFI-16 gene is located at 1q23.1 chromosome, its functions ranging from transcriptional regulation, apoptosis, proliferation and differentiation. IFI-16 is mostly expressed in epithelial, endothelial and hematopoietic tissues, with nuclear localization signal: in the nucleolus it is able to activate and fine-tune the transcription, when in the nucleoplasm probably it is inactivated. In the nucleoli a physical and functional link of IFI-16 to p53 has been reported, as negative regulator of the cell cycle. We have studied IFI-16 expression in 40 low grade and 40 anaplastic gliomas (half of them analysed with their relapse) and 40 glioblastomas using immunohistochemical and molecular techniques, using two antibodies against the C- and N-terminus of IFI-16. Nuclear accumulation of p53, IDH1(R132H), MGMT methylation status and LOH of chromosomes 1p, 19q, 9p, 17p and 10q were also evaluated. We mainly found a nucleolar expression of IFI-16 in astrocytic lower grade gliomas, related to p53: this physical and functional binding was also demonstrated by co-immunoprecipitation and Protein Ligation Assay analysis. In anaplastic gliomas and glioblastomas, IFI-16 is largely expressed in the nucleoplasm, unrelated to p53 expression. This shift of localization suggests a possible loss of its role as protective factor in lower grade astrocytic gliomas. In oligodendrogliomas IFI-16 expression was completely absent and it is strictly related to 1p/19q co-deletion. Our results, related to clinical data, identify IFI-16 as a possible prognostic marker in glioma patients and of interest to define new molecular profiles for their therapy. This is the first study of IFI-16 in gliomas, suggesting an early role of this molecule in proliferation and malignant progression of these tumours.