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Biomedical subjects

Y Kanda

Publications and source records attributed to Y Kanda.

At least 37 records · Page 2Linked to original sources
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

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

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↗
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↗
PubMed2000

The stimulation of beta(3)-adrenoceptor causes phosphorylation of extracellular signal-regulated kinases 1 and 2 through a G(s)- but not G(i)-dependent pathway in 3T3-L1 adipocytes.

The treatment of 3T3-L1 adipocytes with three beta(3)-adrenoceptor agonists, (+/-)-(R*, R*)-(4-[2-([2-(3-chlorophenyl)-2-hydroxyethyl]amino)propyl]phenoxy)ac etic acid (BRL37344), 4-[3-[(1, 1-dimethylethyl)amino]-2-hydroxypropoxy]-1, 3-dihydro-2H-benzimidazol-2-one (CGP12177) and [(7S)7-¿(2R)2-(3-chlorophenyl)-2-hydroxyethyl-amino¿-5,6,7, 8-tetrahydronapht-2-yl]ethyl oxyacetate, hydrochloride (SR58611) induces phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). The phosphorylations were not affected by pretreatment of the adipocytes with pertussis toxin, whereas the same treatment completely abolished lisophosphatidic acid-induced phosphorylation of ERK1/2, suggesting the role of pertussis toxin-insensitive G protein in the ERK1/2 phosphorylation by stimulation with the beta(3)-adrenoceptor agonists. The phosphorylation of ERK1/2 was mimicked by treating the adipocytes with cholera toxin, a direct activator of stimulatory G (G(s)) protein. In addition, the ERK1/2 phosphorylations by the beta(3)-adrenoceptor agonists were completely diminished by long-term treatment of the adipocytes with cholera toxin (100 ng/ml, 24 h), whereas that obtained with lisophosphatidic acid stimulation was not. Our findings strongly suggest that the three beta(3)-adrenoceptor agonists induce ERK1/2 phosphorylation in 3T3-L1 adipocytes through a G(s) protein-dependent cascade.

3T3 Cells↗
PubMed2000

The potentiation of ox-LDL induced apoptosis by inhibition of NF-kappaB.

We previously reported that oxidized low density lipoprotein (ox-LDL) induced apoptosis in vascular smooth muscle cells (VSMCs). However, the transcription factors important for apoptotic signalling have been little clarified. We investigated the involvement of nuclear factor-kappaB (NF-kappaB), by which apoptotic signalling is reported to be mediated, in ox-LDL-induced apoptosis. The effect of ox-LDL on the transcriptional factor NF-kappaB activation was investigated by electrophoretic mobility shift assay (EMSA). Ox-LDL caused NF-kappaB activation in VSMCs. Next, we investigated the effect on ox-LDL-induced apoptosis by introduction of synthetic double-stranded DNA with high affinity for NF-kappaB in vitro as "decoy" cis elements that bind the transcriptional factor. Treatment by transfection of NF-kappaB decoy oligodeoxynucleotides (ODN), but not scramble ones, blunted the activation of NF-kappaB by ox-LDL and caused a significant further induction of ox-LDL-induced apoptosis. Results indicate that the activation of NF-kappaB prevents excessive apoptosis by ox-LDL in VSMCs.

Animals↗
PubMed2000

Discovery and synthesis of a potent sulfonamide ET(B) selective antagonist.

The synthesis and structure activity relationships of a series of sulfonamide endothelin antagonists are described. In the course of our modification studies, we discovered ET(B) selective antagonists. The most potent compound 15f displays IC50 values of 1.7 microM and 0.002 microM to ET(A) and ET(B) receptors, respectively.

Animals↗
PubMed2000

Putative membrane-bound estrogen receptors possibly stimulate mitogen-activated protein kinase in the rat hippocampus.

We investigated whether 17beta-estradiol affects the activity of extracellular signal-regulated kinase (ERK) in the central nervous system in vivo. 17beta-Estradiol was administered intracerebroventricularly, and then ERK activity in the rat hippocampus was measured. We found that ERK activity in the rat hippocampus had increased to approximately threefold its basal level at 5 min. This rapid effect was mimicked by the membrane-impermeable estradiol, bovine serum albumin-conjugated 17beta-estradiol, and was not inhibited by tamoxifen and 7alpha,9-(4,4,5,5, 5-pentafluoropentylsulphinyl)nonylestra-1,3,5(10)-triene-3, 17beta-diol (ICI 182780), classical nuclear estrogen receptor antagonists. These data suggest that the rapid activation of ERK by estradiol in vivo is mediated through a putative membrane estrogen receptor in the rat hippocampus.

Animals↗
PubMed2000

Activation of the luteinizing hormone beta promoter by gonadotropin-releasing hormone requires c-Jun NH2-terminal protein kinase.

