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Biomedical subjects

Shinji Tanaka

Publications and source records attributed to Shinji Tanaka.

At least 127 records · Page 7Linked to original sources
PubMed2003

Clinical significance of angiogenic factor expression at the deepest invasive site of advanced colorectal carcinoma.

Tumor angiogenesis is a complicated process for which the mechanisms remain unclear. The aim of this study was to elucidate the clinical significance of several angiogenic factor expression as a predictor of the invasive/metastatic potential and of the prognosis of advanced colorectal carcinoma (CRC) in relation to their intratumoral histologic heterogeneity. One hundred fifty two patients who had undergone surgical resection for advanced CRC entered this study. PD-ECGF, VEGF, and VEGF-C were examined immunohistochemically with antibodies 1C6-203, A-20, and C-20, respectively. Tumor microvessel density (MVD) was determined immunohistochemically with anti-CD34 antibody. Expression of PD-ECGF, of VEGF, and of VEGF-C at the deepest invasive site were detected in 77 (50.7%), 62 (30.8%), and 71 (46.7%) of the 152 lesions, respectively. PD-ECGF, VEGF, and VEGF-C expression at the deepest invasive site in lesions with liver metastasis (77, 67, and 70%) was significantly higher than that in those without liver metastasis (44, 34, and 41%). In cases with curative surgery, patients with PD-ECGF, VEGF, and VEGF-C expression at the deepest invasive site had a significantly poorer prognosis than those without PD-ECGF, VEGF, and VEGF-C expression at the deepest invasive site. PD-ECGF, VEGF, and VEGF-C expression at the deepest invasive site correlated significantly with MVD. Multivariate analysis with logistic regression for 5-year survival in patients with curative surgery showed that lymph node metastasis and VEGF expression were significant risk factors. Expression of PD-ECGF, VEGF, and VEGF-C was correlated significantly with metastatic potential and prognosis in relation to MVD. Of the several angiogenic factors, VEGF expression at the deepest invasive site of tumor was the most statistically significant indicator of prognosis in advanced CRC.

Aged↗
PubMed2003

Expression of vascular endothelial growth factor and angiogenesis in gastrointestinal stromal tumor of the stomach.

UNLABELLED: Vascular endothelial growth factor (VEGF) is associated with the malignant potential of several types of carcinoma. The aim of this study was to elucidate the clinical significance of VEGF expression in gastrointestinal stromal tumor (GIST). METHODS: Specimens obtained from 53 patients who had underwent surgical resection for GIST of the stomach were used in this study. Specimens were examined immunohistochemically for VEGF expression and Ki-67 expression. Tumor microvessel density (MVD) was determined immunohistochemically with anti-CD31 antibody, and was estimated by averaging the counts from three high-power fields in the area showing the greatest neovascularization. RESULTS: VEGF expression was detected in 14 (26.4%) of the 53 lesions and correlated significantly with tumor size, liver metastasis, Ki-67 labeling index, and MVD. Prognosis was significantly poorer than in patients with tumors expressing VEGF than in patients with tumors lacking VEGF expression. Multiple logistic regression analysis for 10-year survival showed VEGF expression and high mitotic rate to be independent predictor of a poor outcome. CONCLUSIONS: Angiogenesis associated with VEGF may play an important role in the progression of GIST. VEGF expression may serve as an indicator of a poor prognosis.

Adult↗
PubMed2003

Role of H1-calponin in pancreatic AR42J cell differentiation into insulin-producing cells.

Basic or h1-calponin is a smooth muscle-specific, actin-binding protein that is involved in the regulation of smooth muscle contractile activity. We found in this study the expression of mRNA and protein for h1-calponin in AR42J-B13 cells, which is a useful model for investigating islet beta-cell differentiation from pancreatic common precursor cells. Following treatment of AR42J cells with activin A and hepatocyte growth factor, the protein levels of h1-calponin decreased in a time-dependent manner during the course of the cell differentiation. When h1-calponin was continuously overexpressed by utilizing recombinant adenovirus-mediated gene transfer, the percentage of cell differentiation in h1-calponin overexpressing cells was markedly suppressed as compared with that in the cells without overexpression (6.7 +/- 2.5 vs. 28.6 +/- 3.2%, P < 0.001, Student's t test). Finally, overexpression of h1-calponin (65.6 +/- 3.4), or that lacking actin-binding domain (55.9 +/- 3.4%), significantly (P < 0.001) suppressed the activin A-stimulated transcriptional activity of activin responsive element (ARE), whereas calponin homology-domain disruption mutant did not (100.6 +/- 1.9%). These results suggest that regulation of h1-calponin is involved in the regulation of differentiation of AR42J cells into insulin-producing cells at least partly through modulating ARE transcriptional activity.

