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Biomedical subjects

Y Kanda

Publications and source records attributed to Y Kanda.

At least 73 records · Page 4Linked to original sources
PubMed2001

Possible clinical benefits of the use of peripheral blood stem cells over bone marrow in the allogeneic transplantation setting for the treatment of childhood leukemia.

BACKGROUND: The benefits of allogeneic peripheral blood stem/progenitor cell transplantation (PBSCT) over bone marrow transplantation (BMT), if any, have not been seriously evaluated in a pediatric population. We report here our experience with this procedure and demonstrate rapid engraftment to reduce procedure-related complications and enhanced allogeneic immune reaction to reduce leukemic relapse. METHODS: The feasibility of PBSCT was reviewed retrospectively. Four patients (2 AML and 2 ALL, aged 8-18 years) underwent allogeneic PBSCT for relapsed leukemia after primary allogeneic BMT (n = 2), for active hepatosplenic fungal abscess (n = 1) or for refractory relapse with conventional chemotherapy (n = 1). Four healthy donors (aged 10-49 years) received granulocyte colony-stimulating factor (G-CSF) 10 microg/kg/day by subcutaneous injection for 5 days. An individualized cytoreductive regimen was used before transplantation. RESULTS: No significant toxicities were observed in normal donors on G-CSF treatment or at collection of PBSC. After PBSCT, no significant acute toxicities were observed and the median duration to an absolute granulocyte count of 0.5 x 10(9)/l and a platelet count of 20 x 10(9)/l was 16 and 21 days, respectively. Although none of our patients developed acute graft-versus-host disease (GVHD), two developed chronic GVHD involving the liver and skin. Among those who developed chronic GVHD, one died of recurrent disease and another died of pneumonia 235 days after PBSCT. The two remaining patients have been alive without evidence of disease with follow-ups of 193 and 123 days, respectively. CONCLUSIONS: Allogeneic PBSCT can be a safe procedure in a pediatric population with fewer acute complications, although the potential risk of G-CSF treatment in normal donors should be seriously weighed against the existing risks of marrow aspiration under general anesthesia. The risk of chronic GVHD may need to be balanced against a possible graft-versus-leukemia benefit in patients at higher risk of leukemic relapse.

Adolescent↗
PubMed2001

Delayed recovery of neutrophil counts after peripheral stem cell transplantation which improved with administration of a minimal dose of G-CSF: a case report.

G-CSF administration may not affect the rate of engraftment unless sufficient numbers of stem cells are transplanted. However, there might be some cases in which neutrophil recovery is delayed after stem cell transplantation despite a relatively fast recovery of platelet counts and total white blood cell counts. This delayed engraftment might be observed in either autologous or allogeneic stem cell transplantation. Here we report four cases with delayed neutrophil engraftment which subsequently improved with administration of a minimal dose of G-CSF. As the response occurred on the day following G-CSF administration, a mobilization defect is suspected to be the mechanism of this delayed engraftment.

Adult↗
PubMed2001

Evaluation of internal and external doses from 11C produced in the air in high energy proton accelerator tunnels.

Air has been irradiated with high energy protons at the 12 GeV proton synchrotron to obtain the following parameters essential for the internal dose evaluation from airborne 11C produced through nuclear spallation reactions: the abundance of gaseous and particulate 11C, chemical forms, and particle size distribution. It was found that more than 98% of 11C is present as gas and the rest is aerosol. The gaseous components were only 11CO and 11CO2, and their proportions were approximately 80% and 20%, respectively. The particulate 11C was found to be sulphate and/or nitrate aerosols having a log-normal size distribution; the measurement using a diffusion battery showed a geometric mean radius of 0.035 micron and a geometric standard deviation of 1.8 at a beam intensity of 6.8 x 10(11) proton.pulse-1 and an irradiation time of 9.6 min. By taking the chemical composition and particle size into account, effective doses both from internal and from external exposures per unit concentration of 11C were calculated for various room sizes. The values can be used to evaluate the effective dose from the airborne 11C produced in the accelerator tunnels.

Aerosols↗
PubMed2001

Germline mutation of dihydropyrimidine dehydrogenese gene among a Japanese population in relation to toxicity to 5-Fluorouracil.

