In vitro and ex vivo evaluation of second-generation histone deacetylase inhibitors for the treatment of spinal muscular atrophy.

Among a panel of histone deacetylase (HDAC) inhibitors investigated, suberoylanilide hydroxamic acid (SAHA) evolved as a potent and non-toxic candidate drug for the treatment of spinal muscular atrophy (SMA), an alpha-motoneurone disorder caused by insufficient survival motor neuron (SMN) protein levels. SAHA increased SMN levels at low micromolar concentrations in several neuroectodermal tissues, including rat hippocampal brain slices and motoneurone-rich cell fractions, and its therapeutic capacity was confirmed using a novel human brain slice culture assay. SAHA activated survival motor neuron gene 2 (SMN2), the target gene for SMA therapy, and inhibited HDACs at submicromolar doses, providing evidence that SAHA is more efficient than the HDAC inhibitor valproic acid, which is under clinical investigation for SMA treatment.

Ex vivo therapy of malignant melanomas transplanted into organotypic brain slice cultures using inhibitors of histone deacetylases.

Disease progression in patients suffering from malignant melanomas is often determined by metastatic spreading into brain parenchyma. Systemic chemotherapy regimens are, therefore, mandatory for successful treatment. Most recently, inhibitors of histone deacetylases (HDACi) have been shown to significantly inhibit melanoma progression.

Experimental therapy of malignant gliomas using the inhibitor of histone deacetylase MS-275.

Inhibitors of histone deacetylases are promising compounds for the treatment of cancer but have not been systematically explored in malignant brain tumors. Here, we characterize the benzamide MS-275, a class I histone deacetylase inhibitor, as potent drug for experimental therapy of glioblastomas. Treatment of four glioma cell lines (U87MG, C6, F98, and SMA-560) with MS-275 significantly reduced cell growth in a concentration-dependent manner (IC(90), 3.

Molecular neuropathology of epilepsy-associated glioneuronal malformations.

Glioneuronal malformations (malformations of cortical development [MCD]) include focal cortical dysplasias (FCD) as well as highly differentiated glioneuronal tumors (i.e. gangliogliomas) and constitute frequent findings in patients with pharmacoresistent focal epilepsies.

Abundant hypermethylation of SOCS-1 in clinically silent pituitary adenomas.

Janus kinase (JAK)/signal transducers and activators of transcription (STAT) cascade are required for cytokines, growth factors, G-proteins and hormones (growth hormone and prolactin). Gatekeepers in this pathway are the suppressor of cytokine signalling (SOCS) family of proteins. Their expression level is epigenetically regulated by DNA methylation.

Mutational and immunohistochemical analysis of ezrin-, radixin-, moesin (ERM) molecules in epilepsy-associated glioneuronal lesions.

Glioneuronal lesions are frequently observed in biopsy specimens obtained from patients with pharmacoresistant epilepsies, comprising focal cortical dysplasias (FCD) and gangliogliomas. Recent findings point to the phosphoinositide 3-kinase (PI3K) pathway and tuberin/hamartin signaling cascade as being compromised in these lesions. Ezrin, radixin and moesin (ERM-/band-4.

Distinct allelic variants of TSC1 and TSC2 in epilepsy-associated cortical malformations without balloon cells.

Epilepsy-associated malformations of cortical development (MCDs) comprise a variety of dysplastic and neoplastic lesions of yet undetermined molecular pathology. Histopathologic similarities between MCDs and dysplastic brain lesions in the autosomal inherited neurocutaneous phacomatosis tuberous sclerosis (TSC), which affects the TSC1 and/or TSC2 genes, suggest common pathogenetic mechanisms. Previous studies revealed different alterations of TSC1 and TSC2 in epilepsy-associated malformations and glio-neuronal tumors despite histopathologic similarities.

Neuropathological spectrum of cortical dysplasia in children with severe focal epilepsies.

Cortical dysplasias comprise a variable spectrum of clinical, neuroradiological and histopathological findings. We report about a cohort of 25 pediatric patients (mean age 8.1+/-4.

