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  • Wiley  (5)
  • Ishida, Takashi  (5)
  • Narita, Tomoko  (5)
  • 1
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    Online Resource
    Antitumor effects of bevacizumab in a microenvironment‐dependent human adult T ‐cell leukemia/lymphoma mouse model
    Wiley ; 2014
    In:  European Journal of Haematology Vol. 92, No. 3 ( 2014-03), p. 219-228
    Details
    In: European Journal of Haematology, Wiley, Vol. 92, No. 3 ( 2014-03), p. 219-228
    Abstract: The objective of this study was to evaluate the therapeutic potential of bevacizumab with or without systemic chemotherapy for adult T ‐cell leukemia/lymphoma ( ATL ) and clarify the significance of angiogenesis for ATL pathogenesis. Methods NOD / S hi‐ scid , IL ‐2 R γ null ( NOG ) mice were used as recipients of tumor cells from a patient with ATL , which engraft and proliferate in a microenvironment‐dependent manner. The ATL cells could be serially transplanted in NOG mice, but could not be maintained in in vitro cultures. Results Injection of bevacizumab alone significantly increased necrosis and decreased vascularization in the tumor tissue. Levels of human soluble interleukin two receptor in the serum (reflecting the ATL tumor burden) of bevacizumab‐treated mice were significantly lower than in untreated mice. Although bevacizumab monotherapy showed these clear anti‐angiogenesis effects, it did not prolong survival. In contrast, injection of bevacizumab together with cyclophosphamide, doxorubicin, vincristine, prednisolone ( CHOP ) led to a significant prolongation of survival of the ATL mice relative to CHOP alone. Conclusions This is the first report to evaluate the efficacy of bevacizumab for ATL in a tumor microenvironment‐dependent model. Bevacizumab therapy combined with chemotherapy could be a valuable treatment strategy for that subgroup of ATL probably depending to a large extent on angiogenesis via vascular endothelial growth factor.
    Type of Medium: Online Resource
    ISSN: 0902-4441 , 1600-0609
    URL: Issue
    URL: Article
    DOI: 10.1111/ejh.2014.92.issue-3
    DOI: 10.1111/ejh.12231
    Language: English
    Publisher: Wiley
    Publication Date: 2014
    detail.hit.zdb_id: 2027114-1
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  • 2
    Online Resource
    Online Resource
    Tax is a potential molecular target for immunotherapy of adult T ‐cell leukemia/lymphoma
    Wiley ; 2012
    In:  Cancer Science Vol. 103, No. 10 ( 2012-10), p. 1764-1773
    Details
    In: Cancer Science, Wiley, Vol. 103, No. 10 ( 2012-10), p. 1764-1773
    Abstract: We expanded CTL specific for T ax (a human T ‐lymphotropic virus type‐1‐encoded gene product) in vitro from PBMC of several adult T ‐cell leukemia/lymphoma ( ATL ) patients, and document its potential significance as a target for ATL immunotherapy. Tax‐specific CTL responses against tumor cells were restricted by T ax‐expression and the appropriate human leukocyte antigen ( HLA ) type. Tax‐specific CTL recognized HLA/T ax‐peptide complexes on autologous ATL cells, even when their T ax expression was so low that it could only be detected by RT‐PCR but not by flow cytometry. Recognition resulted in interferon gamma ( IFN ‐γ) production and target cell lysis. This would be the first report that T ax‐specific CTL from ATL patients specifically recognized and killed autologous tumor cells that expressed T ax. The T ax‐specific CTL responded to as little as 0.01 p M of the corresponding peptide, indicating that their T ‐cell receptor avidity was much higher than that of any other CTL recognizing viral or other tumor antigens. This is presumably the reason why the T ax‐specific CTL recognized and killed autologous ATL cells despite their very low T ax expression. In addition, cell cycle analyses and experiments with primary ATL cell‐bearing mice demonstrated that ATL cells present at the site of active cell proliferation, such as in the tumor masses, expressed substantial amounts of T ax, but it was minimally expressed by the tumor cells in a quiescent state, such as in the blood. The present study not only provides a strong rationale for exploiting Tax as a possible target for ATL immunotherapy but also contributes to our understanding of the immunopathogenesis of ATL .
