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  • American Society of Hematology  (11)
  • 1
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    Methylation and Hydroxymethylation Status of Tumor Suppressor Genes and Common Fragile Sites Genes in Acute Myeloid Leukemia
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 3535-3535
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3535-3535
    Abstract: Background: 5-methylation (5-mC) is the predominant epigenetic mark in mammalian genomic DNA. When promoter region of certain gene is hypermethylated, the gene becomes transcription silent. Promoter of tumor suppressor genes (TSG) usually exists in CpG islands, and silencing of TSGs in cancer cells is often associated with hypermethylation. p15, CDH1 are frequently methylated in myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Common Fragile Site (CFS) is a fragile site on the chromosomes easy to produce gap and break, and it contains putative TSGs. FHIT, WWOX and PARK2 are the CFS genes known to be frequently methylated in solid tumors, but their status of hematologic malignancies has not been fully elucidated yet. 5-hydroxymethylaiton (5-hmC) is a newly discovered epigenetic modification that is presumably generated by oxidation of 5-mC by the TET family of cytosine oxygenases. Techniques identifying 5-mC cannot distinguish between 5-mC and 5-hmC, therefore 5-hmC status of the genes have not fully elucidated yet too. Recently it has been demonstrated that mutation of epigenetic modifiers (DNMT3A, TET2, IDH1/2) play important role on AML pathogenesis. We tried to clarify 5-mC and 5-hmC status of TSG p15, CDH1 and CFS genes FHIT, WWOX and PARK2 by using new techniques and the relationships with expression levels of epigenetic modifiers in AML. Methods: BM samples obtained from 74 of AML patients are subjected to the study after informed consent. This study was approved by IRB of Gunma University Hospital. DNA, RNA were extracted from BM mononuclear cells. Methylation specific PCR (MSP) was carried out to assay 5-mC of p15, CDH1, WWOX, PARK2. Quantification of 5-mC and 5-hmC (except PARK2) was carried out by methylation sensitive restriction enzyme assay (MSRE) with glucosylation and Q-PCR. Total DNA 5-mC and 5-hmC were analyzed by ELISA. The mRNA expression levels of p15, CDH1, FHIT, WWOX, PARK2, DNMT1, 3A, TET2 were quantified by Q-PCR. Results: MSP revealed that p15, CDH1, WWOX and PARK2 were methylated in 43.1%, 94.3%, 35.7% and 36.9% of AML, respectively. PARK2 methylation was not found in t(15;17) APL, but in 32% of normal karyotype AML (NK-AML), in 67% of t(8;21) CBF-AML. In contrast, the p15 methylation was found in 83.3% of APL, 45.5% of NK-AML, 50% of CBF-AML. WWOX methylation was found in 42.9% of APL, in 16% of NK-AML and 66.7% of CBF-AML. Adverse karyotype AML (adv-AML) tended to show lower % of WWOX, PARK2 and p15 methylation with 15.8%, 21.1% and 18.8% compare to good risk karyotype. The frequency of the methylation of PARK2 and WWOX were varied among karyotypes and the methylation was mutually exclusive. ELISA demonstrated that mean % of total 5-mC DNA was 1.08% and ratio of 5-hmC in 5-mC was 0.95% in AML. Interestingly, 5-hmC was 0% in adv-AML although 5-mC existed (mean: 1.05%). Locus specific MSRE-QPCR demonstrated that mean % of 5-mC of p15, CDH1, WWOX and FHIT were 6.62%, 1.25%, 8.33%, 2.88%, respectively., In adv-AML, 5-hmC of CDH1, WWOX and FHIT were not detected, although 5-mC of these genes were detected (0.41%, 9.0%, 2.14%) in accordance with whole DNA analysis. In good and intermediate AML, 5-hmC of these genes was 3.44%, 1.07%, 2.69% ,respectively. RQ-PCR demonstrated that CDH1, p15, WWOX, PARK2 and epigenetic modifier DNMT1, DNMT3A and TET2 expression were not different among various karyotype risks, but only FHIT expression significantly higher in good risk group (p=0.047). The expression levels of the genes were not significantly different between mentylated and unmethylated. The ratio of 5-hmC/5-mC of the TSGs tended to be associated with the expression levels of the corresponding genes, but the association did not reach statistical significance. DNMT3A expression in AML with 5-mC PARK2 was higher than in other AML (p=0.016). Contrary to the intuition, DNMT3A expression was positively correlated with FHIT, PARK2 expression (r=0.776, p & lt;0.001, r=0.689, p & lt;0.001). CDH1 expression was positively correlated with DNMT1 and negatively correlated with TET2 expression (r=0.447, p=0.009, r=-0.349, p=0.022). OS and EFS were not different among the methylation status of these genes. Conclusion: CFS genes are selectively methylated in AML. MSRE-QPCR can distinguish 5-mC and 5-hmC and quantify the ratio of them with locus specific manner. The relationship between gene expression and 5-hmC, 5-mC should be pursued. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.3535.3535
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 2
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    Clinical Significance of Granulocytic Sarcoma at Relapse In Adult Patients with Acute Myeloid Leukemia
