Biomedical subjects

Michio Ogawa

Publications and source records attributed to Michio Ogawa.

At least 55 records · Page 3Linked to original sources

PubMed2003

Dynamic aspects of granulocyte activation in rat severe acute pancreatitis.

We demonstrated dynamic aspects of granulocyte activation in rat severe acute pancreatitis, which was induced by cerulein and aggravated following lipopolysaccharide (LPS) injection. Pancreatitis induced by cerulein increased intracellular elastase activity of granulocytes in the blood. However, significant systemic cytokinemia was not provoked under such conditions. After induction of severe pancreatitis by LPS, intracellular elastase activity of circulating granulocytes decreased markedly and immediately. This decrease occurred simultaneous to induction of systemic hypercytokinemia and granulocyte migration into the lung. Overall results imply that: (1) circulating granulocytes are activated by induction of mild pancreatitis; (2) activation of granulocytes is mediated by factors other than systemic cytokinemia, such as locally produced cytokines; (3) those priming granulocytes immediately and significantly migrate from the circulation into the extravascular space by induction of endotoxemia; and (4) migration of granulocytes, in turn, may be mediated by systemic cytokinemia.

Acute Disease↗

PubMed2003

Non-occlusive mesenteric ischemia and its associated intestinal gangrene in acute pancreatitis.

BACKGROUND/AIMS: Non-occlusive mesenteric ischemia (NOMI) has been defined as diffuse intestinal ischemia that often results in intestinal gangrene in the presence of a patent arterial trunk. The prevalence and nature of NOMI in acute pancreatitis was investigated. METHODS: A total of 120 consecutive patients with acute pancreatitis managed in the Department of Surgery II, Kumamoto University Medical School, from April 1992 through December 2002, were investigated retrospectively. Among them, 60 patients had the severe form. RESULTS: The overall mortality of acute pancreatitis patients was 8.3% (10/120). The prevalence and mortality of acute pancreatitis associated with NOMI were 6.7% (8/120) and 63% (5/8), respectively, while those of patients with NOMI-associated intestinal gangrene were 4.2% (5/120) and 100% (5/5), respectively. The mortality of patients with severe acute pancreatitis who did not develop NOMI was 10% (5/52). All patients with NOMI-associated intestinal gangrene quickly progressed and subsequently died of multiple organ failure. Plasma creatine phosphokinase (CPK) and lactate levels were elevated significantly in patients with NOMI. CONCLUSION: Acute pancreatitis associated with NOMI was extremely severe. If the plasma CPK and lactate levels are extremely high, NOMI should be suspected.

Adolescent↗

PubMed2003

A pulmonary metastatic model of human non-small cell lung carcinoma cells that produce a neutrophil elastase-like molecule in severe combined immunodeficiency mice.

STUDY OBJECTIVES: To establish a clinically relevant animal model of pulmonary metastases of human non-small cell lung carcinoma (NSCLC) cells in severe combined immunodeficiency (SCID) mice, which can be used for repetitive investigations, so as to improve our understanding and management of the cellular and molecular mechanisms of human lung cancer metastases. METHODS AND RESULTS: SCID mice subcutaneously injected in the flank with 1 x 10(6) EBC-1 cells derived from human lung squamous cell carcinoma were killed weekly for examination until 12 weeks after tumor inoculation. The biological characteristics of implanted tumors and their metastatic foci were investigated by hematoxylin-eosin staining and immunostaining for neutrophil elastase (NE). Three weeks after ectopic implantation, EBC-1 cell lines formed a tumor at the inoculation site and grew steadily to show a plateau at 10 weeks. EBC-1 cells formed multiple metastases in the lung 7 weeks after tumor inoculation; their numbers increased steadily until 12 weeks in all mice. Immunoreactivity for NE was intense in the metastatic tumor cells. Then, to establish the primary tumor amputation/pulmonary metastasis model and to evaluate how primary tumor amputation influences the development of pulmonary metastases at the cellular and molecular level, excision was performed before (3 weeks and 5 weeks after inoculation) and after (7 weeks and 9 weeks after inoculation) formation of lung metastases. When the primary tumor was excised 3 weeks after tumor inoculation, all mice had pulmonary metastasis at 12 weeks after inoculation. Blood samples obtained at 3 weeks after tumor inoculation contained human beta-actin messenger RNA, which represents circulating tumor cells. CONCLUSION: Our NSCLC EBC-1 pulmonary metastasis model is reliable, technically simple, and predictably results in pulmonary metastasis from early hematogenous spread. This model may be useful for elucidating the mechanism of pulmonary metastasis in human lung cancer, and testing anti-metastatic efficacy of therapeutic agents in vivo.

