A miR-297/hypoxia/DGK-α axis regulating glioblastoma survival.

Background: Despite advances in the treatment of the most aggressive form of brain tumor, glioblastoma, patient prognosis remains disappointing. This failure in treatment has been attributed to dysregulated oncogenic pathways, as observed in other tumors. We and others have suggested the use of microRNAs (miRs) as therapeutic tools able to target multiple pathways in glioblastoma.

Hepatocyte growth factor sensitizes brain tumors to c-MET kinase inhibition.

Purpose: The receptor tyrosine kinase (RTK) c-MET and its ligand hepatocyte growth factor (HGF) are deregulated and promote malignancy in cancer and brain tumors. Consequently, clinically applicable c-MET inhibitors have been developed. The purpose of this study was to investigate the not-well-known molecular determinants that predict responsiveness to c-MET inhibitors and to explore new strategies for improving inhibitor efficacy in brain tumors.

Epidermal growth factor receptor-mediated regulation of urokinase plasminogen activator expression and glioblastoma invasion via C-SRC/MAPK/AP-1 signaling pathways.

One of the major pathophysiological features of malignant astrocytomas is their ability to infiltrate surrounding brain tissue. The epidermal growth factor receptor (EGFR) and proteases are known to be overexpressed in glioblastomas (GBMs), but the interaction between the activation of the EGFR and urokinase plasminogen activator (uPA) in promoting astrocytic tumor invasion has not been fully elucidated. Here, we characterized the signal transduction pathway(s) by which EGF regulates uPA expression and promotes astrocytoma invasion.

An extensive invasive intracranial human glioblastoma xenograft model: role of high level matrix metalloproteinase 9.

The lack of an intracranial human glioma model that recapitulates the extensive invasive and hypervascular features of glioblastoma (GBM) is a major hurdle for testing novel therapeutic approaches against GBM and studying the mechanism of GBM invasive growth. We characterized a high matrix metalloproteinase-9 (MMP-9) expressing U1242 MG intracranial xenograft mouse model that exhibited extensive individual cells and cell clusters in a perivascular and subpial cellular infiltrative pattern, geographic necrosis and infiltrating tumor-induced vascular proliferation closely resembling the human GBM phenotype. MMP-9 silencing cells with short hairpin RNA dramatically blocked the cellular infiltrative pattern, hypervascularity, and cell proliferation in vivo, and decreased cell invasion, colony formation, and cell motility in vitro, indicating that a high level of MMP-9 plays an essential role in extensive infiltration and hypervascularity in the xenograft model.

An orally bioavailable c-Met kinase inhibitor potently inhibits brain tumor malignancy and growth.

The receptor tyrosine kinase, c-Met and its ligand hepatocyte growth factor (HGF) are important regulators of malignancy in human cancer including brain tumors. c-Met is frequently activated in brain tumors and has emerged as a promising target for molecular therapies. Recently, an orally bioavailable small molecule kinase inhibitor of c-Met (SGX523) was developed by SGX Pharmaceuticals.

The neuronal microRNA miR-326 acts in a feedback loop with notch and has therapeutic potential against brain tumors.

Little is known of microRNA interactions with cellular pathways. Few reports have associated microRNAs with the Notch pathway, which plays key roles in nervous system development and in brain tumors. We previously implicated the Notch pathway in gliomas, the most common and aggressive brain tumors.

MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes.

MicroRNA-34a (miR-34a) is a transcriptional target of p53 that is down-regulated in some cancer cell lines. We studied the expression, targets, and functional effects of miR-34a in brain tumor cells and human gliomas. Transfection of miR-34a down-regulated c-Met in human glioma and medulloblastoma cells and Notch-1, Notch-2, and CDK6 protein expressions in glioma cells.

ADAM-10-mediated N-cadherin cleavage is protein kinase C-alpha dependent and promotes glioblastoma cell migration.

MMPs (matrix metalloproteinases) and the related "a disintegrin and metalloproteinases" (ADAMs) promote tumorigenesis by cleaving extracellular matrix and protein substrates, including N-cadherin. Although N-cadherin is thought to regulate cell adhesion, migration, and invasion, its role has not been characterized in glioblastomas (GBMs). In this study, we investigated the expression and function of posttranslational N-cadherin cleavage in GBM cells as well as its regulation by protein kinase C (PKC).

Interactions between PTEN and the c-Met pathway in glioblastoma and implications for therapy.

