A driver role for GABA metabolism in controlling stem and proliferative cell state through GHB production in glioma.

Cell populations with differing proliferative, stem-like and tumorigenic states co-exist in most tumors and especially malignant gliomas. Whether metabolic variations can drive this heterogeneity by controlling dynamic changes in cell states is unknown. Metabolite profiling of human adult glioblastoma stem-like cells upon loss of their tumorigenicity revealed a switch in the catabolism of the GABA neurotransmitter toward enhanced production and secretion of its by-product GHB (4-hydroxybutyrate). This switch was driven by succinic semialdehyde dehydrogenase (SSADH) downregulation. Enhancing GHB levels via SSADH downregulation or GHB supplementation triggered cell conversion into a less aggressive phenotypic state. GHB affected adult glioblastoma cells with varying molecular profiles, along with cells from pediatric pontine gliomas. In all cell types, GHB acted by inhibiting α-ketoglutarate-dependent Ten-eleven Translocations (TET) activity, resulting in decreased levels of the 5-hydroxymethylcytosine epigenetic mark. In patients, low SSADH expression was correlated with high GHB/α-ketoglutarate ratios, and distinguished weakly proliferative/differentiated glioblastoma territories from proliferative/non-differentiated territories. Our findings support an active participation of metabolic variations in the genesis of tumor heterogeneity.

Conventional and modified veneered zirconia vs. metalloceramic: fatigue and finite element analysis.

PURPOSE: The purpose of this study was to test the hypothesis that all-ceramic crown core-veneer system reliability is improved by modifying the core design and as a result is comparable in reliability to metal-ceramic retainers (MCR). Finite element analysis (FEA) was performed to verify maximum principal stress distribution in the systems. MATERIALS AND METHODS: A first lower molar full crown preparation was modeled by reducing the height of proximal walls by 1.5 mm and occlusal surface by 2.0 mm. The CAD-based preparation was replicated and positioned in a dental articulator for specimen fabrication. Conventional (0.5 mm uniform thickness) and modified (2.5 mm height, 1 mm thickness at the lingual extending to proximals) zirconia (Y-TZP) core designs were produced with 1.5 mm veneer porcelain. MCR controls were fabricated following conventional design. All crowns were resin cemented to 30-day aged composite dies, aged 14 days in water and either single-loaded to failure or step-stress fatigue tested. The loads were positioned either on the mesiobuccal or mesiolingual cusp (n = 21 for each ceramic system and cusp). Probability Weibull and use level probability curves were calculated. Crack evolution was followed, and postmortem specimens were analyzed and compared to clinical failures. RESULTS: Compared to conventional and MCRs, increased levels of stress were observed in the core region for the modified Y-TZP core design. The reliability was higher in the Y-TZP-lingual-modified group at 100,000 cycles and 200 N, but not significantly different from the MCR-mesiolingual group. The MCR-distobuccal group showed the highest reliability. Fracture modes for Y-TZP groups were veneer chipping not exposing the core for the conventional design groups, and exposing the veneer-core interface for the modified group. MCR fractures were mostly chipping combined with metal coping exposure. CONCLUSIONS: FEA showed higher levels of stress for both Y-TZP core designs and veneer layers compared to MCR. Core design modification resulted in fatigue reliability response of Y-TZP comparable to MCR at 100,000 cycles and 200 N. Fracture modes observed matched with clinical scenarios.

Accelerated aging of intervertebral discs in a mouse model of progeria.

Intervertebral disc degeneration (IDD) is a common and debilitating disorder that results in reduced flexibility of the spine, pain, and reduced mobility. Risk factors for IDD include age, genetic predisposition, injury, and other environmental factors such as smoking. Loss of proteoglycans (PGs) contributes to IDD with advancing age. Currently there is a lack of a model for rapid investigation of disc aging and evaluation of therapeutic interventions. Here we examined progression of disc aging in a murine model of a human progeroid syndrome caused by deficiency of the DNA repair endonuclease, ERCC1-XPF (Ercc1(-/Δ) mice). The ERCC1-deficient mice showed loss of disc height and degenerative structural changes in their vertebral bodies similar to those reported for old rodents. Compared to their wild-type littermates, Ercc1(-/Δ) mice also exhibit other age-related IDD characteristics, including premature loss of disc PG, reduced matrix PG synthesis, and enhanced apoptosis and cell senescence. Finally, the onset of age-associated disc pathologies was further accelerated in Ercc1(-/Δ) mice following chronic treatment with the chemotherapeutic agent mechlorethamine. These results demonstrate that Ercc1(-/Δ) mice represent an accurate and rapid model of disc aging and provide novel evidence that DNA damage negatively impacts PG synthesis.

Effects of geometry on fracture initiation and propagation in all-ceramic crowns.

The complex and patient-unique geometry of posterior all-ceramic dental crowns represents a particularly interesting set of challenges to understanding stress concentration and fracture evolution in response to loading. A series of numerical and physical experiments, with both single cycle and fatigue loading, show that geometry profoundly influences the stress concentration and fracture initiation and propagation. In stylized crowns with uniform axial wall height, stresses concentrate beneath the indenter. As the height of the axial wall increases, loads to cause failure increase linearly. In crowns with variation in axial wall height around the periphery, stresses concentrate both beneath the indenter and at the margin of the core ceramic. The magnitude of the stress concentration at the margin is directly related to the amount of variation in axial wall height around the periphery of the crown. Anatomically correct veneered zirconia core crowns subjected to single-cycle loads, fracture in areas of greatest stress concentration identified by finite element models. Fractures and stress concentrations that occur in response to single-cycle loading are important indicators of initiation sites for fatigue failure. (c) 2008 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2009.