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 4373-4373
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 4373-4373
    Abstract: Abstract 4373 Background We reported that adult AML patients with granulocytic sarcoma (GS) at diagnosis were associated with younger age, higher WBC counts, and monocytic differentiation of leukemia cells and GS adversely affected relapse rate and DFS at the 51st ASH annual meeting. However clinical impact of GS at relapse has not been clear. The objective of this study was to describe the frequency and clinical characteristics of adult AML patients with GS at relapse. Methods Between January, 1990 and March 2010, 517 patients (median age 57 (15-88), male/female; 313/204) diagnosed as AML were included. 58 patients (11.2%) were with GS at diagnosis and 459 patients were without GS. 480 younger patients were treated according to Japan Adult Leukemia Study Group treatment protocols (JALSG AML92, AML95, AML97, GML200, or AML201). 37 older patients were treated with low-dose Ara-C based regimen. The χ2-test was used for the binary variable comparison. The Mann-Whitney U test was used for continuous variable comparison. P 〈 0.05 was considered to indicate statistical significance. Results A total of 295 relapses was occurred in 233 patients. 32 relapses (11.0%) were with GS and 263 were without GS. 30 patients with GS at relapse had the same characteristics as patients with GS at diagnosis, including younger age (p 〈 0.001), higher WBC counts at relapse (p=0.045), and high frequency of FAB M4 (p=0.001) and M5 (p=0.042) morphology. No significant differences in sex, the distribution of cytogenetic risk groups, and the frequency of each cytogenetic change including t(8;21), 11q23, inv(16), and the complex karyotype demonstrated. 38 relapses occurred in 34 patients with GS at diagnosis and 257 relapses in 199 patients without GS. The frequency of relapse with GS in patients with GS at diagnosis was significantly higher than that in patients without GS (29% vs 8%; p=0.0006). 41 relapses occurred in 37 patients after allogenic stem cell transplantation (allo-SCT) and 254 relapses in 196 patients after chemotherapy. 8 patients received allo-SCT from peripheral blood stem cell, 24 from bone marrow, and 6 from cord blood. 31 patients received conditioning regimen containing total body irradiation (TBI) and 6 received non-TBI regimen. The frequency of relapses with GS after allo-SCT was significantly higher than that after chemotherapy (27% vs 9%; p=0.0035). In patients after allo-SCT cell source and conditioning regimen did not affected frequency of GS. 58% of patients achieved CR with any salvage chemotherapy. Patients with GS had a trend of a lower CR rate than without GS (47% vs 63%; p=0.068). Conclusions Patients with GS at relapse had the same characteristics as patients with GS at diagnosis, including younger age, higher WBC counts, and monocytic differentiation of leukemia cells. This study shows the high frequency of relapse with GS in patients with GS at diagnosis and after allo-SCT independently of cell source and the conditioning regimen. As patients with GS at relapse tended to get chemotherapy-resistant we should give the attention to relapse with GS in follow-up of such AML patients. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.4373.4373
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
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  • 3
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    Unique Pharmacokinetic Self-Potentiation of Idarubicin through Induction of Carbonyl Reducing Enzymes in Contrast to Other Anthracyclines, Pharmacologic and Clinical Study
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 4025-4025
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 4025-4025
    Abstract: Idarubicin (IDA) is one of the key drugs for treating hematological malignancies. Severe myelosuppression is one of the major adverse events of IDA. Interestingly, when IDA is administered in 2 consecutive courses of therapy, IDA tends to exert a stronger bone marrow suppressive effect in the second course compared with the first course while other anthracyclines such as daunorubicin tend to milder suppressive effect in the second course compared with the first course (Wiernik PH et al, Blood, 1992). In order to clarify this unique characteristics, in vivo and in vitro studies regarding the pharmacokinetic behavior were performed. When RLN-B2 (a rat liver cell line) was precultured in the presence of IDA, higher carbonyl reducing enzymes (CREs) activity was observed compared with non-precultured cells, suggesting the anthracycline-reducing enzymes was induced in the cells incubated in the presence of IDA. We examined the in vivo effects of IDA administration on the induction of CREs and subsequent enhanced formation of the 13-OH metabolite, idarubicinol (IDAol) which is more active compared with IDA and has a remarkably long half-life in the blood. The rats (F344) preadministered IDA showed higher enzymatic activity