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Susumu Ohwada

Publications and source records attributed to Susumu Ohwada.

At least 37 records · Page 2Linked to original sources
PubMed2004

Mutational analysis of the BAK gene in 192 advanced gastric and colorectal cancers.

The evasion of apoptosis has been linked to the development of cancer. A recent study of a small number of gastric and colorectal cancers found that the BAK gene, which encodes a pro-apoptotic protein, contained somatic mutations in approximately 17% of the samples analyzed. To investigate the precise frequency of BAK mutations, we examined the entire coding sequence of the BAK gene in gastric and colorectal cancers, using polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) analysis and direct sequencing. We could not detect any somatic mutations of the BAK gene in 192 colorectal and gastric cancers. We found only four single-nucleotide substitutions in the coding sequences, which were also found in corresponding normal samples. We conclude that somatic alterations of the BAK gene are rare in colorectal and gastric cancers.

Apoptosis↗
PubMed2003

Lysophosphatidic acid (LPA) in malignant ascites stimulates motility of human pancreatic cancer cells through LPA1.

Cytokines and growth factors in malignant ascites are thought to modulate a variety of cellular activities of cancer cells and normal host cells. The motility of cancer cells is an especially important activity for invasion and metastasis. Here, we examined the components in ascites, which are responsible for cell motility, from patients and cancer cell-injected mice. Ascites remarkably stimulated the migration of pancreatic cancer cells. This response was inhibited or abolished by pertussis toxin, monoglyceride lipase, an enzyme hydrolyzing lysophosphatidic acid (LPA), and Ki16425 and VPC12249, antagonists for LPA receptors (LPA1 and LPA3), but not by an LPA3-selective antagonist. These agents also inhibited the response to LPA but not to the epidermal growth factor. In malignant ascites, LPA is present at a high level, which can explain the migration activity, and the fractionation study of ascites by lipid extraction and subsequent thin-layer chromatography indicated LPA as an active component. A significant level of LPA1 receptor mRNA is expressed in pancreatic cancer cells with high migration activity to ascites but not in cells with low migration activity. Small interfering RNA against LPA1 receptors specifically inhibited the receptor mRNA expression and abolished the migration response to ascites. These results suggest that LPA is a critical component of ascites for the motility of pancreatic cancer cells and LPA1 receptors may mediate this activity. LPA receptor antagonists including Ki16425 are potential therapeutic drugs against the migration and invasion of cancer cells.

Adult↗
PubMed2003

Identification of BMP and activin membrane-bound inhibitor (BAMBI), an inhibitor of transforming growth factor-beta signaling, as a target of the beta-catenin pathway in colorectal tumor cells.

The Wnt signaling pathway is activated in most human colorectal tumors. Mutational inactivation in the tumor suppressor adenomatous polyposis coli (APC), as well as activation of beta-catenin, causes the accumulation of beta-catenin, which in turn associates with the T cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors and activates transcription of their target genes. Here we show that beta-catenin activates transcription of the BMP and activin membrane-bound inhibitor (BAMBI)/NMA gene. The expression level of BAMBI was found to be aberrantly elevated in most colorectal and hepatocellular carcinomas relative to the corresponding non-cancerous tissues. Expression of BAMBI in colorectal tumor cell lines was repressed by a dominant-negative mutant of TCF-4 or by an inhibitor of beta-catenin-TCF interaction, suggesting that beta-catenin is responsible for the aberrant expression of BAMBI in colorectal tumor cells. Furthermore, overexpression of BAMBI inhibited the response of tumor cells to transforming growth factor-beta signaling. These results suggest that beta-catenin interferes with transforming growth factor-beta-mediated growth arrest by inducing the expression of BAMBI, and this may contribute to colorectal and hepatocellular tumorigenesis.

Adenoviridae↗
PubMed2003

RICS, a novel GTPase-activating protein for Cdc42 and Rac1, is involved in the beta-catenin-N-cadherin and N-methyl-D-aspartate receptor signaling.

