Search PubMed⌕ Search

Biomedical subjects

Mine Harada

Publications and source records attributed to Mine Harada.

At least 91 records · Page 5Linked to original sources
PubMed2004

The role of Tyk2, Stat1 and Stat4 in LPS-induced endotoxin signals.

Mice lacking Tyk2, Stat1 or Stat4, which are members of the Jak-Stat signaling cascade, were resistant to LPS-induced endotoxin shock. Interestingly, Tyk2-deficient mice had higher resistance to LPS challenge than mice lacking either Stat1 or Stat4. The activation of MAPK and NF-kappaB by LPS, and the production of TNF-alpha and IL-12 after LPS injection, were not abrogated by the absence of Tyk2, Stat1 or Stat4. In Stat1-deficient mice, the induction of IFN-beta by LPS in macrophages was severely reduced, although the serum level of IFN-gamma was elevated after LPS injection. In contrast, in Stat-4 deficient mice, the induction of IFN-beta by LPS was normal, but the serum level of IFN-gamma remained low after LPS injection. Interestingly, the induction of both IFN-beta and IFN-gamma by LPS was severely reduced in Tyk2-deficient mice. Therefore, Stat1 and Stat4 independently play substantial roles in the susceptibility to LPS. Tyk2 is essential for LPS-induced endotoxin shock, and this signaling pathway is transduced by the activation of Stat1 and Stat4.

Animals↗
PubMed2004

Novel regulatory mechanisms of CD40-induced prostanoid synthesis by IL-4 and IL-10 in human monocytes.

Interleukins IL-4 and IL-10 are considered to be central regulators for the limitation and eventual termination of inflammatory responses in vivo, based on their potent anti-inflammatory effects toward LPS-stimulated monocytes/macrophages and neutrophils. However, their role in T cell-dependent inflammatory responses has not been fully elucidated. In this study, we investigated the effects of both cytokines on the production of PGE(2), a key molecule of various inflammatory conditions, in CD40-stimulated human peripheral blood monocytes. CD40 ligation of monocytes induced the synthesis of a significant amount of PGE(2) via inducible expression of the cyclooxygenase (COX)-2 gene. Both IL-10 and IL-4 significantly inhibited PGE(2) production and COX-2 expression in CD40-stimulated monocytes. Using specific inhibitors for extracellular signal-related kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), we found that both kinase pathways are involved in CD40-induced COX-2 expression. CD40 ligation also resulted in the activation of NF-kappaB. Additional experiments exhibited that CD40 clearly induced the activation of the upstream kinases MAPK/ERK kinase 1/2, MAPK kinase 3/6, and I-kappaB in monocytes. IL-10 significantly inhibited CD40-induced activation of the ERK, p38 MAPK, and NF-kappaB pathways; however, inhibition by IL-4 was limited to the ERK pathway in monocytes. Neither IL-10 nor IL-4 affected the recruitment of TNFR-associated factors 2 and 3 to CD40 in monocytes. Collectively, IL-10 and IL-4 use novel regulatory mechanisms for CD40-induced prostanoid synthesis in monocytes, thus suggesting a potential role for these cytokines in regulating T cell-induced inflammatory responses, including autoimmune diseases.

Antibodies, Monoclonal↗
PubMed2004

Defective fetal liver erythropoiesis and T lymphopoiesis in mice lacking the phosphatidylserine receptor.

Clearance of apoptotic cells by macrophages is considered important for prevention of inflammatory responses leading to tissue damage. The phosphatidylserine receptor (PSR), which specifically binds to phosphatidylserine (PS) exposed on the surface of apoptotic cells, mediates uptake of apoptotic cells in vitro, yet the physiologic relevance of PSR remains unknown. This issue was addressed by generating PSR-deficient (PSR(-/-)) mice. PSR(-/-) mice exhibited severe anemia and died during the perinatal period. In the PSR(-/-) fetal livers, erythroid differentiation was blocked at an early erythroblast stage. In addition, PSR(-/-) embryos exhibited thymus atrophy owing to a developmental defect of T-lymphoid cells. Clearance of apoptotic cells by macrophages was impaired in both liver and thymus of PSR(-/-) embryos. However, this did not induce up-regulation of inflammatory cytokines. These results indicate that during embryonic development, PSR-mediated apoptotic cell uptake is required for definitive erythropoiesis and T lymphopoiesis, independently of the prevention of inflammatory responses.

