Search PubMed⌕ Search

Biomedical subjects

Toshiaki Watanabe

Publications and source records attributed to Toshiaki Watanabe.

At least 91 records · Page 5Linked to original sources
PubMed2004

Diffuse expression of hRFI is correlated with blood vessel invasion in gastric carcinoma.

BACKGROUND: hRFI, which has a relatively high homology to XIAP, is preferentially expressed in esophageal and colorectal carcinomas, and is involved in the initial tumor formation in the colorectal adenoma-carcinoma sequence. Furthermore, its diffuse expression is associated with colorectal carcinogenesis. However, hRFI expression in gastric carcinomas has not been evaluated so far. METHODS: We performed immunohistochemical staining on 76 gastric carcinoma samples using the antibody to hRFI and also analyzed the correlation between the staining pattern of hRFI and the clinico-pathological characteristics. RESULTS: All of the samples were stained focally (31 cases, 40.8%) or diffusely (45 cases, 59.2%) in the cancerous region. On the contrary, most of the normal gastric region showed no staining, except for a few cases that showed slight immunoreactivity in speckles. Furthermore, the proportion of blood vessel involvement was significantly higher in carcinomas with diffuse hRFI expression (28/45, 62.2%) than in carcinomas with focal expression (7/31, 22.6%) (P < 0.001). Liver metastasis was consistently observed in five cases (11.1%) in diffuse, but only one (3.3%) in focal type during the average follow up period of 5 years. However, the 3-year survival rate did not show significant difference between these different staining patterns of hRFI. CONCLUSIONS: These results suggest that the detection of the expression pattern of hRFI in gastric carcinomas can be another useful predictor of liver recurrence, especially when combined with other factors.

Adenocarcinoma↗
PubMed2004

Vaccination with autologous endothelium inhibits angiogenesis and metastasis of colon cancer through autoimmunity.

Overcoming immune tolerance of tumor angiogenesis should be useful for adjuvant therapy of cancer. We hypothesized that vaccination with autologous endothelium would induce an autoimmune response targeting tumor angiogenesis. To test this concept, we immunized BALB/c mice with a vaccine of glutaraldehyde-fixed murine hepatic sinusoidal endothelial cells (HSEs) in a lung metastasis model of Colon-26 cancer. Vaccination with autologous HSEs induced both preventive and therapeutic anti-tumor immunity that significantly inhibited the development of metastases. ELISA revealed an immunoglobulin response involving IgM and IgG subclasses. These antibodies had a strong affinity for antigens of both murine and human endothelium, and lyzed endothelial cells in the CDC assay. Flow-cytometry and chromium-release cytotoxicity assay revealed a specific CTL response against endothelial cells, which were lyzed in an effector: target ratio-dependent manner. Neither antibodies nor CTLs reacted with Colon-26. The effect of autologous HSEs was more pronounced than that of xenogeneic human umbilical vein endothelial cells (HUVECs), which were tested in the same experimental setting. Our results suggest that vaccination with autologous endothelium can overcome peripheral tolerance of self-angiogenic antigens and therefore should be useful for adjuvant immunotherapy of cancer.

Animals↗
PubMed2004

Complete disappearance of pulmonary metastases in a case of hepatocellular carcinoma treated with docetaxel-based systemic chemotherapy.

A case of the complete shrinkage of pulmonary metastases from multiple hepatocellular carcinomas (HCC) after administration of docetaxel, cisplatin and enteric-coated tegafur/uracil is reported. A 54-year-old Japanese man was diagnosed with recurrent multiple HCC associated with pulmonary metastases and compensated liver cirrhosis. Docetaxel, cisplatin and enteric-coated tegafur/uracil were given to this patient. After 2 months of treatment, there was a decrease in tumor markers and a shrinkage of the pulmonary metastases. Image analyses such as chest X-rays and chest computed tomography scans showed a disappearance of the pulmonary metastases, although the multiple HCC did not disappear completely. This was evaluated as a complete remission of metastatic lesions or a partial remission of primary lesions according to the World Health Organization criteria. No recurrence of pulmonary metastasis was seen for 10 months. This combination therapy was well-tolerated for lung cancer and could represent an effective treatment for pulmonary metastases from HCC.

Antineoplastic Agents, Phytogenic↗
PubMed2004

[Research and development of the free radical scavenger edaravone as a neuroprotectant].