5-Fluorouracil (5FU) is most commonly used in chemotherapy for human malignancy. Over 80% of administered 5FU is metabolically degraded by dihydropyrimidine dehydrogenase (DPD), a primary and rate-limiting enzyme in the 5FU metabolic pathway. A DPD-deficient phenotype among cancer patients, which has posed a serious problem in 5FU-based chemotherapy, was reported to be in part ascribed to germline mutations in dihydropyrimidine dehydrogenase (DPYD) gene. Therefore, we for the first time examined the frequencies and types of germline mutations in the DPYD gene among a total of 107 Japanese cancer patients and healthy volunteers. Of 214 alleles examined among them, 181 alleles were of the same type, which was assigned as wild type; 21 alleles revealed a nucleotide substitution resulting in silent mutation; and the remaining 12 alleles showed five types of nucleotide deletion or substitutions resulting in one frameshift and four missense mutations. Three of them, A74G, 812delT and L572V, were novel mutations. None of the study subjects showed homozygous frameshift or missense mutated alleles. We also studied the association between toxic response to 5FU and heterozygous frame shift or missense mutation of the DPYD gene among eight cancer patients who had received 5FU-based chemotherapy. These patients did not show any adverse effects higher than grade 3, suggesting that heterozygotes are not associated with increased toxicity to 5FU. Our results indicate that a very small percentage, about 0.2%, of the Japanese population seems to carry homozygous mutations in DPYD gene, mutations which possibly indicate genetically increased toxicity of 5FU-based chemotherapy.

Antimetabolites, Antineoplastic↗
PubMed2001

Identification of a decidua-specific enhancer on the human prolactin gene with two critical activator protein 1 (AP-1) binding sites.

Deletion analysis of the human PRL promoter in endometrial stromal cells decidualized in vitro revealed a 536-bp enhancer located between nucleotide (nt) -2,040 to -1,505 in the 5'-flanking region. The 536-bp enhancer fragment ligated into a thymidine kinase (TK) promoter-luciferase reporter plasmid conferred enhancer activity in decidual-type cells but not nondecidual cells. DNase I footprint analysis of decidualized endometrial stromal cells revealed three protected regions, FP1-FP3. Transfection of overlapping 100-bp fragments of the 536-bp enhancer indicated that FP1 and FP3 each conferred enhancer activity. Gel shift assays indicated that both FP1 and FP3 bind activator protein 1 (AP-1), and JunD and Fra-2 are components of the AP-1 complex in decidual fibroblasts. Mutation of the AP-1 binding site in either FP1 or FP3 decreased enhancer activity by approximately 50%, while mutation of both sites almost completely abolished activity. Coexpression of the 536-bp enhancer and A-fos, a dominant negative to AP-1, decreased enhancer activity by approximately 70%. Conversely, coexpression of Fra-2 in combination with JunD or c-Jun and p300 increased enhancer activity 6- to 10-fold. Introduction of JunD and Fra-2 into nondecidual cells is sufficient to confer enhancer activity. JunD and Fra-2 protein expression was markedly increased in secretory phase endometrium and decidua of early pregnancy (high PRL content) compared with proliferative phase endometrium (no PRL). These investigations indicate that the 5'-flanking region of the human PRL gene contains a decidua-specific enhancer between nt -2,040/-1,505 and AP-1 binding sites within this enhancer region are critical for activity.

Binding Sites↗
PubMed2001

Increase of cGMP, cADP-ribose and inositol 1,4,5-trisphosphate preceding Ca(2+) transients in fertilization of sea urchin eggs.

Transient increases, or oscillations, of cytoplasmic free Ca(2+) concentration, [Ca(2+)](i), occur during fertilization of animal egg cells. In sea urchin eggs, the increased Ca(2+) is derived from intracellular stores, but the principal signaling and release system involved has not yet been agreed upon. Possible candidates are the inositol 1,4,5-trisphosphate receptor/channel (IP(3)R) and the ryanodine receptor/channel (RyR) which is activated by cGMP or cyclic ADP-ribose (cADPR). Thus, it seemed that direct measurements of the likely second messenger candidates during sea urchin fertilization would be essential to an understanding of the Ca(2+) signaling pathway. We therefore measured the cGMP, cADPR and inositol 1,4,5-trisphosphate (IP(3)) contents of sea urchin eggs during the early stages of fertilization and compared these with the [Ca(2+)](i) rise in the presence or absence of an inhibitor against soluble guanylate cyclase. We obtained three major experimental results: (1) cytosolic cGMP levels began to rise first, followed by cADPR and IP(3) levels, all almost doubling before the explosive increase of [Ca(2+)](i); (2) most of the rise in IP(3) occurred after the Ca(2+) peak; IP(3) production could also be induced by the artificial elevation of [Ca(2+)](i), suggesting the large increase in IP(3) is a consequence, rather than a cause, of the Ca(2+) transient; (3) the measured increase in cGMP was produced by the soluble guanylate cyclase of eggs, and inhibition of soluble guanylate cyclase of eggs diminished the production of both cADPR and IP(3) and the [Ca(2+)](i) increase without the delay of Ca(2+) transients. Taken together, these results suggest that the RyR pathway involving cGMP and cADPR is not solely responsible for the initiating event, but contributes to the Ca(2+) transients by stimulating IP(3) production during fertilization of sea urchin eggs.