Actins↗
PubMed2003

Pulse wave velocity in lower-limb arteries among diabetic patients with peripheral arterial disease.

OBJECTIVE: Patients with type 2 diabetes mellitus are at an increased risk of atherosclerosis including peripheral arterial disease (PAD). The purpose of this study was to examine the possible alteration in pulse wave velocity (PWV) in lower-limb arteries among diabetic patients with PAD. METHODS: We measured brachial-ankle PWV (baPWV) using an automatic device in 101 healthy control subjects and 102 type 2 diabetic patients including those with PAD. RESULTS: Diabetic patients without PAD showed a higher baPWV than the healthy control subjects. There was no significant difference in baPWV between the right and left legs in these groups. In contrast, among diabetic patients with PAD, baPWV was significantly lower in the affected legs than in the non-affected legs, and the reduction in baPWV was greater in those with lower ankle-brachial pressure index (ABI). In the patients with PAD who received percutaneous transluminal angioplasty, both baPWV and ABI were increased following successful vessel dilatation. CONCLUSIONS: These results suggest that baPWV is increased in diabetic patients, whereas it is decreased in the affected legs in diabetic patients with PAD. Widening of the right-left difference in baPWV may be a novel marker of PAD.

Aged↗
PubMed2003

Successful transradial coronary angioplasty and stenting using a self-expandable RADIUS stent to the anomalous left main coronary artery.

Stenting of anomalous coronary artery is technically challenging both from the femoral and radial approaches because of difficulty in cannulating the artery by the guiding catheters with enough back-up support for delivering the stent. We report the first case in the literature of transradial coronary angioplasty and stenting to an anomalous left main coronary artery originating from the right sinus of Valsalva. Left Amplatz guidance from the radial approach provided an adequate platform to advance the stent using a dummy guidewire technique, and a self-expandable RADIUS stent was successfully deployed in a tortuous lesion of the anomalous artery.

Aged↗
PubMed2003

[The roles of H. pylori infection and K-ras gene mutation in gastric carcinogenesis].

To elucidate the significance of K-ras gene mutations in gastric carcinogenesis, we examined the mutations in gastric cancers and in Helicobacter pylori-associated chronic gastritis(H. pylori-CG). In gastric cancers, K-ras gene mutations were detected in intestinal type cancers, but not in diffuse type cancers. K-ras gene mutations in H. pylori-CG were significantly more frequent in gastric cancer patients than in cancer-free patients. These data suggest that K-ras gene mutations may be involved in the early stages of gastric carcinogenesis of the intestinal type. Recently, Uemura, et al. reported that H. pylori eradication suppressed gastric cancer development(Cancer Epidemiol Biomarkers Prev, 1997; N Engl J Med, 2001). Further examination is necessary to clarify the mechanism of suppression of gastric cancer development after H. pylori eradication.

Genes, ras↗
PubMed2003

Monocyte chemoattractant protein-1 expression correlates with macrophage infiltration and tumor vascularity in human gastric carcinomas.

