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Biomedical subjects

Jiro Fujimoto

Publications and source records attributed to Jiro Fujimoto.

At least 37 records · Page 2Linked to original sources
PubMed2005

Sex steroid-dependent angiogenesis in uterine endometrial cancers.

In general, tumors induce angiogenic factors specific to them, which leads to angiogenesis with advancement. However, angiogenesis in uterine endometrial cancers is complicated because hormone dependency in growth also modifies the angiogenic potential. Therefore, anti-angiogenic therapy for tumor dormancy in uterine endometrial cancers must be thoroughly considered. The upstream of vascular endothelial growth factor (VEGF) gene conserves estrogen-responsive elements. Progesterone primed with estrogen induces thymidine phosphorylase (TP) in uterine endometrium. Sex steroid-dependent VEGF and TP are highly expressed in cases of early stage and well-differentiated uterine endometrial cancers, and basic fibroblast growth factor (bFGF) in cases of advanced and poorly differentiated uterine endometrial cancers. A transcriptional factor for angiogenesis, ETS-1, is linked to VEGF in well-differentiated uterine endometrial cancers, and to bFGF in poorly differentiated uterine endometrial cancers. Therefore, even if dedifferentiation and angiogenic switching occur due to advancement and long-term hormone therapy, the inhibition of ETS-1 along with main angiogenic factors might be an effective strategy to suppress uterine endometrial cancers as a novel anti-angiogenic therapy.

Angiogenesis Inhibitors↗
PubMed2005

Contribution of Toll-like receptor/myeloid differentiation factor 88 signaling to murine liver regeneration.

Toll-like receptors (TLRs) act as innate immune signal sensors and play central roles in host defense. Myeloid differentiation factor (MyD) 88 is a common adaptor molecule required for signaling mediated by TLRs. When the receptors are activated, cells bearing TLRs produce various proinflammatory cytokines in a MyD88-dependent manner. Liver regeneration following partial hepatectomy (PH) requires innate immune responses, particularly interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) production by Kupffer cells, although the recognition and activation processes are still unknown. We investigated whether TLR/MyD88 signaling is critical for induction of innate immune responses after PH. In Myd88(-/-) mice after PH, induction of expression of immediate early genes involved in hepatocyte replication and phosphorylation of STAT3 in the liver, and production of TNF-alpha/IL-6 by and activation of NF-kappaB in the Kupffer cells were grossly subnormal and were associated with impaired liver regeneration. However, TLR2, 4 and 9, which recognize gram-negative and -positive bacterial products, are not essential for NF-kappaB activation and IL-6 production after PH, which excludes a possible contribution of TLR2/TLR4 or TLR9 to MyD88-mediated pathways. In conclusion, the TLR/MyD88 pathway is essential for incidental liver restoration, particularly its early phase.

Adaptor Proteins, Signal Transducing↗
PubMed2005

A novel 3D hepatectomy simulation based on liver circulation: application to liver resection and transplantation.

Hepatectomy is a complicated operative procedure because of its anatomical complexity, vascular variability, and impaired hepatic function due to associated hepatitis or cirrhosis. Thus preoperative detailed topography and precise liver resection volume measurements should be obtained for a curative hepatectomy. The aim of this study was to assess the feasibility and accuracy of a novel three-dimensional (3D) virtual hepatectomy simulation software in patients who underwent liver resection or living donor liver transplantation. We developed the hepatectomy simulation software, which was programmed to analyze detailed 3D vascular structure and to predict liver resection volume and margins. In 72 patients receiving hepatectomy, the predicted liver resection volumes and margins revealed a significant correlation with the actual value with a mean difference of 9.3 mL (P < .0001) and 1.6 mm (P < .01), respectively. The drainage area by hepatic veins was quantified to achieve reconstruction of the corresponding venous branch. In conclusion, this hepatectomy simulation software reliably predicted an accurate liver resection volume, the cancer-free margin, and the drainage volume of hepatic vein branches. This software may promote curative hepatectomy and may be used for other interventional therapies in the treatment of liver disease.

Adult↗
PubMed2005

Long-term safety of autotransfusion during hepatectomy for hepatocellular carcinoma.