than that from non-preadministered rats (p & lt; 0.05). At 4 hours after IDA administration, the production of IDAol was facilitated in the preadministered group compared with the non preadministered group (p & lt; 0.05). Clinically, the duration of leucopenia was compared between IDA and mitoxantrone, an CREs independent anthraquinone, in combination with enocytabine, 6-mercaptopurine and etoposide. In 2 consecutive therapy, namely remission-induction and first consolidation therapy, in 30 cases of acute myelogenous leukemias, the duration of leucopenia was substantially equal in IDA group while it was substantially shorter in consolidation therapy compared with induction therapy in mitoxantrone group. These results suggest that CREs was induced by IDA pretreatment in vitro and in vivo, resulting in increased IDAol, which could potentiate the myelosuppressive and probably antitumor effects of IDA in contrast to other anthracyclines. This unique PK/PD characteristics of pharmacokinetic self-potentiation could be important in the safe and effective use of IDA in the therapy for hematological malignancies.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.4025.4025
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 4
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    Retrospective Analysis of Prognostic Factors for Waldenström Macroglobulinemia: A Multicenter Cooperative Study in Japan
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 5028-5028
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 5028-5028
    Abstract: Background: Analysis of prognostic factors and clinical trials of novel agents for Waldenstrӧm macroglobulinemia (WM) are ongoing in Western countries, but few studies of WM have been performed in Japan. As a step toward future investigations, we retrospectively analyzed clinical features and prognostic factors in Japanese patients with WM. Methods: We retrospectively analyzed clinical and laboratory characteristics, treatment and outcomes of 110 patients with WM, IgM-MGUS or lymphoplasmacytic lymphoma (LPL) diagnosed from January 2001 to March 2013 at 12 institutes. Overall survival (OS) was analyzed using Kaplan-Meier methods and survival was compared using log-rank testing. Several clinical characteristics at diagnosis were assessed by Cox regression for uni- and multivariate analysis for OS. Results: Median age at diagnosis was 69 (range, 41-96) years, 73.6% were male, 12.0% had an ECOG performance status 2-4 and 6.4% presented with B-symptoms. Hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobulinemia and cold agglutinin disease were shown in 9.1%, 4.5%, 1.8%, 4.5% and 2.7%, respectively. In 94 patients with available CT findings at diagnosis, lymphadenopathy, hepatosplenomegaly, pleural effusion, lung involvement, bone involvement and skin involvement were shown in 41.5%, 14.9%, 8.5%, 4.3%, 4.3% and 6.4%, respectively. Median serum monoclonal protein level was 2.62 g/dl (range, 0.70-9.35 g/dl). Symptomatic WM was present in 76 patients, asymptomatic WM in 23 and IgM-MGUS in 2 according to criteria of the Second International Workshop on WM. Seven patients showed IgG- or IgA-secreting LPL and 2 showed LPL without bone marrow infiltration. In patients with symptomatic WM, international prognostic scoring system for WM (ISSWM) was low in 9.2%, intermediate in 34.2%, high in 39.5% and unknown in 17.1%. Among patients with asymptomatic and symptomatic WM, watchful waiting was performed in 91.3% and 40.0%, respectively, with 61.9% and 36.7% remaining untreated, respectively. Median time to treatment from diagnosis of asymptomatic or symptomatic WM was 240 days (range, 3-1238 days) and 31 days (range, 0-2011 days), respectively. Oral alkylating agents were administered to 34.7% of patients with WM, 19.4% were treated with CHOP or CHOP-like regimen with or without rituximab, 8.2% received fludarabine mono- or combination therapy and 6.1% received rituximab monotherapy. Rituximab-containing therapy was administered as the initial treatment in 33.8% of patients who received treatment. Overall response rate (ORR) (complete + partial response rate) was 48.6%, and patients treated with rituximab-containing therapy displayed higher ORR (64.0%) compared to those with non-rituximab therapy (40.8%). Plasmapheresis was performed in 3.7% of patients. Three patients (2.7%) showed transformation to diffuse large B-cell lymphoma, and 7 (6.4%) developed second primary malignancies. Median follow-up was 38 months, 5-year OS rate for all patients was 74.9% (95% confidence interval (CI) 62.5-83.7) and rates for those with symptomatic WM, asymptomatic WM and other LPL were 66.0% (95%CI 50.6-77.6), 100% and 88.9% (95%CI 43.3-98.4), respectively. Significant differences in survival between risk groups of ISSWM in patients with symptomatic WM were not seen (5-year OS: high, 62.4%; intermediate, 64.3%; low, 75.0%; p=0.86). Although no significant difference in OS was observed compared to initial treatment (p=0.265), patients treated with rituximab during the observation period showed significantly