Sox11 expression in astrocytic gliomas: correlation with nestin/c-Met/IDH1-R132H expression phenotypes, p-Stat-3 and survival.

BACKGROUND: Sox11 is a transcription factor expressed in foetal and neoplastic brain tissue, including gliomas. It has been shown to suppress the tumourigenicity of glioma stem cells in vivo, thereby being hypothesised to function as a tumour suppressor. METHODS: We investigated the expression of Sox11 in 132 diffuse astrocytomas in relation to the regulator cell marker nestin, c-Met and IDH1-R132H, which have shown to be differentially expressed among the molecular subgroups of malignant gliomas, as well as to an inducer of astrocytic differentiation, that is, signal transducer and activator of transcription (p-STAT-3), clinicopathological features and survival. RESULTS: Sox11 immunoreactivity was identified in all tumours irrespective of grade, but being correlated with p-STAT-3. Three out of seven cases showed partial Sox11 promoter methylation. In >50% of our cases neoplastic cells coexpressed Sox11 and nestin, a finding further confirmed in primary glioblastoma cell cultures. Furthermore, nestin, c-Met and IDH1-R132H expression differed among grade categories. Cluster analysis identified four groups of patients according to c-Met, nestin and IDH1-R132H expression. The c-Met/nestin high-expressor group displayed a higher Sox11 expression. Sox11 expression was an indicator of favourable prognosis in glioblastomas, which remained in multivariate analysis and validated in an independent set of 72 cases. The c-Met/nestin high-expressor group was marginally with shorter survival in univariate analysis. CONCLUSIONS: We highlight the importance of Sox11 expression as a favourable prognosticator in glioblastomas. c-Met/nestin/IDH1-R132H expression phenotypes recapitulate the molecular subgroups of malignant glioma.

Connections of the basal ganglia with the limbic system: implications for neuromodulation therapies of anxiety and affective disorders.

The basal ganglia are best known for their role in motor planning and execution. However, it is currently widely accepted that they are also involved in cognitive and emotional behaviors. Parts of the basal ganglia play a key role in reward and reinforcement, addictive behaviors and habit formation. Pathophysiological processes underlying psychiatric disorders such as depression, obsessive compulsive disorder and even schizophrenia involve the basal ganglia and their connections to many other structures and particularly to the prefrontal cortex and the limbic system. In this article, we aim, on the basis of current research, to describe in a succinct manner the most important connections of the basal ganglia with the limbic system which are relevant to normal behaviors but also to psychiatric disorders. Currently, we possess sufficiently powerful tools that enable us to modulate brain networks such as cortex stimulation (CS) or deep brain stimulation (DBS). Notably, neuromodulation of basal ganglia function for the treatment of movement disorders has become a standard practice, which provides insights into the psychiatric problems that occur in patients with movement disorders. It is clear that a sound understanding of the currently available knowledge on the circuits connecting the basal ganglia with the limbic system will provide the theoretical platform that will allow precise, selective and beneficial neuromodulatory interventions for refractory psychiatric disorders.

Intrathecal baclofen in current neuromodulatory practice: established indications and emerging applications.

Intrathecal baclofen (ITB) has evolved into a standard treatment for severe spasticity of both spinal and cerebral origin. The accumulated promising data from reported series of patients receiving ITB therapy together with the fact that spastic hypertonia commonly coexists with other neurological disorders have constituted a solid basis for offering this kind of treatment to patients suffering from other movement disorders. These include motor disorders such as dystonia, amyotrophic lateral sclerosis, status dystonicus, Hallervorden-Spatz disease, Freidreich's ataxia, "stiff-man" syndrome, but also vegetative states after revere brain trauma, anoxic encephalopathy or other pathology and more recently, various chronic pain syndromes. In this article, on the basis of the established applications of ITB therapy, we review the important emerging indications of this rewarding neuromodulation method and attempt to identify its future potential beneficial role in other chronic and otherwise refractory neurological disorders.

Skeletal growth factor involvement in the regulation of fracture healing process.

Skeletal growth factors are peptides that serve as signalling agents for living cells, thereby participating in the autocrine, paracrine, intracrine and endocrine bioregulation of tissues and organs in human physiology. Growth factors elicit their cellular actions after binding to specific receptors, which are large transmembrane proteins located on target cells. These receptors relay signals via specific intracellular signal transduction pathways capable of regulating gene transcription, thereby modifying cell proliferation, cell function, cell differentiation and apoptosis. Notably, growth factors and their specific receptors are expressed in and around a bone fracture repair site, suggesting strongly that they play a significant role in the physio/pathology of fracture healing. Conceivably, fine adjustments of specific growth factor activity during the different stages of the fracture healing process can serve as potential therapeutic targets, enhancing bone repair capacity and reducing irregularities of the healing process.

Two distinct mechanisms of nitric oxide-mediated neuronal cell death show thiol dependency.

To better understand the mechanism(s) underlying nitric oxide (. NO)-mediated toxicity, in the presence and absence of concomitant oxidant exposure, postmitotic terminally differentiated NT2N cells, which are incapable of producing. NO, were exposed to PAPA-NONOate (PAPA/NO) and 3-morpholinosydnonimine (SIN-1). Exposure to SIN-1, which generated peroxynitrite in the range of 25-750 nM/min, produced a concentration- and time-dependent delayed cell death. In contrast, a critical threshold concentration (>440 nM/min) was required for. NO to produce significant cell injury. Examination of cells by electron microscopy shows a largely necrotic injury after peroxynitrite exposure but mainly apoptotic-like morphology after. NO exposure. Cellular levels of reduced thiols correlated with cell death, and pretreatment with N-acetylcysteine (NAC) fully protected from cell death in either PAPA/NO or SIN-1 exposure. NAC given within the first 3 h posttreatment further delayed cell death and increased the intracellular thiol level in SIN-1 but not. NO-exposed cells. Cell injury from. NO was independent of cGMP, caspases, and superoxide or peroxynitrite formation. Overall, exposure of non-. NO-producing cells to. NO or peroxynitrite results in delayed cell death, which, although occurring by different mechanisms, appears to be mediated by the loss of intracellular redox balance.