Anemia↗
PubMed2004

Nonmyeloablative allogeneic bone marrow transplantation for treatment of myelodysplastic syndrome complicated by recent intracerebral hemorrhage.

A patient with intracerebral hemorrhage is considered ineligible for hematopoietic stem cell transplantation (HSCT). We report a 49-year-old woman with myelodysplastic syndrome (MDS) complicated by refractoriness to platelet transfusion and intracerebral hemorrhage, who underwent allogeneic bone marrow transplantation from an HLA-identical unrelated male donor. Nine days before the scheduled transplantation, she developed dysarthria and right hemiparesis; computed tomography (CT) of the brain disclosed an acute hematoma in the left parietal lobe exceeding 3 cm in diameter. She underwent conditioning with reduced-intensity, including fludarabine (30 mg/m2/day on days -8 to -3), busulfan (4 mg/kg/day on days -6 and -5), and total body irradiation (4 Gy on day -2). Two weeks after transplantation, dysarthria and right hemiparesis began to resolve, and CT showed spontaneous resolution of the hematoma. Simultaneously, engraftment was confirmed. Thus, recent stroke may be not an absolute contraindication for HSCT.

Bone Marrow Transplantation↗
PubMed2004

Association of a four-amino acid residue insertion polymorphism of the HS1 gene with systemic lupus erythematosus: molecular and functional analysis.

OBJECTIVE: To investigate whether polymorphism(s) or mutation(s) in the hematopoietic cell-specific Lyn substrate 1 (HS1) gene are involved in the pathogenesis of systemic lupus erythematosus (SLE). METHODS: The entire coding region of the HS1 gene was analyzed by reverse transcriptase-polymerase chain reaction/single-strand conformational polymorphism analysis. HS1-transfected WEHI-231 cells or B lymphocytes from patients with SLE were studied for apoptosis, activation, and proliferation by flow cytometric analysis and MTT assay. RESULTS: We identified a glutamic acid-proline-glutamic acid-proline insertion between codons 366 and 367 (EPEP366-367ins) and 2 amino acid substitutions (A235T and E361K). The genotype frequency among individuals homozygous for the EPEP+ allele was 0.184 in 201 patients with SLE but only 0.098 in 184 healthy individuals (P = 0.016). The allele frequency of EPEP366-367ins was 0.408 in patients with SLE; this frequency was significantly higher than that in healthy controls (0.312) (P = 0.006). WEHI-231 cells transfected with EPEP+ HS1 were 100-fold more sensitive to B cell receptor (BCR)-mediated apoptosis than were those transfected with HS1 without EPEP. B lymphocytes from SLE patients with the EPEP+ allele were significantly more apoptotic without BCR stimulation and less activated after BCR stimulation than were those from SLE patients without the EPEP allele. CONCLUSION: These results suggest that HS1 with the EPEP insertion polymorphism transmits accelerated signals from BCR and is involved in the pathogenesis of SLE.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Phase I study of CPT-11 and bolus 5-FU/ l-leucovorin in patients with metastatic colorectal cancer.