prolonged OS compared to those treated without rituximab (5-year OS rates: 78.9% vs. 45.6%, p=0.036). In univariate analysis, age, pleural effusion, serum albumin, C-reactive protein and serum IgM levels were poor prognostic factors for OS. In multivariate analysis, age 〉 65 years (hazard ratio (HR)=3.294; 95%CI 1.097-9.888, p=0.0336) and pleural effusion (HR=4.55; 95%CI 1.602-12.930, p=0.0045) were identified as significant prognostic factors for OS. Conclusion: Prognostic factors for WM in Western countries may not be applicable to Japanese patients. This study suggested presence of pleural effusion at diagnosis is associated with poor clinical outcomes. Further investigations including histopathological examinations and molecular analyses are required to elucidate prognostic factors in Japan. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.5028.5028
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 5
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    Th1 Cytokine Polymorphism Gene: TNF-Alpha -857C/T Affects the Pathogenesis and Progression of Acute Myeloid Leukemia
    American Society of Hematology ; 2019
    In:  Blood Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1431-1431
    Details
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1431-1431
    Abstract: Background: Acute myeloid leukemia (AML) is a hematological malignancy characterized by the autonomous growth of immature myeloid cells with impaired differentiation and maturation. Cytokines are low-molecular-weight proteins that play a basic and fundamental role in communication within the immune system. Cytokines induce various effects such as differentiation, proliferation, hematopoiesis, and inflammation of target cells. AML is also closely associated with cytokine networks in terms of proliferation, apoptosis, and differentiation of leukemic cells. Cytokines produced by Th1 involved in cell-mediated immunity are called Th1 cytokines. Th1 cytokine includes TNF-α and IL-2. Several studies have reported that TNF-α is highly expressed in leukemia cells with AML patients. Other studies have also reported that high serum level of TNF-α of AML patients is associated with poor survival outcome. However, the association between Th1 cytokine polymorphisms: TNF-α -857C/T and IL-2-330T/G and the pathogenesis of AML is unclear. Therefore, we investigated the role of these polymorphisms in AML. Materials and Methods: This study included 101 patients with AML [male/female, 56/45; age, 15-86 years; median age, 58 years; MRC classification favorable (n = 38), intermediate (n =56), and adverse (n = 7)] and 202 healthy race-matched controls. All participants provided written informed consent. This study was approved by the Institutional Review Board of Gunma University Hospital. Genotyping was performed by the polymerase chain reaction (PCR)-restriction fragment length polymorphism method. Genotype and allele frequency were compared between patient group and control group by χ2-test. Clinical features were compared using Student's t and χ2 tests. Overall survival (OS) and leukemia free survival (LFS) were calculated using the Kaplan-Meier method. Survival curves were compared using the log-rank test. Analyses were performed using the SPSS software package ver. 25 (IBM, Armonk, NY, USA). P & lt; 0.05 was considered to represent statistical significance. Results: TNF-α -857 C/T nonCC genotype (higher producer type) increases the risk of AML (AML vs. controls = 39.6% vs. 28.2%, OR = 1.67, 95% CI = 1.01-2.75, p = 0.045). Moreover, the frequency of TNF-α -857 C/T T allele (higher producer type) was higher in AML patients compared to controls (AML vs. controls = 24.8% vs. 16.8%, OR = 1.625, 95%CI = 1.078-2.451 p = 0.02). There was no significant difference between AML patients and controls in genotype and allele frequencies of IL-2 -330 T/G. In the analysis of clinical features, the average platelet count was significantly lower in TNF-α -857 C/T TT genotype (higher producer type) (TT vs. nonTT = 2.4±1.4 vs. 4.4±5.9, p & lt; 0.01). TT genotype (higher producer type) was also significantly higher in frequency of MRC classification adverse (TT vs. nonTT = 30.0% vs. 4.4%, p = 0.02) and history of tumor (TT vs. nonTT = 30.0% vs. 6.6%. p =0.04). Moreover, in survival time analysis, patients with TNF-α -857 C/T TT genotype (higher producer type) had significantly shortened OS compared with patients with nonTT genotype (lower producer type) (TT vs. nonTT = 17.2 months vs not reached, p & lt; 0.01). Patients with TT genotype (high producer type) also experienced significantly shortened LFS (TT vs. nonTT = 24.0 months vs not reached, p = 0.04). Furthermore, multivariate analysis of OS revealed TNF-α -857 C/T TT genotype (higher producer type) as an independent prognostic factor (HR = 3.01, 95% CI = 1.04-8.69, p = 0.04), like age and white blood cell count. Conclusion: These results suggest that TNF-α-857 C/T T allele (higher producer type) increases the risk of AML. Furthermore, TNF-α-857 C/T TT genotype (higher producer type) affects the poor prognosis. Therefore, these data suggest the new role of TNF-α polymorphism in AML leukemogenesis. Figure Disclosures Handa: Ono: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2019-129409
