25 results on '"Yoshimoto, G."'
Search Results
2. Perforin gene mutations in adult-onset hemophagocytic lymphohistiocytosis
- Author
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Nagafuji, K., primary, Nonami, A., additional, Kumano, T., additional, Kikushige, Y., additional, Yoshimoto, G., additional, Takenaka, K., additional, Shimoda, K., additional, Ohga, S., additional, Yasukawa, M., additional, Horiuchi, H., additional, Ishii, E., additional, and Harada, M., additional
- Published
- 2007
- Full Text
- View/download PDF
3. 97: Rituximab-related late-onset neutropenia after autologous stem cell transplantation for malignant lymphoma
- Author
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Nagafuji, K., primary, Numata, A., additional, Yoshimoto, G., additional, Harada, N., additional, and Harada, M., additional
- Published
- 2007
- Full Text
- View/download PDF
4. Picosecond Time-Resolved Infrared Absorption Studies on the Photoexcited States of Poly(p-phenylenevinylene)
- Author
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Sakamoto, A., Nakamura, O., Yoshimoto, G., and Tasumi, M.
- Abstract
Picosecond time-resolved infrared absorption spectra of the photoexcited states of poly(p-phenylenevinylene) [(&sbd;C
6 H4 CH&dbd;CH&sbd;)n , PPV] have been observed with tunable picosecond light pulses obtained by difference-frequency generation between signal and idler waves from an optical parametric generator and amplifier. The time-resolved photoinduced infrared absorption bands due to a vibrational transition observed at 1550 cm-1 and an electronic transition at 3000 cm-1 of the photoexcited PPV have fast (≈1.7 ps) and slow (≈50 ps) decay components. By comparison of the picosecond time-resolved infrared absorption spectra of short-lived (fast decay component) and long-lived (slow decay component) transient species with the photoinduced and doping-induced infrared difference spectra of PPV, the short-lived transient species is assigned to bound polaron pairs, and the long-lived transient species is assigned to positive and negative polarons. - Published
- 2000
5. Procalcitonin elevation in febrile recipients during pre-transplant conditioning with anti-thymocyte globulin.
- Author
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Shima T, Minami M, Tochigi T, Kochi Y, Jinnouchi F, Yamauchi T, Mori Y, Yoshimoto G, Mizuno S, Miyamoto T, Kato K, and Akashi K
- Abstract
Infection is a major contributor to non-relapse mortality in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Detecting infectious diseases in febrile patients during pretransplant conditioning is crucial for subsequent transplant success. Procalcitonin (PCT) is an auxiliary diagnostic marker of severe bacterial infections and has been proposed as a useful predictor of infection in patients undergoing allo-HSCT. Pre-transplant use of anti-thymocyte globulin (ATG) can cause side effects, such as fever and hypotension, which must be distinguished from infectious diseases. Although ATG administration may increase PCT levels, data on PCT levels in febrile patients after ATG administration are limited. Furthermore, no studies have compared PCT levels during allo-HSCT conditioning using ATG or non-ATG regimens. To investigate whether ATG increases PCT levels during febrile episodes in pre-transplant conditioning and whether PCT could be used to discriminate infections during this period, we analyzed 17 ATG and 59 non-ATG patients with fever and who underwent PCT level measurements during pre-transplant conditioning. Our findings revealed that ATG administration was the only significant factor that increased PCT positivity during fever ( p = 0.01). In contrast, infectious diseases did not affect PCT positivity in the ATG group ( p = 0.24). Furthermore, bloodstream infection was a significant risk factor for PCT positivity in patients who received non-ATG regimens ( p < 0.01). Incorporating PCT levels into the diagnostic workup for infectious diseases requires careful consideration, particularly for patients receiving ATG regimens., Competing Interests: The authors declare no conflict of interest. Disclosure forms provided by the authors are available on the website., (Copyright Ⓒ2024 Asia-Pacific Blood and Marrow Transplantation Group (APBMT).)
- Published
- 2024
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6. Predictors of impaired antibody response after SARS-CoV-2 mRNA vaccination in hematopoietic cell transplant recipients: A Japanese multicenter observational study.
