Immunohistological study on the histogenesis and malignant transformation of ovarian mucinous tumors, with special reference to the intestinal metaplasia

Mucinous tumors of the ovary are generally considered to have a dual origin in histogenesis. Teratomatous elements, however, have recently been reported as appearing in a process of intestinal metaplasia. Malignant transformation has also been felt to occur through intestinalization. To clarify the matter, the relationships among morphological changes in intestinalization, carcinoembryonic antigen and mucus antigens named IMA and M1, which were isolated from intestinal mucosa and ovarian mucinous cyst fluid respectively, were studied in 4 benign, 8 borderline and 6 malignant mucinous tumors of the ovary. Intestinal type and goblet- like cells were sparse, if any, in benign tumors, but conspicuous in borderline and malignant ones. Carcinoembryonic antigen was located in the glycocalyx of intestinal type cells in the benign tumors, but distributed over the entire cytoplasm increasingly with malignancy. These findings lend support to the theory that malignant transformation may occur through intestinal metaplasia in mucous tumors. M1 was positive in many cells of all mucinous tumors, but IMA was shown in some goblet-like cells of a few tumors, regardless of malignancy or the presence of argyrophil cells. These phenomena could be best understood by postulating that IMA was located in the teratomatous intestinal goblet cells of the tumors.     

Inhibition of tumor-promoting effects by poricoic acids G and H and other lanostane-type triterpenes and cytotoxic activity of poricoic acids A and G from Poria cocos

The structures of two novel 3,4-seco-lanostane-type triterpenes isolated from the sclerotium of Poria cocos were established to be 16alpha-hydroxy-3,4-seco-lanosta-4(28),8,24-triene-3,21-dioic acid (1; poricoic acid G) and 16alpha-hydroxy-3,4-seco-24-methyllanosta-4(28),8,24(24(1))-triene-3,21-dioic acid (2; poricoic acid H) on the basis of spectroscopic methods. These two, and eight other known compounds isolated from the sclerotium, poricoic acid B (3), poricoic acid A (4), tumulosic acid (5), dehydrotumulosic acid (6), 3-epidehydrotumulosic acid (7), polyporenic acid C (8), 25-hydroxy-3-epidehydrotumulosic acid (9), and dehydroabietic acid methyl ester (10), showed potent inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Evaluation of the cytotoxicity of compounds 1 and 4 against human cancer cell lines revealed that 1 was significantly cytotoxic to leukemia HL-60 cells [GI(50) (concentration that yields 50% growth) value 39.3 nM], although it showed only moderate cytotoxicity to the other cells. Compound 4 exhibited moderate cytotoxicity to all of the cancer cell lines tested.     

Interiotherins C and D,two new lignans from Kadsura interior and antitumor-promoting effects of related neolignans on Epstein-Barr virus activation

Two new lignans, interiotherins C (1) and D (2), together with the known compounds interiorin (3), heteroclitin F (4), neokadsuranin (5), heteroclitin D (6), kadsurin (7), gomisin A (8), schisandrin C (9), interiotherin A (10), angeloylgomisin R (11), gomisin G (12), interiotherin B (13), and gomisin C (14), were isolated from the stems of Kadsura interior. The structures and stereochemistries of the new compounds were determined from mass, CD, and NMR spectral data. Fourteen neolignans were screened as potential antitumor promoters by examining their ability to inhibit Epstein-Barr virus early antigen (EBV-EA) activation (induced by 12-O-tetradecanoylphorbol-13-acetate) in Raji cells. Neokadsuranin (5) and schisandrin C (9) were the most potent compounds. These data suggest that some neolignans might be valuable antitumor promoters or chemopreventors.     

Merosin-positive congenital muscular dystrophy with early orthopaedic problems in relation to Ullrich's disease

We report three patients with sporadic merosin-positive congenital muscular dystrophy (CMD) with torticollis and/or developmental dislocation of the hip in early childhood. Diagnosis of merosin-positive CMD was based on their clinical and dystrophic muscle biopsy findings. At the age 13 months, patient 1 was found to have developmental dislocation of both hips, which was surgically treated at 5 years. Patient 2 had severe torticollis and contracture of both hip joints which had been present since the neonatal period, and underwent repair of the torticollis at 2 years. Patient 3 was found to have developmental dislocation of the left hip at one month of age. Although she had generalized muscle hypotonia she learned to walk at 23 months. She had no facial muscle involvement nor contracture of joints, but had hyperlaxity of distal joints. Her muscle biopsy showed complete collagen VI deficiency immunohistochemically. In contrast to merosin-deficient CMD, merosin-positive CMD appears to be a group of heterogeneous diseases. Since collagen VI was reported to be defective in Ullrich's disease, patient 3 may be diagnosed as having Ullrich's disease but had no typical clinical characteristics of the disease. Further study is needed to identify the pathogenetic mechanism of congenital muscular dystrophy with early joint abnormalities to determine whether there is a primary abnormality of the connective tissue including collagen VI.     

