Incidental carcinomas detected by PET/CT scans in patients with malignant lymphoma

According to the international working group response criteria for malignant lymphoma revised in 2007, 18F-fluorodeoxyglucose positron emission tomography (¹⁸FDG-PET) combined with or without computed tomography (CT) is recommended for pre-treatment staging and response assessment among patients with diffuse large B-cell lymphoma and Hodgkin lymphoma. Recently, along with the widespread use of PET/CT, unexpected uptake and accumulation of ¹⁸FDG has been reported. Discussed in the present report are patients with malignant lymphoma and second primary carcinomas that were incidentally found by PET/CT. A total of 497 consecutive PET/CT were performed on 290 patients with malignant lymphoma in our institution from April 2008 through March 2010. Eight patients (2.8%) had pathologically confirmed second primary carcinomas consisting of 4 colon cancers, 3 lung cancers, and 1 pancreatic cancer. Two cases were diagnosed at the initial staging, and the others were detected after treatment for lymphoma. It is noteworthy that PET revealed high accumulations of ¹⁸FDG in 5 (62.5%) of the 8 patients without corresponding tumors in conventional CT. All of the 4 patients with colon carcinoma underwent curative surgery. The present study suggests that incidental findings by PET in malignant lymphoma can lead to early detection and successful treatment of second malignancies.     

Review: Animal models of N-Methyl-N-nitrosourea-induced mammary cancer and retinal degeneration with special emphasis on therapeutic trials

N-Methyl-N-nitrosourea (MNU) is a direct-acting alkylating agent that interacts with DNA. Accumulation of mutations may enhance cancer risk in target organs or cause cell death in susceptible tissues or cells when excessive DNA damage is not repaired. MNU targets various organs in a variety of animal species. MNU-induced carcinogenesis can be used as organ-specific animal models for human cancer, and MNU has been most extensively utilized for the induction of mammary cancer in rats. MNU-induced rat mammary tumors possess many similarities to those of human breast cancer, and the model is utilized for screening cancer modulators. MNU-induced cell disruption is also seen in several organs and tissues, especially when MNU is applied before maturity. However, photoreceptor cells in adults are highly sensitive to MNU, which causes cell death due to apoptosis. MNU-induced photoreceptor apoptosis mimics human retinitis pigmentosa and can be used for studies of therapeutic intervention. In this review, the targets of MNU in various animal species are described, and special emphasis is given to therapeutic trials against MNU-induced mammary cancer and retinal degeneration in animal models.     

Preparation and characterization of directly compactible layer-by-layer nanocoated cellulose

Iontophoresis is a promising technique for enhancing transdermal administration of charged drugs. However, conventional iontophoresis is not sufficient for effective delivery of large, hydrophilic, or electrically neutral molecules. In this study, we utilized charged liposomes as carriers, focused on a transfollicular route for delivery of the liposomes, and optimized iontophoretic conditions and lipid composition for this method in both in vitro and in vivo conditions. As a result, we identified the optimum condition (lipid composition: DOTAP/EPC/Chol=2:2:1, current supply: 0.45mA/cm(2), duration: 1h) for effective iontophoretic delivery of aqueous solution, which cannot be transferred into the skin without charged liposomes. We also examined the pharmacological effects of iontophoresis of liposomes encapsulating insulin (INS-lipo) using a rat model of type I diabetes. Interestingly, iontophoresis of INS-lipo onto a diabetes rat skin resulted in a gradual decrease in blood glucose levels, with levels reaching 20% of initial values at 18h after administration. These lower blood glucose levels were maintained for up to 24h. Significant amount of insulin were also detected in plasma 18h after iontophoresis of INS-lipo. We succeeded in developing a non-invasive and persistent transfollicular drug delivery system that used a combination of liposomes and iontophoresis.     

Protective effect of pretreatment with cilostazol on cytotoxicity of cadmium and arsenite in cultured vascular endothelial cells

Cilostazol, an antiplatelet drug, exhibits antiatherogenic effects. The purpose of the present study was to determine the effect of cilostazol on the cytotoxicity of cadmium (Cd) and arsenite (iAs(III)), which involved in the pathogenesis of vascular disorders such as atherosclerosis, in cultured vascular endothelial cells. Cytotoxicity was evaluated by the lactate dehydrogenase leakage assay and morphological observation. Cd (10 μM) -induced cytotoxicity was prevented by pretreatment with cilostazol (30 and 100 μM) and simultaneous treatment with cilostazol (100 μM). On the other hand, iAs(III)-induced cytotoxicity was blocked by pretreatment with cilostazol (30 and 100 μM) but not simultaneous treatment with cilostazol. The mRNA level and the protein level of metallothionein (MT) were significantly increased by cilostazol in the cells. These results suggested, therefore, that pretreatment with cilostazol effectively prevents the cytotoxicity of Cd and iAs(III) in cultured vascular endothelial cells, at least in part through the induction of MT synthesis.     