Adenosine Diphosphate Ribose↗
PubMed2001

Lack of correlation between clinical characteristics and serum soluble Fas ligand levels in patients with multiple myeloma.

Multiple myeloma is characterized by the accumulation of malignant plasma cells in the bone marrow and rarely cured by chemotherapy. Villunger et al. showed that the neoplastic plasma cells express Fas ligand (FasL), which transmits a signal of apoptosis upon ligation to Fas, and suggested that the FasL suppresses the T-cells activated against malignant cells, resulting in escape from tumour immunity. We examined serum soluble FasL (sFasL) levels in 35 multiple myeloma patients to evaluate the correlation between sFasL levels and clinical characteristics. The serum sFasL levels were not affected by the disease status, serum monoclonal protein levels, or other prognostic factors. We could not determine whether the expression of FasL is involved in the poor clinical course of the disease.

Adult↗
PubMed2001

Pneumocystis carinii pneumonia with an atypical granulomatous response in a patient with chronic lymphocytic leukemia.

We have recently seen a patient who developed Pneumocystis carinii pneumonia (PCP) in the course of treatment for chronic lymphocytic leukemia (CLL). This case showed uncommon pathological findings with extensive formation of granulomatous lesions. Despite advanced CLL associated with poor B-cell function, she responded well to anti-PCP treatment. In contrast to B-cell function, the T-cell functions were well preserved in vitro, and the numbers of peripheral CD4- and CD8-positive cells were normal, and T-cell functions were normal. These findings suggest that the production of granulomatous lesions to PCP may have been associated with the patients' immune status, and that it may constitute a good indicator in PCP infection in patients with underlying hematological malignancy.

Bronchoalveolar Lavage↗
PubMed2001

Clinical value of serial measurement of serum C-reactive protein level in neutropenic patients.

C-reactive protein (CRP) is an acute phase reactant of inflammation. We evaluated the clinical value of serial measurement of CRP in neutropenic patients. CRP was shown to be useful to monitor the response to therapy for febrile episodes in neutropenia. However, we failed to show statistically significant differences in CRP levels between febrile episodes with or without clinically documented infection (p= 0.10) and with or without bacteremia (p = 0.55). Also, we could not predict febrile episodes within three days by the elevation of CRP value. The area under receiver-operating characteristic curve depicting the relationship between CRP levels and forthcoming febrile episodes was only 0.60. In conclusion, serial measurement of CRP was considered to be not useful to predict fever within three days, or to differentiate the types of infection.

Adolescent↗
PubMed2001

TT virus in hematological disorders and bone marrow transplant recipients.

TT virus (TTV) was cloned as a possible causative agent for non A to C posttransfusion hepatitis. Determination of the entire sequence of the virus revealed that the virus is the first human circovirus. The nucleotide sequence of TTV has a wide range of diversity and at least sixteen genotypes have been discovered to date. The prevalence of TTV infection in the normal population differs among countries, but exceeds 10% in several countries. Most of TTV infections are not associated with hepatitis, although there is evidence of TTV-induced hepatitis, especially caused by TTV of genotype I. To determine whether TTV is replicated in the liver is important in order to show that TTV is really a hepatitis virus, because results of a study in bone marrow transplant (BMT) recipients suggested that TTV might be replicated mainly in the hematopoietic cells. The prevalence of TTV infection in patients with hematological disorders who regularly require blood products was extremely high, but most of the infections did not cause liver injury, even in BMT recipients.

Bone Marrow Transplantation↗
PubMed2001

Successful bone marrow transplantation for adult T-cell leukemia from a donor with oligoclonal proliferation of T-cells infected with human T-cell lymphotropic virus.

We describe a patient who underwent successful BMT from her sibling for the treatment of adult T-cell leukemia/lymphoma. Pre-transplant examination of the donor revealed oligoclonal integration of HTLV-I proviruses within the germ line, and our concern was that clinical sequelae of HLTV-I infection might become evident in the setting of post-transplant immunosuppression. However, the patient has been in complete remission for 14 months after transplantation, and no clonality of HTLV-I provirus was detected in the peripheral blood cells using southern blotting analysis. Our experience supports the possibility of transplantation from HTLV-I positive donors.

