Global hypo-methylation in a proportion of glioblastoma enriched for an astrocytic signature is associated with increased invasion and altered immune landscape.

We describe a subset of glioblastoma, the most prevalent malignant adult brain tumour, harbouring a bias towards hypomethylation at defined differentially methylated regions. This epigenetic signature correlates with an enrichment for an astrocytic gene signature, which together with the identification of enriched predicted binding sites of transcription factors known to cause demethylation and to be involved in astrocytic/glial lineage specification, point to a shared ontogeny between these glioblastomas and astroglial progenitors. At functional level, increased invasiveness, at least in part mediated by SRPX2, and macrophage infiltration characterise this subset of glioblastoma.

Cortical neuronal hypertrophy and mTOR pathway activation in CAN regions in SUDEP.

OBJECTIVES: Dysfunctional connectivity and preexisting structural abnormalities of central autonomic network (CAN) regions have been shown on magnetic resonance imaging (MRI) in sudden unexpected death in epilepsy (SUDEP) and may be mechanistically relevant. In a previous postmortem study we reported increased microglia in CAN regions, including the superior temporal gyrus (STG) in SUDEP. In this current study we investigated mammalian target of rapamycin (mTOR) pathway activation and neuronal c-Fos activation in CAN regions in SUDEP compared to control groups. METHODS: In a series of 59 postmortem cases (SUDEP, n = 26; epilepsy controls [EPCs], n = 14; and nonepilepsy controls [NECs], n = 19), we quantified pS6-240/4, pS6-235/6 (markers of mTOR activation) and c-Fos neuronal densities and labeling index in the STG, anterior cingulate, insula, frontobasal, and pulvinar regions using immunohistochemistry with whole-slide automated image analysis. RESULTS: Significantly more pS6-positive neurons were present in the STG in cases with a history of recent seizures prior to death and also in SUDEP compared to other cause of death groups. No differences were noted for c-Fos neuronal labeling in any region between cause of death groups. Cortical neuronal hypertrophy in the STG was observed in some SUDEP cases and associated with pS6-240/4 expression. pS6-235/6 highlighted neuronal intranuclear inclusions, mainly in SUDEP cases and in the STG region. SIGNIFICANCE: Neuronal labeling for pS6 in the STG correlated with both seizure activity in the period prior to death and SUDEP. Further investigations are required to explore the significance of this region in terms of autonomic network dysfunction that may increase the vulnerability for SUDEP.

Combination of BMI1 and MAPK/ERK inhibitors is effective in medulloblastoma.

BACKGROUND: Epigenetic changes play a key role in the pathogenesis of medulloblastoma (MB), the most common malignant pediatric brain tumor. METHODS: We explore the therapeutic potential of BMI1 and MAPK/ERK inhibition in BMI1High;CHD7Low MB cells and in a preclinical xenograft model. RESULTS: We identify a synergistic vulnerability of BMI1High;CHD7Low MB cells to a combination treatment with BMI1 and MAPK/ERK inhibitors. Mechanistically, CHD7-dependent binding of BMI1 to MAPK-regulated genes underpins the CHD7-BMI1-MAPK regulatory axis responsible of the antitumour effect of the inhibitors in vitro and in a preclinical mouse model. Increased ERK1 and ERK2 phosphorylation activity is found in BMI1High;CHD7Low G4 MB patients, raising the possibility that they could be amenable to a similar therapy. CONCLUSIONS: The molecular dissection of the CHD7-BMI1-MAPK regulatory axis in BMI1High;CHD7Low MB identifies this signature as a proxy to predict MAPK functional activation, which can be effectively drugged in preclinical models, and paves the way for further exploration of combined BMI1 and MAPK targeting in G4 MB patients.

Optical properties of human brain and tumour tissue: An ex vivo study spanning the visible range to beyond the second near-infrared window.

Neuro-oncology surgery would benefit from detailed intraoperative tissue characterization provided by noncontact, contrast-agent-free, noninvasive optical imaging methods. In-depth knowledge of target tissue optical properties across a wide-wavelength spectrum could inform the design of optical imaging and computational methods to enable robust tissue analysis during surgery. We adapted a dual-beam integrating sphere to analyse small tissue samples and investigated ex vivo optical properties of five types of human brain tumour (meningioma, pituitary adenoma, schwannoma, low- and high-grade glioma) and nine different types of healthy brain tissue across a wavelength spectrum of 400 to 1800 nm. Fresh and frozen tissue samples were analysed. All tissue types demonstrated similar absorption spectra, but the reduced scattering coefficients of tumours show visible differences in the obtained optical spectrum compared to those of surrounding normal tissue. These results underline the potential of optical imaging technologies for intraoperative tissue characterization.

Inositol treatment inhibits medulloblastoma through suppression of epigenetic-driven metabolic adaptation.

Deregulation of chromatin modifiers plays an essential role in the pathogenesis of medulloblastoma, the most common paediatric malignant brain tumour. Here, we identify a BMI1-dependent sensitivity to deregulation of inositol metabolism in a proportion of medulloblastoma. We demonstrate mTOR pathway activation and metabolic adaptation specifically in medulloblastoma of the molecular subgroup G4 characterised by a BMI1High;CHD7Low signature and show this can be counteracted by IP6 treatment. Finally, we demonstrate that IP6 synergises with cisplatin to enhance its cytotoxicity in vitro and extends survival in a pre-clinical BMI1High;CHD7Low xenograft model.

Increased plasma neurofilament light chain concentration correlates with severity of post-mortem neurofibrillary tangle pathology and neurodegeneration.

Alzheimer's disease (AD) is pathologically characterized by the accumulation of amyloid-ß (Aß) plaques, neurofibrillary tangles and widespread neuronal loss in the brain. In recent years, blood biomarkers have emerged as a realistic prospect to highlight accumulating pathology for secondary prevention trials. Neurofilament light chain (NfL), a marker of axonal degeneration, is robustly elevated in the blood of many neurological and neurodegenerative conditions, including AD. A strong relationship with cerebrospinal fluid (CSF) NfL suggests that these biomarker modalities reflect the same pathological process. Yet, the connection between blood NfL and brain tissue pathology has not been directly compared. In this study, longitudinal plasma NfL from cognitively healthy controls (n = 12) and AD participants (n = 57) were quantified by the Simoa platform. On reaching post-mortem, neuropathological assessment was performed on all participants, with additional frozen and paraffin-embedded tissue acquired from 26 participants for further biochemical (Aß1-42, Aß1-40, tau) and histological (NfL) evaluation. Plasma NfL concentrations were significantly increased in AD and correlated with cognitive decline, independent of age. Retrospective stratification based on Braak staging revealed that baseline plasma NfL concentrations were associated with higher neurofibrillary tangle pathology at post-mortem. Longitudinal increases in plasma NfL were observed in all Braak groupings; a significant negative association, however, was found between plasma NfL at time point 1 and both its rate of change and annual percentage increase. Immunohistochemical evaluation of NfL in the medial temporal gyrus (MTG) demonstrated an inverse relationship between Braak stages and NfL staining. Importantly, a significant negative correlation was found between the plasma NfL measurement closest to death and the level of NfL staining in the MTG at post-mortem. For the first time, we demonstrate that plasma NfL associates with the severity of neurofibrillary tangle pathology and neurodegeneration in the post-mortem brain.