Astrocytic Calcium Waves Signal Brain Injury to Neural Stem and Progenitor Cells.

Brain injuries, such as stroke or trauma, induce neural stem cells in the subventricular zone (SVZ) to a neurogenic response. Very little is known about the molecular cues that signal tissue damage, even over large distances, to the SVZ. Based on our analysis of gene expression patterns in the SVZ, 48 hr after an ischemic lesion caused by middle cerebral artery occlusion, we hypothesized that the presence of an injury might be transmitted by an astrocytic traveling calcium wave rather than by diffusible factors or hypoxia.

CASP9 germline mutation in a family with multiple brain tumors.

We report a novel CASP9 germline mutation that may increase susceptibility to the development of brain tumors. We identified this mutation in a family in which three brain tumors had developed within three generations, including two anaplastic astrocytomas occurring in cousins. The cousins were diagnosed at similar ages (29 and 31 years), and their tumors showed similar histological features.

FOXO3a orchestrates glioma cell responses to starvation conditions and promotes hypoxia-induced cell death.

Forkhead box O (FOXO) transcription factors are homeostatic regulators adjusting diverse cellular processes crucial for metabolism and survival. In gliomas, FOXOs have been shown to modulate cell death, proliferation and differentiation. Here, we investigated the role of FOXO3a in human malignant gliomas with special regard to starvation conditions.

Nucleoside diphosphate kinase B regulates angiogenic responses in the endothelium via caveolae formation and c-Src-mediated caveolin-1 phosphorylation.

Nucleoside diphosphate kinase B (NDPK-B) is an enzyme required for nucleoside triphosphate homeostasis, which has been shown to interact with caveolin-1 (Cav-1). In endothelial cells (ECs), NDPK-B contributes to the regulation of angiogenesis and adherens junction (AJ) integrity. We therefore investigated whether an interaction of NDPK-B with Cav-1 in ECs is required for this regulation and the involvement of VEGF signaling herein.

The angiogenic switch leads to a metabolic shift in human glioblastoma.

Background: Invasion and angiogenesis are major hallmarks of glioblastoma (GBM) growth. While invasive tumor cells grow adjacent to blood vessels in normal brain tissue, tumor cells within neovascularized regions exhibit hypoxic stress and promote angiogenesis. The distinct microenvironments likely differentially affect metabolic processes within the tumor cells.

β-Catenin Is Required for Endothelial Cyp1b1 Regulation Influencing Metabolic Barrier Function.

Unlabelled: The canonical Wnt/β-catenin signaling pathway is crucial for blood-brain barrier (BBB) formation in brain endothelial cells. Although glucose transporter 1, claudin-3, and plasmalemma vesicular-associated protein have been identified as Wnt/β-catenin targets in brain endothelial cells, further downstream targets relevant to BBB formation and function are incompletely explored. By Affymetrix expression analysis, we show that the cytochrome P450 enzyme Cyp1b1 was significantly decreased in β-catenin-deficient mouse endothelial cells, whereas its close homolog Cyp1a1 was upregulated in an aryl hydrocarbon receptor-dependent manner, hence indicating that β-catenin is indispensable for Cyp1b1 but not for Cyp1a1 expression.

A 4-miRNA signature predicts the therapeutic outcome of glioblastoma.

Multimodal therapy of glioblastoma (GBM) reveals inter-individual variability in terms of treatment outcome. Here, we examined whether a miRNA signature can be defined for the a priori identification of patients with particularly poor prognosis.FFPE sections from 36 GBM patients along with overall survival follow-up were collected retrospectively and subjected to miRNA signature identification from microarray data.

Addition of Anti-Angiogenetic Therapy with Bevacizumab to Chemo- and Radiotherapy for Leptomeningeal Metastases in Primary Brain Tumors.

Leptomeningeal dissemination of a primary brain tumor is a condition which is challenging to treat, as it often occurs in rather late disease stages in highly pretreated patients. Its prognosis is dismal and there is still no accepted standard of care. We report here a good clinical effect with a partial response in three out of nine patients and a stable disease with improvement on symptoms in two more patients following systemic anti-angiogenic treatment with bevacizumab (BEV) alone or in combination with chemo- and/or radiotherapy in a series of patients with leptomeningeal dissemination from primary brain tumors (diffuse astrocytoma WHO°II, anaplastic astrocytoma WHO°III, anaplastic oligodendroglioma WHO°III, primitive neuroectodermal tumor and glioblastoma, both WHO°IV).

