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Nobuhiko Emi

Publications and source records attributed to Nobuhiko Emi.

34 records · Page 2Linked to original sources
PubMed2004

Multiplex real-time RT-PCR for prospective evaluation of WT1 and fusion gene transcripts in newly diagnosed de novo acute myeloid leukemia.

Prognostic assessment is crucial for the management of AML. Although the use of karyotype analysis for risk-stratification is widely accepted, prognosis of AML remains ambiguous, particularly for patients categorized into the intermediate cytogenetic risk group and additional markers are required for an accurate prediction of outcome. For this study, we used multiplex real-time RT-PCR, which can simultaneously quantify WT1 and 10 distinct fusion gene transcripts, to prospectively evaluate the pre-treatment bone marrow findings of 53 de novo AML patients. Five patients with normal karyotype or insufficient metaphases detected by conventional karyotype analysis proved to have AML1-MTG8, CBFbeta-MYH11 or PML-RARalpha fusion transcripts. WT1 overexpression was observed in 92% of the patients, and the levels were significantly higher in the cytogenetic favorable risk group, especially patients with PML-RARalpha. WT1 levels also correlated with the percentage of blasts in bone marrow, especially in cases of core-binding factor leukemia. There was no association between initial WT1 levels and outcome in terms of event-free survival or overall survival. These results suggest that multiplex real-time RT-PCR is rapid and useful for the precise cytogenetic stratification of AML, and that WT1 levels at presentation correlate with several biologic features of leukemia, but have no prognostic significance.

Adolescent↗
PubMed2004

Efficacy and safety of imatinib mesylate for patients in the first chronic phase of chronic myeloid leukemia: results of a Japanese phase II clinical study.

Imatinib mesylate is a relatively new drug that targets the BCR-ABL chimeric protein, the molecular basis of chronic myeloid leukemia (CML). A phase II clinical trial in 39 Japanese patients in the first chronic phase of CML was conducted with imatinib mesylate at a dose of 400 mg/day. Hematologic complete response was obtained in 92.3% of the patients, complete cytogenetic response (CR) was obtained in 43.6%, and major partial CR was obtained in 20.5% of the patients. Although 29 of 39 patients required an adjustment of dosing because of grade 3 or 4 adverse events, most of the events were reversible, and 25 of the 29 patients were able to resume therapy. Between day 15 and day 35, grade 3 or 4 neutropenia and/or leukocytopenia occurred in 13 patients, and grade 3 thrombocytopenia occurred in 5 patients. Overall, nonhematologic grade 3 adverse events occurred in 28.2% of the patients. These data support the use of imatinib mesylate as the treatment of choice for chronic-phase CML patients.

Adult↗
PubMed2003

Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia.

Although FLT3 mutations are essentially found in myeloid-lineage leukemia cells, a high level of FLT3 expression was recently observed in MLL gene-rearranged acute lymphoblastic leukemia without FLT3 mutations. Here, we analyzed the biologic and clinical significance of the FLT3 transcript level in comparison with several gene alterations in 181 de novo acute myeloid leukemia (AML) cases. The mean expression level in AML was higher than that in normal mononuclear cells, whereas the range varied widely. A high level of FLT3 is related to internal tandem duplication of the FLT3 gene (FLT3/ITD), the mutations within the activation loop of FLT3 (FLT3/D835Mt), and tandem duplication of the MLL gene (MLL-TD) but not to p53 or N-RAS gene mutations. Furthermore, a high expression level in AML cases with FLT3 mutations was not related to MLL-TD. Overexpressed FLT3 revealed autophosphorylation and had the same sensitivity to the FLT3 inhibitor as FLT3/ITD. Overexpression of FLT3 (more than 200,000 copies/microgRNA) was an unfavorable prognostic factor for overall survival in 91 AML cases without FLT3/ITD. These results indicated that FLT3 overexpression may distinguish a novel disease entity in AML without FLT3 mutations and serve as a therapeutic target for FLT3 inhibitors.

Adult↗
PubMed2003

Transforming growth factor B1 T29C polymorphism and breast cancer risk in Japanese women.

