A Small-Molecule Tankyrase Inhibitor Reduces Glioma Stem Cell Proliferation and Sphere Formation.

Evidence suggests that the growth and therapeutic resistance of glioblastoma (GBM) may be enabled by a population of glioma stem cells (GSCs) that are regulated by typical stem cell pathways, including the WNT/ß-catenin signaling pathway. We wanted to explore the effect of treating GSCs with a small-molecule inhibitor of tankyrase, G007-LK, which has been shown to be a potent modulator of the WNT/ß-catenin and Hippo pathways in colon cancer. Four primary GSC cultures and two primary adult neural stem cell cultures were treated with G007-LK and subsequently evaluated through the measurement of growth characteristics, as well as the expression of WNT/ß-catenin and Hippo signaling pathway-related proteins and genes. Treatment with G007-LK decreased in vitro proliferation and sphere formation in all four primary GSC cultures in a dose-dependent manner. G007-LK treatment altered the expression of key downstream WNT/ß-catenin and Hippo signaling pathway-related proteins and genes. Finally, cotreatment with the established GBM chemotherapeutic compound temozolomide (TMZ) led to an additive reduction in sphere formation, suggesting that WNT/ß-catenin signaling may contribute to TMZ resistance. These observations suggest that tankyrase inhibition may serve as a supplement to current GBM therapy, although more work is needed to determine the exact downstream mechanisms involved.

The impact of blood ethanol concentration on the classification of head injury severity in traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is classified into mild, moderate and severe, based on the Glasgow Coma Score (GCS). However, TBI patients are often influenced by ethanol, which in itself can attenuate the level of consciousness. This study investigated the effect of ethanol on the GCS group classification in TBI patients. METHODS: The Oslo University Hospital trauma database was searched for all patients admitted with a head injury where the blood ethanol concentration (BEC) had been measured (n = 1004). The effect of BEC on GCS groups was analysed using multivariate ordinal logistic regression. RESULTS: This study identified 546, 142 and 316 patients in the mild, moderate and severe groups, respectively. Increasing BEC by 1 g kg(-1) and pre-hospital intubation had OR = 1.34 and 16.34 for being in a more severe GCS group, respectively. Increasing head abbreviated injury scale (head-AIS) was significantly associated with being in a more severe GCS group. The modelled probability of detecting a head-AIS of 4 or 5 in a patient with BEC of 2.0 g kg(-1) was 20%, 38% and 65% in the mild, moderate and severe groups, respectively. CONCLUSIONS: Increasing BEC was associated with increasing odds of being in a more severe GCS group. However, because the modelled probability of significant brain injury was high in patients with high levels of BEC, a reduced level of consciousness in intoxicated patients mandates further radiological investigations.

A comparative study of the structural organization of spheres derived from the adult human subventricular zone and glioblastoma biopsies.

Sphere forming assays have been useful to enrich for stem like cells in a range of tumors. The robustness of this system contrasts the difficulties in defining a stem cell population based on cell surface markers. We have undertaken a study to describe the cellular and organizational composition of tumorspheres, directly comparing these to neurospheres derived from the adult human subventricular zone (SVZ). Primary cell cultures from brain tumors were found to contain variable fractions of cells positive for tumor stem cell markers (CD133 (2-93%)/SSEA1 (3-15%)/CXCR4 (1-72%)). All cultures produced tumors upon xenografting. Tumorspheres contained a heterogeneous population of cells, but were structurally organized with stem cell markers present at the core of spheres, with markers of more mature glial progenitors and astrocytes at more peripheral location. Ultrastructural studies showed that tumorspheres contained a higher fraction of electron dense cells in the core than the periphery (36% and 19%, respectively). Neurospheres also contained a heterogeneous cell population, but did not have an organization similar to tumorspheres. Although tumorspheres clearly display irregular and neoplastic cells, they establish an organized structure with an outward gradient of differentiation. We suggest that this organization is central in maintaining the tumor stem cell pool.

Brain tumor stem cells maintain overall phenotype and tumorigenicity after in vitro culturing in serum-free conditions.

Traditional in vitro culturing of tumor cells has been shown to induce changes so that cultures no longer represent the tumor of origin. Serum-free culturing conditions are used in a variety of cancers to propagate stem-like cells in vitro. Limited reports, however, exist on the effects of such propagation. We have compared cells from brain tumor biopsies cultivated under serum-free conditions at passages 2 and 10 to describe the effects of in vitro culturing. We were able to establish cell lines from 7 of 10 biopsies from patients with glioblastoma. The cell lines adapted to conditions and had 2.2 times increased population doubling rate at later passages. Karyotyping and comparative genomic hybridization analysis revealed that all examined cell lines had cytogenetic aberrations commonly found in glioblastomas, and there were only minor differences between tumor and early and late passages in the same culture. Whole-transcriptome analysis shows that tumors had interindividual differences. Changes in the overall expression patterns through passaging were modest, with a significant change in only 14 genes; the variation among cultures was, however, reduced through passages. The ability to differentiate differed among tumors but was maintained throughout passaging. The cells initiated tumors upon transplantation to immunodeficient mice with differing phenotypes, but a given cell culture maintained tumor phenotype after serial cultivation. The cultures established maintained individual characteristics specific to culture identity. Thus, each cell culture reflects an image of the tumor--or a personalized model--from which it was derived and remains representative after moderate expansion.

Neurosurgery in Oslo.

Neurosurgery in Oslo, Norway, was founded by the pioneer Vilhelm Magnus in the beginning of the 20th century. Through the contributions of important surgeons such as Arne Torkildsen, Kristian Kristiansen, and Helge Nornes, Norwegian neurosurgery has developed into an active clinical and technologically oriented surgical specialty. Since the unification of neurosurgical procedures in Oslo in January 2010 into one department, it is one of the largest neurosurgical departments in Europe with more than 4500 surgeries performed per year covering all aspects of neurosurgery. The department's scientific focus is on clinical studies, in close collaboration with supportive clinical departments; through interaction with basic science stem cell groups, an increasing effort is being made in translational cellular and molecular medicine.