Cadherin adhesion molecules are believed to be important for synaptic plasticity. beta-Catenin, which links cadherins and the actin cytoskeleton, is a modulator of cadherin adhesion and regulates synaptic structure and function. Here we show that beta-catenin interacts with a novel GTPase-activating protein, named RICS, that acts on Cdc42 and Rac1. The RICS-beta-catenin complex was found to be associated with N-cadherin, N-methyl-d-aspartate receptors, and postsynaptic density-95, and localized to the postsynaptic density. Furthermore, the GTPase-activating protein activity of RICS was inhibited by phosphorylation by Ca(2+)/calmodulin-dependent protein kinase II. These results suggest that RICS is involved in the synaptic adhesion- and N-methyl-d-aspartate-mediated organization of cytoskeletal networks and signal transduction. Thus, RICS may regulate dendritic spine morphology and strength by modulating Rho GTPases.

Amino Acid Sequence↗
PubMed2003

Adjuvant therapy with protein-bound polysaccharide K and tegafur uracil in patients with stage II or III colorectal cancer: randomized, controlled trial.

PURPOSE: Intravenous fluorouracil and leucovorin for six to eight months is currently a standard adjuvant treatment for Stage III colon cancer; however, this regimen is complex, inconvenient, and has a high intolerability. Adjuvant chemotherapies are claimed for objective response rates with an acceptable safety profile and complexity. We investigated the benefits of oral protein-bound polysaccharide K added to oral tegafur/uracil on curatively resected Stage II or III colorectal cancer. METHODS: We prospectively randomized 207 patients to treatments of either oral 3.0 g protein-bound polysaccharide K plus 300 mg tegafur/uracil or 300 mg tegafur/uracil alone for two years following 12 mg/m2 and 8 mg/m2 mitomycin treatment on postoperative Days 1 and 2, respectively. The primary end points were disease-free and overall survival, and recurrence rates. RESULTS: Three (1.4 percent) patients were declared ineligible, and three patients did not start treatment. In total, 201 patients were analyzed. The three-year, disease-free survival rate was 80.6 percent (standard error = 3.4 percent) in the protein-bound polysaccharide K group (P = 0.02) compared with 68.7 percent (SE = 5.7 percent) in the control group after a median follow-up of 3.7 years. The estimated relative risk of recurrence in the control group was 1.87 (95 percent confidence interval, 1.10-3.20) at three years. The three-year, overall survival rate was 87.3 percent (standard error = 2.9 percent) in the protein-bound polysaccharide K group and 80.6 percent (standard error = 4.8 percent) in the control group (P = 0.24). The three-year, overall survival rate in 80 pathological TNM Stage III patients was 83.0 percent (standard error = 5.2 percent) in the protein-bound polysaccharide K group and 59.3 percent (standard error = 9.5 percent) in the control group (P = 0.02). Protein-bound polysaccharide K prevented distant metastases (P = 0.05), particularly lung metastases (P = 0.01). The incidence of adverse effects was minimal, and compliance was good. CONCLUSION: Adjuvant therapy using a combination of oral protein-bound polysaccharide K and tegafur/uracil is highly effective in preventing the recurrence of colorectal cancer in Stage II or III patients, and increases overall survival in pathological TNM Stage III. These results will be a sufficient proof to conduct a larger study to compare tegafur/uracil/protein-bound polysaccharide K with 5-fluorouracil/leucovorin.

Adult↗
PubMed2003

Biological properties and gene expression associated with metastatic potential of human osteosarcoma.

Lung metastasis has a great influence on the prognosis of patients with osteosarcoma. We previously established two high-metastatic sublines, M112 and M132, from the HuO9 human osteosarcoma cell line by in vivo selection. In this study, we newly isolated a high-metastatic subline, H3, and three low-metastatic sublines, L6, L12 and L13, from HuO9 by the dilution plating method. Three high-metastatic sublines produced more than 200 metastatic nodules in the lung, while three low-metastatic sublines produced no or few nodules after injection of 2 x 10(6) cells into the tail vein of nude mice. There were significant differences in the motility and invasiveness between high- and low-metastatic sublines, whereas the growth rates in vitro and the tumorigenicity in vivo showed no correlation with their metastatic abilities. Early adherence to culture plates was significantly lower in two of three low-metastatic sublines, which occupied smaller surface areas on the culture plates than other sublines did. Comparison of the expression of 637 cancer-related genes by cDNA microarray revealed that seven genes were differentially expressed between high- and low-metastatic sublines. Among them, five genes (AXL, TGFA, COLL7A1, WNT5A, and MKK6) were associated with adherence, motility, and/or invasiveness. These results suggest that the differences in motility/invasiveness and adhesive abilities are key determinants of lung metastasis in osteosarcoma.