    Type of Medium: Online Resource
    ISSN: 1347-9032 , 1349-7006
    URL: Issue
    URL: Article
    DOI: 10.1111/cas.2012.103.issue-10
    DOI: 10.1111/j.1349-7006.2012.02371.x
    Language: English
    Publisher: Wiley
    Publication Date: 2012
    detail.hit.zdb_id: 2115647-5
    detail.hit.zdb_id: 2111204-6
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  • 3
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    Online Resource
    Clinical significance of tryptophan catabolism in Hodgkin lymphoma
    Wiley ; 2018
    In:  Cancer Science Vol. 109, No. 1 ( 2018-01), p. 74-83
    Details
    In: Cancer Science, Wiley, Vol. 109, No. 1 ( 2018-01), p. 74-83
    Abstract: Indoleamine 2,3‐dioxygenase 1 (IDO) is an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway. The purpose of the present study was to determine the clinical significance of Trp catabolism in newly diagnosed Hodgkin lymphoma (HL) patients. We quantified serum Trp and Kyn in 52 HL patients, and analyzed their associations with different clinical parameters including serum soluble CD30 concentration. The IDO expression was evaluated in the patients’ affected lymph nodes. The cohort comprised 22 male and 30 female patients (age range, 15‐81 years; median, 45 years), with a 5‐year overall survival (OS) of 88.6%. The OS was significantly shorter for patients with a high Kyn/Trp ratio (OS at 5 years, 60.0% vs 92.2%), for those with stage IV disease, and for those with lymphocytopenia ( 〈 600/mm 3 and/or 〈 8% white blood cell count). The latter two parameters are components of the international prognostic score for advanced HL. In contrast, there were no significant differences in OS according to age, serum albumin, hemoglobin, sex, white blood cell count, or serum soluble CD30 (≥ or 〈 285.6 ng/mL). Multivariate analysis using the three variables stage, lymphocytopenia, and serum Kyn/Trp ratio showed that only the latter significantly affected OS. Indoleamine 2,3‐dioxygenase 1 was produced by macrophages/dendritic cells, but not by HL tumor cells, and IDO levels determined by immunohistochemistry had a significant positive correlation with the serum Kyn/Trp ratio. In conclusion, quantification of serum Kyn and Trp is useful for predicting prognosis of individual HL patients.
    Type of Medium: Online Resource
    ISSN: 1347-9032 , 1349-7006
    URL: Issue
    URL: Article
    DOI: 10.1111/cas.2018.109.issue-1
    DOI: 10.1111/cas.13432
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2115647-5
    detail.hit.zdb_id: 2111204-6
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  • 4
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    Online Resource
    Clinical significance of tryptophan catabolism in follicular lymphoma
    Wiley ; 2020
    In:  Hematological Oncology Vol. 38, No. 5 ( 2020-12), p. 742-753
    Details
    In: Hematological Oncology, Wiley, Vol. 38, No. 5 ( 2020-12), p. 742-753
    Abstract: The enzyme, indoleamine 2,3‐dioxygenase 1 (IDO), catabolizes tryptophan (Trp) in the kynurenine (Kyn) pathway, and is important in suppressing antitumor immune responses in the tumor microenvironment. With regard to previously untreated patients with follicular lymphoma (FL), we sought to establish the prognostic significance of Trp catabolism in this disease. Serum Trp and Kyn levels in 110 patients with FL were quantified, and their relationship to different clinical parameters studied. IDO expression in the lymph nodes of affected patients was studied. Study participants included 54 males and 56 females (age range 39–86, median 62 years), showing a 5‐year overall survival (OS) rate of 78.5%. Patients with a high Kyn level (5‐year OS, 65.0% vs. 81.7%; p  = 0.026), high Kyn/Trp ratio (71.1% vs. 81.7%; p  = 0.002), and low hemoglobin (Hb) level ( 〈 12.0 g/dL; p  = 0.001; a component of FL international prognostic indexes) demonstrated a significantly shorter OS. Multivariate analysis included the following 10 variables: age, sex, serum β2‐microglobulin, Hb, longest diameter of the largest involved node, Ann Arbor stage, serum lactate dehydrogenase, histologic grading, B symptoms, and serum Kyn/Trp ratio; a lower Hb level and a high Kyn/Trp ratio (HR, 3.239; 95% CI, 1.296–8.096) led to a significantly inferior OS. In the microenvironment, some CD11c‐positive myeloid dendritic cells but not FL tumor cells were found to produce IDO. Overall, measuring levels of serum Kyn and Trp in individual patients with FL contributed to predicting their prognosis.