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 6
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    The Polymorphism Of Base Excision Repair Gene, XRCC1 Arg399Gln Is Associated With The Therapy-Related Myelodysplastic Syndromes (MDS)
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 4085-4085
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4085-4085
    Abstract: Base excision repair (BER) is critical for genome maintenance, and is mainly responsible for the correction of small base changes of DNA damage. BER pathway involved many enzymes including OGG1, XRCC1, APE1 and MUTYH. Single nucleotide polymorphisms (SNPs) in DNA repair genes result reduced DNA repair capacity, have been reported to be associated with an increased risk of various cancers including hematologic malignancies. However, it is unclear that these polymorphisms alter the susceptibility and clinical outcome of myelodysplastic syndromes (MDS) patients. The aim of this study is to evaluate the association of polymorphisms in gene encoding four key proteins of DNA BER: OGG1 Ser326Cys, XRCC1 Arg399Gln, APE1 Asp148Glu, and MUTYHGln324His with the susceptibility and clinical features of MDS. Methods Our study included 113 MDS patients [median 68.3 years, range 17.1-86.5 years; male/female 76/37; RCUD (n=37), RARS (n=6), RCMD (n=21), MDS-u (n=11), RAEB-1(n=14), RAEB-2 (n=11), others (n=13)] and 192-health control group. Twenty four patients with MDS had the history of cancer. Genetic polymorphisms in BER pathway genes were examined using PCR and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Genotype and allele frequencies were compared between patients group and control group by using χ2-test. All patients and healthy controls received written information about the study. This study was approved by the International Research Board of Gunma University Hospital. Results There was no statistically significant difference in the allele and genotype frequencies of the OGG1 Ser326Cys, XRCC1 Arg399Gln, APE1 Asp148Glu, and MUTYH Gln324His polymorphisms between the MDS patients and the control group. In the analysis of clinical characteristics, XRCC1 non Arg/Arg genotype (low DNA repair type) was significantly associated with lower Hb level (8.64±2.29g/dL vs. 9.96±2.08 g/dL, p 〈 0.005) and higher frequency of the complex karyotype (14.9% vs. 2.8%, p=0.05). Furthermore, XRCC1 non Arg/Arg genotype was associated with therapy- related MDS (OR 3.15, 95% CI 1.24-7.98, p=0.02) and especially the past history of radiotherapy (14.3% vs. 0%, p 〈 0.005). In contrast, the polymorphisms in OGG1 Ser326Cys, APE1 Asp148Glu, and MUTYH Gln324His were not involved in the clinical features of MDS. Conclusion The low DNA repair polymorphism, XRCC1 Arg399Gln is associated with the clinical features of MDS, including therapy- related MDS. Further investigation of BER polymorphisms will provide the understanding of pathogenesis of therapy- related MDS in a larger sample size analysis. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.4085.4085
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 7
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    Tie2 Is Essential for the Development of Lymphangiogenic Endothelial Cell during ES Cell Differentiation.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 844-844
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 844-844
    Abstract: Tie2 is a receptor type tyrosine kinase, and is expressed in the hematopoietic stem cells and endothelial cells. We have recently shown that Tie2 and its ligand Angiopoietin-1 (Ang1) signal play a crucial role for maintenance of long-term repopulating hematopoietic stem cells in adult bone marrow (Cell, Vol 118, 149, 2004). Although Tie2 deficient mice showed defect of endothelial cell development, it is not clear whether Tie2 is critical for the development of hematopoietic and lymphangiogenic endothelial cells. In order to clarify the function of Tie2 during the developmental stage, we have developed the cell culture system of ES cell differentiation. After removing LIF, ES cells were cultured on collagen type IV coated plates to promote the differentiation to mesodermal lineage for two days, and the cells were cultured on OP9 stromal cells. Using our system hematopoietic and endothelial progenitors were differentiated efficiently on OP9 cells from the different ES cell straines, E14, TT2, and R1. Expression study showed that ES cell derived cells expressed Tie2 and Flk1 at day 5 of culture on OP9 cells. When we compared the cell fraction sorted by Tie2 and Flk1 mAb regarding differentiation potential, Tie2+Flk1+ fraction was revealed to be an enriched fraction of progenitors for hematopoietic cells and PECAM-1+ endothelial cells. To detect the lymphangiogenic endothelial cells derived from ES cells, we prepared the monoclonal antibody against LYVE-1, which is the