Animals↗
PubMed2003

Exfoliative rejection after intestinal transplantation in children.

BACKGROUND: Graft rejection is the most significant cause of allograft failure after intestinal transplantation (ITx). Severity can vary and is based on histologic criteria, the most extreme form being exfoliation of the mucosa. We present the characteristics and outcome of children who developed exfoliative rejection (ER) after ITx. METHODS: Between June 1990 and March 2002, 88 patients received 92 ITx which included isolated small bowel (SB, n = 26), combined liver-small bowel (LSB, n = 54), and multivisceral MV n = 12) allografts performed under tacrolimus and steroid immunosuppresson. ER was diagnosed by endoscopy and confirmed by biopsy. RESULTS: Thirteen (15%) of 88 patients developed 15 episodes of ER in 15 intestinal allografts, and included SB (n = 8), LSB (n = 5), and MV (n = 2). Time to ER after ITx ranged from 9 days to 45.5 months (median 22 days). Eight episodes of ER developed within 1 month after ITx. Ten episodes of ER were exacerbations of prior rejection. Five episodes occurred abruptly. All but one received OKT3. Fourteen of 15 allografts were lost; six patients underwent allograft enterectomy acutely as a salvage operation because of ER. The remainder of the allografts were either removed or lost to patient death as a consequence to infection or chronic rejection after resolution of ER. Retransplantation was performed in three patients, with subsequent recurrence of ER in two retransplanted allografts. Inclusion of a liver allograft was a protective factor toward decreasing the incidence of ER. The results of cross-matching, inclusion of a colonic segment, and simultaneous bone marrow infusion did not affect the incidence of ER. Infectious complications included post-transplant lymphoproliferative disease (n = 4), cytomegalovirus (n = 5), and adenovirus infection (n = 2). CONCLUSIONS: Exfoliative rejection is associated with a high morbidity and mortality after ITx. Strategies to improve survival may include up front anti-lymphocyte antibody therapy and, when fail to respond promptly and satisfactorily, early intestinal allograft removal.

Child, Preschool↗
PubMed2002

Effects of a p38 mitogen-activated protein kinase inhibitor as an additive to Euro-Collins solution on reperfusion injury in canine lung transplantation1.

BACKGROUND: The activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in the development of ischemia/reperfusion injury. FR167653 is a novel p38 MAPK inhibitor. This study evaluated the effects of p38 MAPK inhibition during cold ischemia on subsequent reperfusion injury using FR167653 as an additive to Euro-Collins solution in canine lung transplantation. METHODS: Canine orthotopic left lung transplantation was performed after 12-hr cold storage using Euro-Collins solution, with or without FR167653. Fifteen minutes after reperfusion, the right pulmonary artery and the right stem bronchus were ligated, and the animals were observed for 4 hr after reperfusion. Left pulmonary vascular resistance (L-PVR), cardiac output (CO), arterial oxygen pressure (Pao2), and alveolar-arterial oxygen pressure difference (A-aDo2) were measured. Lung specimens were harvested for wet-to-dry lung weight ratio (WDR) measurements, histopathologic studies, and polymorphonuclear neutrophil (PMN) counts. The activities of p38 MAPK in lung grafts were evaluated. RESULTS: The addition of FR167653 significantly (P<0.05) improved Pao2, A-aDo2, L-PVR, CO, and WDR and suppressed PMN infiltration after transplantation. FR167653 also ameliorated histologic damage to the lung graft. During cold storage, p38 MAPK was not activated in the lung graft, whereas it was markedly activated 30 min after reperfusion. FR167653 significantly (P<0.05) inhibited p38 MAPK activation 30 min after reperfusion. CONCLUSIONS: The addition of FR167653 to Euro-Collins solution improved lung graft viability associated with the inhibition of p38 MAPK activation. These results suggest that inhibiting p38 MAPK activation may attenuate ischemia/reperfusion injury in lung transplantation.

