Background: The successful treatment of malignant gliomas remains a challenge despite the current standard of care, which consists of surgery, radiation and temozolomide. Advances in the survival of brain cancer patients require the design of new therapeutic approaches that take advantage of common phenotypes such as the altered metabolism found in cancer cells. It has therefore been postulated that the high-fat, low-carbohydrate, adequate protein ketogenic diet (KD) may be useful in the treatment of brain tumors. We have demonstrated that the KD enhances survival and potentiates standard therapy in a mouse model of malignant glioma, yet the mechanisms are not fully understood.
Methods: To explore the effects of the KD on various aspects of tumor growth and progression, we used the immunocompetent, syngeneic GL261-Luc2 mouse model of malignant glioma.
Results: Tumors from animals maintained on KD showed reduced expression of the hypoxia marker carbonic anhydrase 9, hypoxia inducible factor 1-alpha, and decreased activation of nuclear factor kappa B. Additionally, tumors from animals maintained on KD had reduced tumor microvasculature and decreased expression of vascular endothelial growth factor receptor 2, matrix metalloproteinase-2 and vimentin. Peritumoral edema was significantly reduced in animals fed the KD and protein analyses showed altered expression of zona occludens-1 and aquaporin-4.
Conclusions: The KD directly or indirectly alters the expression of several proteins involved in malignant progression and may be a useful tool for the treatment of gliomas.
The Gray-faced Sengi (Rhynchocyon udzungwensis) is a newly-discovered species of sengi (elephant-shrew) and is the largest known extant representative of the order Macroscelidea. The discovery of R. udzungwensis provides an opportunity to investigate the scaling relationship between brain size and body size within Macroscelidea, and to compare this allometry among insectivorous species of Afrotheria and other eutherian insectivores. We performed a spin-echo magnetic resonance imaging (MRI) scan on a preserved adult specimen of R. udzungwensis using a 7-Tesla high-field MR imaging system. The brain was manually segmented and its volume was compiled into a dataset containing previously-published allometric data on 56 other species of insectivore-grade mammals including representatives of Afrotheria, Soricomorpha and Erinaceomorpha. Results of log-linear regression indicate that R. udzungwensis exhibits a brain size that is consistent with the allometric trend described by other members of its order. Inter-specific comparisons indicate that macroscelideans as a group have relatively large brains when compared with similarly-sized terrestrial mammals that also share a similar diet. This high degree of encephalization within sengis remains robust whether sengis are compared with closely-related insectivorous afrotheres, or with more-distantly-related insectivorous laurasiatheres.
Five immunocompetent C57BL/6-cBrd/cBrd/Cr (albino C57BL/6) mice were injected with GL261-luc2 cells, a cell line sharing characteristics of human glioblastoma multiforme (GBM). The mice were imaged using magnetic resonance (MR) at five separate time points to characterize growth and development of the tumor. After 25 days, the final tumor volumes of the mice varied from 12 mm3 to 62 mm3, even though mice were inoculated from the same tumor cell line under carefully controlled conditions. We generated hypotheses to explore large variances in final tumor size and tested them with our simple reaction-diffusion model in both a 3-dimensional (3D) finite difference method and a 2-dimensional (2D) level set method. The parameters obtained from a best-fit procedure, designed to yield simulated tumors as close as possible to the observed ones, vary by an order of magnitude between the three mice analyzed in detail. These differences may reflect morphological and biological variability in tumor growth, as well as errors in the mathematical model, perhaps from an oversimplification of the tumor dynamics or nonidentifiability of parameters. Our results generate parameters that match other experimental in vitro and in vivo measurements. Additionally, we calculate wave speed, which matches with other rat and human measurements.
Collective cell migration plays a substantial role in maintaining the cohesion of epithelial cell layers and in wound healing. A number of mathematical models of this process have been developed, all of which reduce to essentially a reaction-diffusion equation with diffusion and proliferation terms that depend on material assumptions about the cell layer. In this paper we extend a one-dimensional mathematical model of cell layer migration of Mi et al. [Biophys. J., 93 (2007), pp. 3745–3752] to incorporate stretch-dependent proliferation, and show that this formulation reduces to a generalized Stefan problem for the density of the layer. We solve numerically the resulting partial differential equation system using an adaptive finite difference method and show that the solutions converge to self-similar or traveling wave solutions. We analyze self-similar solutions for cases with no prolifera- tion, and necessary and sufficient conditions for existence and uniqueness of traveling solutions for a wide range of material assumptions about the cell layer.