A neurodevelopmental epigenetic programme mediated by SMARCD3-DAB1-Reelin signalling is hijacked to promote medulloblastoma metastasis.

How abnormal neurodevelopment relates to the tumour aggressiveness of medulloblastoma (MB), the most common type of embryonal tumour, remains elusive. Here we uncover a neurodevelopmental epigenomic programme that is hijacked to induce MB metastatic dissemination. Unsupervised analyses of integrated publicly available datasets with our newly generated data reveal that SMARCD3 (also known as BAF60C) regulates Disabled 1 (DAB1)-mediated Reelin signalling in Purkinje cell migration and MB metastasis by orchestrating cis-regulatory elements at the DAB1 locus.

Radiosurgery to the spinal dorsal root ganglion induces fibrosis and inhibits satellite glial cell activation while preserving axonal neurotransmission.

Objective: Stereotactic radiosurgery (SRS) has been used to treat trigeminal neuralgia by targeting the cisternal segment of the trigeminal nerve, which in turn triggers changes in the gasserian ganglion. In the lumbar spine, the dorsal root ganglion (DRG) is responsible for transmitting pain sensitivity and is involved in the pathogenesis of peripheral neuropathic pain. Therefore, radiosurgery to the DRG might improve chronic peripheral pain.

Evaluation of Clinical and Histologic Effects of High-Dose Radiosurgery on Rat Dorsal Root Ganglion.

Background: Stereotactic radiosurgery (SRS) is an effective technique to create lesions of the trigeminal nerve to treat refractory trigeminal neuralgia. In the lumbar spine, the dorsal root ganglion (DRG) contains the body of the sensory neurons responsible for pain sensitivity. Neuromodulation of the DRG might therefore improve chronic peripheral pain.

Toward Improving Safety in Neurosurgery with an Active Handheld Instrument.

Microsurgical procedures, such as petroclival meningioma resection, require careful surgical actions in order to remove tumor tissue, while avoiding brain and vessel damaging. Such procedures are currently performed under microscope magnification. Robotic tools are emerging in order to filter surgeons' unintended movements and prevent tools from entering forbidden regions such as vascular structures.

The influence of suturectomy on age-related changes in cerebral blood flow in rabbits with familial bicoronal suture craniosynostosis: A quantitative analysis.

Background: Coronal suture synostosis is a condition which can have deleterious physical and cognitive sequelae in humans if not corrected. A well-established animal model has previously demonstrated disruptions in intracranial pressure and developmental abnormalities in rabbits with congenital craniosynostosis compared to wild type rabbits.

Objective: The current study aimed to measure the cerebral blood flow (CBF) in developing rabbits with craniosynostosis who underwent suturectomy compared to those with no intervention and compared to wild type rabbits.

Tip Design for Safety of Steerable Needles for Robot-Controlled Brain Insertion.

Background: Current practice in neurosurgical needle insertion is limited by the straight trajectories inherent with rigid probes. One technique allowing curvilinear trajectories involves flexible bevel-tipped needles, which bend during insertion due to their asymmetry. In the brain, safety will require avoidance of the sharp tips often used in laboratory studies, in favor of a more rounded profile.

Human Connectome-Based Tractographic Atlas of the Brainstem Connections and Surgical Approaches.

Background: The brainstem is one of the most challenging areas for the neurosurgeon because of the limited space between gray matter nuclei and white matter pathways. Diffusion tensor imaging-based tractography has been used to study the brainstem structure, but the angular and spatial resolution could be improved further with advanced diffusion magnetic resonance imaging (MRI).

Objective: To construct a high-angular/spatial resolution, wide-population-based, comprehensive tractography atlas that presents an anatomical review of the surgical approaches to the brainstem.

The influence of surgical correction on white matter microstructural integrity in rabbits with familial coronal suture craniosynostosis.

OBJECT Craniosynostosis is a condition in which one or more of the calvarial sutures fuses prematurely. In addition to the cosmetic ramifications attributable to premature suture fusion, aberrations in neurophysiological parameters are seen, which may result in more significant damage. This work examines the microstructural integrity of white matter, using diffusion tensor imaging (DTI) in a homogeneous strain of rabbits with simple, familial coronal suture synostosis before and after surgical correction.

Traumatic brain injury alters long-term hippocampal neuron morphology in juvenile, but not immature, rats.

