We investigated the biological activity of a novel thiazolidinedione (TZD) derivative, KRP-297, and the molecular basis of this activity. When administered to obese Zucker fatty rats (obese rats) at 10 mg/kg for 2 weeks, KRP-297, unlike BRL-49,653, restored reduced lipid oxidation, that is, CO2 and ketone body production from [14C]palmitic acid, in the liver by 39% (P < 0.05) and 57% (P < 0.01), respectively. KRP-297 was also significantly more effective than BRL-49,653 in the inhibition of enhanced lipogenesis and triglyceride accumulation in the liver. To understand the molecular basis of the biological effects of KRP-297, we examined the effect on peroxisome proliferator-activated receptor (PPAR) isoforms, which may play key roles in lipid metabolism. Unlike classical TZD derivatives, KRP-297 activated both PPAR-alpha and PPAR-gamma, with median effective concentrations of 1.0 and 0.8 micromol/l, respectively. Moreover, radiolabeled [3H]KRP-297 bound directly to PPAR-alpha and PPAR-gamma with dissociation constants of 228 and 326 nmol/l, respectively. Concomitantly, KRP-297, but not BRL-49,653, increased the mRNA and the activity (1.5-fold [P < 0.01] and 1.8-fold [P < 0.05], respectively) of acyl-CoA oxidase, which has been reported to be regulated by PPAR-alpha, in the liver. By contrast, KRP-297 (P < 0.05) was less potent than BRL-49,653 (P < 0.01) in inducing the PPAR-gamma-regulated aP2 gene mRNA expression in the adipose tissues. These results suggest that PPAR-alpha agonism has a protective effect against abnormal lipid metabolism in liver of obese rats.

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Matrix-producing carcinoma of the breast is a well-established entity in the group of metaplastic carcinoma, which is histologically characterized by myxochondroid matrix formation and is extremely rare. We describe here four additional cases of matrix-producing carcinoma of the breast. All cases of matrix-producing carcinoma show nest-like, sheet-like, and cord-like growth of tumor cells with cellular atypia, in addition to scattered cancer cells within myxoid or myxohyalinous stroma. Three of four cases showed an acellular or oligocellular matrix-rich zone in the center of the tumor. Immunohistochemically, cancer cells of all cases were positive for cytokeratins and epithelial membrane antigens and partially positive for sox9 and p63. Aggrecan and type II collagen, which are cartilage-specific matrix molecules, were deposited in the stroma of all cases. Type I and type IV collagens were also deposited on the stroma of all cases. These findings suggest that, although cancer cells of matrix-producing carcinoma of the breast are epithelial, they transdifferentiate to chondrocyte-like cells and produce cartilage-specific matrix molecules, which are useful markers for diagnosing matrix-producing carcinoma. Modern Pathology (2008Pathology ( ) 21, 1282Pathology ( -1292 doi:10.1038/modpathol.2008 published online 11 July 2008 Keywords: aggrecan; collagens; matrix-producing carcinoma; breast; immunohistochemistry; electron-microscopy Matrix-producing carcinoma of the breast is an extremely rare and specialized variant of metaplastic carcinoma of the breast, which is a well-established entity; 1,2 because of its rarity, the features of its stroma have remained unclear.Aggrecan is a cartilage-specific major proteoglycan. 3 This macromolecule deposits in the hypertrophic zones of growth plate cartilage, 4 although it was reported to deposit in the salivary pleomorphic adenoma, which frequently showed mesenchyme-like elements, including myxoid and chondroid tissues. 5,6 Type II collagen, which is a cartilage-specific major collagen, and chondromodulin-I (ChM-I), which is cartilage-specific noncollagenous matrix protein, 4,7,8 are deposited in the normal cartilaginous matrix. These molecules can be useful markers of cartilaginous differentiation. As sox9 is a transcription factor, the expression of which induces cartilaginous differentiation, 9-11 this molecule is also a useful marker of chondroid differentiation in normal and neoplastic tissues. [9][10][11][12] We investigated the deposition of matrix molecules in matrix-producing carcinoma of the breast, histochemically and immunohistochemically.

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CD44 variant 9 (CD44v9) and the heavy chain of 4F2 cell-surface antigen (CD98hc) appear important for regulation of reactive oxygen species defence and tumor growth in gastric cancer. This study examined the roles of CD44v9 and CD98hc as markers of gastric cancer recurrence, and investigated associations with energy metabolism. We applied capillary electrophoresis time-of-flight mass spectrometry to metabolome profiling of gastric cancer specimens from 103 patients who underwent resection with no residual tumor or microscopic residual tumor, and compared metabolite levels to immunohistochemical staining for CD44v9 and CD98hc. Positive expression rates were 40.7% for CD44v9 and 42.7% for CD98hc. Various tumor characteristics were significantly associated with CD44v9 expression. Five-year recurrence-free survival rate was significantly lower for CD44v9-positive tumors (39.1%) than for CD44v9-negative tumors (73.5%; P < 0.0001), but no significant differences in recurrence-free survival were seen according to CD98hc expression. Uniand multivariate analyses identified positive CD44v9 expression as an independent predictor of poorer recurrence-free survival. Metabolome analysis of 110 metabolites found that levels of glutathione disulfide were significantly lower and reduced glutathione (GSH)/ glutathione disulfide (GSSG) ratio was significantly higher in CD44v9-positive tumors than in CD44v9-negative tumors, suggesting that CD44v9 may enhance pentose phosphate pathway flux and maintain GSH levels in cancer cells.Gastric cancer is the fifth most common malignancy (952,000 cases in 2012) and the third leading cause of cancer-related deaths (723,000 deaths in 2012) worldwide (1). Despite the decline in global patient numbers, gastric cancer remains one of the most prevalent cancers in Japan. Although progress in early diagnosis and adjuvant therapy has improved outcomes for gastric cancer patients, radical surgery remains the primary approach for gastric cancer treatment. Outcomes are still unsatisfactory, because gastric cancers relapse with local or distant metastasis even after radical gastrectomy. More specific diagnostic and therapeutic targets are urgently needed to achieve better clinical applications in this field. CD44, a major adhesion molecule for the extracellular matrix, is a single-pass type I transmembrane protein that serves as a cell surface receptor for hyaluronic acid, and has been implicated in vari-