Regulation of the mitogen-activated protein kinase (MAPK) family by gonadotropin-releasing hormone (GnRH) in the gonadotrope cell line LbetaT2 was investigated. Treatment with gonadotropin-releasing hormone agonist (GnRHa) activates extracellular signal-regulated kinase (ERK) and c-Jun NH(2)-terminal kinase (JNK). Activation of ERK by GnRHa occurred within 5 min, and declined thereafter, whereas activation of JNK by GnRHa occurred with a different time frame, i.e. it was detectable at 5 min, reached a plateau at 30 min, and declined thereafter. GnRHa-induced ERK activation was dependent on protein kinase C or extracellular and intracellular Ca(2+), whereas GnRHa-induced JNK activation was not dependent on protein kinase C or on extracellular or intracellular Ca(2+). To determine whether a mitogen-activated protein kinase family cascade regulates rat luteinizing hormone beta (LHbeta) promoter activity, we transfected the rat LHbeta (-156 to +7)-luciferase construct into LbetaT2 cells. GnRH activated the rat LHbeta promoter activity in a time-dependent manner. Neither treatment with a mitogen-activated protein kinase/ERK kinase (MEK) inhibitor, PD98059, nor cotransfection with a catalytically inactive form of a mitogen-activated protein kinase construct inhibited the induction of the rat LHbeta promoter by GnRH. Furthermore, cotransfection with a dominant negative Ets had no effect on the response of the rat LHbeta promoter to GnRH. On the other hand, cotransfection with either dominant negative JNK or dominant negative c-Jun significantly inhibited the induction of the rat LHbeta promoter by GnRH. In addition, GnRH did not induce either the rat LHbeta promoter activity in LbetaT2 cells transfected stably with dominant negative c-Jun. These results suggest that GnRHa differentially activates ERK and JNK, and a JNK cascade is necessary to elicit the rat LHbeta promoter activity in a c-Jun-dependent mechanism in LbetaT2 cells.

Animals↗
PubMed2000

The clinical significance of CD34 expression in response to therapy of patients with acute myeloid leukemia: an overview of 2483 patients from 22 studies.

BACKGROUND: Although many studies have been performed to evaluate the prognostic significance of CD34 expression in acute myeloid leukemia (AML), the findings have been inconsistent. In this study, the authors reviewed such previous studies to establish a definite conclusion. METHODS: Using MEDLINE, the authors identified studies that evaluated the prognostic significance of CD34 expression in AML. The outcome measure was the complete remission rate. They used the random-effect method to combine the results. Results were presented as odds ratios (ORs) with 95% confidence intervals (CIs). The ORs were less than 1 if the complete remission occurred more frequently in the CD34 negative group. RESULTS: Twenty-two studies including 2483 patients were reviewed. The combined OR was 0.38 (95% CI, 0. 26-0.57), which suggested that CD34 expression was associated with a poor remission rate. However, the authors found statistical evidence of marked heterogeneity among trials (P < 0.001), especially according to time of publication. The combined OR in studies published in or after 1994 was 0.70 (95% CI, 0.47-1.09). The authors divided the studies into several subgroups, but they could not determine the reason for the heterogeneity. CONCLUSIONS: At present, CD34 expression should not be considered a marker of poor prognosis because it is not supported by the combined data from recent studies. Further studies should be conducted to investigate the intensity of CD34 expression in specific populations of patients, such as those with t(8;21) or t(15;17) translocations or the AML-M0 subtype.

Acute Disease↗
PubMed2000

Prolactin-releasing peptide activation of the prolactin promoter is differentially mediated by extracellular signal-regulated protein kinase and c-Jun N-terminal protein kinase.

Regulation of the mitogen-activated protein kinase (MAPK) family by prolactin-releasing peptide (PrRP) in both GH3 rat pituitary tumor cells and primary cultures of rat anterior pituitary cells was investigated. PrRP rapidly and transiently activated extracellular signal-regulated protein kinase (ERK) in both types of cells. Both pertussis toxin, which inactivates G(i)/G(o) proteins, and exogenous expression of a peptide derived from the carboxyl terminus of the beta-adrenergic receptor kinase I, which specifically blocks signaling mediated by the betagamma subunits of G proteins, completely blocked the PrRP-induced ERK activation, suggesting the involvement of G(i)/G(o) proteins in the PrRP-induced ERK activation. Down-regulation of cellular protein kinase C did not significantly inhibit the PrRP-induced ERK activation, suggesting that a protein kinase C-independent pathway is mainly involved. PrRP-induced ERK activation was not dependent on either extracellular Ca(2+) or intracellular Ca(2+). However, the ERK cascade was not the only route by which PrRP communicated with the nucleus. JNK was also shown to be significantly activated in response to PrRP. JNK activation in response to PrRP was slower than ERK activation. Moreover, to determine whether a MAPK family cascade regulates rat prolactin (rPRL) promoter activity, we transfected the intact rPRL promoter ligated to the firefly luciferase reporter gene into GH3 cells. PrRP activated the rPRL promoter activity in a time-dependent manner. Co-transfection with a catalytically inactive form of a MAPK construct or a dominant negative JNK, partially but significantly inhibited the induction of the rPRL promoter by PrRP. Furthermore, co-transfection with a dominant negative Ets completely abolished the response of the rPRL promoter to PrRP. These results suggest that PrRP differentially activates ERK and JNK, and both cascades are necessary to elicit rPRL promoter activity in an Ets-dependent mechanism.

Animals↗