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Arteriovenous malformation of the brain (bAVM) is a vascular phenotype related to brain defective angiogenesis. Involved vessels show impaired expression of vascular differentiation markers resulting in the arteriolar to venule direct shunt. In order to clarify aberrant gene expression occurring in bAVM, here we describe results obtained by methylome analysis performed on endothelial cells (ECs) isolated from bAVM specimens, compared to human cerebral microvascular ECs. Results were validated by quantitative methylation-specific PCR and quantitative realtime-PCR. Differential methylation events occur in genes already linked to bAVM onset, as RBPJ and KRAS. However, among differentially methylated genes, we identified EPHB1 and several other loci involved in EC adhesion as well as in EC/vascular smooth muscle cell (VSMC) crosstalk, suggesting that only endothelial dysfunction might not be sufficient to trigger the bAVM phenotype. Moreover, aberrant methylation pattern was reported for many lncRNA genes targeting transcription factors expressed during neurovascular development. Among these, the YBX1 that was recently shown to target the arteridin coding gene. Finally, in addition to the conventional CpG methylation, we further considered the role of impaired CHG methylation, mainly occurring in brain at embryo stage. We showed as differentially CHG methylated genes are clustered in pathways related to EC homeostasis, as well as to VSMC-EC crosstalk, suggesting as impairment of this interaction plays a prominent role in loss of vascular differentiation, in bAVM phenotype.

By regulating several phases of gene expression, RNA editing modifications contribute to maintaining physiological RNA expression levels. RNA editing dysregulation can affect RNA molecule half-life, coding/noncoding RNA interaction, alternative splicing, and circular RNA biogenesis. Impaired RNA editing has been observed in several pathological conditions, including cancer and Alzheimer’s disease. No data has been published yet on the editome profile of endothelial cells (ECs) isolated from human cerebral cavernous malformation (CCM) lesions. Here, we describe a landscape of editome modifications in sporadic CCM-derived ECs (CCM-ECs) by comparing editing events with those observed in human brain microvascular endothelial cells (HBMECs). With a whole transcriptome-based variant calling pipeline, we identified differential edited genes in CCM-ECs that were enriched in pathways related to angiogenesis, apoptosis and cell survival, inflammation and, in particular, to thrombin signalling mediated by protease-activated receptors and non-canonical Wnt signalling. These pathways, not yet associated to CCM development, could be a novel field for further investigations on CCM molecular mechanisms. Moreover, enrichment analysis of differentially edited miRNAs suggested additional small noncoding transcripts to consider for development of targeted therapies.

Abstract Background The differential diagnosis between radiation necrosis, tumor recurrence and tumor progression is crucial for the evaluation of treatment response and treatment planning. The appearance of treatment-induced tissue necrosis on conventional Magnetic Resonance Imaging (MRI) is similar to brain tumor recurrence and it could be difficult to differentiate the two entities on follow-up MRI examinations. Dynamic Susceptibility Contrast-enhanced (DSC) and Dynamic Contrast-Enhanced (DCE) are MRI perfusion techniques that use an exogenous, intravascular, non-diffusible gadolinium-based contrast agent. The aim of this study was to compare the diagnostic accuracy of DSC and DCE perfusion MRI in the differential diagnosis between radiation necrosis and tumor recurrence, in the follow-up of primary and metastatic intra-axial brain tumors after Stereotactic RadioSurgery (SRS) performed with CyberKnife. Methods A total of 72 enhancing lesions (57 brain metastases and 15 primary brain tumors) were analyzed with DCE and DSC, by means of MRI acquisition performed by 1,5 Tesla MR scanner. The statistical relationship between the diagnosis of tumor recurrence or radiation necrosis, decided according to clinicoradiologically criteria, rCBV and Ktrans was evaluated by the point-biserial correlation coefficient respectively. Results The statistical analysis showed a correlation between the diagnosis of radiation necrosis or recurrent tumor with Ktrans (rpb = 0.54, p

Molecular signaling that leads to brain arteriovenous malformation (bAVM) is to date elusive and this is firstly due to the low frequency of familial cases. Conversely, sporadic bAVM is the most diffuse condition and represents the main source to characterize the genetic basis of the disease. Several studies were conducted in order to detect both germ-line and somatic mutations linked to bAVM development and, in this context, next generation sequencing technologies offer a pivotal resource for the amount of outputted information. We performed whole exome sequencing on a young boy affected by sporadic bAVM. Paired-end sequencing was conducted on an Illumina platform and filtered variants were validated by Sanger sequencing. We detected 20 likely gene-disrupting variants affecting as many loci. Of these variants, 11 are inherited novel variants and one is a de novo nonsense variant, affecting STK4 gene. Moreover, we also considered rare known variants affecting loci involved in vascular differentiation. In order to explain their possible involvement in bAVM pathogenesis, we analyzed molecular networks at Cytoscape platform. In this study we focus on some genetic point variations detected in a child affected by bAVM. Therefore, we suggest these novel affected loci as prioritized for further investigation on pathogenesis of bAVM lesions.