Purpose: Pediatric traumatic brain injury (TBI) represents a prominent yet understudied medical condition that can profoundly impact brain development. As the juvenile injured brain matures in the wake of neuropathological cascades during potentially critical periods, circuit alterations may explain neurological consequences, including cognitive deficits. We hypothesize that experimental brain injury in juvenile rats, with behavioral deficits that resolve, will lead to quantifiable structural changes in hippocampal neurons at chronic time points post-injury.

Premetastatic soil and prevention of breast cancer brain metastasis.

Background: As therapies for systemic cancer improve and patients survive longer, the risk for brain metastases increases. We evaluated whether immune mechanisms are involved in the development of brain metastasis.

Methods: We conducted our studies using BALB/c mice bearing syngeneic 4T1 mammary adenocarcinoma cells in the mammary gland.

Morris water maze function and histologic characterization of two age-at-injury experimental models of controlled cortical impact in the immature rat.

Purpose: Controlled cortical impact (CCI) is commonly used in adult animals to study focal traumatic brain injury (TBI). Our study aims to further study injury mechanisms in children and variable models of pathology in the developing brain.

Methods: Develop a focal injury model of experimental TBI in the immature, postnatal days (PND) 7 and 17 rats that underwent a CCI at varying depths of deflection, 1.

Dipyrone inhibits neuronal cell death and diminishes hypoxic/ischemic brain injury.

Background: Dipyrone is an analgesic and antipyretic drug usually prescribed for patients with inflammatory conditions. We recently identified dipyrone as an antiapoptotic agent by screening a library of 1040 compounds for their ability to inhibit cytochrome c release from isolated mitochondria.

Objective: We investigated the potential neuroprotective properties of dipyrone in cerebral ischemia.

Injection parameters affect cell viability and implant volumes in automated cell delivery for the brain.

The technique of central nervous system cell implantation can affect the outcome of preclinical or clinical studies. Our goal was to evaluate the impact of various injection parameters that may be of consequence during the delivery of solute-suspended cells. These parameters included (1) the type and concentration of cells used for implantation, (2) the rate at which cells are injected (flow rate), (3) the acceleration of the delivery device, (4) the period of time between cell loading and injection into the CNS (delay), and (5) the length and gauge of the needle used to deliver the cells.

COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells.

Epidemiologic studies have highlighted associations between the regular use of nonsteroidal anti-inflammatory drugs (NSAID) and reduced glioma risks in humans. Most NSAIDs function as COX-2 inhibitors that prevent production of prostaglandin E₂ (PGE₂). Because PGE₂ induces expansion of myeloid-derived suppressor cells (MDSC), we hypothesized that COX-2 blockade would suppress gliomagenesis by inhibiting MDSC development and accumulation in the tumor microenvironment (TME).

Manual vs automated delivery of cells for transplantation: accuracy, reproducibility, and impact on viability.

Background: Cellular transplantation holds promise for the management of a variety of neurological disorders. However, there is great variability in cell type, preparation methods, and implantation technique, which are crucial to clinical outcomes.

Objective: We compared manual injection with automated injection using a prototype device to determine the possible value of a mechanized delivery system.

Resveratrol attenuates behavioral impairments and reduces cortical and hippocampal loss in a rat controlled cortical impact model of traumatic brain injury.

Resveratrol (3,5,4'-trihydroxystilbene) is a plant-derived small molecule that is protective against multiple neurological and systemic insults. To date, no studies have explored the potential for resveratrol to provide behavioral protection in adult animals in the setting of traumatic brain injury (TBI). Using 50 male Sprague-Dawley rats, we employed the controlled cortical impact (CCI) model to ascertain whether post-injury administration of resveratrol would reduce the severity of the well-described cognitive and motor deficits associated with the model.

Flumazenil administration attenuates cognitive impairment in immature rats after controlled cortical impact.

Evidence suggests that the gamma-aminobutyric acid (GABA)ergic system may be involved in cognitive dysfunction following traumatic brain injury (TBI). We investigated the effect of flumazenil treatment, a benzodiazepine antagonist approved by the U.S.

Cellular transplantation for the nervous system: impact of time after preparation on cell viability and survival.

Object: Cell transplantation has shown promise for the treatment of various neurological disorders, but the factors that influence cell survival and integration following transplantation are poorly understood. In fact, little is known regarding how simple but potentially critical variables, including the method of cellular preparation and administration, might affect transplant success. The goal of the present study was to determine the impact of time between tissue preparation and implantation on cellular viability.

Identification of ATP citrate lyase as a positive regulator of glycolytic function in glioblastomas.