Animals↗
PubMed2002

Frameshift mutations in the MBD4/MED1 gene in primary gastric cancer with high-frequency microsatellite instability.

MBD4/MED1 is a newly identified mismatch repair gene, which is mutated in colon, endometrial, and pancreatic high-frequency microsatellite instability (MSI-H) tumors. To assess its role in gastric cancers, we investigated MBD4/MED1 mutations in sporadic gastric cancers, compared with colon cancers. Frameshift mutations were found in 29% of gastric and 20% of colon MSI-H cancers, but not in any low-frequency microsatellite instability/microsatellite stable cancers. MBD4/MED1 is mutated in gastric cancers as frequently as in colon cancers; these mutations reduce the accuracy of DNA repair, and may lead to cancer progression.

Aged↗
PubMed2002

Overexpression of Icat induces G(2) arrest and cell death in tumor cell mutants for adenomatous polyposis coli, beta-catenin, or Axin.

Aberrant activation of Wnt signaling caused by mutations in adenomatous polyposis coli (APC) or beta-catenin is a critical event in the development of human colorectal tumors. Wnt signaling stabilizes beta-catenin, which in turn associates with TCF/LEF family transcription factors, ultimately altering the expression of Wnt target genes. We have recently identified ICAT, a beta-catenin-interacting protein that interferes with the interaction between beta-catenin and TCF-4, thereby negatively regulating Wnt signaling. In the present study, we generated a recombinant adenovirus encoding ICAT and examined its effect on the growth of tumor cells. We found that Icat inhibits proliferation of colorectal tumor cells mutated in APC or beta-catenin and hepatocellular carcinoma cells mutated in AXIN: By contrast, Icat did not inhibit growth of either normal or tumor cells containing the wild-type APC, beta-catenin, and Axin genes. Icat also inhibited the anchorage-independent growth of colorectal tumor cells and tumorigenic growth of colorectal tumor xenografts. Furthermore, we found that Icat inhibits both dephosphorylation of Cdc2 and nuclear translocation of cyclin B1 and induces G(2) arrest followed by cell death in colorectal tumor cells. These results suggest that Wnt signaling is critical for the growth of colorectal tumors and some hepatocellular carcinomas and that expression of ICAT or drugs which mimic its effects may be useful in the treatment of these tumors.

Adaptor Proteins, Signal Transducing↗
PubMed2002

In situ vs ex situ pancreatic duct stents of duct-to-mucosa pancreaticojejunostomy after pancreaticoduodenectomy with billroth I-type reconstruction.

BACKGROUND: Pancreatic fistula is a leading cause of morbidity and mortality after pancreaticoduodenectomy, and an external stent of pancreaticojejunostomy has been recommended to prevent pancreatic fistula. HYPOTHESIS: Duct-to-mucosa pancreaticojejunostomy should not require placement of an external stent. DESIGN: Nonrandomized control study. SETTING: University hospital. PATIENTS: Seventy-four patients undergoing pancreaticoduodenectomy with duct-to-mucosa pancreaticojejunostomy were allocated to either the ex situ group (external pancreatic stent drainage) or the in situ group (no external drainage). MAIN OUTCOME MEASURES: Operative mortality; postoperative complications, particularly pancreatic fistula; and patency of duct-to-mucosa pancreaticojejunostomy. RESULTS: Preoperative factors, indicated disorders, and intraoperative factors were similar for both groups. Mortality rates were 1% (1/74) overall, 3% (1 death) for the in situ group, and 0% for the ex situ group. Morbidity rates were 32% (12/37) for the in situ group and 35% (13/37) for the ex situ group. The incidence of pancreatic fistula was 5.4% and was the same for the in situ and ex situ groups. The incidence of delayed gastric emptying was similar for the in situ (19% [7/37]) and ex situ (14% [5/37]) groups. Ampullary tumors and pancreatic ducts 2 mm or less in diameter had a higher incidence of pancreatic fistula, but the incidence was similar in both treatment groups. Nasogastric tube drainage day, the median hospital stay, and pancreaticojejunostomy patency were similar in both groups. CONCLUSIONS: The results were considered to show equivalent outcomes for ex situ and in situ pancreatic stenting of the duct-to-mucosa pancreaticojejunostomy after pancreaticoduodenectomy. The use of transanastomotic stents has to be selective according to the individual characteristics of each patient. We recommend their use with ampullary tumors or small ducts (< or =2 mm).