Pbx1 is required for adult subventricular zone neurogenesis.

TALE-homeodomain proteins function as components of heteromeric complexes that contain one member each of the PBC and MEIS/PREP subclasses. We recently showed that MEIS2 cooperates with the neurogenic transcription factor PAX6 in the control of adult subventricular zone (SVZ) neurogenesis in rodents. Expression of the PBC protein PBX1 in the SVZ has been reported, but its functional role(s) has not been investigated.

Prognostic factors in recurrent glioblastoma patients treated with bevacizumab.

The value of bevacizumab (BEV) in recurrent glioblastoma is unclear. Imaging parameters and progression-free survival (PFS) are problematic endpoints. Few data exist on clinical factors influencing overall survival (OS) in unselected patients with recurrent glioblastoma exposed to BEV.

Downstream effects of plectin mutations in epidermolysis bullosa simplex with muscular dystrophy.

Mutations of the human plectin gene (PLEC) on chromosome 8q24 cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). In the present study we analyzed the downstream effects of PLEC mutations on plectin protein expression and localization, the structure of the extrasarcomeric desmin cytoskeleton, protein aggregate formation and mitochondrial distribution in skeletal muscle tissue from three EBS-MD patients. PLEC gene analysis in a not previously reported 35-year-old EBS-MD patient with additional disease features of cardiomyopathy and malignant arrhythmias revealed novel compound heterozygous (p.

Immature teratoma of the tectum mesencephali with histopathological detection of rudimentary eye anlage in a 3-year-old boy: Report of a rare case.

Intracranial teratoma is a rare neoplasm derived from omnipotent germinal cells that can contain mesoderm, endoderm and/or ectoderm layer tissue. Histologically teratomas are characterized by abnormal structures like teeth or bone that can be further subdivided into mature and immature according to the presence of incompletely differentiated tissue. Characteristic intracranial teratomas are space-occupying lesions in the pineal region and often present with hydrocephalic symptoms due to aqueduct stenosis.

Blood-Brain Barrier Breakdown Determines Differential Therapeutic Outcome in Genetically Diverse Forms of Medulloblastoma.

Medulloblastoma driven by Wnt/β-catenin and Sonic hedgehog pathway mutations show favorable and poor patient survival upon treatment, respectively. In this Cancer Cell issue, Phoenix and colleagues (2016) report disruption of the blood-brain barrier by Wif1 specifically in Wnt-driven medulloblastoma, resulting in increased treatment response and survival in mouse models.

Decrease of VEGF-A in myeloid cells attenuates glioma progression and prolongs survival in an experimental glioma model.

Background: Glioblastomas are highly vascularized tumors with a prominent infiltration of macrophages/microglia whose role in promoting glioma growth, invasion, and angiogenesis has not been fully elucidated.

Methods: The contribution of myeloid-derived vascular endothelial growth factor (VEGF) to glioma growth was analyzed in vivo in a syngeneic intracranial GL261 glioma model using a Cre/loxP system to knock out the expression of VEGF-A in CD11b + myeloid cells. Changes in angiogenesis-related gene expression profile were analyzed in mutant bone marrow-derived (BMD) macrophages in vitro.

Angiopoietin-2-induced blood-brain barrier compromise and increased stroke size are rescued by VE-PTP-dependent restoration of Tie2 signaling.

The homeostasis of the central nervous system is maintained by the blood-brain barrier (BBB). Angiopoietins (Ang-1/Ang-2) act as antagonizing molecules to regulate angiogenesis, vascular stability, vascular permeability and lymphatic integrity. However, the precise role of angiopoietin/Tie2 signaling at the BBB remains unclear.

Methylation-based classification of benign and malignant peripheral nerve sheath tumors.

The vast majority of peripheral nerve sheath tumors derive from the Schwann cell lineage and comprise diverse histological entities ranging from benign schwannomas and neurofibromas to high-grade malignant peripheral nerve sheath tumors (MPNST), each with several variants. There is increasing evidence for methylation profiling being able to delineate biologically relevant tumor groups even within the same cellular lineage. Therefore, we used DNA methylation arrays for methylome- and chromosomal profile-based characterization of 171 peripheral nerve sheath tumors.