PURPOSE: To evaluate the long-term safety of autotransfusion (AT) in hepatectomy for hepatocellular carcinoma (HCC). METHODS: Between 1988 and 1989, 46 patients with HCC underwent hepatectomy with AT (group 1). For a comparison, we matched 50 patients with HCC who underwent hepatectomy, and received homologous but not autologous blood (group 2). The 10-year cumulative survival curves and cancer-free curves of the two groups were examined, and the pattern of recurrence was compared. RESULTS: Group 1 had a significantly higher cumulative 10-year survival rate than group 2, at 20% vs 8%, respectively (P < 0.05). Among the patients who underwent curative resection, those in group 1 had significantly better cumulative survival and cancer-free survival rates than those in group 2, at 27% vs 11% (P < 0.05) and 13% vs 0% (P < 0.05), respectively. Among the patients with stage I-II HCC, those in group 1 had significantly better cumulative survival and cancer-free survival rates than those in group 2, at 30% vs 5% (P < 0.01) and 20% vs 5% (P < 0.05), respectively. However, the rates were similar among patients with stage III-IV disease in both groups. The pattern of recurrence in the two groups was similar. CONCLUSION: Autotransfusion promoted survival in patients undergoing hepatectomy for stage I or II HCC.

Blood Transfusion, Autologous↗
PubMed2005

Oncostatin M inhibits proliferation of rat oval cells, OC15-5, inducing differentiation into hepatocytes.

Oval cells of the liver participate in liver regeneration when hepatocytes are prevented from proliferating in response to liver damage. To clarify the role of oncostatin M (OSM) in the liver regeneration involving oval cells, we examined the expression of OSM and OSM-specific receptor (OSM-R) in the liver undergoing regeneration in the 2-acetylaminofluorene/partial hepatectomy model. Expression levels of OSM-R changed in correlation to the number of oval cells, and its expression was exclusively observed in oval cells. On the other hand, OSM was expressed in both oval cells and Kupffer cells. To examine the effect of OSM on the growth and differentiation of oval cells, rat oval cells (OC15-5) were incubated in conditioned medium of 293T cells expressing rat OSM cDNA. This resulted in suppression of growth, changes in morphology (microvilli and large cytoplasm with developed organelles), and expression of hepatocyte markers (albumin, tyrosine amino transferase, and tryptophan oxygenase). The effects of the conditioned medium with rat OSM were abrogated by introducing a small interfering RNA specifically targeting rat OSM-R into OC15-5 cells. These results indicate that OSM is a key mediator for inducing differentiation of OC15-5 cells into hepatocytes and suggest that the OSM/OSM-R system is pivotal in the differentiation of oval cells into hepatocytes, thereby promoting liver regeneration.

2-Acetylaminofluorene↗
PubMed2004

Ameliorating effect of hepatocyte growth factor on inflammatory bowel disease in a murine model.

Hepatocyte growth factor (HGF), a multifunctional cytokine, accelerates intestinal epithelial proliferation. We studied the effects of HGF in mice with trinitrobenzene sulfonic acid-induced colitis, which shows clinical and molecular resemblance to Crohn's disease. Mice with colitis repeatedly were transfected intramuscularly with human HGF cDNA. Weight, survival, histopathology, proinflammatory cytokine mRNAs, and leukocyte infiltration were assessed. Treatment with HGF cDNA induced tyrosine phosphorylation of intestinal c-Met/HGF receptors, inhibited apoptosis, and promoted mitosis in intestinal epithelial cells, accelerating intestinal epithelial restoration and suppressing inflammation. Transfection with HGF cDNA markedly suppressed intestinal mRNA expression of T-helper 1 cytokines such as interleukin-12 and -1beta, interferon-gamma, and tumor necrosis factor-alpha. Numbers of total and CD4-positive T cells, neutrophils, and myloperoxidase activity in intestinal epithelium were diminished by HGF gene transfer, which also prevented weight loss, and improved survival. HGF might prove useful for controlling inflammatory bowel disease.

Animals↗
PubMed2004

ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth.

Anaplastic lymphoma kinase (ALK) is a receptor-type protein tyrosine kinase that is expressed preferentially in neurons of the central and peripheral nervous systems at late embryonic stages. To elucidate the role of ALK in neurons, we developed an agonist monoclonal antibody (mAb) against the extracellular domain of ALK. Here we show that mAb16-39 elicits tyrosine phosphorylation of endogenously expressed ALK in human neuroblastoma (SK-N-SH) cells. Stimulation of these cells with mAb16-39 markedly induces the tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), Shc, and c-Cbl and also their interaction with ALK and activation of ERK1/2. Furthermore, we show that continuous incubation with mAb16-39 induces the cell growth and neurite outgrowth of SK-N-SH cells. These responses are completely blocked by MEK inhibitor PD98059 but not by the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin, indicating an essential role of the mitogen-activated protein kinase (MAP kinase) signaling cascade in ALK-mediated growth and differentiation of neurons.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Hepatocyte growth factor preserves graft-versus-leukemia effect and T-cell reconstitution after marrow transplantation.