Increasing data suggest that oxygen free radical species play detrimental roles in ischemic diseases. A free radical scavenger capable of inhibiting oxidative injury is expected to become a new drug for the treatment of ischemic diseases such as cerebral ischemia. Edaravon (3-methyl-1-phenyl-2-pyrazolin-5-one), which has been developed as an neuroprotective agent for more than 15 years since its discovery, is approved for the treatment of acute cerebral infarction. In this paper, the pharmacologic characteristics and clinical effects of edaravone are reviewed. In early stage of investigation, edaravone was found to have promising activities as an antioxidative radical scavenger, quenching hydroxyl radical (.OH) and inhibiting both .OH-dependent and .OH-independent lipid peroxidation. Edaravone showed inhibitory effects on both water-soluble and lipid-soluble peroxyl radical-induced peroxidation systems, which are different from the inhibitory effects of vitamins C and E in each system, respectively. Oxidative injury to cultured endothelial cells caused by arachidonate (AA) peroxides is prevented in the existence of edaravone. To clarify the characteristics of this free radical scavenger, further investigation was carried out. Edaravone ameliorated exacerbation of cortical edema induced by a focal ischemia-reperfusion model in rats, suggesting inhibitory effects on oxidative injury to the blood-brain barrier (BBB). Additionally, edaravone also prevented rat cortical edema caused by intracortical AA infusion in which free radical production and subsequent oxidative injury to the BBB are involved. With advances in in vivo measurement technology of oxygen radicals, edaravone was shown to inhibit postischemic increases in .OH production and tissue injury in the penumbral or recirculated area in rat cerebral ischemia models. In clinical studies, edaravone improved the core neurologic deficits, activities of daily living, and functional outcome of stroke patients. Furthermore, a study using proton magnetic resonance spectroscopic techniques showed that edaravone preserved N-acetyl-aspartate in stroke patients, a promising neuronal marker in the brain. Further investigation is essential for a better understanding of free radical-mediated cerebral injury during ischemia followed by recirculation. We hope that edaravone represents a promising neuroprotectant for drug therapy in acute cerebral ischemia.

Animals↗
PubMed2004

Up-regulation of DNA-dependent protein kinase activity and Sp1 in colorectal cancer.

Tumor tissues and adjacent normal tissues in 12 colorectal cancers were examined for quantitative differences in: i) activity of DNA-dependent protein kinase (DNA-PK), which functions in DNA double-strand breads repair, and ii) protein and mRNA levels of Ku70, Ku80, DNA-PKcs and transcriptional factor Sp1. DNA-PK activity and protein/mRNA levels of Ku70, Ku80, DNA-PKcs and Sp1 were significantly higher in the tumor tissues compared with the normal tissues. Significant correlations between DNA-PK activity and protein/mRNA levels of Ku70, Ku80, DNA-PKcs and Sp1 were observed. Because Ku80 and DNA-PKcs have consensus Sp1 recognition elements in their promoter region, the DNA sequence of Ku70 promoter region was analyzed. Analysis of Ku70 promoter region reveled that Ku70 gene has consensus Sp1 recognition elements in its promoter region. mRNA levels of Ku70, Ku80 and DNA-PKcs were correlated with one another, and significant correlations between Sp1 protein level and mRNA levels of Ku70 and Ku80 were observed. These results suggest that DNA-PK activity and protein- and mRNA-levels of Ku70, Ku80 and DNA-PKcs were elevated in tumor tissues in patients with colorectal cancer because of elevated Sp1 protein levels in tumor tissues.

Adenocarcinoma↗
PubMed2003

Lysophosphatidic acid (LPA) enhances the metastatic potential of human colon carcinoma DLD1 cells through LPA1.

Lysophosphatidic acid (LPA) is a lipid mediator with diverse effects on various cells. Here, we investigated the effects of LPA on human colon carcinoma DLD1 cells. Northern blot analysis revealed that DLD1 highly expressed LPA1/Edg-2 but showed only low expression of LPA2/Edg-4 and no expression of LPA3/Edg-7 at the mRNA level. Western blot analysis revealed that DLD1 cells highly expressed LPA1 at the protein level. Using the Boyden chamber assay, LPA markedly increased DLD1 cell migration at concentrations as low as 10 nM, with maximum stimulation at 100 nM (3.6-fold increase). Checkerboard analysis indicated that LPA stimulated both the chemotactic and chemokinetic migration of DLD1 cells. LPA induced a dose-dependent increase in the proliferation of DLD1 cells (3.2-fold increase at 20 microM). Furthermore, LPA stimulated DLD1 cell adhesion to collagen type I (2.0-fold increase at 10 microM) and also stimulated the secretion of both vascular endothelial growth factor (1.4-fold increase at 20 microM) and interleukin 8 (19-fold increase at 20 microM) by ELISA. In contrast, as for matrix metalloproteinase, LPA had no significant effect on pro-matrix metalloproteinase-2 secretion and its activation, as measured by Western blot analysis. Thus, LPA, at concentrations that are present physiologically, enhanced DLD1 cell migration, proliferation, adhesion, and secretion of angiogenic factors, all of which are crucial for cancer metastasis. In comparison, other human colon carcinoma cells (HT29 and WiDR) exclusively expressed LPA2. LPA enhanced their proliferation and secretion of angiogenic factors, whereas LPA did not enhance migration or adhesion. Our results suggest that LPA acts as a potent stimulator of colon cancer progression, although the binding to LPA1 and LPA2 induces slightly different responses.

