Genetic Profiling of Sebaceous Carcinoma Arising from an Ovarian Mature Teratoma: A Case Report

Ovarian mature teratomas (OMTs) originate from post-meiotic germ cells. Malignant transformation occurs in approximately 1–2% of OMTs; however, sebaceous carcinoma arising from OMTs is rare. This is the first report of a detailed genomic analysis of sebaceous carcinoma arising from an OMT. A 36-year-old woman underwent evaluation for abdominal tumors and subsequent hysterectomy and salpingo-oophorectomy. Pathologically, a diagnosis of stage IA sebaceous carcinoma arising from an OMT was established. Eight months post-surgery, the patient was alive without recurrence. Immunohistochemically, the tumor was negative for mismatch repair proteins. A nonsense mutation in TP53 (p.R306*) and a deletion in PIK3R1 were identified. Single nucleotide polymorphisms across all chromosomes displayed a high degree of homozygosity, suggestive of uniparental disomy. Herein, the OMT resulting from the endoreduplication of oocytes underwent a malignant transformation to sebaceous carcinoma via TP53 as an early event and PIK3R1 as a late event

Evaluation of approach to predict the contribution of multiple cytochrome P450s in drug metabolism using relative activity factor: Effects of the differences in expression levels of NADPH-cytochrome P450 reductase and cytochrome b5 in the expression system and the differences in the marker activities

金沢大学大学院医学系研究科機能分子医薬学金沢大学薬学部The concept of relative activity factor (RAF) to extrapolate data obtained with recombinant cytochrome P450(CYP)s to human liver microsomes has been proposed. To evaluate the approach to predict the contribution of multiple CYPs using RAF, we investigated the effects of the differences in the expression levels of NADPH- cytochrome P450 reductase (OR) and cytochrome b5 (b5) in recombinant CYPs from baculovirus-infected insect cells and the differences in the marker activities. Because we previously clarified that azelastine, an antiallergy and antiasthmatic drug, is N-demethylated by CYP1A2, CYP2D6, and CYP3A4 in humans, the reaction was used as a model. For calculation of RAF, three lots of recombinant CYP1A2, CYP2D6, and CYP3A4 from baculovirus-infected insect cells with different expression levels of OR and b5 were used. The OR/CYP ratios for recombinant CYP1A2, CYP2D6, and CYP3A4 were 3.9-4.8, 5.1-8.7, and 8.0-11.3, respectively. The b5/CYP ratio for recombinant CYP3A4 was 2.1-18.7. As marker activities, ethoxyresorufin O-deethylation and phenacetin O-deethylation for CYP1A2, bufuralol 1′-hydroxylation and debrisoquin 4-hydroxylation for CYP2D6, testosterone 6β-hydroxylation and midazolam 1′-hydroxylation for CYP3A4 were compared. Our results indicated that the differences in the expression levels of OR and b5 coexpressed in baculovirus-infected insect cells would not be a critical factor for the quantitative prediction using RAF. In addition, we confirmed that differences in the marker activities did not significantly affect the calculation of RAF values, when the marker activities are specific for a certain CYP isoform. It was suggested that the RAF approach using recombinant CYPs from baculovirus-infected insect cells coexpressing OR (and b5 if required) could be valuable for the prediction of the contribution of each CYP in drug metabolism. © 2002 Wiley-Liss, Inc

The G protein‐coupled receptor ligand apelin‐13 ameliorates skeletal muscle atrophy induced by chronic kidney disease

Abstract Background Targeting of the apelin–apelin receptor (Apj) system may serve as a useful therapeutic intervention for the management of chronic kidney disease (CKD)‐induced skeletal muscle atrophy. We investigated the roles and efficacy of the apelin–Apj system in CKD‐induced skeletal muscle atrophy. Methods The 5/6‐nephrectomized mice were used as CKD models. AST‐120, a charcoal adsorbent of uraemic toxins (8 w/w% in diet), or apelin (1 μmol/kg) was administered to CKD mice to investigate the mechanism and therapeutic potential of apelin on CKD‐induced skeletal muscle atrophy. The effect of indoxyl sulfate, a uraemic toxin, or apelin on skeletal muscle atrophy was evaluated using mouse myoblast cells (C2C12 cells) in vitro. Results Skeletal muscle atrophy developed over time following nephrectomy at 12 weeks, as confirmed by a significant increase of atrogin‐1 and myostatin mRNA expression in the gastrocnemius (GA) muscle and a decrease of lower limb skeletal muscle weight (P < 0.05, 0.01 and 0.05, respectively). Apelin expression in GA muscle was significantly decreased (P < 0.05) and elabela, another Apj endogenous ligand, tended to show a non‐significant decrease at 12 weeks after nephrectomy. Administration of AST‐120 inhibited the decline of muscle weight and increase of atrogin‐1 and myostatin expression. Apelin and elabela expression was slightly improved by AST‐120 administration but Apj expression was not, suggesting the involvement of uraemic toxins in endogenous Apj ligand expression. The administration of apelin at 1.0 μmol/kg for 4 weeks to CKD mice suppressed the increase of atrogin‐1 and myostatin, increased apelin and Apj mRNA expression at 30 min after apelin administration and significantly ameliorated weight loss and a decrease of the cross‐sectional area of hindlimb skeletal muscle. Conclusions This study demonstrated for the first time the association of the Apj endogenous ligand–uraemic toxin axis with skeletal muscle atrophy in CKD and the utility of therapeutic targeting of the apelin–Apj system

Morphological, histological and gene-expression analyses on stolonization in the Japanese Green Syllid, Megasyllis nipponica (Annelida, Syllidae)

Abstract Benthic annelids belonging to the family Syllidae (Annelida, Errantia, Phyllodocida) exhibit a unique reproduction mode called “schizogamy” or “stolonization”, in which the posterior body part filled with gametes detaches from the original body, as a reproductive unit (stolon) that autonomously swims and spawns. In this study, morphological and histological observations on the developmental processes during stolonization were carried out in Megasyllis nipponica. Results suggest that the stolon formation started with maturation of gonads, followed by the formation of a head ganglion in the anteriormost segment of the developing stolon. Then, the detailed stolon-specific structures such as stolon eyes and notochaetae were formed. Furthermore, expression profiles of genes involved in the anterior–posterior identity (Hox genes), head determination, germ-line, and hormone regulation were compared between anterior and posterior body parts during the stolonization process. The results reveal that, in the posterior body part, genes for gonadal development were up-regulated, followed by hormone-related genes and head-determination genes. Unexpectedly, Hox genes known to identify body parts along the anterior–posterior axis showed no significant temporal expression changes. These findings suggest that during stolonization, gonad development induces the head formation of a stolon, without up-regulation of anterior Hox genes