- Author
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Mori Y, Uchida N, Harada T, Katayama Y, Wake A, Iwasaki H, Eto T, Morishige S, Fujisaki T, Ito Y, Kamimura T, Takahashi T, Imamura Y, Tanimoto K, Ishitsuka K, Sugita J, Kawano N, Tanimoto K, Yoshimoto G, Choi I, Hidaka T, Ogawa R, Takamatsu Y, Miyamoto T, Akashi K, and Nagafuji K
- Subjects
- Humans, Antibodies, Viral, Antibody Formation, COVID-19 Vaccines administration & dosage, COVID-19 Vaccines adverse effects, East Asian People, RNA, Messenger, SARS-CoV-2, Transplant Recipients, Vaccination, Japan, COVID-19 prevention & control, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
HCT recipients reportedly have a high mortality rate after developing COVID-19. SARS-CoV-2 vaccination is generally useful to prevent COVID-19. However, its safety and efficacy among HCT recipients remain elusive. This large-scale prospective observational study including 543 HCT recipients with 37-months interval from transplant demonstrated high safety profiles of mRNA vaccine: only 0.9% of patients avoided the second dose due to adverse event or GVHD aggravation following the first dose. Regarding the efficacy, serological response with a clinically relevant titer (≥250 BAU/mL) was obtained in 397 (73.1%) patients. We classified the remaining 146 patients as impaired responders and compared the clinical and immunological parameters between two groups. In allogeneic HCT recipients, multivariable analysis revealed the risk factors for impaired serological response as follows: age (≥60, 1 points), HLA-mismatched donor (1 points), use of systemic steroids (1 points), absolute lymphocyte counts (<1000/μL, 1 points), absolute B-cell counts (<100/μL, 1 points), and serum IgG level (<500 mg/dL, 2 points). Notably, the incidence of impaired serological response increased along with the risk scores: patients with 0, 1-3, and 4-7 points were 3.9%, 21.8%, and 74.6%, respectively. In autologous HCT recipients, a shorter interval from transplant to vaccination was the only risk factor for impaired serological response. Our findings indicate that two doses of SARS-CoV-2 vaccine are safe but insufficient for a part of HCT recipients with higher risk scores. To improve this situation, we should consider additional treatment options, including booster vaccination and prophylactic neutralizing antibodies during the SARS-CoV-2 pandemic., (© 2022 Wiley Periodicals LLC.)
- Published
- 2023
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7. Early-onset cardiac dysfunction following allogeneic haematopoietic stem cell transplantation.
- Author
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Moriyama S, Fukata M, Hieda M, Yokoyama T, Yoshimoto G, Kusaba H, Nakashima Y, Miyamoto T, Maruyama T, and Akashi K
- Subjects
- Humans, Retrospective Studies, Stroke Volume, Ventricular Function, Left, Graft vs Host Disease etiology, Heart Diseases complications, Hematologic Neoplasms complications, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Objective: Heart failure following allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a serious complication that requires early detection; however, the clinical implications of early-onset cancer therapy-related cardiac dysfunction (CTRCD) following allo-HSCT remain unclear. We investigated the determinants and prognostic impact of early-onset CTRCD in allo-HSCT recipients., Methods: The records of 136 patients with haematological malignancies who underwent allo-HSCT at our institute were retrospectively reviewed. Early-onset CTRCD was defined as a decrease in left ventricular ejection fraction (LVEF) of ≥10% and an LVEF of ≤53% within 100 days after HSCT., Results: Early-onset CTRCD was diagnosed in 23 out of 136 included patients (17%), and the median duration from HSCT to CTRCD diagnosis was 24 (9-35) days. Patients were followed up for 347 (132-1268) days. In multivariate logistic regression analysis, cumulative doxorubicin dosage (each 10 mg/m
2 ) and severity of acute graft-versus-host disease (GVHD/grade) were independent indicators of early-onset CTRCD (OR (95% CI) 1.04 (1.00 to 1.07); p=0.032; OR (95% CI) 1.87 (1.19 to 2.95), p=0.004, respectively). The overall and primary disease death rates were significantly higher in allo-HSCT recipients with early-onset CTRCD than in those without early-onset CTRCD (HR (95% CI) 1.98 (1.11 to 3.52), p=0.016; HR (95% CI) 2.96 (1.40 to 6.29), p=0.005, respectively), independent of primary disease type, remission status and transplantation type., Conclusions: Severe acute GVHD and higher cumulative anthracycline are two significant determinants of early-onset CTRCD. Early-onset CTRCD following allo-HSCT regulates survival in patients with haematological malignancies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)- Published
- 2022
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8. HTLV-1 seropositive patients with lung cancer treated with PD-1 inhibitors.