Animals↗

PubMed2003

Genetic pathways of 'de novo' colorectal carcinomas with reference to fetal-type glycogen phosphorylase positive foci.

'De novo' carcinogenesis has been advocated besides 'adenoma carcinoma sequence' as another dominant pathway leading to the colorectal carcinoma. Our previous study demonstrated that brain (fetal)-type glycogen phosphorylase (BGP) positive foci in the transitional mucosa (BGP foci) have frequent p53 mutations and that the distribution of BGP foci has a close relationship with the location of 'de novo' carcinoma. The aims of the present study were to investigate further genetic alterations in the BGP foci and to clarify the mechanism of 'de novo' carcinogenesis. Twenty-eight colorectal carcinomas with invasion into submucosa or superficial muscularis propria without any adenoma component expressing immunoreactive p53 protein were selected from 168 resected specimens. Investigations of the p53, K-ras and APC mutations was performed in the BGP foci, BGP negative colorectal mucosa and 'de novo' carcinoma using PCR-SSCP and DNA squencing. In all 28 cases, immunoreactive BGP was positive in the carcinomas and the BGP foci were observed sporadically in the mucosa adjacent to the carcinoma. No K-ras mutation was observed in either carcinoma or BGP foci in any of the cases. Mutations of p53 and APC were 14 (50.0%) and 9 (32.1%) in 'de novo' carcinomas, and 11 (39.3%) and 1 (3.6%) in BGP foci, respectively. Both p53 and APC mutations were detected in 8 and 1, p53 mutation alone in 6 and 10, APC mutation alone in 1 and 0 out of 28 carcinomas and BGP positive foci, respectively. These results suggest that the BGP foci may play a very important role in the 'de novo' colorectal carcinogenesis from the frequent genetic alterations of p53, and that there may be two major pathways, i.e., the p53-APC pathway and the p53 alone pathway, from the chain of genetic alterations between BGP foci and 'de novo' carcinoma.

Brain↗

PubMed2003

Expression of proteinase-activated receptor-2 in human pancreatic cancer: a possible relation to cancer invasion and induction of fibrosis.

The proteinase-activated receptor-2 (PAR-2) is a G protein-coupled receptor that is cleaved and activated by trypsin. To clarify the presence of PAR-2 in human pancreatic cancer, the expression of PAR-2 was analyzed by RT-PCR, immunoblotting and immunocytochemistry using 5 human pancreatic cancer cell lines. And to evaluate the biological significance, immunohistochemical expression of PAR-2 in malignant and non-malignant human pancreatic tissues was examined using paraffin-embedded sections. The presence of PAR-2 was confirmed in all 5 pancreatic cancer cell lines and all 21 paraffin-embedded specimens from human pancreatic cancer examined. The expression of PAR-2 was found to be higher in the tissues with infiltrative growth pattern than those with expansive growth pattern. Moreover, significantly higher expression of PAR-2 was observed in the tissues which were accompanied by severe fibrosis. Even in the same specimen, the intensity of immunoreactivity tended to be stronger in the part with severe fibrosis than that with mild fibrosis. Similarly, the higher expression of PAR-2 was observed in chronic pancreatitis with severe fibrosis than with mild fibrosis. Taken together, these results suggest that the activation of PAR-2 is involved in cancer invasion and the induction of fibrosis in human pancreatic cancer.