Methylation profiling of choroid plexus tumors reveals 3 clinically distinct subgroups.

Background: Choroid plexus tumors are intraventricular neoplasms derived from the choroid plexus epithelium. A better knowledge of molecular factors involved in choroid plexus tumor biology may aid in identifying patients at risk for recurrence.

Methods: Methylation profiles were examined in 29 choroid plexus papillomas (CPPs, WHO grade I), 32 atypical choroid plexus papillomas (aCPPs, WHO grade II), and 31 choroid plexus carcinomas (CPCs, WHO grade III) by Illumina Infinium HumanMethylation450 Bead Chip Array.

Comparative transcriptomics reveals similarities and differences between astrocytoma grades.

Background: Astrocytomas are the most common primary brain tumors distinguished into four histological grades. Molecular analyses of individual astrocytoma grades have revealed detailed insights into genetic, transcriptomic and epigenetic alterations. This provides an excellent basis to identify similarities and differences between astrocytoma grades.

Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma.

Glioblastoma multiforme (GBM) is treated by surgical resection followed by radiochemotherapy. Bevacizumab is commonly deployed for anti-angiogenic therapy of recurrent GBM; however, innate immune cells have been identified as instigators of resistance to bevacizumab treatment. We identified angiopoietin-2 (Ang-2) as a potential target in both naive and bevacizumab-treated glioblastoma.

Differential expression of vascular endothelial growth factor A, its receptors VEGFR-1, -2, and -3 and co-receptors neuropilin-1 and -2 does not predict bevacizumab response in human astrocytomas.

Background: A major hallmark of malignant progression in human astrocytomas is the formation of new blood vessels. Antiangiogenic therapy using the anti-vascular endothelial growth factor (VEGF)-antibody bevacizumab leads to increased progression-free survival in glioblastoma patients but does not influence their overall survival. To date, it is unclear why antiangiogenic therapy fails in many glioblastoma patients, while a small subpopulation profits considerably from this treatment.

Bevacizumab and radiotherapy for the treatment of glioblastoma: brothers in arms or unholy alliance?

Glioblastoma (GBM) represents the most frequent primary brain tumor in adults and carries a dismal prognosis despite aggressive, multimodal treatment regimens involving maximal resection, radiochemotherapy, and maintenance chemotherapy. Histologically, GBMs are characterized by a high degree of VEGF-mediated vascular proliferation. In consequence, new targeted anti-angiogenic therapies, such as the monoclonal anti-VEGF-A antibody bevacizumab, have proven effective in attenuating tumor (neo)angiogenesis and were shown to possess therapeutic activity in several phase II trials.

Genetic Alterations in Gliosarcoma and Giant Cell Glioblastoma.

The majority of glioblastomas develop rapidly with a short clinical history (primary glioblastoma IDH wild-type), whereas secondary glioblastomas progress from diffuse astrocytoma or anaplastic astrocytoma. IDH mutations are the genetic hallmark of secondary glioblastomas. Gliosarcomas and giant cell glioblastomas are rare histological glioblastoma variants, which usually develop rapidly.

Alterations in the NF2/LATS1/LATS2/YAP Pathway in Schwannomas.

Schwannomas are benign nerve sheath tumors composed of well-differentiated Schwann cells. Other than frequent NF2 (neurofibromatosis type 2) mutations (50%-60%), their molecular pathogenesis is not fully understood. LATS1 and LATS2 are downstream molecules of NF2 and are negative regulators of the yes-associated protein (YAP) oncogene in the Hippo signaling pathway.

Multiple Antenatal Dexamethasone Treatment Alters Brain Vessel Differentiation in Newborn Mouse Pups.

Antenatal steroid treatment decreases morbidity and mortality in premature infants through the maturation of lung tissue, which enables sufficient breathing performance. However, clinical and animal studies have shown that repeated doses of glucocorticoids such as dexamethasone and betamethasone lead to long-term adverse effects on brain development. Therefore, we established a mouse model for antenatal dexamethasone treatment to investigate the effects of dexamethasone on brain vessel differentiation towards the blood-brain barrier (BBB) phenotype, focusing on molecular marker analysis.