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (BMT). When GVHD is controlled by T-cell-depleted grafts or immunosuppressants, BM transplant recipients often suffer from an increased rate of leukemic relapse and impaired reconstitution of immunity. Using a mouse BMT model, we investigated the effects of hepatocyte growth factor (HGF) gene transfection on the severity of GVHD, the graft-versus-leukemia effect, and the reconstitution of T cells after BMT. After HGF gene transfer, acute GVHD was reduced, while mature donor T-cell responses to host antigens were preserved, resulting in a significant improvement of leukemia-free survival. HGF gene transfer promoted regeneration of bone marrow-derived T cells and the responsiveness of these cells to alloantigens. Furthermore, HGF preserved the thymocyte phenotype and thymic stromal architecture in mice with GVHD. This suggested that HGF exerts a potent protective effect on the thymus, which in turn promotes reconstitution of bone marrow-derived T cells after allogeneic BMT. These results indicate that HGF gene transfection can reduce acute GVHD preserving the graft-versus-leukemia effect, while promoting thymic-dependent T-cell reconstitution after allogeneic BMT.

Animals↗
PubMed2004

Interleukin 18 acts on memory T helper cells type 1 to induce airway inflammation and hyperresponsiveness in a naive host mouse.

Interleukin (IL)-18 was originally regarded to induce T helper cell (Th)1-related cytokines. In general, factors favoring interferon (IFN)-gamma production are believed to abolish allergic diseases. Thus, we tested the role of IL-18 in regulation of bronchial asthma. To avoid a background response of host-derived T cells, we administered memory type Th1 or Th2 cells into unsensitized mice and examined their role in induction of bronchial asthma. Administration of antigen (Ag) induced both airway inflammation and airway hyperresponsiveness (AHR) in mice receiving memory Th2 cells. In contrast, the same treatment induced only airway inflammation but not AHR in mice receiving memory Th1 cells. However, these mice developed striking AHR when they were coadministered with IL-18. Furthermore, mice having received IFN-gamma-expressing Th1 cells sorted from polarized Th1 cells developed severe airway inflammation and AHR after intranasal administration of Ag and IL-18. Thus, Th1 cells become harmful when they are stimulated with Ag and IL-18. Newly polarized Th1 cells and IFN-gamma-expressing Th1 cells, both of which express IL-18 receptor alpha chain strongly, produce IFN-gamma, IL-9, IL-13, granulocyte/macrophage colony-stimulating factor, tumor necrosis factor alpha, regulated on activation, normal T cell expressed and secreted, and macrophage inflammatory protein 1alpha upon stimulation with Ag, IL-2, and IL-18 in vitro. Thus, Ag and IL-18 stimulate memory Th1 cells to induce severe airway inflammation and AHR in the naive host.

Animals↗
PubMed2004

Expression of E26 transformation specific (ETS-1) related to angiogenesis in ovarian endometriosis.

ETS-1 in ovarian endometriomas was significantly positively correlated with microvessel counts (MVCs), but ETS-1 and MVC were not significantly altered during the menstrual cycle. Because ETS-1 persistently expresses in the subepithelial area of endometriotic endometrium, this might contribute to the growth of ovarian endometriomas via subepithelial angiogenesis independently of the menstrual cycle.

Adult↗
PubMed2004

Hepatic venoplasty to overcome outflow block in living related liver transplantation.

A 14-year-old boy with congenital biliary atresia underwent living related liver transplantation. Because of anatomic variation in donor hepatic vein, there were small and double orifices of hepatic veins in the harvested left hemiliver graft. To minimize the risk of outflow block after reperfusion, the recipient's native hepatic vein was used as an autologous patch for hepatic vein reconstruction. After 3 years of follow-up, the patient is alive and well with normal liver function. Follow-up duplex ultrasound scan showed adequate hepatic vein outflow without signs of late obstruction. The new technique of the autologous vascular patch grafting for successful hepatic vein reconstruction is described.

Adolescent↗
PubMed2004

Drastic decrease of progesterone receptor form B but not A mRNA reflects poor patient prognosis in endometrial cancers.

OBJECTIVES: Progesterone receptor (PR) has been recognized as an important factor that correlates with success of endocrine treatment and patients' prognoses in endometrial cancers (EC). This study was designed to determine the clinical implications of expression of PR form A (PR-A) and B (PR-B) in EC. METHODS: We have quantified the mRNA levels of total PR (PR-AB) and PR-B by real-time RT-PCR in 120 EC and 40 normal endometria (NE). We then analyzed the correlation between expression levels of each receptor and clinical characteristics including clinical stages, histological grades, depth of myometrial invasion and patients' prognoses. RESULTS: Although the expression level of PR-B is correlated with that of PR-A, the expression pattern of PR-B classified according to clinical characteristics was different from that of PR-A. We found that high PR-B mRNA levels but not PR-A mRNA levels correlated significantly with survival, independent of clinical characteristics including clinical stages, histological grades and depth of myometrial invasion. Percentage of PR-B to total PR (B/AB) in EC is widely distributed and the ratios of middle B/AB group (0.15 < B/AB < 0.35) are 75% in NE, 47% in surviving cases of EC and 18% in dead cases of EC at 5 years, respectively. CONCLUSIONS: These results taken together indicate that PR-B may have a different function from PR-A and the intact coordinate expression of PR isoforms was disrupted in EC, especially in poor prognostic case. The measurement of PR isoforms has prognostic value in EC.

