Biomedical subjects

Mitsuo Shimada

Publications and source records attributed to Mitsuo Shimada.

At least 37 records · Page 2Linked to original sources

PubMed2005

Overexpression of a novel superoxide-producing enzyme, NADPH oxidase 1, in adenoma and well differentiated adenocarcinoma of the human colon.

A superoxide-producing enzyme, NADPH oxidase 1 (Nox1), dominantly expressed in the colon, is implicated in the pathogenesis of colon cancer. Immunohistochemistry showed that Nox1 was constitutively expressed in surface mucous cells. Adenomas and well differentiated adenocarcinomas up-regulated Nox1 expression. Ki-67-negative, well differentiated tumor cells contained abundant Nox1, whereas Ki-67-positive, proliferating cells did not express it. This differentiation-dependent expression in normal as well as tumor tissues suggests distinct roles of Nox1 besides mitogenic function. Nuclear factor (NF)-kappaB was predominantly activated in adenoma and adenocarcinoma cells expressing abundant Nox1, suggesting that Nox1 may stimulate NF-kappaB-dependent antiapoptotic pathways in colon tumors.

Adenocarcinoma↗

PubMed2005

The newly established human hepatocyte cell line: application for the bioartificial liver.

BACKGROUND/AIMS: Human hepatocyte cell lines are reported to lose many of their biochemical functions in a hybrid artificial liver support system (HALSS). Differentiation therapy is useful to up-regulate liver function. METHODS: The human hepatoblastoma cell line HepG2 was transfected with HSV/tk gene. Albumin synthesis and ammonia removal activity were evaluated when HepG2/tk was cultured with histone deacetylase inhibitor (FR228) and peroxisome proliferator activated receptor-gamma ligand (pioglitazone). To investigate the function of HepG2/tk in vivo, cell transplantation for 90% hepatectonized rats was conducted. RESULTS: We established stable cell lines which expressed HSV/tk and were sensitive to gancyclovir in vitro and in vivo. Both albumin synthesis rate and ammonia removal rate improved for HepG2/tk incubated with FR228 and pioglitazone for 3 days, which induced nuclear transport of p21. Rats with intrasplenic injection of HepG2/tk precultured for 3 days with FR228 and pioglitazone survived significantly longer than the control rats. The ammonia and total bilirubin concentrations were significantly lower in the test group than in the control group. The injection of gancyclovir inhibited the prolonged survival of the rats with precultured HepG2/tk. CONCLUSIONS: HepG2/tk is safe as well as enhancing high levels of liver function. It will be a potential cell source for HALLS in the future.

Animals↗

PubMed2005

Effect of liver transplantation on multiple bone fractures in an infant with end-stage biliary atresia: a case report.

Osteodystrophy is frequently found in children with chronic cholestatic liver disease. We herein report an end-stage case of biliary atresia that was associated with multiple bone fractures and severe growth retardation. The patient, an 8-month-old female, underwent a living-related liver transplantation and thereafter showed a dramatic improvement in growth and decrease in bone fractures. A correction of the liver function is therefore considered to be a key factor in treating osteodystrophy that is related to chronic cholestatic liver disease. It is also essential to perform liver transplantation at the most appropriate time to enhance and support the growth of these patients.

Biliary Atresia↗

PubMed2005

Surgical outcome of patients with hepatocellular carcinoma originating in the caudate lobe.