receptor for extracellular matrix, glycosaminoglycan. And we confirmed that LYVE-1 was expressed in the embryonic lymphatic endothelium. By using LYVE-1 mAb, we sorted out LYVE-1+ cells from differentiated ES cells and carried out RT-PCR assay. LYVE-1+ cells expressed lymphangiogenic endothelial cell-specific genes, VEGFR-3, Podoplanin, and Prox-1, moreover LYVE-1+ cells took up the DiI-Ac-LDL. These findings indicate that LYVE-1+ cells derived from ES cells have a character of lymphangiogenic endothelial cells. When we compared the cell fraction sorted by Tie2 and Flk1 mAb, LYVE-1+ cells were differentiated from Tie2+Flk1+ fraction dominantly, but not from the other fractions, Tie2-Flk1+, Tie2+Flk1−, and Tie2-Flk1− fraction. These findings suggest that Tie2 is crucial for development of lymphangiogenic endothelial cells as well as hematopoietic cells and endothelial cells. In order to analyze the function of Tie2 during the developmental stage, we differentiated Tie2−/− ES cells using our system. The LYVE-1+ and PECAM-1+ cells derived from Tie2−/− ES cells dramatically decreased as culturing days went by, and at day6 of culture the LYVE-1+ and PECAM-1+ cells derived from Tie2−/− ES cells were one sixth and one third of Tie2+/− cells respectively. When we added 100μM of caspase inhibitor in the culture media, the number of both LYVE-1+ cells and PECAM-1+ cells were recovered. These findings suggest that developmental defect of lymphangiogenic endothelial and endothelial cells are caused by apoptosis because of the blockage of Tie2 signaling. However we could not detect abnormal development of hematopoietic cells from Tie2−/− ES cells. In conclusion, Tie2+Flk1+ fraction derived from ES cells is an enriched fraction of progenitors for lymphangiogenic endothelial cells, and Tie2 signaling is dispensable for lymphangiogenic endothelial cell development as well as endothelial cell development as an anti-apoptotic signaling during ES cell differentiation, but Tie2 is not essential for hematopoietic development.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.844.844
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
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  • 8
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    Base Excision Repair Gene OGG1 Affects the Relapse Risk of Acute Myeloid Leukemia
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 2901-2901
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 2901-2901
    Abstract: Background: Approximately 80% of acute myeloid leukemia (AML) patients can achieve complete remission, but around half of them relapse within five years. Recent studies have shown that AML relapse is associated with additional genetic mutation calls gclonal evolutionh in leukemic cell population (Ding, et al. Nature. 2012 & Parkin B, et al. Blood. 2013). These studies suggested that cytotoxic chemotherapy damaged cellular DNA and caused genetic mutation. In fact, anthracycline can produce 8-oxoguanine (8-OG) through induction of oxidative stress. 8-OG is most common DNA damage, which cause G:C to T:A transversion mutation. It is reported that transversion mutation more frequently observed in relapsed AML than primary AML. Base excision repair (BER) plays important role to correct base lesion including 8-OG and suppress genetic mutation. Therefore, we hypothesized BER gene polymorphisms may affect the risk of AML relapse, and focused five major functional polymorphisms: OGG1 S326C, MUTYH Q324H, APE1 D148E, XRCC1 R194W and XRCC1 R399Q. Material & Method: Ninety-four consecutive adults with AML who had achieved their first complete remission were recruited (male: 52, female: 42, age: 15-83 years, median age: 55.7 years). To remove the bias of the group, we also evaluated the risk in patients of non-M3 and under 65 years old (male: 22, female: 19, age: 15-64 years, median age: 49.0 years) (trimming group). These patients treated on Japan Adult Leukemia Study Group (JALSG) treatment protocols consisted of daunorubicin or idarubicin plus cytarabine (JALSG AML95, AML97, AML201, AML209). Genotyping was performed by PCR-RFLP method. The X2-test was used to compare the distribution of genotype and allele frequencies in patients. Leukemia-free survival (LFS) was calculated using the Kaplan-Meier method. Survival curves were compared using the log-rank test. In multivariate analysis, a stepwise selection procedure was performed using the proportional hazards Cox model for LFS. The variables were chosen with reference to previous studies; age, sex, white blood cell count and lactate dehydrogenase at diagnosis, number of induction courses, stem cell transplantation, MRC classification and history of tumor. This study was approved by the Institutional Review Board of Gunma University Hospital. Results: The OGG1 S326C CC genotype was observed significantly more often in the relapsed group (28.9% vs. 8.9%, OR = 4.10, 95% CI = 1.35-12.70, p = 0.01). In trimming group, the CC genotype was also observed more frequently in the relapsed group (50.0% vs. 6.9%, OR = 13.5, 95% CI = 