BACKGROUND: A cohort study for Caucasians aged 65 years or older demonstrated a marked breast cancer risk reduction for those with the CC genotype of transforming growth factor B1 (TGF B1) T29C polymorphism. This is a prevalent case-control study to examine the reported risk reduction for Japanese women. PATIENTS AND METHODS: A total of 232 histologically diagnosed breast cancer patients who visited Aichi Cancer Center Hospital between June 1999 and March 2000 were enrolled. The controls were 172 female outpatients without cancer at the same hospital. DNA was extracted from peripheral blood, and TGF B1 genotype was determined by PCR-CTPP. RESULTS: The genotype frequency was 23.7% for TT, 49.2% for TC, and 27.1% for CC among controls, and 28.9%, 46.1%, and 25.0%, respectively, among cases. Age-adjusted odds ratio (OR) relative to the TT genotype was 0.81 (95% confidence interval, 0.50-1.31) for the TC genotype and 0.77 (0.45-1.34) for the CC genotype. For premenopausal women, the CC genotype was significantly associated with reduced risk of breast cancer in comparison with the TT genotype (OR=0.45, 0.20-0.98). The association was not observed for postmenopausal women (OR=1.40, 0.64-3.08). CONCLUSION: The present study showed risk reduction for Japanese premenopausal women with the CC genotype, but not for postmenopausal Japanese women.

Adult↗
PubMed2003

Recovery of normal hematopoiesis after severe bone marrow aplasia induced by interferon-alpha in a patient with chronic myelogenous leukemia.

We describe an interesting case of a patient with chronic myelogenous leukemia (CML) who developed sustained severe bone marrow aplasia after 2 years and 11 months of interferon-alpha (IFN-alpha) therapy but demonstrated recovery of normal hematopoiesis when treated with immunosuppressive therapy with granulocyte-colony stimulating factor (G-CSF). Administration of G-CSF resulted in a partial recovery of hematopoiesis, and after starting immunosuppressive therapy, the patient was no longer dependent on blood transfusions. Moreover, her bone marrow had no Philadelphia chromosome-positive clones. According to the results of the present case, bone marrow recovery can be achieved with immunosuppressive therapy and a fatal outcome avoided, even in CML patients suffering from sustained bone marrow aplasia during IFN-alpha treatment.

Adult↗
PubMed2003

Polymorphism in the hMSH2 gene (gIVS 12-6T-->C) and risk of non-Hodgkin lymphoma in a Japanese population.

We conducted a hospital-based prevalent case-control study in a Japanese population (cases=103, controls=487) to ascertain the previous report about the association between the polymorphism in exon 13 of the hMSH2 gene (gIVS 12-6T-->C) and the risk of non-Hodgkin lymphoma in an Ecuadorian population. When the TT genotype was defined as the reference, none of the CT genotypes (OR=1.52; 95% CI, 0.97-2.37), CC genotypes (OR=1.06, 95% CI, 0.44-2.54), or CT and CC genotypes combined together (OR=1.44, 95% CI, 0.94-2.23) demonstrated significant OR. Further investigations with sufficiently larger populations and in other ethnicities are required to verify this association.

Adenosine Triphosphatases↗
PubMed2003

DR1-like element in human topoisomerase IIalpha gene involved in enhancement of etoposide-induced apoptosis by PPARgamma ligand.

OBJECTIVE: The nuclear peroxisome proliferator-activated receptor gamma (PPARgamma) ligands may enhance the etoposide-induced apoptosis by modulating the topoisomerase (Topo) IIalpha expression through binding to direct repeat 1 (DR1)-like element. METHODS: To investigate the effect of etoposide-induced apoptosis by PPARgamma ligands, leukemia cell lines were treated with troglitazone and 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) in the presence of etoposide and studied about various biological responses. RESULTS: We found the enhancement of etoposide-induced apoptosis by PPARgamma ligands in several leukemia cell lines, which was dependent on the expression of PPARgamma and specific for TopoIIalpha inhibitor. We also observed the increased expression of TopoIIalpha protein by 15d-PGJ2 in Jurkat and HUVEC cells, which might lead to the increased sensitivity to etoposide. Furthermore, we demonstrated that 15d-PGJ2 enhanced the promoter activity of human TopoIIalpha promoter construct with a DR1-like site by sevenfold when expressed with PPARgamma and RXRalpha. The mutation of DR1-like site decreased the promoter activity, although the direct binding between DR1-like site and PPARgamma/RXRalpha heterodimer was not demonstrated. CONCLUSIONS: We conclude that the induction of TopoIIalpha expression by PPARgamma ligands via DR1-like site is an important mechanism for the enhancement of etoposide-induced apoptosis and a DR1-like site in TopoIIalpha promoter is involved in transcriptional regulation dependent on PPARgamma ligands and PPARgamma/RXRalpha heterodimer.

Antigens, Neoplasm↗
PubMed2003

Cytogenetic heterogeneity of acute myeloid leukaemia (AML) with trilineage dysplasia: Japan Adult Leukaemia Study Group-AML 92 study.