BACKGROUND: Hepatocellular carcinoma (HCC) originating in the caudate lobe is rare, and the treatment for this type of carcinoma is difficult because of its unique anatomic location. METHODS: This retrospective study assessed the surgical outcome of patients with caudate lobe HCC. There were 20 cases of HCC originating in the caudate lobe among 435 patients with primary HCC who underwent hepatic resection in our department from 1990 to 2002. The caudate tumors were located in the Spiegel lobe in 3 patients, the paracaval portion in 15 patients, and the caudate process in 2 patients. Surgical procedures consisted of limited resection of the caudate lobe in 6 patients and extended caudate lobectomy in 14 patients. Recurrence was recognized in 12 patients, including 8 patients with multiple intrahepatic recurrences, 1 with peritoneal dissemination, and 1 with lymph node metastasis. RESULTS: There was no significant difference in postoperative survival rate between patients who underwent limited resection of the caudate lobe and those who underwent extended caudate lobectomy. Compared with 415 patients with HCC originating in other locations, the 20 patients with caudate lobe HCC showed significantly more intraoperative blood loss (P<.05), longer operation time (P<.0001), and more postoperative complications (P<.005). Intrahepatic recurrence was more frequent in the caudate lobe HCC compared with HCC originating in other locations (40% vs 17.6%; P<.05). There was a significantly poor survival rate in the postoperative patients with caudate HCC (25.9% vs 54.1% for five-year survival; P=.01). Intrahepatic multiple recurrences were frequently recognized in the patients with caudate lobe HCC, indicating no significance for extended caudate lobectomy. CONCLUSIONS: Because of the relatively poor prognosis in patients with caudate lobe HCC, adjuvant therapy combined with surgical operation should be considered.

Aged↗

PubMed2005

Fatty liver caused by portal vein thrombosis after living donor liver transplantation: a case report.

Portal vein thrombosis (PVT) is a rare complication that occurs after liver transplantation: however, it cannot be ignored as a cause of graft loss and death. We herein report a pediatric case of PVT that caused a fatty change in the graft after living donor liver transplantation. The portal vein was successfully reconstructed using the left great saphenous vein of the same donor. Moreover, the fatty liver recovered after the operation. Our case suggests that the finding of fatty liver is an important marker of PVT and immediate portal reconstruction is performed.

Fatty Liver↗

PubMed2005

Effect of intraportal infusion to improve small for size graft injury in living donor adult liver transplantation.

The most important problem in the living donor adult liver transplantation (LDALT) is a small for size graft. Although a right lobe graft is used in many cases in order to avoid small for size graft, for a donor, the risk has few in left lobe graft. We evaluate the effect of an intraportal infusion treatment to the small for size graft. One hundred and twelve patients who underwent LDALT were studied. The graft weight recipient standard liver volume ratio (GV/SLV) of these patients were 50% or less. We divided the patients into following two groups; infusion group (n = 53) and control group (n = 59). For the infusion group, 16 G double lumen catheter was inserted into portal vein and nafamostat mesilate (protease inhibitor which stabilize coagulofibrinolytic state; 200 mg/day), prostaglandin E(1) (vasodilator and hepatoprotective effect; 500 microg/day) and thromboxane A(2) synthetase inhibitor (vasodilator and anticoagulant effect; 160 mg/day) were administrated continuously for 7 days. Small-for-size graft syndrome was defined as bilirubin >10 mg/dl and ascites >1000 cc on postoperative day (POD) 14. Comparison examination of a background factors and postoperative bilirubin and amount of ascites was carried out. The mean GV/SLV did not have the difference at 39.1% of infusion group, and 38.3% of control group (P = 0.58). By the control group, 15 patients (25.4%) were small-for-size graft syndrome, however, there was only two (3.8%) small-for-size graft syndrome in infusion group (P = 0.04). The bilirubin levels of infusion and control group on 7 and 14 POD were 9.9 and 7.8 vs. 9.5 and 10.5 mg/dl, respectively. The amount of ascites of infusion group on 7 and 14 POD were 870 and 430 cc, respectively. On the contrary, in control group, the amount of ascites on 7 and 14 POD were 1290 and 1070 cc, respectively. Bilirubin levels and the amount of ascites on 7 and 14 POD were lower in the patients with infusion group then those with control group. There were no differences between infusion group and control group in age, sex and Child's classification. The intraportal infusion had an effect in prevention of hyperbilirubinemia and loss in quality of excessive ascites in the patients with small for size graft. This was suggested to be what is depended on the improvement of the microcirculation insufficiency considered one of the causes of small-for-size graft syndrome.

