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Biomedical subjects

A Kanamaru

Publications and source records attributed to A Kanamaru.

At least 19 recordsLinked to original sources
PubMed2005

Dichotomy of all-trans retinoic acid inducing signals for adult T-cell leukemia.

We previously reported that all-trans retinoic acid (ATRA) inhibits growth in human T-cell leukemia virus type 1 (HTLV-1)-positive T-cell lines and fresh cells from patients with adult T-cell leukemia. However, the mechanism of this inhibition is not clear. In the present study, we observed that NF-kappaB transcriptional activity as well as cell growth decreased significantly in HTLV-1-positive T-cell lines in the presence of ATRA. Furthermore, we observed that ATRA reduced HTLV-1 proviral DNA, HTLV-1 genes (gag, tax, or pol mRNA) using the real-time quantitative polymerase chain reaction. SIL-2R was reduced by ATRA in both protein level (culture supernantant) and mRNA level in HTLV-1-positive T-cell lines. Interestingly, ATRA significantly inhibited RT activity similar to azidothimidine (AZT) in HTLV-1-positive T-cell lines. Moreover, AZT inhibited proviral DNA but not NF-kappaB transcriptional activity, and sIL-2R on HTLV-1; however, ATRA inhibited of NF-kappaB, proviral DNA and sIL-2R on HTLV-1. These results suggested that the decrease in sIL-2R induced by ATRA may be caused by the actions of a NF-kappaB inhibitor acting on the NF-kappaB/sIL-2R signal pathway. These results suggested that ATRA could have two roles, as a NF-kappaB inhibitor and as an RT inhibitor.

Adult↗
PubMed2005

The beneficial effects of treatment with all-trans-retinoic acid plus corticosteroid on autoimmune nephritis in NZB/WF mice.

Corticosteroids are highly effective anti-inflammatory or immunosuppressive drugs used commonly to treat human systemic lupus erythematosus (SLE). All-trans-retinoic acid (ATRA), which belongs to a class of retinoids that exert immunomodulatory and anti-inflammatory functions, can also suppress the development of lupus nephritis in an animal model. However, both agents can inflict serious adverse effects. Here, we have asked whether ATRA can serve as a steroid-sparing drug in the treatment of lupus nephritis. To examine the efficacy of combining predonisolone (PSL) with ATRA, we treated intraperitoneally New Zealand black/white F1 (NZB/W F1) mice with PSL, ATRA or both agents. Survival rate and proteinuria were determined once a month. Cytokine and anti-DNA antibody production were determined by enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR). Renal histopathology was observed by haematoxylin and periodic acid Schiff (PAS), immunoperoxidase and immunohistochemical assay. Survival rate and proteinuria were improved in all experimental groups, and were much improved in the mice receiving the combination of ATRA and PSL (P <0.05). A single administration of ATRA reduced the Th1 [interleukin (IL)-2, interferon (IFN)-gamma and IL-12], and a Th2 (IL-4) cytokine level, as effectively as administration of PSL. ATRA also suppressed the expression of inducible nitric oxide synthetase (iNOS) and monocyte chemoattractant protein-1 (MCP-1) in the kidney. The combination of PSL and ATRA significantly reduced IgG2 (especially IgG2b)-specific anti-DNA antibody levels in comparison with administration of either agent alone. These data suggest that ATRA might have the potential to act as a new therapeutic and steroid-sparing drug against lupus nephritis.

Animals↗
PubMed2004

Predominant inhibition of Th1 cytokines in New Zealand black/white F1 mice treated with FK506.

The T-helper 1/T-helper 2 (Th1/Th2) cell balance was examined in 6-month-old New Zealand black/white F1 (B/WF1) mice treated with an immunosuppressive agent, FK506. The survival rate of mice treated with 10 mg/kg/day of FK506 was 7/8, while that of those treated with 2.5 mg/kg/day was 5/8, and 4/8 after treatment for 8 weeks with placebo. Proteinuria, which was already positive in all mice before the treatment, in the seven of eight mice treated with 10 mg/kg/day remained mildly positive (< or = 1+), while seven of eight mice treated with 2.5 mg/kg/day and six of eight mice treated with the placebo showed severe proteinuria (> or = 2+). Pathological changes in the kidneys of mice treated with 10 mg/kg/day of FK506 were less severe than in mice treated with the placebo or 2.5 mg/kg/day of FK506. Expression of mRNA was unchanged for all cytokines determined in the groups treated with 2.5 mg/kg/day of FK506 or placebo. In contrast, expression of mRNA for interleukin (IL)-2, and interferon (IFN)-gamma was suppressed, while that for IL-4 and IL-10 was not suppressed in the group treated with 10 mg/kg of FK506. The serum levels of IgG-class anti-DNA antibodies, which had been elevated before the treatment, were suppressed--especially in the IgG2a subclass--and the deposition of IgG2a and IgG2b in the glomeruli was reduced in the group treated with 10 mg/kg/day of FK506 compared with the other groups. These findings suggest that an improvement in the lupus nephritis of 6-month-old B/WF1 mice induced by FK506 might be associated with a predominant inhibition of Th1 cytokine.