Acute myeloid leukaemia (AML) with trilineage dysplasia (AML/TLD) is de novo AML recognized by the morphological dysplasia of three mature cell lines in the presence of leukaemic blasts. We studied the karyotypes of AML/TLD of patients with de novo AML, except for those with the French-American-British classification M3, who were enrolled onto the Japan Adult Leukaemia Study Group (JALSG)-AML 92 trial. Morphological and cytogenetic analyses were performed in 559 patients and TLD phenotype was found in 155 patients (27.7%). The 511 patients with informative morphological and cytogenetic data were classified into three groups according to karyotype: favourable, intermediate and adverse risk groups (92, 375 and 44 patients respectively). Normal karyotype was the most frequent as a total, and among both the non-TLD and TLD patients (164 patients 45.3% and 78 patients 52.7% respectively). All but one patient with AML/TLD was classified into the intermediate or adverse cytogenetic risk group. TLD phenotype was associated with lower remission rate and shorter overall survival but it did not influence disease-free survival. Although we did not find any specific cytogenetic abnormalities for AML/TLD, the rarity of favourable karyotypes among TLD patients indicates the biological difference between AML/TLD and AML/non-TLD.

Acute Disease↗
PubMed2003

Associations between polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and susceptibility to malignant lymphoma.

BACKGROUND AND OBJECTIVES: Polymorphisms in thymidylate synthase (TS) 28-bp tandem repeats in the promoter region and in cytosolic serine hydroxymethyltransferase (SHMT1 C1420T) have been reported to modulate the risk of adult acute lymphocytic leukemia (ALL). We examined the associations between susceptibility to malignant lymphoma and these polymorphisms. DESIGN AND METHODS: A hospital-based prevalent case-control study was conducted in Aichi Cancer Center. One hundred and eight patients with histologically confirmed lymphoma and 494 control subjects without cancer were evaluated. RESULTS: In a risk estimation of each genotype, those who harbored at least one TS 2 repeat (2R) allele had a 1.6-fold increase in the risk of malignant lymphoma (OR=1.63; 95%CI, 1.05-2.53, p=0.030) when using those without the TS 2R allele as a reference. For the SHMT1 C1420T polymorphism, those harboring at least one T allele showed a 2.2-fold decrease in risk (OR =0.46; 95% CI, 0.23-0.93, p=0.031). Moreover, combined analysis of TS and SHMT1 polymorphisms revealed that the OR for lymphoma in patients with SHMT1 1420 CC and the TS 2R allele, which might be expected to provide the basis for the highest susceptibility, was 2.88 (95% CI, 1.26-6.58, p=0.013). INTERPRETATIONS AND CONCLUSIONS: This study suggests that genetic traits involving low penetrance polymorphisms in folate-metabolizing genes may modulate the risk of malignant lymphoma.

Adult↗
PubMed2002

Insulin-enhanced liposome-mediated gene transfer into a gastric carcinoma cell line.

1. Liposome-mediated transfection is useful due to no DNA constraints, lower immunogenicity and easy preparation. However, it has the disadvantage of low transfection efficiency. We aimed to test whether lipofection efficiency could be enhanced in gastrointestinal cell lines by the growth-promoting effect of insulin. 2. To assess the effect of insulin on lipofection efficiency and the cell cycle, expression of green fluorescent protein (GFP) and DNA distribution in gastric (MKN1), colonic (HT29) and pancreatic (BxPC3) carcinoma cell lines was analysed using flow cytometry. 3. The percentage of positive cells with GFP was significantly higher in MKN1 cells in culture medium with 5 mg/mL insulin than without insulin, whereas the percentage was the same in HT29 and BxPC3 cells with insulin as without insulin. The percentage of S phase fraction MKN1 cells with insulin was greater than without insulin, whereas the percentage of S phase fractions of HT29 and BxPC3 cells was the same with or without insulin. Lipofection efficiency correlated with the percentage of S phase fraction. 4. Insulin has the potential to enhance efficiency of lipofection into a sensitive cell line by increasing cellular proliferation.

Cell Cycle↗
PubMed2002

Prediction of sensitivity to STI571 among chronic myeloid leukemia patients by genome-wide cDNA microarray analysis.

One of the most critical issues to be solved in regard to cancer chemotherapy is the establishment of ways to predict the efficacy of anti-cancer drugs for individual patients. To develop a prediction system based on expression of specific genes, we analyzed expression profiles of mononuclear cells from 18 chronic myeloid leukemia (CML) patients who were treated with the tyrosine kinase inhibitor STI571. cDNA microarrays representing 23 040 genes identified 79 genes that were expressed differentially between responders and non-responders to STI571. On the basis of the expression patterns of 15 or 30 of these genes among the patients, we developed a "Prediction Score" system that could clearly separate the responder group from the non-responder group. Verification of this system using four additional ("test") cases succeeded in predicting the response of each of those four patients to the drug. These results provide the first evidence that gene-expression profiles can predict sensitivity of CML cells to STI571, and may eventually lead to the achievement of "personalized therapy" for this disease.