Adult↗

PubMed2005

Influence of HLA compatibility and lymphocyte cross-matching on acute cellular rejection following living donor adult liver transplantation.

BACKGROUND: Reports on the relevance of immunogenetic factors in living donor adult liver transplantation (LDALT) are often conflicting or inconclusive. We therefore investigated the human leukocyte antigen (HLA) mismatches, lymphocyte crossmatch positivity, and the reactivity in mixed lymphocyte culture (MLC) in a series of LDALT. METHODS: A total of 104 LDALT patients were studied. The minimum follow-up was 12 months, and the graft survival rates were assessed. The incidence of the most common complications was analyzed. And the influence of HLA, the flow cytometric analysis findings, enhanced cytotoxic cross-matching and MLC on graft survival, and acute rejection was also investigated. RESULTS: As a result, 96 negative cross-matching and eight positive cross-matching cases were identified. Positive cytotoxic cross-matching had a significant effect on graft survival (P<0.05), while flow cytometric cross-matching also had an additional effect on acute rejection (P<0.05). The MLC of the patients with three HLA mismatches was significantly higher than the MLC of patients with zero HLA mismatches. The incidence of acute cellular rejection (ACR) was higher in the patients with three mismatches than in the other patients, and moderate rejection only occurred in the patients with three mismatches. CONCLUSION: HLA mismatching was not statistically associated with the overall graft survival after LDALT. The graft failure rates were higher in the positive cross-matching cases and therefore a strong immuosuppressant might be needed for positive cross-matching cases.

Acute Disease↗

PubMed2005

Prevention of hepatitis B virus infection from hepatitis B core antibody-positive donor graft using hepatitis B immune globulin and lamivudine in living donor liver transplantation.

BACKGROUND: Hepatic grafts from hepatitis B surface antigen-negative and anti-core antibody (HBcAb)-positive donors have been shown to transmit hepatitis B virus (HBV) infection. Recently, it has been reported that combined hepatitis B immune globulin (HBIG) and lamivudine therapy is effective in the prevention of hepatitis B recurrence after living donor liver transplantation (LDLT). In this report, we assessed the efficacy of combined HBIG and lamivudine therapy in preventing HBV transmission by graft with HBcAb-positive donors. METHODS: We studied 22 patients who had undergone LDLT with allografts from HBcAb-positive living donors at Gunma University Hospital and Kyushu University Hospital. Long-term combined HBIG and lamivudine therapy were administrated to all recipients. Serum samples from the donor and recipient were tested for HBcAb, HBV DNA, and hepatitis B surface antibody. Liver biopsies from grafts were tested for HBV DNA. RESULTS: All recipients were HBcAb negative before LDLT. All of the donor livers were HBV DNA positive at the time of LDLT. All of the recipients had HBsAb titers greater than 300 mIU/ml 4 weeks after LDLT, and remained 100 mIU/ml thereafter. None of the recipients have become infected with HBV with a follow-up of 25-86 months. CONCLUSIONS: Perioperative combined HBIG and lamivudine therapy can prevent HBV infection in recipients who receive liver grafts from HBcAb-positive donors.

Adolescent↗

PubMed2005

Balloon occluded retrograde transvenous obliteration and percutaneous transhepatic obliteration for ruptured duodenal varices after operation for rectal cancer with multiple liver metastasis: report of a case.

We report a patient with duodenal varices oozing blood who had undergone low anterior resection of the rectum and resection of the liver tumor because of multiple liver metastasis from rectal cancer 80 months previously. Although endoscopic variceal ligation (EVL) was carried out for the ruptured duodenal varices, their bleeding persisted and hepatic encephalopathy also appeared. Finally, balloon occluded retrograde transvenous obliteration (BRTO) with percutaneous transhepatic obliteration (PTO) was carried out for the duodenal varices. Percutaneous transhepatic portography revealed detailed hemodynamics. Following PTO, the duodenal varices were stagnated by BRTO, and no complications were recognized. No re-bleeding episode has been observed since the treatment. In addition, the hepatic encephalopathy was also improved.