Cell Adhesion↗
PubMed2003

5-Fluorouracil efficiently enhanced apoptosis induced by adenovirus-mediated transfer of caspase-8 in DLD-1 colon cancer cells.

BACKGROUND: In order to develop a safe and effective gene therapy for cancer, more powerful therapeutic genes must be selected and a gene transduction methodology needs to be devised that minimizes the total dose of vector required. We investigated the combination effect of 5-fluorouracil (5-FU), a first-choice drug for the treatment of colorectal cancer and adenovirus-mediated transfer of caspase-8 in DLD-1 colon cancer cells. METHODS: The degree of cell death was assessed by determining the percentage of cells which had died, and the degree of DNA fragmentation. The protein expression levels and degree of activation of caspase-8 were analyzed by Western blot analysis. The degree of transgene expression was assessed using adenoviral vectors expressing lacZ and GFP. RESULTS: Combination treatment led to a significant induction of apoptosis, whereas treatment with either approach alone resulted in only minimal cytotoxicity. Caspase-8 was only activated in cells that received the combined treatment. Exposure to 5-FU increased the quantity of transgene expression per cell, 48 h post-infection. A potentiating effect of adenoviral treatment was also seen when 5-FU treatment was substituted by the overexpression of cyclin-dependent kinase inhibitors, p21(WAF1/CIP1) and p27(KIP1), suggesting that the cytostatic effect of 5-FU augmented apoptosis induced by caspase-8 gene transduction by inhibiting the dilution of gene products associated with cell division. CONCLUSIONS: This combination strategy may be very useful in the treatment of 5-FU-resistant colorectal cancers and may also be more generally helpful in minimizing the dose of therapeutic vectors used in cancer gene therapy.

Adenoviridae↗
PubMed2003

A case of diabetic mastopathy with multiple lesions mimicking breast cancer.

We report a case of diabetic mastopathy with multiple unilateral lesions in an insulin dependent patient. The patient was a 62-year-old woman with two hard tumors in the right breast, who had been treated with insulin for diabetes mellitus. Mammography revealed a highly dense tumor in the right breast, while ultrasonography showed two irregular hypoechoic lesions with marked posterior acoustical shadowing, suggesting scirrhous carcinoma. On magnetic resonance imaging the two lesions had slightly heterogeneous enhancement. Aspiration breast cytology showed insufficient cellular material for evaluation. Excisional biopsy was performed because the patient wanted confirmation and treatment. Fibrosis with dense lymphocytic infiltration around the lobules and ducts was diagnosed histopathologically. These findings were compatible with diabetic fibrous mastopathy. Although this disease is thought to be a diabetes-induced reaction of autoimmune origin, multiple lesions are rare. This is the first case of unilateral multiple lesions of diabetic mastopathy.

Breast Neoplasms↗
PubMed2003

Expression of platelet-derived endothelial cell growth factor in inflammatory bowel disease.

BACKGROUND: Platelet-derived endothelial cell growth factor (PD-ECGF) is reported to be highly expressed in tumors and inflammatory tissues, but its expression and role in inflammatory bowel disease (IBD) are still unclear. In this study we examined the location and tissue density of cells immunoreactive for PD-ECGF in the colonic mucosa of IBD. METHODS: Paraffin-embedded sections of colonic tissue from patients with ulcerative colitis (UC) or Crohn's disease (CD) were immunostained for PD-ECGF. As controls, noninflamed mucosa of IBD, as well as normal colonic mucosa from patients with colorectal cancer, were used. Also, cancer tissues were evaluated. In addition, changes in the expression of PD-ECGF in human umbilical vein endothelial cells (HUVEC) after treatment with inflammatory cytokines and angiogenic factors, as well as after coculture with colon cancer cell lines, were evaluated by flow cytometry. RESULTS: In normal colonic mucosa and noninflamed mucosa of IBD, PD-ECGF expression was negligible. In inflamed colonic mucosa, strong expression was observed, predominantly in macrophages and fibroblasts. Vascular endothelial cells of the inflamed colonic mucosa, but not of normal colonic mucosa or of neoplastic tissues, stained for PD-ECGF, and the microvessel density was significantly increased in the severely inflamed mucosa. Flow cytometry demonstrated that PD-ECGF was constitutively expressed in HUVEC. Inflammatory cytokines and vascular endothelial growth factor (VEGF) increased its expression, whereas basic fibroblast growth factor (bFGF) decreased it. Coculture with colon cancer cell lines in direct contact, but not in those without contact, also resulted in an important decrease in the expression of PD-ECGF in HUVEC. CONCLUSIONS: Autocrine production of PD-ECGF by endothelial cells may be a mechanism of inflammatory angiogenesis, but not tumor angiogenesis, and may be particularly important for the maintenance of damaged vasculature in IBD.

