The authors estimated abdominal fat distribution on the basis of measurements at computed tomography (CT). The attenuation range for fat tissue was defined as the interval within the mean plus or minus 2 SDs considered to be individual variation. Fat areas found with this method were closely correlated with those obtained by means of the computed planimetric method or with a fixed attenuation range from -190 to -30 HU as the standard of reference. Although the average CT numbers obtained with different scanners were distributed widely, the calculated fat areas were almost identical. This method might be a practical and standardized method at CT.

Wee1 is a tyrosine kinase that phosphorylates and inactivates CDC2 and is involved in G 2 checkpoint signaling. Because p53 is a key regulator in the G 1 checkpoint, p53-deficient tumors rely only on the G 2 checkpoint after DNA damage. Hence, such tumors are selectively sensitized to DNA-damaging agents by Wee1 inhibition. Here, we report the discovery of a potent and selective smallmolecule inhibitor of Wee1 kinase, MK-1775. This compound inhibits phosphorylation of CDC2 at Tyr15 (CDC2Y15), a direct substrate of Wee1 kinase in cells. MK-1775 abrogates G 2 DNA damage checkpoint, leading to apoptosis in combination with DNA-damaging chemotherapeutic agents such as gemcitabine, carboplatin, and cisplatin selectively in p53-deficient cells. In vivo, MK-1775 potentiates tumor growth inhibition by these agents, and cotreatment does not significantly increase toxicity. The enhancement of antitumor effect by MK-1775 was well correlated with inhibition of CDC2Y15 phosphorylation in tumor tissue and skin hair follicles. Our data indicate that Wee1 inhibition provides a new approach for treatment of multiple human malignancies.

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Scavenger receptor BI (SR-BI) is known to mediate the selective uptake of high density lipoprotein (HDL) cholesteryl ester (CE) in liver and steroidogenic tissues. To evaluate the role of SR-BI in plasma lipoprotein metabolism, we have generated transgenic mice with liverspecific overexpression of murine SR-BI. On a chow diet SR-BI transgenic (SR-BI Tg) mice have decreased HDL-CE, apoA-I, and apoA-II levels; plasma triglycerides, low density lipoprotein (LDL) cholesterol, and very low density lipoprotein (VLDL) and LDL apoB were also decreased, compared with control mice. Turnover studies using non-degradable CE and protein labels showed markedly increased total and selective uptake of HDL-CE in the liver and increased HDL protein catabolism in both liver and kidney. To evaluate the changes in apoB further, mice were challenged with high fat, high cholesterol diets. In SR-BI Tg mice plasma apoB levels were only 3-15% of control levels, and the dietary increase in VLDL and LDL apoB was virtually abolished. These studies show that steady state overexpression of hepatic SR-BI reduces HDL levels and increases reverse cholesterol transport. They also indicate that SR-BI can play a role in the metabolism of apoB-containing lipoproteins. The dual effects of increased reverse cholesterol transport and lowering of apoB-containing lipoproteins that result from hepatic SR-BI overexpression could have anti-atherogenic consequences.The risk of coronary heart disease is inversely correlated with the levels of plasma high density lipoproteins (HDL) 1 (1, 2). HDL appears to transport cholesterol from peripheral tissues to the liver for catabolism and secretion (reverse cholesterol transport) (3, 4). A putative cell-surface receptor for this process has been identified (5). This receptor, scavenger receptor BI (SR-BI), mediates high affinity binding of HDL and the selective uptake of HDL cholesteryl ester (CE) (5), a process for delivery of cholesteryl ester into cells without degradation of HDL proteins (6). Furthermore, SR-BI mRNA and protein levels are highest in adrenal gland, ovary, testis, and liver, tissues that display greatest selective cholesteryl ester uptake from HDL (7-9). SR-BI expression in steroidogenic cells is regulated by hormones and mutations that alter cholesterol supply or metabolism in those tissues in vivo (8 -11). More recently, strong support for the role of SR-BI in HDL metabolism has been provided by studies of mice with a targeted mutation resulting in decreased SR-BI gene expression (12, 13). These mice demonstrate increased plasma HDL cholesterol, decreased adrenal cholesterol content (12, 13), and decreased hepatic fractional clearance rate (FCR) for HDL-CE (13), suggesting that SR-BI is the major molecule mediating HDL-CEselective uptake in the liver. By contrast, adenovirus-mediated, hepatic overexpression of SR-BI in mice results in depletion of plasma HDL and an increase in biliary cholesterol concentration (14). Although these studies nicely demonstrate the effect of acute overexpression of ...

Compared with tricuspid AS, TAVR in bicuspid AS was associated with a similar prognosis, but lower device success rate. Procedural differences were observed in patients treated with the early-generation devices, whereas no differences were observed with the new-generation devices.

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The major mutagenic base lesion in DNA caused by exposure to reactive oxygen species is 8-hydroxyguanine or 7,8-dihydro-8-oxoguanine (8-OH-G). Products of the human MMH͞OGG1 gene are known to catalyze in vitro the reactions repairing this DNA lesion. To analyze the function of Mmh in vivo, we generated a mouse line carrying a mutant Mmh allele by targeted gene disruption. Mmh homozygous mutant mice were found to have a physically normal appearance, but to have lost nicking activity in liver extracts for substrate DNA containing 8-OH-G, exhibiting a 3-fold increased accumulation of this adduct at 9 weeks of age compared with wild-type or heterozygous mice. Further elevation to 7-fold was observed in 14-week-old animals. Substantial increase of spontaneous mutation frequencies was clearly identified in Mmh mutant mice bearing transgenic gpt genes. These results indicate that exposure of DNA to endogenous oxidative species continuously produces the mutagenic adduct 8-OH-G in mice, and Mmh plays an essential role in repair of this DNA damage.