Adult↗

PubMed2005

Multiple hepatic angiomyolipomas with a solitary omental angiomyolipoma.

Angiomyolipoma (AML) is a rare benign tumor that occurs most commonly in the kidney. Lesions in the liver are usually solitary and multiple AMLs of the liver are extremelyrare. Furthermore, extra renal or hepatic AML are rarely found. We report an unusual case of a 34-year-old man with a solitary omental AML and multiple hepatic AMLs. At the age of 23, the patient underwent right nephrectomy and enucleation of a left renal tumor because of bilateral AMLs. At the age of 34, more than 6 lesions in the liver and an enlarged solitary omental AML were discovered. The omental tumor, 50 x 40mm, 49g, was extirpated; it was well-defined and encapsulated a soft elastic mass. Histologically it was an epithelioid AML and positive for the melanogenesis-related marker HMB-45, the same as the earlier right renal tumor. We describe the first case of a solitary omental AML, which had metastasized, and with more than 6 hepatic AMLs.

Adult↗

PubMed2005

Living-donor liver transplantation: present status and future perspective.

About 15 years have passed since the first liver transplant from a living donor (living donor liver transplantation: LDLT), and the status of the procedure has since been established as a standard cure for end-stage liver disease in Japan where liver transplantation (LTx) from deceased donors has not yet been accepted. However, the following problems are surfacing with the increase in the number of LDLTs between adults: graft size mismatching, an ABO blood-type incompatible transplantation, the expansion of LDLT indication to hepatocellular carcinoma (HCC), the relapse of hepatitis C after LDLT, marginal donors, and the freedom from immunosuppressive treatment. In this article we outline the present conditions of these problems and the future view of the LDLT.

ABO Blood-Group System↗

PubMed2005

Detection of combined hepatocellular and cholangiocarcinomas on enhanced CT: comparison with histologic findings.

OBJECTIVE: The purpose of this study was to evaluate the performance of enhanced CT in making a diagnosis of combined hepatocellular and cholangiocarcinomas (HCC-CCs) by comparing CT findings with histologic findings. CONCLUSION: One third (nine of 27 cases) of the combined HCC-CCs were correctly diagnosed on enhanced CT by detailed analysis of the enhancing pattern around or within the mass. Various factors such as an atypical enhancing pattern, the size of each component, and the presence of a mass composed of intermediate tumor cells-that is, cells with intermediate characteristics between HCC and CC-were found to be the causes of misdiagnosis of combined HCC-CC on enhanced CT.

Adult↗

PubMed2005

[A case of advanced rectal cancer responding to 5-fluorouracil based preoperative chemoradiation therapy].

We report a case of a 67-year-old female with advanced rectal cancer that showed a significant response after administration of preoperative chemoradiation therapy. 5-fluorouracil (5-FU, 300 mg/m2/day) was administered by 24-hour continuous intravenous infusion after the cancer had been decreased in size by radiation (2 Gy) administered for 20 days preoperatively. Consequently, the patient underwent a low anterior resection with lymph node dissection (D 2), which resulted in a curative resection of the cancer cells macroscopically. Histological examination revealed no residual cancer cells in the resected specimen (CR). Preoperative chemoradiation therapy appears a promising regimen for patients with advanced lower rectal cancer, and can be considered to extend the indication for laparoscopic operations for advanced rectal cancer.

Adenocarcinoma↗

PubMed2004

IL-12 gene therapy is an effective therapeutic strategy for hepatocellular carcinoma in immunosuppressed mice.