Colitis, Ulcerative↗
PubMed2003

Detection of cancer cells in mesenteric vein and peripheral vessels by measuring telomerase activity in patients with colorectal cancer.

BACKGROUND: Liver metastasis is an important factor determining prognosis in colorectal cancer. The objective of this study was to assess whether colorectal cancer cells in the drainage veins can be detected by measuring telomerase activity and its detection is correlated with liver metastasis. METHODS: Telomeric repeat amplification protocol assay in combination with an immunomagnetic sorting was used for measuring telomerase activity of epithelial cells in blood samples collected from mesenteric (tumor-drainage) vein and peripheral vessels of 41 colorectal cancer patients. Telomerase activity was calculated as relative telomerase activity (RTA) against a control template and analyzed in terms of liver metastasis. RESULTS: RTA of mesenteric blood samples was significantly higher in patients with liver metastasis (60.8%; n=7) than in those without metastasis (19.7%; n=34; P=.019). The RTA of peripheral blood sample was also higher in patients with liver metastasis (26.8%) than in those without metastasis (11.1%; p=.17). Moreover, 57% of cases with liver metastasis exhibited a positive telomerase activity in mesenteric blood sample, whereas it was 18% in cases without metastasis. CONCLUSIONS: Our assay was proven to be a feasible method for detecting cancer cells in tumor-drainage veins. High telomerase activity of mesenteric blood samples reflected the existence of liver metastasis of colorectal cancer.

Adult↗
PubMed2003

Epigallocatechin gallate, the main component of tea polyphenol, binds to CD4 and interferes with gp120 binding.

BACKGROUND: Epigallocatechin gallate (EGCG), the major component of tea polyphenol, has been reported to have various physiologic modulatory activities. Several reports also have shown that catechin has a protective effect against HIV infection, part of which is mediated by inhibiting virions to bind to the target cell surface. OBJECTIVE: We investigated the effect of EGCG on the expression of CD4 molecules and on its ability to bind gp120, an envelope protein of HIV-1. METHODS: Peripheral blood CD4+ T cells were incubated in the presence of EGCG, and the expression of CD4 was evaluated by means of flow cytometry. The effect of EGCG on the antibody binding to CD4 was investigated by using a sandwich ELISA, and the effect on the gp120 binding to CD4 was analyzed by means of flow cytometry. RESULTS: EGCG efficiently inhibited binding of anti-CD4 antibody to its corresponding antigen. This effect was mediated by the direct binding of EGCG to the CD4 molecule, with consequent inhibition of antibody binding, as well as gp120 binding. CONCLUSION: The present results suggest a potential preventive effect of EGCG on HIV-1 infection by modulating binding to CD4.

Antibodies, Monoclonal↗
PubMed2003

Sustained biochemical remission after interferon treatment may closely be related to the end of treatment biochemical response and associated with a lower incidence of hepatocarcinogenesis.

Clinical background and incidence of hepatocellular carcinoma (HCC) of patients with chronic hepatitis C who obtained biochemical remission without eradication of virus (biochemical response) after interferon (IFN) treatment was retrospectively analyzed for 755 patients. Annual incidence of HCC was significantly lower in the patients with biochemical response and sustained response than that of the patients that did not show these responses. Logistic regression analysis showed that only the normalization of alanine aminotransferase (ALT) value at the end of IFN treatment was a significant factor for biochemical response. Annual incidence of HCC was significantly lower in the patients who obtained normalization of ALT values at the end of treatment than those who did not. Patients who were younger, who had a lower level of activity and fibrosis indices in histology, higher platelet count, and who were given more higher total dose of IFN were more likely to attain normalization of ALT levels at the end of treatment, and this was related to biochemical response. Low incidence of HCC in patients who obtained normalization of ALT values at the end of treatment was likely because they were in the earlier stage of chronic hepatitis. Active treatment of chronic hepatitis C with interferon in the early phase of the disease may bring about a biochemical response in some patients, even if sustained virological response is not obtained.

Adult↗