    Type of Medium: Online Resource
    ISSN: 0278-0232 , 1099-1069
    URL: Issue
    URL: Article
    DOI: 10.1002/hon.v38.5
    DOI: 10.1002/hon.2804
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2001443-0
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  • 5
    Online Resource
    Online Resource
    Human T‐cell lymphotropic/leukemia virus type 1 ( HTLV ‐1) Tax‐specific T‐cell exhaustion in HTLV ‐1‐infected individuals
    Wiley ; 2018
    In:  Cancer Science Vol. 109, No. 8 ( 2018-08), p. 2383-2390
    Details
    In: Cancer Science, Wiley, Vol. 109, No. 8 ( 2018-08), p. 2383-2390
    Abstract: Adult T‐cell leukemia/lymphoma ( ATL ) is caused by Human T‐cell lymphotropic/leukemia virus type 1 ( HTLV ‐1), and a higher HTLV ‐1 provirus load in PBMC is a risk factor for ATL development. Here, we document a significant inverse correlation between the function of HTLV ‐1 Tax‐specific CTL (Tax‐ CTL ), as assessed by ex vivo cytokine production in response to cognate peptide, and the HTLV ‐1 provirus load in PBMC in both HTLV ‐1 asymptomatic carriers ( AC ) (Spearman rank correlation coefficient [ R s] = −0.494, P  = .037, n = 18) and ATL patients ( R s = −0.774, P  = .001, n = 15). There was also a significant correlation between the HTLV ‐1 provirus load and the percentage of PD ‐1‐positive Tax‐ CTL in both HTLV ‐1 AC ( R s = 0.574, P  = .013) and ATL patients ( R s = 0.676, P  = .006). Furthermore, the percentage of PD ‐1‐positive Tax‐ CTL was inversely correlated with their function in HTLV ‐1 AC ( R s = −0.542, P  = .020), and ATL patients ( R s = −0.639, P  = .010). These findings indicate that the function of Tax‐ CTL decreased as their programmed cell death protein 1 ( PD ‐1) levels increased, parallel to the increased HTLV ‐1 provirus load in PBMC . We propose that functional Tax‐ CTL are crucial for determining the HTLV ‐1 provirus load in PBMC , not only in HTLV ‐1 AC , but also in ATL , and that PD ‐1 expression levels are reliable markers of Tax‐ CTL function. Thus, modulating the immunological equilibrium between Tax‐ CTL and HTLV ‐1‐infected cells to achieve dominance of functional effectors could represent an ideal strategy for controlling HTLV ‐1‐associated disease.
    Type of Medium: Online Resource
    ISSN: 1347-9032 , 1349-7006
    URL: Issue
    URL: Article
    DOI: 10.1111/cas.2018.109.issue-8
    DOI: 10.1111/cas.13654
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2115647-5
    detail.hit.zdb_id: 2111204-6
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