Immunosuppressive therapy for organ transplantation is essential for controlling rejection. When liver transplantation is performed as a therapy for hepatocellular carcinoma (HCC), recurrent HCC is one of the most fatal complications. In this study, we show that intratumoral murine IL-12 (mIL-12) gene therapy has the potential to be an effective treatment for malignancies under immunosuppression. C3H mice (H-2(k)), injected with FK506 (3 mg/kg) i.p., were s.c. implanted with 2.5 x 10(6) MH134 cells (H-2(k)) and we treated the established HCC with electroporation-mediated gene therapy using mIL-12 plasmid DNA. Intratumoral gene transfer of mIL-12 elevated intratumoral mIL-12, IFN-gamma, and IFN-gamma-inducible protein-10, significantly reduced the number of microvessels and inhibited the growth of HCC, compared with HCC-transferred control pCAGGS plasmid. The inhibition of tumor growth in immunosuppressed mice was comparable with that of mIL-12 gene therapy in immunocompetent mice. Intratumoral mIL-12 gene therapy enhanced lymphocytic infiltration into the tumor and elicited the MH134-specific CTL response even under FK506. The dose of FK506 was sufficient to prevent the rejection of distant allogenic skin grafts (BALB/c mice, H-2(d)) and tumors, B7-p815 (H-2(d)) used as transplants, during mIL-12 gene therapy against MH134. Ab-mediated depletion studies suggested that the inhibition of tumor growth, neovascularization, and spontaneous lung metastasis by mIL-12 was dependent almost entirely on NK cells and partially on T cells. These results suggest that intratumoral mIL-12 gene therapy is a potent effective strategy not only to treat recurrences of HCC in liver transplantation, but also to treat solid malignant tumors in immunosuppressed patients with transplanted organ.

Angiogenesis Inhibitors↗

PubMed2004

Rab13 mediates the continuous endocytic recycling of occludin to the cell surface.

During epithelial morphogenesis, adherens junctions (AJs) and tight junctions (TJs) undergo dynamic reorganization, whereas epithelial polarity is transiently lost and reestablished. Although ARF6-mediated endocytic recycling of E-cadherin has been characterized and implicated in the rapid remodeling of AJs, the molecular basis for the dynamic rearrangement of TJs remains elusive. Occludin and claudins are integral membrane proteins comprising TJ strands and are thought to be responsible for establishing and maintaining epithelial polarity. Here we investigated the intracellular transport of occludin and claudins to and from the cell surface. Using cell surface biotinylation and immunofluorescence, we found that a pool of occludin was continuously endocytosed and recycled back to the cell surface in both fibroblastic baby hamster kidney cells and epithelial MTD-1A cells. Biochemical endocytosis and recycling assays revealed that a Rab13 dominant active mutant (Rab13 Q67L) inhibited the postendocytic recycling of occludin, but not that of transferrin receptor and polymeric immunoglobulin receptor in MTD-1A cells. Double immunolabelings showed that a fraction of endocytosed occludin was colocalized with Rab13 in MTD-1A cells. These results suggest that Rab13 specifically mediates the continuous endocytic recycling of occludin to the cell surface in both fibroblastic and epithelial cells.

Adherens Junctions↗

PubMed2004

Selenoprotein P, as a predictor for evaluating gemcitabine resistance in human pancreatic cancer cells.

Gemcitabine is a new standard chemotherapeutic agent used in the treatment of pancreatic cancer, but the mechanisms of gemcitabine sensitivity are still controversial. In our study to determine a mechanism that regulates gemcitabine sensitivity, we carried out molecular analysis on the susceptibility of the pancreatic cancer cells. Using a gemcitabine-sensitive pancreatic cancer cell line KLM1, we established a resistant cell line KLM1-R exhibiting a 20-fold IC50-value (the concentration of gemcitabine causing 50% growth inhibition). Microarray analysis of genes showed specific expression of selenoprotein P, one of the anti-oxidants, in the KLM1-R cell line but not in the KLM1 cell line. Administration of selenoprotein P inhibited the gemcitabine-induced cytotoxicity in the pancreatic cell lines. The levels of intracellular reactive oxygen species (ROS) were increased in the KLM1 cells by gemcitabine, but selenoprotein P suppressed the gemcitabine-induced ROS levels. Furthermore interferon-gamma suppressed the expression of selenoprotein P mRNA and increased intracellular ROS level, leading to the recovery of the gemcitabine sensitivity in KLM1-R. These results suggest a novel mechanism that selenoprotein P reduces the intracellular ROS levels, resulting in the insusceptibility to gemcitabine.

