Glioblastoma multiforme (GBM) is an aggressive brain tumor for which current immunotherapy approaches have been unsuccessful. Here, we explore the mechanisms underlying immune evasion in GBM. By ...serially transplanting GBM stem cells (GSCs) into immunocompetent hosts, we uncover an acquired capability of GSCs to escape immune clearance by establishing an enhanced immunosuppressive tumor microenvironment. Mechanistically, this is not elicited via genetic selection of tumor subclones, but through an epigenetic immunoediting process wherein stable transcriptional and epigenetic changes in GSCs are enforced following immune attack. These changes launch a myeloid-affiliated transcriptional program, which leads to increased recruitment of tumor-associated macrophages. Furthermore, we identify similar epigenetic and transcriptional signatures in human mesenchymal subtype GSCs. We conclude that epigenetic immunoediting may drive an acquired immune evasion program in the most aggressive mesenchymal GBM subtype by reshaping the tumor immune microenvironment.
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•Disease-relevant TME is recapitulated in immunocompetent GBM mouse models•Stable reconfiguration of the transcriptome occurs in GSCs following immune attack•Immune evasive GSCs deploy “myeloid mimicry” to establish a myeloid-enriched TME•Acquired transcriptional changes consistent with a process of epigenetic immunoediting
Glioblastoma stem cells deploy a myeloid mimicry program through epigenetic immunoediting, rather than subclonal selection, to drive a myeloid-enriched tumor microenvironment, thereby enabling immune evasion and tumor progression.
Background: IDH-wildtype glioblastoma is the most common malignant primary brain tumour in adults. As there is limited information on prognostic factors outside of clinical trials; thus, we conducted ...a retrospective study to characterise the glioblastoma population at our centre. Methods: Demographic, tumour molecular profiles, treatment, and survival data were collated for patients diagnosed with glioblastoma at our centre between July 2011 and December 2015. We used multivariate proportional hazard model associations with survival. Results: 490 patients were included; 60% had debulking surgery and 40% biopsy only. Subsequently, 56% had standard chemoradiotherapy, 25% had non-standard chemo/radio-therapy, and 19% had no further treatment. Overall survival was 9.2 months. In the multivariate analysis, longer survival was associated with debulking surgery vs. biopsy alone (14.9 vs. 8 months) (HR 0.54 95% CI 0.41−0.70), subsequent treatment after diagnosis (HR 0.12 0.08−0.16) (standard chemoradiotherapy 16.9 months vs. non-standard regimens 9.2 months vs. none 2.0 months), tumour MGMT promotor methylation (HR 0.71 0.58−0.87), and younger age (hazard ratio vs. age < 50: 1.70 1.26−2.30 for ages 50−59; 3.53 2.65−4.70 for ages 60−69; 4.82 3.54−6.56 for ages 70+). Conclusions: The median survival for patients with glioblastoma is less than a year. Younger age, debulking surgery, treatment with chemoradiotherapy, and MGMT promotor methylation are independently associated with longer survival.
Mutations in the glucocerebrosidase (gba) gene cause Gaucher disease (GD), the most common lysosomal storage disorder, and increase susceptibility to Parkinson’s disease (PD). While the clinical and ...pathological features of idiopathic PD and PD related to gba (PD-GBA) mutations are very similar, cellular mechanisms underlying neurodegeneration in each are unclear. Using a mouse model of neuronopathic GD, we show that autophagic machinery and proteasomal machinery are defective in neurons and astrocytes lacking gba. Markers of neurodegeneration—p62/SQSTM1, ubiquitinated proteins, and insoluble α-synuclein—accumulate. Mitochondria were dysfunctional and fragmented, with impaired respiration, reduced respiratory chain complex activities, and a decreased potential maintained by reversal of the ATP synthase. Thus a primary lysosomal defect causes accumulation of dysfunctional mitochondria as a result of impaired autophagy and dysfunctional proteasomal pathways. These data provide conclusive evidence for mitochondrial dysfunction in GD and provide insight into the pathogenesis of PD and PD-GBA.