The purpose of this study was to investigate the role of interactions between tumor cells and macrophages during angiogenesis in human gastric carcinomas. Macrophage infiltration into tumors and monocyte chemoattractant protein-1 (MCP-1) expression was assessed in 72 archival specimens of gastric carcinoma for comparison with tumor vascularity. The mRNA expression of MCP-1 was examined by RT-PCR in 6 gastric carcinoma cell lines and in fresh biopsy specimens from 18 patients. Immunolocalization of representative angiogenic factors, vascular endothelial growth factor (VEGF), and platelet-derived endothelial cell growth factor (PD-ECGF) was also done. MCP-1 expression in tumor cells increased with the depth of tumor invasion (Tis 9.5%, T1 19.4%, T2-4 60.0%), as did microvessel density and macrophage infiltration. Macrophage counts correlated with vessel counts, and both were significantly higher in MCP-1-positive than in negative tumors. Of the 6 gastric carcinoma cell lines, 2 constitutively expressed MCP-1 mRNA. In 6 (33.3%) of 18 biopsy samples, MCP-1 mRNA was expressed at higher levels in tumor tissues than in normal mucosa. VEGF protein was expressed by gastric carcinoma cells, whereas PD-ECGF protein was expressed mainly by stromal mononuclear cells. MCP-1 expression correlated significantly with VEGF but not PD-ECGF expression in gastric carcinomas. These results suggest that MCP-1 produced by human gastric carcinoma cells plays a role in angiogenesis via macrophage recruitment and activation.

Carcinoma↗
PubMed2003

[Feasibility of combination mapping utilizing a duo-decapolar electrode catheter and the CARTO system for incisional reentrant atrial tachycardia with cycle length alternation: a case report].

A 43-year-old woman had undergone patch closure operation for atrial septal defect 27 years ago. She was referred to our hospital for evaluation of frequent palpitations since 1 year ago. Electrophysiological study was performed with recording of the coronary sinus, His bundle, and low lateral right free wall electrography utilizing a steerable duo-decapolar electrode catheter(Livewire, Daig). Supraventricular tachycardia with cycle length alternation of 300 and 320 msec similar to atrial flutter was reproducibly provoked by burst pacing from the coronary sinus. During the supraventricular tachycardia, abnormal atrial potentials occurred in the low lateral right free wall region with very low amplitude and splitting potentials. The cycle length alternation of the supraventricular tachycardia depended on the occurrence of the splitting potentials, that is, the splitting potentials were present during the supraventricular tachycardia with a long cycle and the splitting potentials were absent during the supraventricular tachycardia with a short cycle. This phenomenon suggested that the splitting potentials resulted from 2:1 functional intra-atrial local conduction block. In addition, during sinus rhythm the abnormal electrograms revealed fractionated activity. Thus, these findings strongly imply that the supraventricular tachycardia is due to a macro-reentrant right atrial tachycardia utilizing an anatomical obstacle caused by the atrial septal defect operation as a central area, namely incisional reentrant atrial tachycardia. Three-dimensional electroanatomical mapping using the CARTO system(Biosense-Webster) was conducted to investigate whether the low lateral right free wall area possessed the critical isthmus essential to the reentry circuit. Electroanatomical mapping revealed that the very low amplitude potentials and the splitting potentials corresponded to the scars and the functional conduction block area detected by mapping using the multipolar catheter, respectively. According to the propagation mapping, the incisional reentrant atrial tachycardia slowly conducted the channel created by multiple neighboring scars clockwise and the alternation of the tachycardia cycle length was dependent on the development of the functional local intra-atrial conduction block within the channel. An approximately 1.5 cm successful linear lesion was created by radiofrequency catheter ablation to transect the isthmus based on the electroanatomical mapping findings. Afterwards, the incisional reentrant atrial tachycardia could not be induced by burst stimuli from the coronary sinus even under administration of isoproterenol. The use of three dimensional electroanatomical mapping(CARTO system) to evaluate the reentry circuit after the detection of abnormal potentials by using multipolar catheter in advance is a very useful method to determine optimal target site of ablation for a patient with incisional reentrant atrial tachycardia.

Adult↗
PubMed2003

Angiogenic switch as a molecular target of malignant tumors.