Lessons from the bone marrow: how malignant glioma cells attract adult haematopoietic progenitor cells.

Stem and progenitor cells (PCs) of various lineages have become attractive vehicles to improve therapeutic gene delivery to cancers, notably glioblastoma. Here we report that adult human and murine haematopoietic PCs display a tropism for intracerebral gliomas but not for normal brain tissue in mice. Organotypic hippocampal slice culture and spheroid confrontation assays confirm a directed PC migration towards glioma cells ex vivo and in vitro.

Absence of immunoglobulin class switch in primary lymphomas of the central nervous system.

Primary lymphomas of the central nervous system (PCNSLs) were investigated for their capacity to perform further maturation steps. We studied a series of 11 PCNSLs derived from immunocompetent patients for immunoglobulin (Ig) class switch recombination (CSR) by performing reverse transcriptase-polymerase chain reaction (RT-PCR) for transcripts of Ig constant region gene segments (IGHC). This analysis revealed exclusive transcription of IgM and IgD mRNA in the absence of IgG, IgA, or IgE transcription.

Malignant glioma-induced neuronal cell death in an organotypic glioma invasion model. Technical note.

Rapid growth and diffuse brain infiltration are hallmarks of malignant gliomas. The underlying molecular pathomechanisms of these tumors, however, remain to be determined. The authors present a novel glioma invasion model that allows researchers to monitor consecutively tumor cell proliferation and migration in an organotypic brain environment.

Suberoylanilide hydroxamic acid (SAHA) has potent anti-glioma properties in vitro, ex vivo and in vivo.

Current treatment modalities for malignant gliomas do not allow long-term survival. Here, we identify suberoylanilide hydroxamic acid (SAHA), an inhibitor of histone deacetylases (HDAC), as an effective experimental anti-glioma agent. Administration of SAHA to various glioma cell lines obtained from human, rat and mouse inhibited tumour cell growth in a range of 1-10 microm.

Proton magnetic resonance spectroscopic imaging integrated into image-guided surgery: correlation to standard magnetic resonance imaging and tumor cell density.

Objective: In this study, we attempted to improve the delineation of the infiltration zone in gliomas using proton magnetic resonance spectroscopic imaging (1H MRSI). In conventional magnetic resonance imaging (MRI), the boundaries of gliomas sometimes are underestimated. 1H MRSI is a noninvasive tool that can be used to investigate the spatial distribution of metabolic changes in brain lesions.

Evidence for a clinically distinct new subtype of grade II astrocytomas in patients with long-term epilepsy.

Objective: The authors tested the hypothesis that among Grade II astrocytomas with a particularly long seizure history, a subgroup is hidden with a different prognosis and possibly histological characteristics. To do so, clinical and histological characteristics of two groups of World Health Organization Grade II astrocytoma patients were analyzed: the long-term epilepsy-associated tumor (LEAT) astrocytoma group, with a mean duration of 12.5 years of seizures (n = 19), and the ordinary astrocytomas (n = 87), with a mean length of seizure history of 1.

Analysis of chromosomal instability in focal cortical dysplasia of Taylor's balloon cell type.

Focal cortical dysplasias (FCD) represent a frequent finding in patients with chronic intractable epilepsy. Neuropathological hallmarks include localized dyslamination of the neocortex and neuronal heterotopias in white matter. Balloon cells, similar to those occurring in cortical tubers of patients with tuberous sclerosis (TSC) are observed in numerous patients.

Supratentorial gangliogliomas: histopathologic grading and tumor recurrence in 184 patients with a median follow-up of 8 years.

Background: Supratentorial gangliogliomas (GGs) are rare tumors of the central nervous system and are commonly associated with chronic seizures. To date, only case reports and small series of patients with short-term follow-up have been available for the assessment of the potential of GGs to recur and progress.

Methods: Data from 184 patients who underwent resection of GGs between 1988 and 2001 were available from the University of Bonn Epilepsy Surgery Center (Bonn, Germany).