The tyrosine kinase receptor c-Met and its ligand hepatocyte growth factor (HGF) are frequently overexpressed and the tumor suppressor PTEN is often mutated in glioblastoma. Because PTEN can interact with c-Met-dependent signaling, we studied the effects of PTEN on c-Met-induced malignancy and associated molecular events and assessed the potential therapeutic value of combining PTEN restoration approaches with HGF/c-Met inhibition. We studied the effects of c-Met activation on cell proliferation, cell cycle progression, cell migration, cell invasion, and associated molecular events in the settings of restored or inhibited PTEN expression in glioblastoma cells.

H-Ras increases urokinase expression and cell invasion in genetically modified human astrocytes through Ras/Raf/MEK signaling pathway.

Previous study reported that the activation of Ras pathway cooperated with E6/E7-mediated inactivation of p53/pRb to transform immortalized normal human astrocytes (NHA/hTERT) into intracranial tumors strongly resembling human astrocytomas. The mechanism of how H-Ras contributes to astrocytoma formation is unclear. Using genetically modified NHA cells (E6/E7/hTERT and E6/E7/hTERT/Ras cells) as models, we investigated the mechanism of Ras-induced tumorigenesis.

Protein kinase C-alpha-mediated regulation of low-density lipoprotein receptor related protein and urokinase increases astrocytoma invasion.

Aggressive and infiltrative invasion is one of the hallmarks of glioblastoma. Low-density lipoprotein receptor-related protein (LRP) is expressed by glioblastoma, but the role of this receptor in astrocytic tumor invasion remains poorly understood. We show that activation of protein kinase C-alpha (PKC-alpha) phosphorylated and down-regulated LRP expression.

Rho kinase and matrix metalloproteinase inhibitors cooperate to inhibit angiogenesis and growth of human prostate cancer xenotransplants.

The purpose of this study was to determine the effects of inhibitors of Rho kinase (ROK) and matrix metalloproteinases (MMPs) on angiogenesis and tumor growth and to evaluate ROK activity in human prostate cancer PC3 cells and endothelial cells (HUVECs). Vacuolation by endothelial cells and lumen formation, the earliest detectable stages of angiogenesis, were inhibited by the ROK inhibitor Wf-536. Combining Wf-536 with the MMP inhibitor Marimastat greatly enhanced in vitro inhibition of endothelial vacuolation, lumen and cord formation, and VEGF- and HGF-stimulated endothelial sprout formation from aorta.

Ultrastructural changes of neuronal mitochondria after transient and permanent cerebral ischemia.

Background And Purpose: Mitochondrial swelling is one of the most striking and initial ultrastructural changes after acute brain ischemia. The purpose of the present study was to examine the role of reperfusion of the cerebral cortex after transient focal cerebral ischemia on neuronal mitochondrial damage.

Methods: Male Sprague-Dawley rats (n=16) were subjected to either temporary or permanent occlusion of the middle cerebral artery and bilateral carotid arteries.

Cerebral ischemia-reperfusion injury: a novel therapeutic approach with TAK-218.

The goal of the present study was to evaluate the potential neuroprotective effect of TAK-218 in an in vivo rat focal cerebral ischemia/reperfusion model. TAK-218 is a novel compound with multiple antiischemic properties, including suppression of aberrant dopamine release, modulation of sodium channels, and inhibition of lipid peroxidation. The study was a blinded, randomized, placebo-controlled study of TAK-218 in a three-vessel focal ischemic rat model.

Human RhoA/RhoGDI complex expressed in yeast: GTP exchange is sufficient for translocation of RhoA to liposomes.

The human small GTPase, RhoA, expressed in Saccharomyces cerevisiae is post-translationally processed and, when co-expressed with its cytosolic inhibitory protein, RhoGDI, spontaneously forms a heterodimer in vivo. The RhoA/RhoGDI complex, purified to greater than 98% at high yield from the yeast cytosolic fraction, could be stoichiometrically ADP-ribosylated by Clostridium botulinum C3 exoenzyme, contained stoichiometric GDP, and could be nucleotide exchanged fully with [3H]GDP or partially with GTP in the presence of submicromolar Mg2+. The GTP-RhoA/RhoGDI complex hydrolyzed GTP with a rate constant of 4.

Optimizing accuracy in magnetic resonance imaging-guided stereotaxis: a technique with validation based on the anterior commissure-posterior commissure line.