Aged↗
PubMed2002

Advantages of Celsior solution in graft preservation from non-heart-beating donors in a canine liver transplantation model.

BACKGROUND: The optimal method for preserving livers from non-heart-beating donors (NHBD) is still unknown. We compared the Celsior solution, a new extracellular-type, low-potassium, low-viscosity preservation solution, with the University of Wisconsin (UW) solution in a canine orthotopic liver transplantation from NHBD. MATERIALS AND METHODS: Fourteen adult mongrel dogs, weighing 9 to 17 kg, were divided into two groups: the Celsior or the UW group (n = 7 each). The thoracic descending aorta and supradiaphragmatic inferior vena cava were cross-clamped for 20 min to induce warm ischemia as a NHBD model. The liver was flushed with the respective cold preservation solution and then stored at 4 degrees C for 4 h. The grafts were transplanted using the piggy-back technique under portal decompression by leaving the native right lobe as a temporary shunt. RESULTS: The duration of liver flushing out (min) was shorter (P < 0.05), and the serum glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, lactate dehydrogenase, lactate, and alpha-glutathione S-transferase concentrations 2 and 6 h after reperfusion of the graft (RPF) were lower (P < 0.05) in the Celsior group than in the UW group. Hepatic tissue blood flow (HTBF) did not deteriorate as much (P < 0.05) in the Celsior group. The serum endothelin-1 level was lower (P < 0.05) in the Celsior group 2 h after RPF. Histopathology of liver specimens revealed portal congestion and hepatocyte necrosis with neutrophil infiltration in the UW group, while these findings were mild in the Celsior group. CONCLUSIONS: The Celsior solution improves vascular endothelial injury in livers from NHBDs and may have advantages in graft flush and preservation of grafts from NHBDs.

Adenosine↗
PubMed2002

A hemophagocytic syndrome-like condition after emergency colectomy for perforated colon cancer: report of a case.

Hemophagocytic syndrome is a rare but often fatal condition, and little is known about why this disorder can occur following surgery. We report herein the case of a patient successfully treated for a hemophagocytic syndrome-like condition that developed after emergency right hemicolectomy for a retroperitoneal abscess secondary to perforated colon cancer. The 62-year-old man initially presented after the sudden development of severe right back pain, and computerized tomography scans revealed a retroperitoneal abscess continuous with a tumor in the ascending colon. An emergency right hemicolectomy was subsequently performed. On postoperative day (POD) 2, his blood platelet count suddenly dropped to 1 x 10(4)/microl and histological examination of a bone marrow specimen taken on POD 5 showed abnormal histiocytes that had phagocytosed not only megakaryocytes, but also erythrocytes and leukocytes, and a normocellular marrow with a normal number of megakaryocytes. Hemophagocytic syndrome was suspected, and predonine was administered. The patient's condition improved remarkably and he was discharged on POD 51.

Abscess↗
PubMed2002

Ileal perforation caused by cytomegalovirus infection in a patient with recurrent gastric cancer: report of a case.

We report a case of ileal perforation caused by cytomegalovirus (CMV) infection in a patient with peritoneal recurrence of gastric cancer. Emergency laparotomy revealed a pinhole-sized perforation in a reddish segment of the small bowel, 100 cm proximal to the terminal ileum, and peritoneal carcinosis of recurrent gastric cancer invading the transverse colon and the gastrojejunal anastomosis of a Billroth-II procedure. The affected ileum was resected, a primary anastomosis was performed, and a colostomy was made in the ascending colon. The histology of the ileum revealed acute inflammation with vasculitis and CMV inclusions in the macrophages and endothelial cells and evidence of CMV on immunostaining. There was no evidence of cancer cell invasion or any other pathogens. Although the prognosis associated with bowel perforation due to CMV infection is poor, emergency surgery saved our patient's life.