Antimetabolites, Antineoplastic↗

PubMed2004

The critical role of Fas-Fas ligand interaction in donor-specific transfusion-induced tolerance to H-Y antigen.

BACKGROUND: Donor-specific transfusion (DST) has been clinically used to enhance the survival of transplanted organs, and it has been shown in mice to induce tolerance to male (H-Y) antigen (Ag). Although the biologic mechanisms that initiate and maintain DST-induced tolerance involve clonal deletion, induction of anergy, and generation of regulatory cells, the molecules essential to tolerance induction are still unclear. In this study, we investigated the role of Fas-FasL interaction in DST-induced tolerance to H-Y Ag. METHODS: C57BL/6 (B6) or B6-Fas(lpr) (lpr) female mice were intravenously injected with B6, lpr, or B6-FasL(gld) (gld) male spleen cells (SC). B6 male skin grafts, mixed lymphocyte reaction (MLR) assay, and cytotoxicity assay (CTL) were performed 7 days after DST. In some experiments, purified B-cells were used as transfused cells. RESULTS: B6 female mice treated with B6 male SC permanently accepted B6 male skins, whereas untreated B6 or lpr female mice rejected B6 male skins. On the other hand, B6 female mice treated with gld male SC acceleratingly rejected male skin, as did lpr female mice treated with B6 or gld male SC. The recipient mice in the experimental groups, in which DST resulted in the accelerated rejection of the skin grafts, had strong allo-responses to H-Y Ag in MLR and CTL. Further, B6 female mice treated with gld male B-cells acceleratingly rejected male skins, whereas B6 female mice treated with B6 or lpr male B-cells from mice accepted male skins. CONCLUSIONS: These findings suggest that the interaction between FasL upon infused SC, especially upon B-cells and Fas in a recipient, is essential in DST-induced tolerance to H-Y Ag.

Animals↗

PubMed2004

Involvement of Rho-kinase in cold ischemia-reperfusion injury after liver transplantation in rats.

BACKGROUND: Reperfusion of ischemic tissues is known to cause the generation of reactive oxygen species (ROS) with resultant tissue damage. However, the sources of ROS in reperfused tissues are not fully characterized. We hypothesized that the small GTPase Rho and its target effector Rho-kinase/ROK/ROCK are involved in the oxidative burst in reperfused tissue with resultant reperfusion injury. METHODS: In an in vivo rat model of liver transplantation using cold ischemia for 12 hr followed by reperfusion, a specific Rho-kinase inhibitor, fasudil (30 mg/kg), was administered orally 1 hr before the transplantation. RESULTS: Fasudil suppressed the ischemia-reperfusion (I/R)-induced generation of ROS after reperfusion (P<0.01) and also suppressed the release of inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta) 3 hr after reperfusion, resulting in a significant reduction of I/R-induced hepatocellular injury (P<0.05), necrosis, apoptosis (P<0.01), and neutrophil infiltration (P<0.0001) 12 hr after reperfusion. All animals receiving a graft without fasudil died within 3 days, whereas 40% of those receiving fasudil survived (P<0.001). CONCLUSIONS: The present study demonstrates that Rho-kinase-mediated production of ROS and inflammatory cytokines are substantially involved in the pathogenesis of hepatocellular necrosis and apoptosis induced by cold I/R in vivo and that Rho-kinase may be regarded as a novel therapeutic target for the disorder.

Alanine Transaminase↗