Bone Marrow Transplantation↗
PubMed2001

Early full donor myeloid chimerism after reduced-intensity stem cell transplantation using a combination of fludarabine and busulfan.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate lineage-specific chimerism reconstitution after reduced-intensity allogeneic stem cell transplantation (RIST) using a combination of fludarabine (30 mg/m2 for 6 days) and busulfan (4 mg/kg for 2 days). DESIGN AND METHODS: We prospectively enrolled 8 consecutive patients with hematologic malignancies who were not candidates for conventional transplantation because of either high age or organ dysfunction. Host-donor chimerism was evaluated using polymerase chain reaction-based amplification of a polymorphic short tandem repeat region. RESULTS: All of our patients achieved engraftment within a median of 11 days after transplantation. On day 30, full donor myeloid cell chimerism (>90%) was achieved in 7 patients whereas full donor T-cell chimerism was achieved in only one patient. Thus, in contrast to other reported results, full donor chimerism was achieved earlier in the myeloid lineage than the T-cell lineage. On day 60, however, T-cell chimerism caught up with myeloid chimerism. Two patients developed grade II-IV acute graft-versus-host disease (GVHD) before the detection of full donor T-cell chimerism. INTERPRETATION AND CONCLUSIONS: Our findings suggest that the kinetics of lineage-specific chimerism depend on the agents used in the conditioning regimen, and may provide insight into the chimerism kinetics and pathogenesis of GVHD. Thus, the strategy for controlling immunosuppression after RIST should be modified according to the type of conditioning regimen applied.

Adult↗
PubMed2001

[Non-myeloablative/reduced-intensity hematopoietic stem cell transplantation for chronic myelogenous leukemia].

Allogeneic hematopoietic stem cell transplantation(HSCT) is a curative therapy against a variety of hematological disorders. However, its application has been limited to younger patients without organ dysfunctions due to transplant-related toxicities. Recently, non-myeloablative stem cell transplantation(NST) or reduced-intensity stem cell transplantation(RIST) has been developed as a less toxic HSCT, which enables the application of HSCT to patients of advanced age or with organ dysfunction. The anti-leukemia effect mainly depends on the graft-versus-leukemia(GVL) effect. Chronic myelogenous leukemia(CML) has been known to be one of the best targets for GVL effect, supported by the observation of durable molecular remission after donor lymphocyte infusion for relapse after HSCT. RIST could be a promising treatment modality for patients with CML.

Graft vs Host Disease↗
PubMed2000

Inhibition of BAD phosphorylation either at serine 112 via extracellular signal-regulated protein kinase cascade or at serine 136 via Akt cascade sensitizes human ovarian cancer cells to cisplatin.

We studied the roles of the phosphatidylinositol 3-kinase (PI-3K)-protein kinase B/Akt-BAD cascade in both cisplatin-resistant Caov-3 and -sensitive A2780 human ovarian cancer cell lines. Treatment of both Caov-3 and A2780 cells with cisplatin but not with the trans-diaminodichloroplatinum (transplatin) isomer stimulated the activation of Akt, and the PI-3K inhibitor wortmannin blocked the cisplatin-induced activation of Akt. Treatment of both Caov-3 and A2780 cells with cisplatin but not with the trans-diaminodichloroplatinum isomer also stimulated the phosphorylation of BAD at both the Ser-112 and Ser-136 sites. Whereas the phosphorylation of BAD at Ser-136 was blocked by treatment with wortmannin, its phosphorylation at Ser-112 was blocked by a MAP/ERK kinase inhibitor, PD98059. Exogenous expression of a dominant-negative Akt in both Caov-3 and A2780 cells decreased the cell viability after treatment with cisplatin. In contrast, no sensitization to cisplatin was observed in cells expressing wild-type Akt. We further examined the role of BAD in the viability after cisplatin treatment using BAD mutants. Exogenous expression of each of the singly substituted BADS112A or BADS136A in both Caov-3 and A2780 cells decreased the viability after treatment with cisplatin to a degree intermediate between that caused by exogenous expression of wild-type BAD and doubly substituted BAD2SA. Cisplatin did not stimulate the phosphorylation of BAD Ser-136, but did stimulate the phosphorylation of BAD Ser-112 in cells expressing a dominant-negative Akt, suggesting that BAD Ser-136 but not Ser-112 was phosphorylated by Akt. Our findings suggest that cisplatin-induced DNA damage causes the phosphorylation of both BAD Ser-112 via an extracellular signal-regulated protein kinase (ERK) cascade and BAD Ser-136 via a PI-3K-protein kinase B/Akt cascade and that inhibition of either of these cascades sensitizes ovarian cancer cells to cisplatin.