Abstract Trigeminal neuralgia (TN) is a form of neuropathic pain that affects the fifth cranial nerve, the most widely distributed nerve in the head. Although TN has been associated with a variety of pathological conditions, neurovascular compression on the trigeminal nerve as it exits the brainstem is the most frequent reported cause. This compression causes progressive demyelination of the nerve and subsequent aberrant neural transmission. Although several studies have clarified some pathophysiological mechanisms underlying TN, the molecular basis remains vague. Very recently the substitution of methionine 136 by valine (MET126Val) in sodium channel Nav1.6 in a case study of typical TN has suggested a new possible mechanism for TN. The findings of this new mutation provide novel information that warrants further conclusive investigation.

Brain metastases (BM) are the most common intracranial tumors and their incidence is increasing. Untreated brain metastases are associated with a poor prognosis and a poor performance status. Metastasis development involves the migration of a cancer cell from the bulk tumor into the surrounding tissue, extravasation from the blood into tissue elsewhere in the body, and formation of a secondary tumor. In the recent past, important results have been obtained in the management of patients affected by BM, using surgery, radiation therapy, or both. Conventional chemotherapies have generally produced disappointing results, possibly due to their limited ability to penetrate the blood–brain barrier. The advent of new technologies has led to the discovery of novel molecules and pathways that have better depicted the metastatic process. Targeted therapies such as bevacizumab, erlotinib, gefitinib, sunitinib and sorafenib, are all licensed and have demonstrated improved survival in patients with metastatic disease. In this review, we will report current data on targeted therapies. A brief review about brain metastatic process will be also presented.

Traumatic brain injury (TBI) is a leading cause of death and disability in the modern society. Although primary prevention is the only strategy that can counteract the primary brain damage, numerous preclinical studies have been accumulated in order to find therapeutic strategies against the secondary damage. In this scenario erythropoietin (EPO) has been shown to be a promising candidate as neuroprotective agent. A recent clinical trial, however, has shown that EPO has not an overall effect on outcomes following TBI thus renewing old concerns. However, the results of a prespecified sensitivity analysis indicate that the effect of EPO on mortality remains still unclear. In the light of these observations, further investigations are needed to resolve doubts on EPO effectiveness in order to provide a more solid base for tailoring conclusive clinical trials.

BACKGROUND: Telomeres alteration during carcinogenesis and tumor progression has been described in several cancer types. Telomeres length is stabilized by telomerase (h-TERT) and controlled by several proteins that protect telomere integrity, such as the Telomere Repeat-binding Factor (TRF) 1 and 2 and the tankyrase-poli-ADP-ribose polymerase (TANKs-PARP) complex. OBJECTIVE: To investigate telomere dysfunction in astroglial brain tumors we analyzed telomeres length, telomerase activity and the expression of a panel of genes controlling the length and structure of telomeres in tissue samples obtained in vivo from astroglial brain tumors with different grade of malignancy. MATERIALS AND METHODS: Eight Low Grade Astrocytomas (LGA), 11 Anaplastic Astrocytomas (AA) and 11 Glioblastoma Multiforme (GBM) samples were analyzed. Three samples of normal brain tissue (NBT) were used as controls. Telomeres length was assessed through Southern Blotting. Telomerase activity was evaluated by a telomere repeat amplification protocol (TRAP) assay. The expression levels of TRF1, TRF2, h-TERT and TANKs-PARP complex were determined through Immunoblotting and RT-PCR. RESULTS: LGA were featured by an up-regulation of TRF1 and 2 and by shorter telomeres. Conversely, AA and GBM were featured by a down-regulation of TRF1 and 2 and an up-regulation of both telomerase and TANKs-PARP complex. CONCLUSIONS: In human astroglial brain tumours, up-regulation of TRF1 and TRF2 occurs in the early stages of carcinogenesis determining telomeres shortening and genomic instability. In a later stage, up-regulation of PARP-TANKs and telomerase activation may occur together with an ADP-ribosylation of TRF1, causing a reduced ability to bind telomeric DNA, telomeres elongation and tumor malignant progression.