Adenocarcinoma↗

PubMed2003

Mechanisms of peritoneal metastasis after operation for non-serosa-invasive gastric carcinoma: an ultrarapid detection system for intraperitoneal free cancer cells and a prophylactic strategy for peritoneal metastasis.

PURPOSE: This aims of this study are to establish an ultra-rapid quantitative reverse transcription-PCR (RT-PCR) protocol that enables the diagnosis of i.p. cancer spread during operation, to reveal the mechanisms of peritoneal metastasis from non-serosa-invasive gastric carcinoma, and to evaluate the effect of the extensive intraoperative peritoneal lavage (EIPL) using the ultra-rapid quantitative RT-PCR as a prophylactic strategy for peritoneal metastasis. EXPERIMENTAL DESIGN: Peritoneal lavage samples from 63 patients with non-serosa-invasive gastric carcinoma were obtained at laparotomy and immediately after lymph node dissection. To identify the free cancer cells in the samples, carcinoembryonic antigen- and cytokeratin 20-specific RT-PCRs were performed using the LightCycler method in combination with an automated mRNA extractor. In addition, EIPL was performed in five cases with serosa-invasive gastric carcinoma, and its efficacy was evaluated by the ultra-rapid quantitative RT-PCR protocol. RESULTS: The method enabled us to complete the detection of cancer cells within approximately 70 min. Both the carcinoembryonic antigen and cytokeratin 20 mRNA in i.p. lavages after lymph node dissection were identified in three (14.3%), four (26.7%), and six (46.2%) patients with submucosal, muscularis propria, and subserosal tumors, respectively. Lymph node metastasis was the independent predictor of the existence of i.p. free cancer cells. The ultra-rapid quantitative RT-PCR demonstrated that EIPL reduced free cancer cells from 3.8 x 10(5) +/- 1.4 x 10(5) cells to 2.8 +/- 1.5 cells/100 ml lavage after six to eight washes, and they disappeared after seventh to ninth wash. CONCLUSIONS: The present study proved that lymph node dissection opened lymphatic channels and spread viable cancer cells into the peritoneal cavity. It is suggested that the combination of the novel detection system with the intraoperative therapy of EIPL can be a useful prophylactic strategy for peritoneal metastasis from gastric carcinoma.

Aged↗

PubMed2003

From acute to chronic pancreatitis: the role of mutations in the pancreatic secretory trypsin inhibitor gene.

Pancreatic secretory trypsin inhibitor (PSTI) is a potent natural inhibitor of trypsin. We proposed the hypothesis that, if the function of the PSTI is impaired by its genetic mutation, trypsin may easily promote autodigestion causing pancreatitis and we performed a mutational analysis of the PSTI gene in patients with pancreatitis. Two exonic mutations (N34S and R67C) were thought to be associated with a predisposition to pancreatitis. The N34S mutation was co-segregated with two intronic mutations, IVS1-37T>C and IVS3-69insTTTT. Although we analyzed the function of the recombinant N34S protein, we could not demonstrate the loss of function of this protein. Intronic mutations, rather than N34S itself (IVS1-37T>C + N34S + IVS3-69insTTTT complex), may be associated with the decreased function of the PSTI. Alternatively, increased digestion of N34S in vivo may be applicable. As for R67C, the conformational alteration of the protein by forming intra-molecular or inter-molecular disulfide bonds with 67Cys was strongly suggested. These results, along with the brand-new findings in PSTI knockout mice, suggest that the genetic mutation of the PSTI is one of the important mechanisms for predisposition to pancreatitis by lowering the trypsin inhibitory function.

Acute Disease↗

PubMed2003

Pre- and post-operative adjuvant chemotherapy in colorectal cancer.