BACKGROUND: Irinotecan (CPT-11) and bolus 5-fluorouracil (5-FU)/leucovorin (LV) administered weekly for 4 weeks every 42 days (Saltz regimen) is active but substantially toxic in patients with metastatic colorectal cancer (CRC). The efficacy and toxicity of this regimen, however, have not been determined in Japanese patients with metastatic CRC. METHODS: We investigated the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and recommended phase II dose (RD) for CPT-11 given i.v. (90-min infusion) and bolus 5-FU plus biologically active l-LV administered weekly for 3 weeks every 28 days (modified Saltz regimen) in Japanese patients with metastatic CRC. Eighteen patients with measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, and adequate organ functions were enrolled. RESULTS: At dose level 2 (CPT-11, 100 mg/m(2); 5-FU, 400 mg/m(2); and l-LV, 25 mg/body), 1 of 6 patients had DLT (febrile neutropenia). At dose level 3 (CPT-11, 100 mg/m(2); 5-FU, 500 mg/m(2); and l-LV, 25 mg/body), 2 of 6 patients had DLT (febrile neutropenia and grade 4 neutropenia lasting more than 4 days). To determine whether level 3 was the MTD level, an additional 3 patients were treated at this level, but no DLT was observed. Consequently, 2 of 9 patients had DLT at level 3, this level thus being considered as the RD. At this level, grade 3-4 neutropenia was common but manageable. Nonhematological toxicities were mild. Seven partial responses were observed in the 18 enrolled patients (response rate [RR], 39%), and 8 patients (44%) experienced stable disease. CONCLUSION: This CPT-11/5-FU/ l-LV regimen administered weekly for 3 weeks every 28 days has substantial antitumor activity, with manageable toxicities. A multicenter phase II study is currently underway. Irinotecan (CPT-11) and bolus 5-fluorouracil (5-FU)/leucovorin (LV) administered weekly for 4 weeks every 42 days (Saltz regimen) is active but substantially toxic in patients with metastatic colorectal cancer (CRC). The efficacy and toxicity of this regimen, however, have not been determined in Japanese patients with metastatic CRC.

Adult↗
PubMed2004

MPO-ANCA-positive Wegener's granulomatosis presenting with hypertrophic cranial pachymeningitis: case report and review of the literature.

We describe a case of hypertrophic cranial pachymeningitis (HCP) associated with Wegener's granulomatosis (WG) in a 60-year-old man presenting with chronic headache and multiple cranial nerve neuropathies. A test for antibodies to the neutrophil cytoplasmic protein myeloperoxidase (MPO-ANCA) was positive in this case. We review the literature on perinuclear (p)-ANCA-related HCP, including our case. This case indicates the link between MPO-ANCA-positive WG and HCP.

Journal Article↗
PubMed2004

Growth and apoptosis of human natural killer cell neoplasms: role of interleukin-2/15 signaling.

Interleukin (IL)-15 plays an important role in the survival of human natural killer (NK) cells. We investigated IL-2/15 signaling in NK cell neoplasms from five patients and in five cell lines (NK-92, KHYG-1, SNK-6, HANK1 and MOTN-1) compared to mature peripheral NK cells from 10 healthy subjects. Apoptosis of NK cell lines was prevented by addition of IL-15 in vitro. Blocking IL-2/15Rbeta on IL-2-stimulated NK-92 cells resulted in reduced expression of Bcl-X(L) and phosphorylated Stat5, which paralleled early apoptosis without altering Bcl-2 expression. These data add IL-2/15Rbeta to the list of factors important for the survival of NK cell neoplasms.

Adult↗
PubMed2004

Hypercalcemia-leukocytosis syndrome associated with lung cancer.