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•Autophagic and proteasomal pathways are suppressed in gba knockout mice•α-Synuclein accumulates and forms deposits in gba knockout mouse brainstem•Neurons and astrocytes from gba knockout mice harbor dysfunctional mitochondria•Mitochondria do not recruit Parkin and accumulate in gba knockout neurons
IntroductionIntraneural perineurioma (IP) classically causes a progressive, painless mononeuropathy, usually in young adults, and most frequently affecting the sciatic nerve or its branches. ...Pathological features are pathognomonic, but the radiological findings are also diagnostic; focal fusiform hypertro- phy and high signal on T2 MRI, with avid homogeneous enhancement. We present two cases of diffuse disease causing upper-limb plexopathy.MethodsPatients were evaluated at two specialist neuromuscular centres.ResultsPatient 1, a 20 year-old male, presented with a 12-year history of progressive distal then proximal, bilateral upper limb amyotrophy and sensory loss. Neurophysiology suggested an axonal process without evidence of conduction block or dispersion. MRI showed bilateral brachial plexus hypertrophy with avid enhancement. Dorsal ulnar nerve biopsy confirmed IP. Patient 2, a 41 year-old male, presented with more than a 20-year history of right lower cranial nerve palsies and right shoulder girdle amyotrophy, with distal left upper limb amyotrophy. Imaging was near identical to Patient 1, and brachial plexus biopsy confirmed IP, which in this case extended to the cranial nerves.ConclusionsDiffuse IP is extremely rare. We report cases of progressive upper-limb disease confirmed on distal and proximal biopsy. The phenotype and radiological findings should prompt consideration of the diagnosis.
Glioblastomas are hierarchically organised tumours driven by glioma stem cells that retain partial differentiation potential. Glioma stem cells are maintained in specialised microenvironments, but ...whether, or how, they undergo lineage progression outside of these niches remains unclear. Here we identify the white matter as a differentiative niche for glioblastomas with oligodendrocyte lineage competency. Tumour cells in contact with white matter acquire pre-oligodendrocyte fate, resulting in decreased proliferation and invasion. Differentiation is a response to white matter injury, which is caused by tumour infiltration itself in a tumoursuppressive feedback loop. Mechanistically, tumour cell differentiation is driven by selective white matter upregulation of SOX10, a master regulator of normal oligodendrogenesis. SOX10 overexpression or treatment with myelination-promoting agents that upregulate endogenous SOX10, mimic this response, leading to niche-independent pre-oligodendrocyte differentiation and tumour suppression in vivo. Thus, glioblastoma recapitulates an injury response and exploiting this latent programme may offer treatment opportunities for a subset of patients.
Highlights • Prognostic value of S100B in TBI, SAH and meningitis at 6 months following treatment. • Significant correlation between serum S100B and GOS in overall cohort, TBI and SAH (p < 0.05). • ...Significant correlation between CSF S100B and GOS in SAH (p < 0.05). • Serum S100B >0.7 μg/l correlated with 100% mortality. • CSF S100B sensitive to small influences with EVD exchange causing significant increase (p < 0.005).
Amyloid‐β transmission has been described in patients both with and without iatrogenic Creutzfeldt–Jakob disease; however, there is little information regarding the clinical impact of this acquired ...amyloid‐β pathology during life. Here, for the first time, we describe in detail the clinical and neuroimaging findings in 3 patients with early onset symptomatic amyloid‐β cerebral amyloid angiopathy following childhood exposure to cadaveric dura (by neurosurgical grafting in 2 patients and tumor embolization in a third). Our observations provide further in vivo evidence that cerebral amyloid angiopathy might be caused by transmission of amyloid‐β seeds (prions) present in cadaveric dura and have diagnostic relevance for younger patients presenting with suspected cerebral amyloid angiopathy. Ann Neurol 2019; 1–7 ANN NEUROL 2019;85:284–290.
We sought to investigate, whether texture analysis of diffusional kurtosis imaging (DKI) enhanced by support vector machine (SVM) analysis may provide biomarkers for gliomas staging and detection of ...the IDH mutation. First-order statistics and texture feature extraction were performed in 37 patients on both conventional (FLAIR) and mean diffusional kurtosis (MDK) images and recursive feature elimination (RFE) methodology based on SVM was employed to select the most discriminative diagnostic biomarkers. The first-order statistics demonstrated significantly lower MDK values in the IDH-mutant tumors. This resulted in 81.1% accuracy (sensitivity = 0.96, specificity = 0.45, AUC 0.59) for IDH mutation diagnosis. There were non-significant differences in average MDK and skewness among the different tumour grades. When texture analysis and SVM were utilized, the grading accuracy achieved by DKI biomarkers was 78.1% (sensitivity 0.77, specificity 0.79, AUC 0.79); the prediction accuracy for IDH mutation reached 83.8% (sensitivity 0.96, specificity 0.55, AUC 0.87). For the IDH mutation task, DKI outperformed significantly the FLAIR imaging. When using selected biomarkers after RFE, the prediction accuracy achieved 83.8% (sensitivity 0.92, specificity 0.64, AUC 0.88). These findings demonstrate the superiority of DKI enhanced by texture analysis and SVM, compared to conventional imaging, for gliomas staging and prediction of IDH mutational status.
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