A multi-center randomized controlled study was conducted in order to investigate the usefulness of pre- and post-operative adjuvant chemotherapy in colorectal cancer. The patients were stratified into those with colon cancer and those with rectal cancer and divided into 2 groups, Group A and Group B. The patients in Group A received tegafur suppositories (750 mg/day) from 1 to 2 weeks prior to surgery, to 2 weeks following surgery and then oral administration of tegafur and uracil (UFT) (260 mg/m(2)) for 1 year. The patients in Group B, on the other hand, received only UFT (260 mg/m(2)) for 1 year beginning week 2 after surgery. Although there was no significant difference between Groups A and B in the 5-year survival rate, the 5-year disease-free survival rate was significantly higher in Group A, especially for rectal cancer (p<0.05). In addition, remote metastases tended to be suppressed for both colon and rectal cancer in Group A (p=0.08 and p=0.072). There was no serious adverse reaction to tegafur. Pre- and post-operative adjuvant chemotherapy with tegafur had fewer adverse reactions and was convenient to administer. Thus, it was considered useful for suppression of postoperative distant metastasis in colorectal cancer.

Aged↗

PubMed2003

Functional disturbance of biliary indocyanine green excretion in rat cerulein pancreatitis followed by endotoxemia: role of the prime and the second attack.

CONTEXT: Hepatic injury is considered one of the critical complications associated with acute pancreatitis. It was proposed that initial insults to the liver in the early phase of the attack have an important priming effect, and the subsequent infectious attack (e.g. infectious pancreatic necrosis, bacterial translocation episode) constitutes a second attack on the liver. OBJECTIVE: To evaluate the role of priming by induction of cerulein pancreatitis and a following second attack by endotoxemia. MAIN OUTCOME MEASURES: Plasma clearance and biliary excretion of indocyanine green (a hepatophillic hydrophobic organic anion). DESIGN: A model of acute pancreatitis in rats. SETTING: Four groups of rats: untreated control, cerulein pancreatitis, endotoxemia and endotoxemia following the induction of cerulein pancreatitis (pancreatitis + endotoxemia). RESULTS: Biliary indocyanine green excretion was significantly disturbed only in the pancreatitis + endotoxemia group. Plasma clearance (a reflection of hepatic uptake) of indocyanine green from the blood was only slightly affected in endotoxemia group. CONCLUSION: Biliary secretion is quite sensitive to this hepatic injury model. Both the preceding priming insult and the following second attack are important in the development of hepatic injury.

Acute Disease↗

PubMed2003

Angiographic features in acute pancreatitis: the severity of abdominal vessel ischemic change reflects the severity of acute pancreatitis.

CONTEXT: Assessment of tissue microcirculation is one of the important aspects of pathological evaluation in acute pancreatitis. Severe ischemic change sometimes leads to the development of organ dysfunction and/or infectious complications. OBJECTIVE: To evaluate the angiographic features of acute pancreatitis and correlate them with the severity of the disease. DESIGN: Retrospective study. PATIENTS: Twenty-seven consecutive patients with acute pancreatitis who had undergone angiography were retrospectively investigated. MAIN OUTCOME MEASURES: Vascular findings and Ranson score. RESULTS: Ischemic changes were found in 18 patients (66.7%); 11 (40.7%) were severe changes. Pseudoaneurysm, bleeding, and staining were seen in 4 (14.8%), 2 (7.4%) and 5 (18.5%) patients, respectively. The rate of severe ischemic changes was significantly correlated with the Ranson score (P=0.012). Conclusions Angiographic findings are useful for the evaluation of severe acute pancreatitis.

Acute Disease↗

PubMed2003

[Endoscopic local ablation therapy (ELAT) for hepatocellular carcinoma--inventive approaches to achieve radical treatment and to expand the indication of ELAT].

We introduce some inventive approaches in endoscopic local ablation therapy (ELAT) for patients with hepatocellular carcinoma (HCC). ELAT is applied in cases of HCC when the tumor is smaller than 3 cm on the surface of the liver (smaller than 4 cm with extrahepatic growth), and tumor numbers < or = 3. Appropriate use of the laparoscopic, thoracoscopic and hand-assisted approaches, suitable preceding embolizations with the angiographic technique, a combination of ablation therapy, and the use of CO2-angio US, DIMON puncture system and cluster needle are important. If necessary, additional surgeries such as endoscopic hepatectomy, laparoscopic cholecystectomy or laparoscopic devascularization must be performed together. As a result, it will be possible to expand the indication of ELAT safely and radically.