In vivo progression to malignancy is characterized by the switch to an angiogenic phenotype. The angiogenic switch is a critical control point for tumor expansion. The ability of a tumor to become neovascularized permits rapid expansion of tumor growth and increases the likelihood of metastases. The genetic alterations that accompany the switch to the angiogenic phenotype are unknown. Discoveries of such genes lead to comprehension of molecular mechanisms of the tumor progression, as well as development of novel therapeutic tools. We have isolated a novel "angiogenic switch molecule," angiopoietin-2, upregulated specifically in hypervascular hepatocellular carcinoma (HCC). Angiopoietin family proteins have been originally identified as ligands of the vascular endothelial receptor of tyrosine kinase Tie2. Ectopic expression of angiopoietin-2 promotes the rapid development of human HCCs and produces hemorrhage within tumors in nude mice. These results suggest a role for angiopoietin-2 in the neovascularization of HCC. In vitro expression of a dominant-negative construct, containing a soluble Tie2 ectodomain (sTie2), led to Angiopoietin protein interaction, inhibition of endogenous Tie2 phosphorylation in vascular endothelial cells. Tumorigenicity with angiogenesis was suppressed by in vivo gene transfer and sTie2 expression in a murine HCC model, suggesting a possible role for angiopoietin/Tie2 signaling in the induction of HCC neovascularization and disease progression. More important, inhibition of the angiopoietin/Tie2 signal transduction cascade is a promising approach for HCC treatment.

Angiogenesis Inducing Agents↗
PubMed2003

Somatic mutation of mitochondrial DNA in Helicobacter pylori-associated chronic gastritis in patients with and without gastric cancer.

Somatic mutations of the mitochondrial DNA (mtDNA) are associated with development of various types of human cancer. To elucidate the significance of somatic mutations of the mtDNA in gastric carcinogenesis, we examined mtDNA mutations in gastric cancers and in Helicobacter pylori-associated chronic gastritis (H. pylori-CG), which is associated with an increased risk for gastric cancer development. Specimens of gastric cancer and gastric mucosa were obtained from 73 gastric cancer patients with H. pylori-CG, 75 cancer-free H. pylori-CG patients and 30 H. pylori-negative healthy subjects. Mutations of a specific mononucleotide repeat (D310) of the mtDNA were examined by microsatellite assay. mtDNA mutations were detected in 9 of 56 (16%) gastric cancers, in 10 of 148 (7%) H. pylori-CG and none of the 30 H. pylori-negative healthy subjects. mtDNA mutations in H. pylori-CG were significantly more frequent in gastric cancer patients than in cancer-free patients (12% vs. 1%, p=0.008). In addition, mtDNA mutations in H. pylori-CG were significantly more frequent in patients with mtDNA mutated gastric cancer than in patients with mtDNA unmutated gastric cancer (66% vs. 4%, p<0.001). These data suggest that somatic mutations of the mtDNA may be involved in the early stages of gastric carcinogenesis.

Chronic Disease↗
PubMed2003

Transcriptional repressor snail and progression of human hepatocellular carcinoma.

PURPOSE: Snail protein is a suppressive transcriptional factor of E-cadherin that mediates cell-to-cell adhesion, tumor progression, and metastases. We explored the expression and function of Snail and its family member Slug in human hepatocellular carcinoma (HCC) to identify its role in tumor progression. EXPERIMENTAL DESIGN AND RESULTS: Transfection of Snail cDNA in Li-7, endogenous E-cadherin-positive human HCC cells, selectively induced the loss of E-cadherin protein expression. We then investigated the expression of Snail and Slug mRNA in 43 human tissue samples of HCC. Using in situ hybridization, Snail mRNA was determined to dominantly express in HCC cells, but not in bile duct cells, blood vessels or infiltrating leukocytes. The mRNA of Snail and Slug were quantified using real-time reverse transcriptase-PCR, and correlations with E-cadherin expression and clinicopathological factors were investigated. Snail mRNA was overexpressed in 7 cases (16%) of HCC compared with adjacent noncancerous liver tissue. E-Cadherin protein expression determined in the same 43 cases by immunohistochemistry was significantly down-regulated in those cases with Snail mRNA overexpression (P = 0.04). The tumor and nontumor ratio of Snail mRNA independently correlated with tumor invasiveness (P = 0.04). However, Slug mRNA correlated with neither E-cadherin expression nor tumor invasiveness. CONCLUSIONS: The data indicate that Snail both down-regulates E-cadherin expression and promotes the invasion in human HCC.