Animals↗
PubMed2003

Endothelial damage caused by cytomegalovirus and human herpesvirus-6.

Infection with cytomegalovirus (CMV) or human herpesvirus-6 (HHV-6) may have a role in vascular endothelial damage after bone marrow transplantation (BMT). In total, 41 patients who underwent BMT were classified into four groups (12, 10, 7, and 12 patients who were infected with both CMV and HHV-6, CMV alone, HHV-6, and neither virus, respectively). Levels of thrombomodulin, plasminogen activator inhibitor-1, and cyclic GMP were 7.5+/-1.7 FU/ml, 76.4+/-24.1 ng/ml, and 9.51+/-1.1 pmol/ml, respectively, in the patients with both viruses, while the respective values were 2.9+/-0.67 FU/ml, 33.8+/-8.09 ng/ml, and 2.90+/-1.4 pmol/ml in patients infected with CMV alone, 4.8+/-0.96 FU/ml, 47.7+/-9.21 ng/ml, and 5.48+/-0.55 pmol/ml in patients with HHV-6 alone, and 1.6+/-0.39, 17.5+/-7.88 ng/ml, and 0.45+/-0.3 in those with neither virus. All three markers were significantly higher in the three groups with at least one virus than in the uninfected patients (P<0.05), and were also higher in patients with HHV-6 alone than in those with CMV alone (P<0.05). These results suggest that infection by CMV or HHV-6 causes vascular endothelial injury, with HHV-6 having a stronger effect than CMV, and combined infection having a stronger effect than either virus alone. Such viral infection may be a cause of thrombotic microangiopathy after BMT.

Acyclovir↗
PubMed2003

Effects of liposteroid on the hemophagocytic syndrome in systemic lupus erythematosus.

Hemophagocytic syndrome (HPS) is a life-threatening disorder characterized by pancytopenia and activation of macrophages. Recently, corticosteroid incorporated in lipid microspheres (liposteroid) has been reported to be taken up by macrophages and to suppress their functions. Here we present a case of systemic lupus erythematosus complicated by HPS that was successfully treated with liposteroid in addition to an oral corticosteroid and intravenous high-dose cyclophosphamide therapy. The serum levels of tumor necrosis factor-alpha and ferritin that have been reported to be associated with activity of macrophages remarkably reduced after liposteroid administration. This case suggests that liposteroid is useful for the treatment of HPS.

Administration, Oral↗
PubMed2002

Superior vena cava syndrome after bone marrow transplantation caused by aspergillosis: a case report.

Aspergillosis is known for the variety of unusual presentations in immuno-suppressed patients. We report a patient in whom aspergillosis caused the superior vena cava (SVC) syndrome. A 37-year-old woman became febrile soon after bone marrow transplantation (BMT). Chest radiography demonstrated a 5-cm mass extending from the right lung apex to the right supraclavicular fossa beside her Hickman catheter. She then developed SVC syndrome, which progressed despite treatment. Despite recovery of the white blood cell count, the patient continued to deteriorate, became comatose, suffered a cardiac arrest and died 31 days after BMT. Autopsy revealed Aspergillus infection at the apex of the right lung associated with innominate artery thrombosis.

Adult↗
PubMed2002

Similarity between eruptions induced by sulfhydryl drugs and acute cutaneous graft-versus-host disease after bone marrow transplantation.

Cutaneous GVHD is histologically similar to eruptions induced by drugs containing a sulfhydryl group. The levels of interleukin-2 and interleukin-2 receptor were determined in a group of patients undergoing bone marrow transplantation (BMT) without graft-versus-host disease or any other complications and in a group with cutaneous graft-versus-host disease (GVHD) alone. In patients who only developed cutaneous GVHD, both interleukin-2 and inter-leukin-2 receptor levels were elevated when the disease was evident. As the elevation of these parameters became more marked, the grade of cutaneous graft versus-host disease also increased. In some patients, only one of the two parameters was elevated and the grade of graft-versus-host disease was low or no skin manifestations were seen. These findings suggest that interleukin-2 and interleukin-2 receptor act together in the development of cutaneous GVHD. This study also showed that the mechanism of cutaneous GVHD resembles that involved in the induction of eruptions by sulfhydryl-containing drugs.

