No abstract

BackgroundGlioblastomas are largely unresponsive to all available treatments and there is therefore an urgent need for novel therapeutics. Here we have probed the antineoplastic effects of a bacterial protein toxin, the cytotoxic necrotizing factor 1 (CNF1), in the syngenic GL261 glioma cell model. CNF1 produces a long-lasting activation of Rho GTPases, with consequent blockade of cytodieresis in proliferating cells and promotion of neuron health and plasticity.MethodsWe have tested the antiproliferative effects of CNF1 on GL261 cells and human glioma cells obtained from surgical specimens. For the in vivo experiments, we injected GL261 cells into the adult mouse visual cortex, and five days later we administered either a single intracerebral dose of CNF1 or vehicle. To compare CNF1 with a canonical antitumoral drug, we infused temozolomide (TMZ) via minipumps for 1 week in an additional animal group.ResultsIn culture, CNF1 was very effective in blocking proliferation of GL261 cells, leading them to multinucleation, senescence and death within 15 days. CNF1 had a similar cytotoxic effect in primary human glioma cells. CNF1 also inhibited motility of GL261 cells in a scratch-wound migration assay. Low dose (2 nM) CNF1 and continuous TMZ infusion significantly prolonged animal survival (median survival 35 days vs. 28 days in vehicle controls). Remarkably, increasing CNF1 concentration to 80 nM resulted in a dramatic enhancement of survival with no obvious toxicity. Indeed, 57% of the CNF1-treated animals survived up to 60 days following GL261 glioma cell transplant.ConclusionsThe activation of Rho GTPases by CNF1 represents a novel potential therapeutic strategy for the treatment of central nervous system tumors.

The microsurgical anatomy of cerebellar peduncles and their relationships with neighbouring fasciculi were investigated by using a fibre dissection technique. As the dissection progressed, photographs of each progressive layer were obtained and stereoscopic images were created using the 3D anaglyphic method. These findings provided the anatomical basis for a conceptual division of cerebellar peduncles into segments. The middle cerebellar peduncle (MCP) was divided into two segments: cisternal and intracerebellar segments. The inferior cerebellar peduncle (ICP) was divided into three segments: cisternal, ventricular and intracerebellar segments. The superior cerebellar peduncle (SCP) was divided into three segments: intracerebellar, intermediate and intrategmental segments. The fibre dissection technique disclosed a constant course of peduncular fibres inside the white core of the cerebellum. The pontocerebellar fibres of the MCP pass over and laterally to the bundles of the ICP and SCP. The centripetal fibres of the ICP wrap around the radiation of the SCP and the dentate nucleus, directed towards the cortex of the vermis. The centrifugal bundle of the SCP ascends towards the mesencephalon where it sinks passing below the fibres the lateral lemniscus. The knowledge gained by studying the intrinsic anatomy of the cerebellum is useful to accomplish appropriate surgical planning and, ultimately, to understand the repercussions of surgical procedures on the white matter tracts in this region.

Resection of at least one lesion seems to play a significant role in the management of selected patients with multicentric malignant gliomas. Multi-institutional studies on larger series are warranted to define how aggressively the patients with malignant multicentric gliomas should be treated.