2.17-84.0, p = 0.002). In addition, the OGG1 S326C CC genotype experienced a shorter median LFS than those with a non-CC genotype (CC vs. non-CC = 27.0 months vs. not reached, p = 0.02) (Figure 1). This genotype was also associated with poor LFS in trimming group (CC vs. non-CC = 11.0 months vs. not reached, p 〈 0.001) (Figure 1). Furthermore, multivariate analysis of LFS revealed OGG1 S326C CC genotype as an independent prognostic factor (HR = 4.32, 95% CI = 1.70-11.0, p = 0.002), like age, number of induction courses, and MRC classification (Table 1). Other polymorphisms had no significant effect on the risk of relapse. Conclusion: We previously reported that mutations by 8-OG were more efficiently suppressed in OGG1-S326 transduced cells than in OGG1-C326 transduced cells. Therefore, we hypothesized that low OGG1 activity promotes relapse of AML. To the best of our knowledge, this is the first report to show an association between BER gene polymorphisms and the relapse of AML. Our data suggest that OGG1 S326C can be a prognostic factor for AML relapse. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.2901.2901
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 9
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    Elevated Serum Soluble Interleukin-2 Receptor Level Is a Useful Prognostic Factor for Disease-Specific Overall Survival in Patients with Newly Diagnosed Follicular Lymphoma before Initiation of Treatment
    American Society of Hematology ; 2019
    In:  Blood Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3985-3985
    Details
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3985-3985
    Abstract: Introduction: Serum soluble interleukin-2 receptor (sIL-2R) is recognized as a tumor-related biomarker of malignant lymphomas, including follicular lymphoma (FL). The objective of this study is to assess the prognostic significance of pretreatment serum sIL-2R level for disease-specific overall survival (DSS) in patients with FL. Methods: We retrospectively analyzed medical records of our 10 individual institutions to identify all patients (pts) ≥ 18 years old with newly diagnosed FL between 01/01/2008 and 12/31/2018. Only pts with FL grade 1-3b, confirmed at pathological review, were included. Pts with histological transformation at diagnosis were excluded. Serum sIL-2R was determined by sandwich enzyme-linked immunosorbent assay. Clinical characteristics, therapies, response, relapse patterns and follow up status were collected and analyzed in the cohort. DSS was defined from the time of initial diagnosis to death due to lymphoma or last follow up. DSS was analyzed according to Kaplan Meier method and differences between subgroups were compared with log-rank test. Multivariate cox regression analysis was used to investigate associations of sIL-2R, FL International Prognostic Index (FLIPI) and progression or relapse within 24 months after diagnosis (POD24) with DSS. Serum levels of sIL-2R was measured before initiation of treatment and the data on the nearest date of the diagnostic biopsy within six months was adopted. Results: We recorded 565 pts and 535 pts of them with pretreatment serum sIL-2R levels available were included in the analysis with median age 64 years (range: 30-90) and 305 females (57%). Clinical characteristics are summarized in Table 1. The median of the serum sIL-2R level was 896 IU/mL (range: 145 - 23800). We decided an optimal cutoff value of 1800 IU/mL by using receiver operating characteristic (ROC) analysis, which showed it was 1830 IU/mL (AUC : 0.76, 95%CI : 0.67 - 0.84). Various poor prognostic indicators, such as bulky mass, increased LDH, ≥5 nodal lesions, poor performance status (PS), bone marrow invasion, FLIPI and FLIPI-2 high-risk, decreased Hb, advanced disease, high tumor burden, increased β2MG and existence of B symptoms, were strongly associated with high serum sIL-2R level (≥1800 IU/mL), and high sIL-2R level correlated with POD24 (P 〈 0.001, Chi-squared test). The estimated 10-year DSS rate was 87.2% with a median follow up duration of 4.4 years. In pts with POD24 (96 pts, 18%), DSS was significantly worse than those with non-POD24; 64.3% vs 93.0% (P 〈 0.001) and rituximab maintenance did not improve DSS in both groups (P=0.85 and 0.98, respectively). In patients with sIL-2R level of ≥1800 (high sIL-2R, 378 pts, 71%), DSS was significantly worse than those with sIL-2R level of 〈 1800 IU/mL (low sIL-2R, 157 pts, 29%); 68.2% vs 96.0% (P 〈 0.001), respectively (Figure 1). Multivariate analyses employing sex, PS, sIL-2R, FLIPI and POD24 demonstrated that high sIL-2R was an independent prognostic factor for DSS (HR : 2.88, 95% CI : 1.15-7.21, P 〈 0.05). Regardless of POD24 status, pts with high sIL-2R had significantly worse DSS than those with low sIL-2R; 44.6% vs 91.5% in pts with POD24 (P 〈 0.05) and 82.6% vs 96.8% in pts without POD24 (P 〈 0.001), respectively. Among pts treated with rituximab plus anthracycline-containing chemotherapy as the 1st line regimen (222 pts, 41%), pts with high sIL-2R had significantly worse DSS than those with