Citations

Inactive cortisone is converted to active cortisol within the liver by 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1), and impaired regulation of this process may be related to increased hepatic glucose production (HGP) in individuals with type 2 diabetes. The primary aim of this study was to investigate the effect of acute 11β-HSD1 inhibition on HGP and fat metabolism during insulin deficiency. Sixteen conscious, 42-h-fasted, lean, healthy dogs were studied. Somatostatin was infused to create insulin deficiency, and the animals were treated with a specific 11β-HSD1 inhibitor (compound 531) or placebo for 5 h. 11β-HSD1 inhibition completely suppressed hepatic cortisol production, and this attenuated the increase in HGP that occurred during insulin deficiency. PEPCK and glucose-6-phosphatase expression were decreased when 11β-HSD1 was inhibited, but gluconeogenic flux was unchanged, implying an effect on glycogenolysis. Since inhibition of hepatic cortisol production reduces HGP during insulin deficiency, 11β-HSD1 is a potential therapeutic target for the treatment of excess glucose production that occurs in diabetes.

Abstract Apoptosis induction by BH3 mimetics is a therapeutic strategy for human cancer. These mimetics exert single-agent activity in cells “primed” for cell death. Primed cells are dependent upon antiapoptotic Bcl-2 proteins for survival and are characterized by the ability of the BH3 mimetic to induce cytochrome c release from their isolated mitochondria. Our aim was to examine the single-agent activity of obatoclax, a BH3 mimetic in cholangiocarcinoma cell lines. In clonogenic assays, inhibition of colony formation was observed by obatoclax treatment. Despite single-agent activity by obatoclax, the mitochondria from these cells did not release cytochrome c after incubation with this BH3 mimetic. However, immunofluorescence and cell fractionation studies identified Bax activation and translocation to mitochondria after treatment with obatoclax. shRNA targeted knockdown of Bax doubled the IC50 for obatoclax but did not abrogate its cytotoxicity, whereas knockdown of Bak did not alter the IC50. In a cell-free system, obatoclax induced an activating conformational change of Bax, which was attenuated by a site-directed mutagenesis of a previously identified protein activation site. Finally, the drug also elicited a significant in vivo response in a rodent model of this disease. In conclusion, single-agent obatoclax treatment results in Bax activation, which contributes, in part, to cell death in cholangiocarcinoma cells. These data indicate that BH3 mimetics may also function as direct activators of Bax and induce cytotoxicity in cells not otherwise primed for cell death. Cancer Res; 70(5); 1960–9

The purpose of this study was to evaluate a magnetic resonance imaging (MRI) compatible knee positioning device to aid in minimizing intratechnologist and intertechnologist differences of minimum joint space width (JSW) measurements. Five subjects were scanned by two separate technologists, with and without an MRI-compatible positioning device. A semi-automated program calculated the minimum JSW of the tibiofemoral and patellofemoral joints. The scan-to-scan repeatability was evaluated from measurements between serial scans without subject repositioning, and the intratechnologist and intertechnologist repeatabilities were evaluated when the subject was removed from the magnet and repositioned by an individual technologist. The root mean square (RMS) error of the JSW measurements was also calculated. All measures of scan-to-scan repeatability and intratechnologist repeatability were unchanged with the MRI-compatible positioning device. The intertechnologist repeatability decreased from 0.70 to 0.42 mm, and the RMS error was significantly reduced ( P = 0.0006) from 0.26 to 0.15 mm for the tibiofemoral joint. The variability of patellofemoral JSW measurements increased when using the positioning device; however, the increases were not statistically significant. The intertechnologist repeatability increased from 1.55 to 1.79 mm, and the RMS error increased from 0.58 to 0.73 mm. The MRI-compatible positioning device was successful at reducing JSW measurement variability at the tibiofemoral joint. The increase in measurement variability at the patellofemoral joint may be due to local incongruities of the articular surfaces. An MRI-compatible positioning device may be beneficial for quantitative longitudinal studies evaluating knee joint health.