CD34-immunoreactive balloon cells in cortical malformations.

Balloon cells are histopathological hallmarks of various cortical malformations, i.e., focal cortical dysplasia (Taylor's type, FCD IIb), hemimegalencephaly (HME) or cortical tubers (tuberous sclerosis, TSC).

MR imaging in the presurgical workup of patients with drug-resistant epilepsy.

Background And Purpose: Whether an epileptic lesion is detected with MR imaging depends on the quality of the images and the expertise of the reader. We analyzed the role of 1.5-T MR imaging in the presurgical evaluation of patients with drug-resistant epilepsy at one center.

Microtubule-associated protein-2 immunoreactivity: a useful tool in the differential diagnosis of low-grade neuroepithelial tumors.

Complex and variable morphological phenotypes pose a major challenge to the histopathological classification of neuroepithelial tumors. This applies in particular for low-grade gliomas and glio-neuronal tumors. Recently, we and others have identified microtubule-associated protein-2 (MAP2) as an immunohistochemical marker expressed in the majority of glial tumors.

Analysis of different types of resection for pediatric patients with temporal lobe epilepsy.

Objective: Resection strategies for the treatment of temporal lobe epilepsy (TLE) are a matter of discussion. Few data on the significance of resection type are available for pediatric patients with TLE.

Methods: Data for a series of 89 children who were surgically treated for TLE were analyzed.

An isomorphic subtype of long-term epilepsy-associated astrocytomas associated with benign prognosis.

The semi-benign nature of diffuse astrocytomas is characterized by an increased risk for tumor recurrence and malignant transformation. In patients with intractable seizures, however, length of history and clinical follow-up studies indicate a better prognosis of this tumor entity. Here, we present a clinico-neuropathological study of 19 patients with chronic seizures and diffuse astrocytomas.

Correlated stage- and subfield-associated hippocampal gene expression patterns in experimental and human temporal lobe epilepsy.

Epileptic activity evokes profound alterations of hippocampal organization and function. Genomic responses may reflect immediate consequences of excitatory stimulation as well as sustained molecular processes related to neuronal plasticity and structural remodeling. Using oligonucleotide microarrays with 8799 sequences, we determined subregional gene expression profiles in rats subjected to pilocarpine-induced epilepsy (U34A arrays, Affymetrix, Santa Clara, CA, USA; P < 0.

Functional network integration of embryonic stem cell-derived astrocytes in hippocampal slice cultures.

Embryonic stem (ES) cells provide attractive prospects for neural transplantation. So far, grafting strategies in the CNS have focused mainly on neuronal replacement. Employing a slice culture model, we found that ES cell-derived glial precursors (ESGPs) possess a remarkable capacity to integrate into the host glial network.

The spectrum of long-term epilepsy-associated tumors: long-term seizure and tumor outcome and neurosurgical aspects.

Purpose: To describe the histologic spectrum and clinical characteristics of patients with neuroepithelial tumors and drug-resistant epilepsy and to analyze clinical data and treatment related to seizure outcome and survival.

Methods: Data were analyzed from 207 consecutive patients with intractable epilepsy (aged 2-54 years), who between 1988 and 1999 had >or=50% resection of supratentorial, neuroepithelial tumors. Extent of resection was assessed on postoperative magnetic resonance imaging (MRI); seizure outcome was classified according to Engel's outcome scale; and follow-up data were prospectively updated.

Cellular pathology of amygdala neurons in human temporal lobe epilepsy.

The amygdala complex substantially contributes to the generation and propagation of focal seizures in patients suffering from temporal lobe epilepsy (TLE). A cellular substrate for increased excitability in the human amygdala, however, remains to be identified. Here, we analyzed the three-dimensional morphology of 264 neurons from different subregions of the amygdaloid complex obtained from 17 "en bloc" resected surgical specimens using intracellular Lucifer Yellow (LY) injection and confocal laser scanning microscopy.