low sIL-2R; 68.1% vs 97.2% (P 〈 0.001). Among pts treated with rituximab-bendamustine as the 1st line regimen (48 pts, 9%), there was no significant difference between high and low sIL-2R populations (P=0.2), however, among pts treated with bendamustine-containing regimen at least once in their life time (180 pts, 34%), there was significant difference between them; 63.1% vs 87.8% (P 〈 0.05). Even in pts achieving complete metabolic response after 1st line treatment (178 pts, 33%), high pretreatment sIL-2R level was a significant factor affecting poor DSS; 75.9% vs 94.3% (P 〈 0.05). Conclusions: High sIL-2R level ( ≥1800 IU/mL) is a significant and independent adverse prognostic factor for DSS in pts with newly diagnosed FL. This study provides us useful information to predict population with worse DSS before initiation of treatment. Disclosures Nozaki: Chugai: Honoraria; Celgene: Honoraria. Kida:Eisai Co., Ltd: Honoraria. Kosugi:Novartis Pharma Co.: Honoraria; Bristol-Myers Squibb Co.: Honoraria; Eisai Co., Ltd: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; NIPPON SHINYAKU CO.,LTD.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Celgene K.K.: Honoraria; Pfizer Inc.: Honoraria. Shibayama:Astellas, Teijin, MSD, Shionogi, Eisai, Sumitomo Dainippon, Taiho, Nippon Shinyaku: Research Funding; Celgene, Chugai, Eisai, AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Takeda, Novartis, Janssen, Chugai, Eisai, Mundi Pharma, Ono, Otsuka, Kyowa Kirin, Sumitomo Dainippon, AstraZeneca, Avvie, DaiichiSankyo, Fujimoto, Nippon Shinyaku, Sanofi, Bristol-Myers Squibb, Pfizer: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2019-126399
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 10
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    P-Glycoprotein Is Related to the Achievement of Complete Remission but Not to Disease-Free Survival in Adult Acute Lymphoblastic Leukemia: A Prospective Analysis in the JALSG-ALL97 Study.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 1095-1095
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 1095-1095
    Abstract: In a part of the prospective multicenter study of the Japan Adult Leukemia Study Group (JALSG-ALL97), we studied the amount and function of three important multidrug resistant (MDR) proteins: P-glycoprotein (P-gp), multidrug resistance associated protein (MRP) and lung resistance related protein (LRP), in the leukemia cells of adult acute lymphobastic leukemia (ALL) at the diagnosis. We related the results with patients’ biological and clinical features and their treatment outcome. From May 1997 to December 2001, newly diagnosed patients with de novo ALL except B-ALL were registered and received an induction therapy including cyclophosphamide (1200 mg/m2, d1), daunorubicin (45 mg/m2, d1-3), vincristine (1.3 mg/m2, d1, 8, 15, 22), L-asparaginase (3000 U/m2, d1, 9, 11, 13, 16, 18, 20) and predonisolone (60mg/m2, d1-14). Patients achieving complete remission (CR) received 8 courses of consolidation/intensification therapy followed by maintenance therapy. Median age was 38 years old. Out of 175 patients tested, 169 were evaluable. The amount and function of the MDR proteins were analyzed in CD45-gated leukemia cells by flow cytometry. After incubating with biotinylated MRK16 (IgG2a (Fab’)), anti-MRP or anti-LRP antibodies, cells were post-stained with SA-RED670. The function of P-gp and MRP was determined by Rhodamin-123 (Rh-123) accumulation with PSC833 and carcein-AM efflux with probenecid, respectively. Factors to predict CR were age, performance status (PS), chromosome, pretreatment WBC count, CD25 expression and the function of P-gp in univariative analyses. Logistic regression analysis shows that favorable prognostic factors for the achievement of CR were PS (Ps=0) and the lower ( 〈 9%) function of P-gp (p=0.013 and 0.010, respectively). Factors predict of disease free survival (DFS) were pretreatment WBC count, LDH value, chromosome (non Ph) and lack of CD25 expression in univariative analyses. Cox’s proportional hazard analysis shows that chromosome and CD25 were favorable for longer DFS (p=0.040 and 0.001, respectively). Neither the amount nor function of P-gp related to longer DFS. There was no significant relationship between the amount of other MDR proteins and DFS. The clinical importance of MDR proteins has been discussed in the treatment acute leukemias. We prospectively analyzed them in patients receiving the same treatment. Our study demonstrates that the function of P-gp in de novo ALL is one of the independent unfavorable factors for CR. However, it did not change the survival rates in the treatment of ALL with combination chemotherapy. Other MDR proteins relate to neither CR rate nor survival. We have also investigated these proteins in AML (Blood 102, 605a). The MDR proteins in the treatment of ALL are possibly less important as compared to those of AML.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.1095.1095
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
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