Acute Disease↗
PubMed2002

Oral eicosapentaenoic acid for acute colonic graft-versus-host disease after bone marrow transplantation.

We investigated whether pretreatment with eicosapentaenoic acid, an inhibitor of leukotriene (LT) B4, could ameliorate acute colonic graft-versus-host disease (GVHD) after bone marrow transplantation (BMT). Seventeen patients undergoing unrelated BMT were divided into two groups, with eight patients receiving eicosapentaenoic acid and nine not receiving it. The grade of GVHD after transplantation was compared with that estimated from the pretransplantation LTB4 level. The levels of LTB4 and several cytokines were also monitored. The actual grade of GVHD was lower than that estimated from LTB4 levels in three of the eight patients from the treated group, and there was a significant difference between the treated and untreated groups (p < 0.05, chi 2 test). The levels of LTB4, tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) were all significantly lower in the treated group (p < 0.05, Student's t-test). These findings suggest that eicosapentaenoic acid may ameliorate acute colonic GVHD when administered from before BMT.

Acute Disease↗
PubMed2001

Serum KL-6 levels in patients with pulmonary complications after allogeneic bone marrow transplantation.

KL-6, a mucinous high-molecular weight glycoprotein expressed on type 2 pneumocytes, has been shown to be elevated in the serum and bronchoalveolar lavage fluid of patients with interstitial pneumonitis (IP). We measured the serum levels of KL-6 in patients after they had undergone allogeneic bone marrow transplantation (BMT) to determine whether KL-6 could be a clinically useful indicator for the development of IP. The serum concentrations of KL-6 were determined by a sandwich-type enzyme-linked immunosorbent assay using an anti-KL-6 monoclonal antibody. A total of 1028 samples were tested from 76 patients (78 transplantations) who received BMTs. The KL-6 values were markedly elevated in patients with pulmonary complications, but not in those with acute and chronic graft-versus-host disease, hemorrhagic cystitis, herpes encephalitis, sepsis, and veno-occlusive disease. The serum levels of KL-6 from patients with pulmonary complications were significantly higher than from those without pulmonary complications (P < .001) and those with other complications (P < .001). Of the 12 patients with pulmonary complications, 6 had idiopathic IP (IIP). The levels were not high at the onset of IIP. Four of 6 IIP patients showed marked elevations of KL-6 levels in parallel with the severity of IP and died of respiratory failure without response to treatment. Assessment of serum KL-6 levels might not be useful for the early diagnosis of IP, but may be a useful indicator for monitoring the severity of IP after BMT.

Adolescent↗
PubMed2001

Analysis of prognostic factors in newly diagnosed patients with acute promyelocytic leukemia: the APL92 study of the Japan Adult Leukemia Study Group (JALSG).

All-trans-retinoic acid (ATRA) has been incorporated in front-line therapy for newly diagnosed acute promyelocytic leukemia (APL). We conducted a multicenter study of differentiation therapy with ATRA alone or in combination with chemotherapy followed by intensive postremission chemotherapy in patients with APL (the JALSG APL92 study), and analyzed prognostic factors to increase the cure rate in our subsequent trial. From 1992 to 1997, adult patients with newly diagnosed APL received oral ATRA 45 mg/m2 daily alone until complete remission (CR) if initial leukocyte counts were < 3.0x10(9)/l, and ATRA daily plus daunorubicin (DNR) 40 mg/m2x3 days plus enocitabine (BHAC) 200 mg/m2x5 days if leukocyte counts were > or =3.0 x 10(9)/l. If peripheral blasts exceeded 1.0x10(9)/l during therapy, DNRx3 days plus BHACx5 days was added. After CR was achieved, three courses of consolidation and six courses of maintenance/intensification chemotherapy were administered. Of 376 patients enrolled, 369 were evaluable (median age 46 years, range 15-86 years; median leukocyte counts 2.0x10(9)/l), and 333 (90%) achieved CR (94% of patients treated with ATRA alone, 88% with ATRA plus later chemotherapy, 89% with ATRA plus initial chemotherapy, and 86% with ATRA plus initial and later chemotherapy). At a median follow-up of 45 months, the predicted 6-year overall and event-free survival (EFS) rates for all patients were 65% and 52%, respectively. Favorable prognostic factors for CR were younger age, no or mild purpura, high serum total protein level, low lactate dehydrogenase level, and no or mild disseminated intravascular coagulation (DIC). Favorable prognostic factors for EFS were leukocyte counts < 10.0x10(9)/l, mild DIC, and no sepsis during induction therapy. In the JALSG APL97 study, we intensified chemotherapy for patients with leukocyte counts > or =3.0x10(9)/l, and are randomly testing whether further chemotherapy is required for APL patients with negative PCR for PML/retinoic acid receptor alpha in the maintenance phase.