Hypercalcemia and leukocytosis are two of the most common paraneoplastic syndromes associated with various malignancies. Of note, concomitant manifestation of hypercalcemia and leukocytosis are occasionally observed in the same cancer patients. However, the relationship between these two paraneoplastic syndromes and clinical outcome is unclear. In the present study, we retrospectively investigated the occurrence of hypercalcemia (> or = 10.2 mg/dl after adjustment for serum albumin concentration), leukocytosis (> or = 14,000/mm3 with no evidence of infection) or both in lung cancer patients (1149 cases). There were 65 cases (5.7%) of hypercalcemia, 16 cases (1.4%) of leukocytosis and six cases (0.5%) of both hypercalcemia and leukocytosis at the time of first presentation. The occurrence of these two distinct paraneoplastic syndromes in the same patients was more frequent than could have been expected by chance alone (P < 0.001). There was a significant correlation between the hypercalcemia-leukocytosis syndrome and performance status (P = 0.002). Survivals of patients with hypercalcemia alone (median survival time: MST 3.8 months, n = 59), leukocytosis alone (MST 1.9 months, n = 10), and the hypercalcemia-leukocytosis syndrome (MST 1.5 months, n = 6) were significantly shorter than those without them (MST 9.5 months, n = 1074; P < 0.001). Moreover, survival of patients with the hypercalcemia-leukocytosis syndrome was significantly shorter than that of patients with hypercalcemia alone (P = 0.013). On the other hand, there was no significant difference in survival between the hypercalcemia-leukocytosis syndrome and leukocytosis alone (P = 0.47). Multivariate analysis of prognostic factors using the Cox proportional hazards model could not demonstrate that the hypercalcemia-leukocytosis syndrome had independent prognostic significance. In conclusion, our results suggest that the hypercalcemia-leukocytosis syndrome is an additional clinical entity of paraneoplastic syndrome and is an indicator for poorer outcome in lung cancer patients, although the frequency of the combined syndrome is very rare (0.5% of cases over a 10 year interval.

Adult↗
PubMed2004

Factors for PBPC collection efficiency and collection predictors.

Factors affecting collection efficiency of peripheral blood stem cells (PBSCs) include patient's age, diagnosis, preceding chemoradiotherapy, disease invasion of the bone marrow and mobilizing chemotherapy in PBSC collection for autologous transplants. Mobilizing cytokines, timing for apheresis, machines and operating software would affect mobilization and collection of PBSCs both for autologous and allogeneic transplantation. Also donor's age and gender would affect PBSC yield for allogeneic transplantation. Surrogate markers including peripheral blood CD34+ cell counts before mobilization and on day of collection have been reported to predict the yield of PBSC harvest. A number of standard procedures have been developed based on these findings. Newer agents for PBSC mobilization are being evaluated and still other factors affecting mobilization are being sought to better predict and cope with poor mobilization.

Blood Component Removal↗
PubMed2004

Suppressed erythropoiesis after ABO-minor-mismatched living-donor lobar lung transplantation.

Anti-A and/or anti-B antibodies synthesized by lymphoid tissues contained in ABO-mismatched solid organ grafts have been reported to cause hemolytic anemia, but not suppressed red blood cell production. A case of living-donor lobar lung transplantation is presented in which suppression of erythropoiesis was associated with ABO mismatched organ transplantation.

ABO Blood-Group System↗
PubMed2004

Elevation of serum hepatocyte growth factor during granulocyte colony-stimulating factor-induced peripheral blood stem cell mobilization.

We examined serum levels of the angiogenic factors, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and hepatocyte growth factor (HGF), in normal donors for allogeneic peripheral blood stem cell (PBSC) transplantation. Granulocyte colony-stimulating factor (G-CSF) (filgrastim 400 microg/m2/d) was administered to 23 donors for 5 d and aphereses were performed on days 4 and 5. Although bFGF remained at similar levels after G-CSF treatment, serum VEGF and HGF levels increased 1.5-fold (n = 13; P = 0.02) and 6.8-fold (n = 23; P < 0.0001) respectively. The serum HGF level before G-CSF administration on day 1 correlated inversely with mobilized CD34+ cell numbers. Time course kinetics of HGF showed that on the day after G-CSF administration (day 2), serum HGF levels increased to 3678 pg/ml. For auto PBSC mobilization with chemotherapy and G-CSF 200 microg/m2/d (n = 8), we observed similar HGF elevation, which appeared to be dose-dependent on the G-CSF administered.

Antineoplastic Agents↗
PubMed2004

Recurrence of cervical carcinoma manifesting as cardiac metastasis three years after curative resection.