Adult↗
PubMed2004

Involvement of BREK, a serine/threonine kinase enriched in brain, in NGF signalling.

We identified AATYK2 (Apoptosis-Associated Tyrosine Kinase 2) through a database search as a kinase specifically expressed in the brain. After characterization, we renamed it BREK (Brain-Enriched Kinase). Mouse BREK mRNA is expressed predominantly in brain, especially in olfactory bulb, olfactory tubercle, hippocampus, striatum, cerebellum, and cerebral cortex. Levels of expression and phosphorylation of BREK were high at 0-2 weeks after birth, suggesting that BREK is involved in neural development and functions during the early postnatal period. Phosphoamino acid analysis following in vitro kinase reaction revealed that BREK is a catalytically active, serine/threonine kinase. In PC12 cells, BREK was phosphorylated rapidly upon stimulation with nerve growth factor (NGF) in a protein kinase C-dependent pathway. In differentiated PC12 cells, BREK was enriched in cell bodies and growth cones, and also present along neurites. Introduction of a kinase-defective mutant of BREK into PC12 cells enhanced both ERK phosphorylation and neurite outgrowth in response to NGF, suggesting that BREK is a negative regulator of NGF-induced neuronal differentiation. Thus, we conclude that BREK is a new member of the family of protein serine/threonine kinases and that it plays important roles in NGF-TrkA signalling.

Amino Acid Sequence↗
PubMed2004

Clinical implications of expression of ETS-1 related to angiogenesis in metastatic lesions of ovarian cancers.

OBJECTIVE: ETS-1 has been identified as a proto-oncogene and a transcription factor for tumor angiogenesis, which is essential for the growth, invasion and metastasis of solid tumors. The aim is to investigate the clinical implications of ETS-1 expression in peritoneal metastatic lesions of ovarian cancers. METHODS: In primary tumors and peritoneal metastatic lesions from 30 patients with stage III ovarian cancers, ETS-1 histoscores and ets-1 mRNA levels were determined by immunohistochemistry and competitive RT-PCR-Southern blot analysis using recombinant RNA, respectively. RESULTS: Immunohistochemical staining revealed that ETS-1 was expressed in the cancer cells and vascular endothelial cells. ETS-1 histoscores in the endothelial cells and ets-1 mRNA levels were significantly (p < 0.05) increased in 20 of 30 peritoneal metastatic lesions of ovarian cancers. There was a significant correlation between microvessel counts (MVCs) and ETS-1 histoscores in the endothelial cells (p < 0.001) and between MVCs and ets-1 mRNA levels in the primary tumor and the peritoneal metastatic lesion of ovarian cancers (p < 0.001). Furthermore, the 24-month survival rate of patients with significantly increased ets-1 mRNA level (2/20, 10%) was significantly (p < 0.01) lower than that of patients with no change in the level (6/10, 60%) from the primary tumor to the peritoneal metastatic lesion. CONCLUSIONS: ETS-1 might be associated with peritoneal metastasis dominantly as an angiogenic mediator and additionally as an oncogene product to activate tumor invasion in ovarian cancers.

Adult↗
PubMed2004

Coexpression of Gas6/Axl in human ovarian cancers.

OBJECTIVES: Gas6, the protein product of the growth arrest-specific gene 6 (gas6), a member of the vitamin K-dependent protein family, was identified as a ligand for the Axl/Sky family of receptor tyrosine kinases. The aim is to study for the presence of Gas6 and its receptor Axl and Sky related to specific growth in the ovarian cancers, and to evaluate their plausible growth potential and mechanism. METHODS: In ovarian cancers of 90 cases, the histoscores and mRNA levels of Gas6, Axl and Sky were determined by immunohistochemistry and competitive reverse transcription-polymerase chain reaction-Southern blot analysis using the recombinant RNA, respectively. RESULTS: The histoscores and mRNA levels of Gas6 and Axl in ovarian cancers were significantly higher than in normal ovaries, regardless of histopathological type or clinical stage of ovarian cancers. CONCLUSIONS: Gas6/Axl pathway could play a role in the complex events taking place during the early changes of ovarian cancer progression.

Adult↗