Adenocarcinoma, Papillary↗
PubMed2000

Estrogen induces the Akt-dependent activation of endothelial nitric-oxide synthase in vascular endothelial cells.

Although estrogen is known to activate endothelial nitric oxide synthase (eNOS) in the vascular endothelium, the molecular mechanism responsible for this effect remains to be elucidated. In studies of both human umbilical vein endothelial cells (HUVECs) and simian virus 40-transformed rat lung vascular endothelial cells (TRLECs), 17beta-estradiol (E2), but not 17alpha-E2, caused acute activation of eNOS that was unaffected by actinomycin D and was specifically blocked by the pure estrogen receptor antagonist ICI-182,780. Treatment of both TRLECs and HUVECs with 17beta-E2 stimulated the activation of Akt, and the PI3K inhibitor wortmannin blocked the 17beta-E2-induced activation of Akt. 17beta-E2-induced Akt activation was also inhibited by ICI-182,780, but not by actinomycin D. Either treatment with wortmannin or exogenous expression of a dominant negative Akt in TRLECs decreased the 17beta-E2-induced eNOS activation. Moreover, 17beta-E2-induced Akt activation actually enhances the phosphorylation of eNOS. 17beta-E2-induced Akt activation was dependent on both extracellular and intracellular Ca(2+). We further examined the 17beta-E2-induced Akt activity in Chinese hamster ovary (CHO) cells transiently transfected with cDNAs for estrogen receptor alpha (ERalpha) or estrogen receptor beta (ERbeta). 17beta-E2 stimulated the activation of Akt in CHO cells expressing ERalpha but not in CHO cells expressing ERbeta. Our findings suggest that 17beta-E2 induced eNOS activation through an Akt-dependent mechanism, which is mediated by ERalpha via a nongenomic mechanism.

Animals↗
PubMed2000

Prophylactic action of oral fluconazole against fungal infection in neutropenic patients. A meta-analysis of 16 randomized, controlled trials.

BACKGROUND: Fluconazole is used widely for fungal prophylaxis. Although studies with bone marrow transplantation (BMT) recipients clearly showed the usefulness of oral fluconazole, results of the studies in neutropenic patients other than BMT recipients have been inconsistent. Therefore, the authors performed a meta-analysis to evaluate the efficacy of fluconazole prophylaxis during chemotherapy-induced neutropenia. METHODS: The authors identified reports that were not restricted to those in English and not restricted to published trials through MEDLINE, CANCERLIT, or the data base of the Pfizer company. The authors included prospective, randomized studies comparing oral fluconazole with placebo, no treatment, or oral polyenes as prophylaxis for fungal infections in neutropenic patients. Two independent authors extracted data from 16 trials with 3734 patients enrolled. The outcome measures were the development of fungal-related death, systemic and superficial fungal infections, the use of empiric intravenous amphotericin-B, and infections or colonization with fluconazole-resistant fungi. The summarized odds ratios (ORs) were calculated using the Mantel-Haenszel method and the DerSimonian-Laird method. RESULTS: Prophylactic fluconazole was not effective in reducing fungal-related death or in reducing proven, systemic fungal infections in non-BMT patients (OR, 0.91; 95% confidence interval [CI], 0.30-2.82 and OR, 0.85; 95% CI, 0.47-1.55, respectively). However, fluconazole was very effective in reducing superficial fungal infections (OR, 0.44; 95% CI, 0.24-0.80), even when it was given in lower doses (50-200 mg per day). There was no increase in proven, systemic infection of fluconazole-resistant fungi, although colonization of those fungi increased. When the results were combined in studies in which the incidence of systemic fungal infections was > 15%, fluconazole was effective in reducing such infections (OR, 0.23; 95% CI, 0.15-0.36). CONCLUSIONS: The current analyses failed to find an effect of fluconazole on both fatal fungal infection and systemic fungal infection in non-BMT patients. Further studies on severely neutropenic patients are warranted because prophylactic fluconazole seemed to be effective when the incidence of systemic fungal infection was expected to be > 15%.

Administration, Oral↗