Inhibition of glioblastoma cell proliferation and invasion by the choline-kinase inhibitor JAS239 varies with cell type and hypoxia.

Background: Elevated choline kinase alpha (ChoK) is observed in most solid tumours including glioblastomas (GBM), yet until recently, inhibitors of ChoK have demonstrated limited efficacy in GBM models. Given that hypoxia is associated with GBM therapy resistance, we hypothesised that tumour hypoxia could be responsible for such limitations. We therefore evaluated in GBM cells, the effect of hypoxia on the function of JAS239, a potent ChoK inhibitor.

Metabolic changes in glioblastomas in response to choline kinase inhibition: In vivo MRS in rodent models.

Changes in glioblastoma (GBM) metabolism was investigated in response to JAS239, a choline kinase inhibitor, using MRS. In addition to the inhibition of phosphocholine synthesis, we investigated changes in other key metabolic pathways associated with GBM progression and treatment response. Three syngeneic rodent models of GBM were used: F98 (N = 12) and 9L (N = 8) models in rats and GL261 (N = 10) in mice.

Assessing Tumour Haemodynamic Heterogeneity and Response to Choline Kinase Inhibition Using Clustered Dynamic Contrast Enhanced MRI Parameters in Rodent Models of Glioblastoma.

To investigate the utility of DCE-MRI derived pharmacokinetic parameters in evaluating tumour haemodynamic heterogeneity and treatment response in rodent models of glioblastoma, imaging was performed on intracranial F98 and GL261 glioblastoma bearing rodents. Clustering of the DCE-MRI-based parametric maps (using Tofts, extended Tofts, shutter speed, two-compartment, and the second generation shutter speed models) was performed using a hierarchical clustering algorithm, resulting in areas with poor fit (reflecting necrosis), low, medium, and high valued pixels representing parameters Ktrans, ve, Kep, vp, τi and Fp. There was a significant increase in the number of necrotic pixels with increasing tumour volume and a significant correlation between ve and tumour volume suggesting increased extracellular volume in larger tumours.

Diffusion kurtosis imaging for characterizing tumor heterogeneity in an intracranial rat glioblastoma model.

The utility of diffusion kurtosis imaging (DKI) for assessing intra-tumor heterogeneity was evaluated in a rat model of glioblastoma multiforme. Longitudinal MRI including T -weighted and diffusion-weighted MRI (DWI) was performed on six female Fischer rats 8, 11 and 14 days after intracranial transplantation of F98 cells. T -weighted images were used to measure the tumor volumes and DWI images were used to compute diffusion tensor imaging (DTI) and DWI based parametric maps including mean diffusivity (MD), mean kurtosis (MK), axial diffusivity (AD), axial kurtosis, radial diffusivity, radial kurtosis, fractional anisotropy (FA) and kurtosis fractional anisotropy (KFA).

Participant experience of invasive research in adults with intellectual disability.

Clinical research is a necessity if effective and safe treatments are to be developed. However, this may well include the need for research that is best described as 'invasive' in that it may be associated with some discomfort or inconvenience. Limitations in the undertaking of invasive research involving people with intellectual disabilities (ID) are perhaps related to anxieties within the academic community and among ethics committees; however, the consequence of this neglect is that innovative treatments specific to people with ID may not be developed.