We report a rare case of cardiac metastasis from carcinoma of the uterine cervix. A 58-year-old woman presented with multiple pulmonary emboli, disseminated intravascular coagulation, and right heart failure 43 months after a curative resection of cervical carcinoma (stage IB1). Transthoracic echocardiography and computed tomography revealed large tumors in the right ventricle and right main pulmonary artery. No evidence of recurrence was obtained in the pelvis and abdomen. Surgical removal of the tumors remarkably improved her general condition, which had been declining progressively. The patient declined further treatment, including adjuvant chemotherapy, and was followed in the outpatient clinic. The right ventricular tumor recurred 4 months later and she died of heart failure. The possibility of late recurrence of cervical carcinoma in the heart should be considered even after curative resection.

Female↗
PubMed2004

Inhibition of RL male 1 tumor growth in BALB/c mice by introduction of the RLakt gene coding for antigen recognized by cytotoxic T-lymphocytes and the GM-CSF gene by in vivo electroporation.

A DNA vaccine for inducing a tumor immune response was investigated using a well-characterized murine model tumor antigen. We demonstrated that in vivo electroporation augmented the induction of IFNgamma enzyme-linked immunospot (ELISPOT) and cytotoxic T lymphocyte (CTL) generation against pRL1a peptide in BALB/c spleen cells upon immunization with RLakt plasmid. Immunization without in vivo electroporation resulted in only a marginal induction of IFNgamma ELISPOT and CTL generation. Furthermore, co-injection of GM-CSF and RLakt plasmids significantly enhanced the induction of IFNgamma ELISPOT and CTL generation compared to the injection of RLakt plasmid alone. Inhibition of RL male 1 tumor growth was observed by injecting BALB/c mice with GM-CSF and RLakt plasmids using in vivo electroporation, although no effect was observed against an established tumor using the same treatment. No growth inhibition was observed without in vivo electroporation. Immunization with either RLakt plasmid alone, or GM-CSF and pCIneo control plasmids using in vivo electroporation did not inhibit RL male 1 tumor growth.

Animals↗
PubMed2004

Comparative analysis of clinical outcomes after allogeneic bone marrow transplantation versus peripheral blood stem cell transplantation from a related donor in Japanese patients.

A reduced incidence of graft versus host disease (GvHD) has been documented among Japanese allogeneic bone marrow transplantation (BMT) patients, as the Japanese are genetically more homogeneous than western populations. To clarify whether this ethnic difference affects the results of allogeneic peripheral blood stem cell transplantation (PBSCT), we conducted a nationwide survey to compare clinical outcomes of allogeneic PBSCT (n = 214) and BMT (n = 295) from a human leucocyte antigen-identical-related donor in Japanese patients. The cumulative incidence of grades II-IV acute GvHD was 37.4% for PBSCT and 32.0% for BMT. The cumulative incidence of extensive chronic GvHD at 1 year was significantly higher after PBSCT than BMT (42% vs. 27%; P < 0.01). The organ involvement patterns of GvHD were different between the two groups. By multivariate analyses, the incidence of chronic GvHD was significantly increased in PBSCT, whereas the stem cell source did not affect the incidence of acute GvHD, transplant-related mortality, relapse or survival. We concluded that Japanese PBSCT patients have an increased risk of chronic GvHD compared with BMT patients, but the incidence of acute GvHD was still lower than in western populations. Thus, the choice of haematopoietic stem cell source should be considered based on data for individual ethnic populations.

Acute Disease↗
PubMed2004

Expression of FoxP3, a key molecule in CD4CD25 regulatory T cells, in adult T-cell leukaemia/lymphoma cells.

Adult T-cell leukaemia/lymphoma (ATLL) is an aggressive neoplastic disease that usually exhibits a CD4(+)CD25(+) phenotype. Regulatory T cells (Treg), which suppress T-cell effector function, are characterized by the co-expression of CD4 and CD25. We analysed the expression of forkhead/winged helix transcription factor (FoxP3), a specific marker that is important for the function of Treg, on ATLL cells from 17 patients (peripheral blood, n = 8; lymph node, n = 9). Real-time polymerase chain reaction and immunostaining detected FoxP3 expression in 10 ATLL cases, but was relatively down-regulated compared with Treg from normal subjects. These results indicate the association of ATLL and Treg.

Adult↗