Detection of anti-Borna Disease Virus (BDV) antibodies from patients with schizophrenia and mood disorders in Japan

The relationship between infection with the Borna Disease Virus (BDV) and the clinical symptoms of schizophrenia and mood disorders (DMS-IV) was investigated. Western blotting techniques were used to examine anti-p10-BDV antibodies in serum from 32 patients with schizophrenia and 33 patients with mood disorders in Japan. The results showed that 1 out of 25 controls (4.0%), 7 out of 32 patients with schizophrenia (21.9%) and 9 out of 33 patients with mood disorders (27.3%) were positive for anti-BDV-p10 antibodies. Compared with levels of anti-BDV-p10 antibodies in controls, the production of anti-BDV-p10 antibodies failed to show a statistically significant relationship with schizophrenia but did show a significant relationship with mood disorder. The subgroup of schizophrenia patients with positive syndromes had a non-significantly higher frequency of anti-BDV-p10 antibodies than the subgroup of patients with negative syndromes. Similarly, the production of anti-BDV-p10 antibodies was non-significantly higher among patients with the unipolar subtype of mood disorder than in those with the bipolar subtype.     

Role of peroxisome proliferator-activated receptor-gamma in maintenance of the characteristics of mature 3T3-L1 adipocytes

Peroxisome proliferator-activated receptor (PPAR)-gamma plays an important role in adipogenesis. However, the functions of PPAR-gamma in differentiated adipocytes have remained unclear. The role of PPAR-gamma in mature 3T3-L1 adipocytes was therefore investigated by overexpression of a dominant negative mutant of this protein (PPAR-gamma-DeltaC) that lacks the 16 COOH-terminal amino acids and that has been shown to prevent the thiazolidinedione-induced differentiation of 3T3-L1 cells into adipocytes. Overexpression of PPAR-gamma-DeltaC in mature 3T3-L1 adipocytes by adenovirus gene transfer resulted in a decrease in both cell size and intracellular triglyceride content, an increase in the extent of lipolysis, and a reduction in the rate of free fatty acid uptake. Furthermore, overexpression of this mutant reduced the abundance of mRNAs for several key enzymes that contribute to triglyceride and free fatty acid metabolism as well as the amounts of GLUT4, insulin receptor, insulin receptor substrate (IRS), and C/EBPalpha mRNAs. It also reduced both the concentration of IRS2 and the insulin-stimulated glucose uptake. These results suggest that PPAR-gamma plays an important role in mature 3T3-L1 adipocytes at least in part by maintaining the expression of genes that confer the characteristics of mature adipocytes.     

Inhibitory effect of a selective cyclooxygenase-2 inhibitor on liver metastasis of colon cancer

COX-2 overexpression is recognized in various cancers, but the role of COX-2 in the progression of cancer, including the liver metastasis of colon cancer, is not clearly understood. We examined the role of COX-2 in the mechanism of liver metastasis of colon cancer, using a highly metastasizable colon carcinoma cell line, LM-H3. A COX-2 inhibitor, JTE-522, inhibited cell proliferation and invasion of LM-H3 in vitro and clearly reduced the number of metastatic nodules on the surface of nude mouse livers in vivo. We also examined the effects of JTE-522 on the production of growth factors and MMPs through the use of ELISA and gelatin zymography, respectively. JTE-522 downregulated PDGF production by LM-H3 but had no influence on VEGF production. JTE-522 also inhibited MMP-2 secretion by LM-H3. JTE-522 downregulated PGE(2) production, but the associated changes in PGE(2) did not affect PDGF and VEGF production by LM-H3. We conclude that JTE-522 downregulated the cell proliferation and invasive potential of LM-H3 by reducing the production of PDGF and MMP-2 and hypothesize that these inhibitory effects on the production of PDGF and MMP-2 can lead to inhibition of liver metastasis of colon cancer. These data indicate that the COX-2 inhibitor JTE-522 has a high potential for use as a clinical agent for the treatment of liver metastasis of colon cancer.     

Carotenoids in cancer chemoprevention

Various natural carotenoids, besides -carotene, were proven to have anticarcinogenic activity, and some of them showed more potent activity than -carotene. Thus, these carotenoids (-carotene, lutein, zeaxanthin, lycopene, rbeta -cryptoxanthin, fucoxanthin, astaxanthin, capsanthin, crocetin and phytoene), as well as -carotene, may be useful for cancer prevention. In the case of phytoene, the concept of 'bio-chemoprevention', which means biotechnology-assisted method for cancer chemoprevention, may be applicable. In fact, establishment of mammalian cells producing phytoene was succeeded by the introduction of crtB gene, which encodes phytoene synthase, and these cells were proven to acquire the resistance against carcinogenesis. Antioxidative phytoene-containing animal foods may be classified as a novel type of functional food, which has the preventive activity against carcinogenesis, as well as the ability to reduce the accumulation of oxidative damages, which are hazardous for human health.     

Cancer chemopreventive effect of quassinoid derivatives. Introduction of side chain to shinjulactone C for enhancement of inhibitory effect on Epstein-Barr virus activation

A series of shinjulactone C (1) derivatives (2-8) were synthesized and evaluated for their anti-tumor promoting effects against Epstein-Barr virus early antigen activation introduced by 12-O-tetradecanoylphorbol-13-acetate in Raji cells. The succinate and 3',3'-dimethylsuccinate derivatives of 1 exhibited higher inhibitory effects than 1. From the point of view of structure-activity relationships, the succinate derivatives (2, 4) demonstrated better potency than the glutarate derivatives (3, 5-8). As substituted moieties of 3'-position became bulky, the inhibitory effects of the glutarate derivatives (7, 8) significantly decreased.