Glioblastomas, the most malignant type of glioma, are more glycolytic than normal brain tissue. Robust migration of glioblastoma cells has been previously demonstrated under glycolytic conditions and their pseudopodia contain increased glycolytic and decreased mitochondrial enzymes. Glycolysis is suppressed by metabolic acids, including citric acid which is excluded from mitochondria during hypoxia.

Age-related peridural hyperemia in craniosynostotic rabbits.

Objective: Craniosynostosis is the premature fusion of the calvarial sutures and is associated with aesthetic impairment and secondary damage to brain growth. Associated neurological injuries can result from increased intracranial pressure (ICP) and abnormal cerebral blood flow (CBF). Arterial spin-labeling (ASL) MRI was used to assess regional CBF in developing rabbits with early-onset coronal suture synostosis (EOCS) and age-matched wild-type controls (WT).

Therapeutic efficacy of a herpes simplex virus with radiation or temozolomide for intracranial glioblastoma after convection-enhanced delivery.

The herpes simplex virus-1 (HSV-1)-infected cell protein 0 (ICP0) is an E3 ubiquitin ligase implicated in cell cycle arrest and DNA repair inhibition. Convection-enhanced delivery (CED) of either the replication-defective, ICP0-producing HSV-1 mutant, d106, or the recombinant d109, devoid of all viral genome expression, was performed to determine the in vivo efficacy of ICP0 in combination with ionizing radiation (IR) or systemic temozolomide (TMZ) in the treatment of glioblastoma multiforme (GBM). Intracranial U87-MG xenografts were established in athymic nude mice.

Toll like receptor-3 ligand poly-ICLC promotes the efficacy of peripheral vaccinations with tumor antigen-derived peptide epitopes in murine CNS tumor models.

Background: Toll-like receptor (TLR)3 ligands serve as natural inducers of pro-inflammatory cytokines capable of promoting Type-1 adaptive immunity, and TLR3 is abundantly expressed by cells within the central nervous system (CNS). To improve the efficacy of vaccine strategies directed against CNS tumors, we evaluated whether administration of a TLR3 ligand, polyinosinic-polycytidylic (poly-IC) stabilized with poly-lysine and carboxymethylcellulose (poly-ICLC) would enhance the anti-CNS tumor effectiveness of tumor peptide-based vaccinations.

Methods: C57BL/6 mice bearing syngeneic CNS GL261 glioma or M05 melanoma received subcutaneous (s.

Testing causal mechanisms of nonsyndromic craniosynostosis using path analysis of cranial contents in rabbits with uncorrected craniosynostosis.

Objective: Various causal mechanisms of familial nonsyndromic craniosynostosis have been presented. One hypothesis suggests that overproduction of bone at the suture is the primary origin of craniosynostosis, which affects brain and cranial growth secondarily through altered intracranial pressure (Primary Suture Fusion Model). Other hypotheses suggest that decreased cranial base growth or abnormal brain growth are the primary cause of craniosynostosis (Cranial Base, Brain Parenchyma Models, respectively).

Delivery of dendritic cells engineered to secrete IFN-alpha into central nervous system tumors enhances the efficacy of peripheral tumor cell vaccines: dependence on apoptotic pathways.

We tested whether modulation of the CNS-tumor microenvironment by delivery of IFN-alpha-transduced dendritic cells (DCs: DC-IFN-alpha) would enhance the therapeutic efficacy of peripheral vaccinations with cytokine-gene transduced tumor cells. Mice bearing intracranial GL261 glioma or MCA205 sarcoma received peripheral immunizations with corresponding irradiated tumor cells engineered to express IL-4 or GM-CSFs, respectively, as well as intratumoral delivery of DC-IFN-alpha. This regimen prolonged survival of the animals and induced tumor-specific CTLs that expressed TRAIL, which in concert with perforin and Fas ligand (FasL) was involved in the tumor-specific CTL activity of these cells.

Epidermal growth factor receptor-transfected bone marrow stromal cells exhibit enhanced migratory response and therapeutic potential against murine brain tumors.

We have created a novel cellular vehicle for gene therapy of malignant gliomas by transfection of murine bone marrow stroma cells (MSCs) with a cDNA encoding epidermal growth factor receptor (EGFR). These cells (EGFR-MSCs) demonstrate enhanced migratory responses toward glioma-conditioned media in comparison to primary MSCs in vitro. Enhanced migration of EGFR-MSC was at least partially dependent on EGF-EGFR, PI3-, MAP kinase kinase, and MAP kinases, protein kinase C, and actin polymerization.