Cytomegalovirus Infections↗
PubMed2002

Effects of a bradykinin B(2) receptor antagonist, FR173657, on pulmonary ischemia-reperfusion injury in dogs.

BACKGROUND: This study investigated the effects of a bradykinin B(2) receptor antagonist, FR173657 (FR), on pulmonary ischemia-reperfusion (I/R) injury. METHODS: Twenty-four mongrel dogs were divided into four groups (n = 6 each). In Groups I, II and III, FR doses of 33, 100 and 300 nmol/kg per hour, respectively, were administered continuously beginning 30 minutes before ischemia and continuing for 2 hours after reperfusion. In Group IV, vehicle alone was administered. Warm ischemia was induced for 3 hours by clamping the left pulmonary artery and veins. Simultaneously, the left stem bronchus was bisected and then anastomosed before reperfusion. Fifteen minutes after reperfusion, the right pulmonary artery and bronchus were ligated. Left pulmonary vascular resistance (L-PVR), cardiac output (CO), arterial oxygen pressure (PaO(2)) and the alveolar - arterial oxygen pressure difference (A-aDO2) were measured for 4 hours after reperfusion. Lung tissue was harvested for wet-to-dry weight ratio (WDR) measurements, histopathologic studies and polymorphonuclear neutrophil (PMN) counts. Serum thromboxane (TX) B(2), 6-keto-prostaglandin (PG) F(1alpha) and leukotriene (LT) B(4) levels were also measured. RESULTS: PaO(2), A-aDO2, L-PVR and CO were significantly (p < 0.05) improved and WDR was significantly (p < 0.05) lower in Groups II and III than in Group IV. Histologic tissue edema was mild, and PMN infiltration was significantly (p < 0.05) reduced in Groups I, II and III compared with Group IV. TXB(2) levels were significantly (p < 0.05) lower in Group II than in Group IV, whereas 6-keto-PGF(1alpha) levels were not significantly different. LTB(4) levels were significantly (p < 0.05) lower in Groups II and III than in Group IV. CONCLUSIONS: FR appears to have a protective effect on pulmonary I/R injury stemming from the inhibition of eicosanoid release.

Animals↗
PubMed2002

Compressed spectral arrays of patients with fulminant hepatic failure in hepatic coma undergoing liver transplantation.

Assessing the coma status of patients with fulminant hepatic failure (FHF) is important for determining the reversibility of brain damage and for properly timing liver transplantation. The compressed spectral array (CSA) method is a frequency analysis technique that processes electroencephalogram signals by computer to facilitate on-line interpretation. This method has been used to monitor the consciousness levels of neurointensive care unit patients. In this study, we determined whether CSA could be used to assess the coma status of patients with FHF, and whether CSA provided information that was useful in deciding when to proceed with liver transplantation. CSA recording was carried out in 17 FHF patients with encephalopathy (coma grade III-IV) who underwent living-related liver transplantation between August 1997 and May 1999. Recording was performed with a Neuromonitor OEE-72044 (NIHON KOHDEN, Osaka, Japan) every 24 h before and after transplantation, until the patients regained consciousness. The CSAs of healthy controls were distributed almost equally between 0 and 16 Hz. The CSAs of FHF patients in hepatic coma were classified into three patterns. Eight of the 17 patients showed very prominent slow waves of about 2 Hz (group A), and seven patients showed strongly suppressed rapid waves between 8 and 16 Hz (group B). The remaining two patients showed CSA patterns that were similar to those of healthy controls, even though these patients were comatose (group C). Abnormal CSA patterns were observed in 15 of the 17 patients (88%). Group B patients seemed to have higher coma grades than did group A patients. Sixteen patients underwent liver transplantation, completely recovered from hepatic encephalopathy, and subsequently showed CSA patterns similar to those of healthy controls. One patient died without regaining consciousness. These results suggest that CSA is useful in assessing the coma status of FHF patients and in evaluating electrophysiological recovery from hepatic coma after liver transplantation.

Adolescent↗