Galactose-modified cationic liposomes as a liver-targeting delivery system for small interfering RNA

We have developed a galactose-modified cationic liposome for delivery of small interfering RNA (siRNA) to the liver. The liposomes were designed to be transported into hepatocytes via the asialoglycoprotein receptor, which recognizes galactose residues. The liposomes contained a novel galactose-modified lipid, 1,2-dioleoyl-sn-glycerol-3-phosphatidyl-N-(1-deoxylactito-1-yl)ethanolamine (GDOPE). Delivery of siRNA to hepatocytes by the liposomes was evaluated by measuring the gene-silencing activity of liposome : siRNA complexes in two human hepatoma cell lines. A formulation with a cationic lipid : GDOPE ratio of 3 : 5 by weight, LIC-G5, showed the strongest activity. In mice, intravenous injection of LIC-G5 complexed with (3)H-labeled siRNA led to accumulation of radioactivity in the liver. When the hepatic cellular uptake was determined after intravenous injection into mice followed by collagenase liver perfusion, the distribution of siRNA to parenchymal cells was 1.9 times higher when LIC-G5 rather than nongalactosylated LIC was used as the carrier. The concentration of siRNA accumulated was 45 μg/ml, 30 times the concentration that produced strong gene silencing in vitro and therefore presumably sufficient for a therapeutic effect. Because increasing the cationic-lipid content of a liposome carrier generally enhances the uptake of siRNA by the liver at the expense of increased cell toxicity, we used only a moderate amount of cationic lipid in our galactose-modified carrier. LIC-G5 enhanced the uptake of siRNA by the liver without cytotoxic effects and is a promising candidate delivery system for liver-targeted siRNA therapy.     

Prediction and <Emphasis Type="Italic">In Vitro</Emphasis> Evaluation of Selected Protease Inhibitor Antiviral Drugs as Inhibitors of Carboxylesterase 1: A Potential Source of Drug-Drug Interactions

Purpose  

To predict and determine whether the protease inhibitors (PIs) nelfinavir, amprenavir, atazanavir, ritonavir, and saquinavir could serve as metabolic inhibitors of the human CES1 (hCES1) using both molecular modeling techniques and in vitro inhibition assays.     

β-Amyrin oxidation by oat CYP51H10 expressed heterologously in yeast cells: the first example of CYP51-dependent metabolism other than the 14-demethylation of sterol precursors

CYP51 has been recognized as a unique CYP family that consists of one isolated molecular species, a sterol 14-demethylase essential for sterol biosynthesis. However, another CYP51 gene classified as the CYP51H subfamily has been identified in higher plants, in addition to a sterol 14-demethylase gene, CYP51G1. To shed light on the function of this "second CYP51", oat CYP51H10 was introduced into the β-amyrin-producing yeast cells, and the effect of the expressed CYP51H10 on β-amyrin metabolism in the host cells was examined. In the CYP51H10-introduced cells, β-amyrin was converted to a metabolite with 12,13-epoxy and one additional hydroxyl group. Since the 12,13-epoxy group introduced into β-amyrin ring is an essential structure of avenacin A-1, a triterpene glycoside produced in oat from β-amyrin, the present findings indicate the contribution of CYP51H10 to avenacin A-1 biosynthesis from β-amyrin. This is the first study showing a second function of the CYP51 family.     

Translocase of outer mitochondrial membrane 70 expression is induced by hepatitis C virus and is related to the apoptotic response

The localization of hepatitis C virus (HCV) proteins in cells leads to several problems. The translocase of outer mitochondrial membrane 70 (TOM70) is a mitochondrial import receptor. In this study, TOM70 expression was induced by HCV infection. TOM70 overexpression induced resistance to tumor necrosis factor-alpha (TNF-α)-mediated apoptosis but not to Fas-induced apoptosis in HepG2 cells. TOM70 was found to be induced by the HCV non-structural protein (NS)3/4A protein, and silencing of TOM70 decreased the levels of the NS3 and Mcl-1 proteins. These results indicate that TOM70 can directly interact with the NS3 protein. In hepatoma cells, silencing of TOM70 induced apoptosis and increased caspase-3/7 activity but did not modify caspase-8 and caspase-9 activity. TOM70 silencing-induced apoptosis was impaired in HCV NS3/4A protein-expressing cells. Thus, this study revealed a novel finding, that is, TOM70 is linked with the NS3 protein and the apoptotic response.