Adolescent↗
PubMed2001

A mechanism of apoptosis induced by all-trans retinoic acid on adult T-cell leukemia cells: a possible involvement of the Tax/NF-kappaB signaling pathway.

In this study, five single clones were randomly established by limiting dilution method from each of the HTLV-I positive T cell lines - HUT 102 and ATL-2, and examined for the all-trans retinoic acid (ATRA) sensitivity, respectively. For each clone, we found a significant correlation between the reduction in 3[H]-thymidine incorporation and the reduction in CD25 expression (r=0.701, P<0.05) following treatment with 10(-5) M ATRA for 48 h. Agarose gel electrophoresis revealed DNA fragmentation of the cell lines treated with ATRA, indicative of apoptosis. These results suggested that the tax gene in the HTLV-I genome might be a key molecule involved in cell proliferation and CD25 expression. Thereafter, we transfected the tax gene in the expression vector (pCMV-Tax-neo) into the HTLV-I(-) T cell line Jurkat and examined the effects of ATRA on cell growth. The results showed that ATRA sensitivity was acquired by the Jurkat cells transfected with the tax gene expression vector, but not in those transfected with the control vector. We also observed NF-kappaB transcriptional activity on Jurkat cells transfected with the tax gene by CAT assay in the presence or absence of ATRA. NF-kappaB transcriptional activity was decreased significantly on Jurkat cells transfected with the tax gene after ATRA treatment. Taken together, these results indicate that ATRA may affect or block the Tax/NF-kappaB signaling pathway in ATL cells.

Adult↗
PubMed2001

Urinary trypsin inhibitor concentration can predict the immunological insult of chemotherapy and complications after bone marrow transplantation.

Urinary trypsin inhibitor has attracted attention as an index of the systemic inflammatory response syndrome. In this study, the urine concentration of trypsin inhibitor was measured to compare the immunological insult of conventional chemotherapy and conditioning chemotherapy for bone marrow transplantation. We also investigated whether urinary trypsin inhibitor was a useful index of the complications and outcome of bone marrow transplantation. Urinary trypsin inhibitor concentration was determined before chemotherapy, on the day after finishing chemotherapy (day 0 of transplantation), and during recovery of the white cell count, in 17 patients (seven receiving conventional chemotherapy and 10 receiving conditioning for bone marrow transplantation). Urinary trypsin inhibitor concentrations were significantly higher after conditioning for bone marrow transplantation than after conventional chemotherapy (P < 0.001), indicating that conditioning was more invasive. After bone marrow transplantation, the incidence of severe complications and the mortality rate were higher in patients whose urinary trypsin inhibitor concentrations rose during recovery of the white cell count. Comparison of urinary trypsin inhibitor concentrations suggested that conditioning for bone marrow transplantation was more invasive than conventional chemotherapy. This study also suggested that the urine concentration of trypsin inhibitor could be useful for predicting the risk of complications and outcome of bone marrow transplantation.

Adolescent↗
PubMed2001

Phase III study comparing tacrolimus (FK506) with cyclosporine for graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation.

We report the results of a phase III trial comparing tacrolimus (FK506) with cyclosporine for GVHD prophylaxis after allogeneic BMT. From February 1995 to July 1996, 136 patients were enrolled and followed up to September 1997. During the first 100 days post-transplant the incidence of grade II-IV acute GVHD (the primary end-point) was lower in the tacrolimus group (17.5%) compared with the cyclosporine group (48.0%, P < 0.0001). A significant difference was observed between the tacrolimus and cyclosporine groups when subset analyses were performed based on recipients from HLA-matched siblings (13.3% vs 41.3%, P = 0.015) or donors other than HLA-matched siblings (21.4% vs 53.8%, P= 0.0029). The incidence of chronic GVHD (47.3% and 47.8%) and Kaplan-Meier estimate of overall survival (62.9% and 65.2%) were similar between the tacrolimus and cyclosporine groups, respectively. The overall leukemia relapse rate was not significantly different between the tacrolimus and cyclosporine groups (19.6% and 11.4%, respectively). However, the relapse rate among recipients from HLA-matched siblings was significantly higher in the tacrolimus group (30.9%) compared with the cyclosporine group (3.6%, P = 0.013). These results suggest the merit of tacrolimus for the prophylaxis of acute GVHD, but a lack of merit for a graft-versus-leukemia effect among recipients from HLA-matched sibling donors.

Adolescent↗