Carcinoma, Hepatocellular↗

PubMed2003

[Significance of local ablation therapy following portal embolization therapy for hepatocellular carcinoma with portal vein tumor thrombus].

We have performed ablation therapy for 4 patients who had hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). In order to avoid intrahepatic metastasis due to ablation, we treated portal venous embolization before ablation. After treatment, computed tomography revealed no viable area in the treated lesion and no dissemination in the portal vein. A complication was encountered in 1 patient, in the form of a collection of ascites due to portal hypertension. We conclude that ablation therapy is the choice for unresectable HCC with PVTT in multidisciplinary therapy.

Carcinoma, Hepatocellular↗

PubMed2003

[Multidisciplinary treatment for hepatocellular carcinoma invading the stomach].

The patient was a 69-year-old man who was found to be positive for the hepatitis C antibody in 1996. Hepatocellular carcinoma (HCC) was found in S4 and S7 in April 2000. He received treatment by transcatheter arterial chemoembolization (TACE) 3 times and by percutaneous ethanol injection therapy 1 time. At that point pulmonary metastasis was found. In November 2001 he was urgently admitted with hematemesis to the Department of Gastroenterology and Hepatology of our hospital. Bleeding from the HCC invading the stomach was found by endoscopy. Bleeding was successfully stopped by TACE. Because of the dangerousness of severe bleeding due to the disintegration of the HCC, we carried out a partial hepatectomy with partial gastrectomy and partial excision of the diaphragm. He recuperated at home after being discharged from the hospital, and sufficient QOL was maintained. In April of the same year, he vomited blood again and was readmitted. Endoscopy showed bleeding from a recurrence of the HCC in the stomach and a metastatic tumor at the lower esophagus. Bleeding was controlled by TACE and endoscopic procedures. The patient could maintain QOL under multidisciplinary therapy including surgery for the HCC, which was impossible to treat curatively. In such cases, it is important to use IVR or endoscopic procedures or a combination including them. Furthermore, in case of good hepatic reserve, surgery may then be added.

Aged↗

PubMed2003

[Control of the biological response to planned and unplanned injuries].

The biological response to planned and unplanned injuries is discussed in terms of the time course and both local and systemic states. In the systemic and local inflammatory response syndrome, the excess systemic cytokine reaction must be controlled. However, in the local inflammation-induced systemic immunosuppression syndrome, the fundamental defensive response should be maintained or even reinforced. Uniform measures for cytokine reaction are inadequate.

Cytokines↗

PubMed2002

Isolation of a novel human gene, APCDD1, as a direct target of the beta-Catenin/T-cell factor 4 complex with probable involvement in colorectal carcinogenesis.

To clarify the molecular mechanisms of human carcinogenesis associated with abnormal beta-catenin/T-cell factor (Tcf) signaling, we have been using cDNA microarrays to search for genes whose expression is significantly altered after introduction of wild-type APC into SW480 colon cancer cells. These experiments identified a novel human gene, termed APCDD1, that was down-regulated in the cancer cells by exogenous wild-type APC; its expression was also reduced in response to transduction of AXIN1. Moreover, we documented elevated expression of APCDD1 in 18 of 27 primary colon cancer tissues compared with corresponding noncancerous mucosae. A reporter gene assay using the 5'-flanking region of APCDD1 indicated that transfection of beta-catenin together with wild-type Tcf4 into HeLa cells increased the reporter activity through two putative Tcf/lymphoid enhancer factor-binding motifs upstream of the transcription start site, indicating that APCDD1 is one of the direct targets of this transcription complex. Exogenous APCDD1 promoted growth of colon cancer cells both in vitro and in vivo, whereas transfection with antisense S-oligodeoxynucleotides decreased cell/tumor growth. These data suggest that APCDD1 is directly regulated by the beta-catenin/Tcf complex and that its elevated expression is likely to contribute to colorectal tumorigenesis.