Aged↗
PubMed2003

Clinical significance of thrombospondin-1 expression in relation to vascular endothelial growth factor and interleukin-10 expression at the deepest invasive tumor site of advanced colorectal carcinoma.

Various angiogenic and angiostatic factors regulate angiogenesis. Tumor angiogenesis is a complicated process for which the detailed mechanisms remain unclear. The aim of this study was to elucidate the clinical significance of TSP-1 expression in relation to expression of VEGF and IL-10 and angiogenesis at the deepest invasive tumor site as a predictor of invasive/metastatic potential and prognosis of advanced colorectal carcinoma (CRC). Patients (n=152) who had undergone surgical resection for advanced CRC were entered in this study. Expression of TSP-1, VEGF, and IL-10 was examined immunohistochemically with specific antibodies. Tumor microvessel density (MVD) was also determined immunohistochemically with anti-CD34 antibody (NU-4A1). Expression of TSP-1, VEGF, and IL-10 at the deepest invasive tumor site was detected in 46 (30.3%), 62 (40.8%), and 39 (25.7%) of 152 lesions, respectively. TSP-1, VEGF, and IL-10 expression at the superficial part was detected in 60 (39.5%), 35 (23.0%), and 46 (30.3%) of 152 lesions, respectively. Although there was no significant difference between the incidence of TSP-1 and IL-10 expression at the deepest invasive site or at the superficial part, there was a significant difference between the incidence of VEGF expression at the deepest invasive site and that at the superficial part. Expression of TSP-1 and IL-10 at the deepest invasive tumor site was inversely correlated with metastatic potential and prognosis in relation to MVD. Furthermore, lesions that were TSP-1-negative and VEGF-positive at the deepest invasive tumor site showed the strongest association with MVD. The 5-year survival rate for patients with TSP-1-negative or IL-10 negative lesions at the deepest invasive tumor site was significantly poorer than that for patients with TSP-1-positive or IL-10-positive lesions, respectively. The 5-year survival rate for patients with VEGF expression at the deepest invasive tumor site was significantly poorer than that for patients without VEGF expression. The 5-year survival rate for patients with TSP-1-negative, VEGF-positive lesions at the deepest invasive site were significantly poorer than that for patients with lesions without these characteristics. Multivariate analysis with logistic regression for 5-year survival in patients with curative surgery showed that lymph node metastasis and VEGF expression were significant prognostic factors. Although lack of TSP-1 or IL-10 expression was associated significantly with poorer prognosis, this may be less important in poorer prognosis than the presence of VEGF expression.

Aged↗
PubMed2003

Clinical significance of Fhit expression in development of colorectal carcinoma of various macroscopic types.

It is unclear how expression of the FHIT (fragile histidine triad) gene by the colorectal neoplasm correlates with histogenesis and progression of the disease. We studied the association between expression of Fhit protein and development of colorectal carcinoma (CRC). We also examined relations between Fhit protein expression, macroscopic type, Ki-67 labeling index (LI), and p53 overexpression in carcinoma in situ. We examined 27 colorectal adenomas, 82 carcinomas in situ and 21 invasive CRCs resected endoscopically or surgically. The carcinomas in situ comprised three macroscopic types: polypoid (n=27), superficial (flat elevated, n=27; depressed, n=10) and granulonodular laterally spreading tumor (G-LST, n=23). Fhit, Ki-67, and p53 overexpression were examined immunohistochemically. Levels of Fhit protein were lower in invasive CRC than in adenoma and carcinoma in situ (p<0.01). In carcinoma in situ, reduced Fhit expression was observed in 7 of 22 (31.8%) polypoid types, 13 of 27 (48.1%) superficial flat elevated types, 8 of 10 (80%) superficial depressed types and 7 of 23 (30.4%) G-LST. Frequencies of reduced Fhit expression were significantly higher in the polypoid type and G-LST lesions than in the depressed type (p<0.05). Reduced expression of Fhit protein was related significantly to Ki-67 LI and p53 overexpression in carcinoma in situ (p<0.01). The present findings suggest that reduced expression of Fhit protein is related to development of colorectal neoplasm. Polypoid CRC and G-LST appear to differ from superficial depressed CRC in terms of Fhit expression.