Object: Some of the earliest successful frame-based stereotactic interventions directed toward the thalamus and basal ganglia depended on identifying the anterior commissure (AC) and posterior commissure (PC) in a sagittal ventriculogram and defining the intercommissural line that connects them in the midsagittal plane. The AC-PC line became the essential landmark for the localization of neuroanatomical targets in the basal ganglia and diencephalon and for relating them to stereotactic atlases. Stereotactic/functional neurosurgery has come to rely increasingly on magnetic resonance (MR) imaging guidance, and methods for accurately determining the AC-PC line on MR imaging are being developed.

Sutureless repair of major intracranial vessels with the Sundt clip-graft: technical note.

Major intracranial vessels can be damaged during tumor resection. With the availability of refined microvascular techniques, direct repair or by-pass of the damaged segment is possible. These methods, however, often require temporary occlusion of the offending vessel, can result in a less than optimal angiographic result, and are difficult to perform in a deep field.

Acquired lumbar stenosis: topic review and a case series.

Stenosis of the central and lateral lumbar vertebral canal can be congenital or acquired; the latter is most often caused by a degenerative process. The associated neurogenic claudication and/or radiculopathic symptom complexes are thought to result from compression of the cauda equina and lumbosacral nerve roots by hypertrophy of or encroachment by any combination of the following: canal walls, ligamenta flava, intervertebral discs, posterior longitudinal ligament, or epidural fat. The authors' technique for the treatment of lumbar stenosis involves extensive unilateral decompression with undercutting of the spinous process and obviates the need for instrumentation by using a contralateral autologous bone fusion.

Recovery of useful hearing after posterior fossa surgery: the role of otoacoustic emissions: case report.

Objective And Importance: Hearing preservation has become an important issue in surgical procedures involving the cerebellopontine angle (CPA). Although several prognostic factors for hearing preservation in patients with "useful" preoperative hearing have been described, it is difficult to predict which patients have the potential for hearing preservation or recovery. Otoacoustic emission measurement is a new technique that allows recording of sounds produced by the cochlear outer hair cells as a normal byproduct of the receptor process and can be used to assess cochlear involvement in patients with hearing loss.

One century after the description of the "sign": Joseph Babinski and his contribution to neurosurgery.

One hundred years ago, in 1896, Joseph Babinski published a preliminary report on "réflexe cutané plantaire" (cutaneous plantar reflex), which became widely known as the Babinski sign. However, Babinski did not view the description of the sign as his major achievement. Instead, he considered his greatest contribution to medicine to be his having ".

Utilization of type I collagen gel, demineralized bone matrix, and bone morphogenetic protein-2 to enhance autologous bone lumbar spinal fusion.

Autologous bone grafts are currently considered "gold standard" material for achieving long-term spinal arthrodesis. The present study was performed to determine whether demineralized bone matrix (DBM), type I collagen gels, or bone morphogenetic protein-2 (BMP-2) can improve autologous bone spinal fusions. Using a unilateral decompression-contralateral fusion technique in dogs, each of these materials was added to an autologous bone graft.

Molecular methods of enhancing lumbar spine fusion.

Objective: An optimal method for spinal fusion would induce rapid growth of bone via an osteoconductive and osteoinductive implant. This study examines the spinal fusion enhancement potential of some osteoconductive and osteoinductive biomaterials.

Methods: Four similar canines received unilateral posterolateral fusions on the left side at T13-L1 and L4-L5 and on the right side at L2-L3 and L6-L7.

Treatment of lumbar spinal stenosis by extensive unilateral decompression and contralateral autologous bone fusion: operative technique and results.

A new surgical technique for the treatment of lumbar spinal stenosis features extensive unilateral decompression with undercutting of the spinous process and, to preserve stability, uses contralateral autologous bone fusion of the spinous processes, laminae, and facets. The operation was performed in 29 patients over a 19-month period ending in December of 1991. All individuals had been unresponsive to conservative treatment and presented with low-back pain in addition to signs and symptoms consistent with neurogenic claudication or radiculopathy.

Acquired lumbar spinal stenosis.

Based on the individual clinical presentation and radiographic findings, an operation that completely decompresses the neural elements in the spinal canal and neural foramina followed by posterior, posterolateral, or interbody fusion, with or without instrumentation should be the procedure of choice in the future. The introduction of pharmacological agents to decrease scarring around the decompressed nerve roots will also increase the number of successful procedures. It must be stressed, however, that any new operative technique must be tested in a rigorous fashion, ideally with a prospective randomized clinical trial.