This study, to our knowledge, is the first to explore the effects of nivolumab against ovarian cancer. The encouraging safety and clinical efficacy of nivolumab in patients with platinum-resistant ovarian cancer indicate the merit of additional large-scale investigations (UMIN Clinical Trials Registry UMIN000005714).

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Sterol regulatory element-binding protein 2 (SREBP-2) transcription factor has been identified as a key protein in cholesterol metabolism through the transactivation of the LDL receptor and cholesterol biosynthesis genes. Here, we generated mice lacking microRNA (miR)-33, encoded by an intron of the Srebp2, and showed that miR-33 repressed the expression of ATP-binding cassette transporter A1 (ABCA1) protein, a key regulator of HDL synthesis by mediating cholesterol efflux from cells to apolipoprotein A (apoA)-I. In fact, peritoneal macrophages derived from miR-33-deficient mice showed a marked increase in ABCA1 levels and higher apoA-I-dependent cholesterol efflux than those from WT mice. ABCA1 protein levels in liver were also higher in miR-33-deficient mice than in WT mice. Moreover, miR-33-deficient mice had significantly higher serum HDL cholesterol levels than WT mice. These data establish a critical role for miR-33 in the regulation of ABCA1 expression and HDL biogenesis in vivo.A TP-binding cassette transporter A1 (ABCA1), a 254-kDa cytoplasmic membrane protein, is a pivotal regulator of lipid efflux from cells to apolipoproteins (1). ABCA1 mediates the ratecontrolling step in HDL particle formation and plays an important role in reverse cholesterol transfer (2, 3). Mutations in the ABCA1 gene cause Tangier disease, which is characterized by the near absence of plasma HDL cholesterol associated with storage of cholesterol esters in reticuloendothelial tissues (4-7). Abca1 mRNA and protein are very unstable, with a half life of 1-2 h in murine macrophages (8), which indicates that new transcription and translation are major factors in ensuring constant and inducible ABCA1 expression.Sterol regulatory element-binding proteins (SREBPs), including SREBP-1a, -1c, and -2, modulate the transcription of a number of genes involved in the synthesis and receptor-mediated uptake of cholesterol and fatty acids (9-11). In sterol-depleted cells, SREBPs are cleaved by proteases in the Golgi, releasing the N-termini, which translocate into the nucleus and bind to SREs in the enhancers of multiple genes encoding enzymes and proteins involved in cholesterol biosynthesis and lipid uptake (11-13). Results to date support the notion that SREBP-1 primarily activates the fatty acid triglyceride and phospholipid pathways, whereas SREBP-2 is the prominent isoform for cholesterol synthesis and uptake (9,10,12).MicroRNAs (miRs) are small, non-protein-coding RNAs that base pair with specific mRNAs and inhibit translation or promote mRNA degradation. Recent reports have indicated that miR-33 controls cholesterol homeostasis based on knockdown experiments using antisense technology (14-16). Antisense inhibition of miRNA function has been an important tool for elucidating miRNA biology. However, to determine the potential developmental function of specific miRNAs and to perform longer-term studies, it is necessary to generate mice lacking each miRNA. We generated miR-33-deficient mice, which were born at the expected Mendelian ratio, a...

In this study, we questioned whether in vivo probucol could prevent the progression of atherosclerosis in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model for familial hypercholesterolemia. At 2 months of age, eight WHHL rabbits were divided into two groups. Group A (n = 4) was fed standard rabbit chow for 6 months. Group B (n = 4) was fed standard rabbit chow containing 1% probucol for 6 months. At the end of the experiments, average plasma concentrations of cholesterol were 704 ± 121 mg/dl in group A and 584 ± 61 mg/dl in group B, respectively. The percentage of surface area of total thoracic aorta with visible plaques in group A versus group B was 54.2% ± 18.8% versus 7.0% ± 6.3%, respectively. What was noteworthy was that the percentage of plaque in the descending thoracic aorta was almost negligible (0.2% ± 0.2%) in group B rabbits compared to that in group A rabbits (41.1% + 20.2%). Low density lipoproteins (LDL) isolated from WHHL rabbits under treatment with probucol (group B) were shown to be highly resistant to oxidative modification by cupric ion and to be minimally recognized by macrophages. On the contrary, LDL from group A rabbits incubated with cupric ion showed a 7.4-fold increase in peroxides (thiobarbituric acidreactive substances) and a 4.3-fold increase in the synthesis of cholesteryl ester in macrophages compared to those of LDL from group B rabbits. Thus, probucol could definitely prevent the progression of atherosclerosis in homozygous WHHL rabbits in vivo by limiting oxidative LDL modification and foam cell transformation of macrophages.Familial hypercholesterolemia (FH) is one of the most common human genetic diseases. Homozygous FH patients have inherited allelic mutations in the gene specifying the low density lipoprotein (LDL) receptor located on the cell surface (1). In these patients, few or no functional LDL receptors are synthesized in the body. As a result, not only impairment of catabolism but also overproduction of LDL occurs in FH homozygotes, subsequently leading to a 6-fold to 8-fold increase in plasma LDL levels before birth (1-3). Elevation of plasma levels of LDL leads to characteristic xanthoma formation in tendons and skin and accelerated atherosclerosis (4). Symptomatic coronary atherosclerosis typically develops before the age of 20 years in homozygous FH patients (5). To protect FH patients against atherosclerosis including coronary artery disease, it is necessary to reduce the plasma levels of LDL to as normal a level as possible. In FH homozygotes, liver transplantation is the only treatment so far (6), and plasmapheresis and the portal-caval shunt operation are partially successful (5, 7). None of the antilipidemic drugs is effective in homozygous FH patients.The foam cell has been recognized as a characteristic feature of xanthomas in skin and tendons and also of the atheromas. Many foam cells in these lesions share properties characteristic of the macrophages. Therefore, the macrophage may be the progenitor of certain foam cel...