Acid Anhydride Hydrolases↗
PubMed2002

Catalytic Leuckart-Wallach-type reductive amination of ketones.

A CpRh(III) complex catalyzes reductive amination of ketones using HCOONH(4) at 50-70 degrees C to give the corresponding primary amines in high yields. The reaction is clean and operationally simple and proceeds at a lower temperature and with higher chemoselectivity than the original Leuckart-Wallach reaction. The new method has been applied to the synthesis of alpha-amino acids directly from alpha-keto acids.

Journal Article↗
PubMed2002

Monocyte chemoattractant protein-1 expression correlates with macrophage infiltration and tumor vascularity in human esophageal squamous cell carcinomas.

Tumor angiogenesis requires the production of angiogenic factors by tumor and stromal cells. Macrophages are key effectors of angiogenesis and reported to contribute to tumor angiogenesis in several carcinomas. To investigate interactions between tumor cells and macrophages in angiogenesis, we examined macrophage infiltration, tumor vascularity and expression of monocyte chemoattractant protein (MCP)-1, CC chemokine receptor 2 (CCR2) and vascular endothelial growth factor (VEGF) in 57 archival specimens from patients with esophageal dysplasia (n = 9) and squamous cell carcinomas (n = 48). Expression of MCP-1 mRNA was also examined by reverse transcriptase-polymerase chain reaction (RT-PCR) in 7 esophageal carcinoma cell lines and fresh biopsy specimens from 14 patients. The number of infiltrating macrophages correlated closely with expression of VEGF by tumor cells and with neovascularization. Of the 7 cell lines, 4 (TE-1, 3, 5 and 13) constitutively expressed MCP-1 mRNA. In 9 (64.3%) of the 14 patients, MCP-1 mRNA was expressed at high levels in tumor tissues as compared to normal mucosa. MCP-1 immunoreactivity increased with the depth of tumor invasion (Tis 0%, T1 26.3%, T2, T3 42.1%). Moreover, macrophage and vessel counts were significantly higher in MCP-1-positive tumors than in MCP-1-negative tumors. Normal and dysplastic esophageal squamous epithelium showed no staining or faint cytoplasmic staining of MCP-1. Expression of CCR2 immunoreactivity was detected in the cytoplasm of mononuclear cells but not of vascular endothelial cells. These results suggest that interactions between cancer cells and macrophages are important for tumor angiogenesis. MCP-1 may play a role in progression of human esophageal carcinoma through its role in angiogenesis.

Carcinoma, Squamous Cell↗
PubMed2002

Fibrillar collagen regulation of plasminogen activator inhibitor-1 is involved in altered smooth muscle cell migration.

OBJECTIVE: Vascular smooth muscle cells (SMCs) cultured on polymerized type I collagen fibrils are arrested in the G1 phase of the cell cycle, and their phenotypic markers and pattern of expressed genes are markedly altered. In this study, we examined polymerized collagen regulation of plasminogen activator inhibitor (PAI)-1 and its involvement in SMC migration. METHODS AND RESULTS: We demonstrate that secretion and cell surface accumulation of PAI-1 are suppressed in SMCs cultured on polymerized collagen compared with SMCs cultured on monomer collagen. SMCs replated on vitronectin after culture on monomer collagen result in PAI-1 accumulation at focal adhesions and colocalization with alpha(v)beta3 integrins. In contrast, polymerized collagen inhibits PAI-1 accumulation at focal adhesions when the SMCs are replated on vitronectin. Furthermore, for SMCs cultured on polymerized collagen, platelet-derived growth factor-stimulated migration on vitronectin is enhanced by PAI-1, with its function counteracted by urinary plasminogen activator. Finally, exogenous addition of PAI-1 appears to partly restore platelet-derived growth factor-stimulated alpha(v)beta3-dependent SMC migration that is specifically suppressed by polymerized collagen. CONCLUSIONS: Polymerized type I collagen fibrils dynamically regulate PAI-1, which may be involved in altered alpha(v)beta3 integrin-dependent SMC migration.

Cell Movement↗