Cell Division↗

PubMed2002

Curcumin inhibits interleukin 8 production and enhances interleukin 8 receptor expression on the cell surface:impact on human pancreatic carcinoma cell growth by autocrine regulation.

BACKGROUND: Curcumin, the yellow pigment in turmeric, has been shown to prevent tumor progression in a variety of tissues in rodents. The authors investigated the effect of curcumin on human carcinoma cell lines to determine whether constitutive interleukin-8 (IL-8) production of tumor cells was correlated with nuclear factor kappaB (NF-kappaB) activation and cell growth activity. METHODS: A human pancreatic carcinoma cell line, SUIT-2, was incubated with various concentrations of curcumin for 2 hours. Biologic features, including IL-8 production, DNA binding activity, transactivation of NF-kappaB, cell growth activity, cell viability, and the expression of IL-8 receptors (CXCR1 and CXCR2) were analyzed. RESULTS: The constitutive production of IL-8 was inhibited by curcumin at concentrations of 10-100 microM in a dose dependent manner. NF-kappaB activity was reduced significantly by curcumin treatment. Pretreatment with curcumin inhibited the growth rate of carcinoma cells significantly. Such cell growth inhibition by curcumin was not recovered by exogenous recombinant IL-8. The investigation of expression in IL-8 receptors, CXCR1 and CXCR2, revealed that the expression of both receptors was enhanced remarkably by curcumin. Exogenous IL-8 could not recover this enhancement of IL-8 receptors. These results suggest that curcumin inhibits IL-8-induced receptor internalization. CONCLUSIONS: The authors concluded that curcumin contributed not only to the inhibition of IL-8 production but also to signal transduction through IL-8 receptors. These data suggest that curcumin reduces numerous IL-8 bioactivities that contribute to tumor growth and carcinoma cell viability. From this point of view, curcumin is a potent anticancer agent that inhibits the production of proinflammatory cytokines, including IL-8, by tumor cells.

Antineoplastic Agents↗

PubMed2002

Expression profile analysis of colon cancer cells in response to sulindac or aspirin.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have a preventive effect against colorectal cancer. Although inhibition of cyclooxygenase-2 plays a crucial role in the suppression of tumors, precise mechanisms of their action remain to be disclosed. To identify genes involved in the growth-suppressive effect of NSAIDs, we utilized cDNA microarray containing 23,040 genes and analyzed time-dependent alteration of gene expression in response to sulindac or aspirin in NSAIDs-sensitive SW480 and SW948 colon-cancer cells as well as in relatively resistant SNU-C4 cells. Consequently we identified 112 genes with commonly altered expression by sulindac and 176 with commonly altered expression by aspirin in the three lines. Addition of sulindac and that of aspirin altered expression levels of 130 and 140 genes, respectively, in SW480 and SW948 cells but not in SNU-C4 cells. These data may lead to a better understanding of growth-suppressive effects on colonic epithelium, and may provide clues for identifying novel therapeutic and/or preventive molecular targets of colon cancer.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2002

Functional analysis of recombinant pancreatic secretory trypsin inhibitor protein with amino-acid substitution.

BACKGROUND: We hypothesized that mutation of the pancreatic secretory trypsin inhibitor ( PSTI) gene may promote a predisposition to pancreatitis, possibly by reducing the inhibition of trypsin activity. Based on this hypothesis, we performed a biochemical analysis of recombinant PSTI protein. METHODS: The trypsin inhibitory activity of the recombinant protein was analyzed. The activity of PSTI protein with a point mutation of the most common type: (34)Asn (AAT)-to-Ser (AGT)(101A>G N34S: N34S) in exon 3, was compared with that of the wild type. RESULTS: The function of N34S PSTI remained unchanged under both the usual alkaline and acidic conditions compared with the wild-type PSTI. The calcium concentration did not affect the activity of recombinant PSTI. The trypsin susceptibility of the N34S protein was not increased either. CONCLUSIONS: Mechanisms other than the conformational change of PSTI associated with amino-acid substitution, such as abnormal splicing, may underlie the predisposition to pancreatitis in patients with the N34S mutation.

Amino Acid Substitution↗