Adult↗
PubMedDate not supplied

Synthesis of novel cationic lipids having polyamidoamine dendrons and their transfection activity.

We designed a novel type of cationic lipid, lipids with a cationic polar group in the polyamidoamine dendron, because these dendron-bearing lipids are expected to form complexes with plasmid DNA and achieve efficient transfection of cells by synergy of endosome buffering and membrane fusion with the endosome, both of which are useful for the promotion of the transfer of plasmid DNA from endosome to cytosol. Four kinds of lipids with polyamidoamine dendrons of first to fourth generations, DL-G1, DL-G2, DL-G3, and DL-G4, were synthesized. The lipid with a dendron of a higher generation exhibited greater ability to form lipoplexes with plasmid DNA, as estimated by agarose gel electrophoresis. While the DL-G1 lipoplex did not transfect CV1 cells, the lipoplexes containing the DL-G2, DL-G3, or DL-G4 could induce transfection of the cells, and their activity was elevated with increasing generation of the dendron. Addition of dioleoylphosphatidylethanolamine (DOPE), which is known to increase fusion ability of a lipid membrane, into the lipoplexes greatly enhanced their transfection activity. In addition, the comparison with DC-Chol-containing lipoplex, which is widely used as a nonviral vector, showed that the DL-G3-DOPE lipoplex exhibits more efficient transfections. These findings imply that these dendron-bearing lipids may form the basis for a novel family of cationic lipids for efficient gene delivery.

Animals↗
PubMedDate not supplied

Preparation of efficient gene carriers using a polyamidoamine dendron-bearing lipid: improvement of serum resistance.

In a previous study, we developed a novel cationic lipid consisting of polyamidoamine dendron of third generation and two dodecyl chains, designated as DL-G3, which in combination with a fusogenic lipid dioleoylphosphatidylethanolamine (DOPE) achieves efficient transfection of CV1 cells by synergetic action of the proton sponge effect and membrane fusion. This study examines the effect of serum on the transfection activity of the DL-G3-DOPE-plasmid DNA lipoplexes. The transfection activity of a lipoplex with a composition optimized in the absence of serum decreased markedly in the presence of serum. However, the lipoplexes that induce efficient transfection in the presence of serum were obtainable by controlling the charge ratio of the primary amine of the DL-G3 to the phosphate group (N/P ratio) and DOPE content. The complex, which exhibited the highest transfection activity in the presence of serum, has a lower N/P ratio and higher DOPE content than that optimized in the absence of serum. Whereas disintegration of these complexes was induced by addition of heparin, which is a polysaccharide with negatively charged groups, the complex that retained transfection activity in the presence of serum required more negative charges of heparin for complex disintegration. That result implies its higher stability against negatively charged serum proteins. Comparison of the serum-resistant complex with some commercially available transfection reagents, such as Lipofectamine and SuperFect, indicates that the DL-G3 complex achieved more efficient transfection of these cells in the presence of serum.

Amination↗
PubMedDate not supplied

GSTT1 and GSTM1 deletions, NQO1 C609T polymorphism and risk of chronic myelogenous leukemia in Japanese.

We conducted a prevalent case-control study with 51 chronic myelogenous leukemia (CML) cases and 476 controls to investigate the associations between glutathione S-transferase T1 (GSTT1), glutathione S-transferase M1 (GSTM1) deletions, and the NAD(P)H:quinone oxidoreductase 1 (NQO1) C609T polymorphism with risk of chronic myelocytic leukemia in Japanese. For the GSTT1 deletion, when the GSTT1 positive genotype was defined as the reference, the OR for the GSTT1 deletion genotype was 1.32 (95%CI; 0.74-2.36). For the GSTM1 deletion, when the GSTM1 positive genotype was defined as the reference, the OR for the GSTM1 deletion genotype was 0.95 (95%CI; 0.53-1.69). For NQO1 C609T polymorphism, when the NQO1 609CC genotype was defined as the reference, the ORs for the CT genotype, TT genotype, and CT and TT genotypes combined together were 2.37 (95%CI, 1.21-4.67, P=0.012), 1.44 (0.55-3.74, P=0.012) and 2.12 (1.10-4.08, P=0.025), respectively. The present study revealed that the risk of CML was modulated little by GSTT1 and GSTM1 deletions, but a statistically significant association between NQO1 C609T polymorphism and CML was observed for Japanese. Incidence case-control studies with a larger statistical power are now required to confirm our findings.

Adolescent↗