- Author
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Yoneshima Y, Kato K, Minami H, Ikeda M, Watanabe H, Yoshimoto G, Miyamoto T, Akashi K, Nakanishi Y, and Okamoto I
- Subjects
- Aged, Antibodies, Monoclonal, Humanized adverse effects, Asymptomatic Infections, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung immunology, Carrier State blood, Carrier State immunology, Carrier State virology, Follow-Up Studies, HTLV-I Antibodies blood, HTLV-I Antibodies immunology, HTLV-I Infections chemically induced, HTLV-I Infections immunology, HTLV-I Infections virology, Human T-lymphotropic virus 1 isolation & purification, Humans, Lung Neoplasms drug therapy, Lung Neoplasms immunology, Male, Middle Aged, Nivolumab adverse effects, Programmed Cell Death 1 Receptor immunology, Retrospective Studies, Antineoplastic Agents, Immunological adverse effects, Carrier State diagnosis, HTLV-I Infections diagnosis, Human T-lymphotropic virus 1 immunology, Programmed Cell Death 1 Receptor antagonists & inhibitors
- Published
- 2020
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9. Epstein-Barr Virus-Associated Encephalopathy Presenting with Nonconvulsive Status Epilepticus in an Immunosuppressive State.
- Author
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Ohya Y, Nakamura K, Wakisaka Y, Sato H, Wakisaka K, Kumamoto M, Muraya Y, Kuroda J, Nakane H, Yoshimoto G, Kitazono T, and Ago T
- Abstract
Epstein-Barr virus (EBV) infection is occasionally accompanied by central nervous system (CNS) complications, particularly in immunosuppressed patients. However, the symptoms and clinical features of EBV infection in the CNS are rather heterogeneous and remain unknown. We herein describe the first reported adult case manifesting nonconvulsive status epilepticus (NCSE), possibly associated with reactivation of EBV in an immunosuppressive state. A 63-year-old man with a history of acute myeloid leukemia and taking immunosuppressants was admitted due to progressively impaired consciousness without any focal neurological signs, including paralysis or convulsions. Arterial spin labeling magnetic resonance imaging (ASL-MRI) and brain perfusion single-photon emission computed tomography showed hyperperfusion in the right temporal region, despite no morphological abnormalities in other MRI sequences. White blood cell counts, EBV viral load, and virus-capsid antigen IgG in cerebrospinal fluid were elevated. We diagnosed him with EBV-associated encephalopathy presenting with NCSE. Administration of levetiracetam, an antiepileptic, improved the consciousness and the abnormal hyperperfusion. This case suggests a new concept of EBV-associated encephalopathy leading to epilepsy, particularly in immunosuppressed patients., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2020 by S. Karger AG, Basel.)
- Published
- 2020
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10. Human Herpes Virus-6-Associated Encephalitis/Myelitis Mimicking Calcineurin Inhibitor-Induced Pain Syndrome in Allogeneic Stem Cell Transplantation Recipients.
- Author
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Yoshimoto G, Mori Y, Kato K, Shima T, Miyawaki K, Kikushige Y, Kamezaki K, Numata A, Maeda T, Takenaka K, Iwasaki H, Teshima T, Akashi K, and Miyamoto T
- Subjects
- Adolescent, Adult, Female, Humans, Male, Middle Aged, Pain pathology, Young Adult, Calcineurin Inhibitors adverse effects, Encephalitis, Viral etiology, Herpesvirus 6, Human pathogenicity, Pain chemically induced, Stem Cell Transplantation adverse effects, Transplantation, Homologous adverse effects
- Abstract
Human herpes virus-6 (HHV6)-associated myelitis and calcineurin inhibitor-induced pain syndrome (CIPS) are serious complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because these 2 complications cause similar sensory nerve-related symptoms, such as paresthesia, pruritus, and severe pain occurring around the engraftment, it can be difficult to differentially diagnose the 2 conditions. We retrospectively analyzed 435 recipients to distinguish clinical symptoms of these 2 complications. Twenty-four patients (5.5%) developed HHV6-associated encephalitis/myelitis; of these, 11 (2.5%) presented only with myelitis-related symptoms (HHV6-associated myelitis), which was confirmed by the detection of HHV6 DNA, and 8 (1.8%) had CIPS, with undetected HHV6 DNA. All patients with HHV6-associated myelitis or CIPS exhibited similar sensory nerve-related symptoms. Diagnostic images did not provide definite evidence specific for each disease. Symptoms of all patients with CIPS improved after switching to another immunosuppressant. Overall survival rate at 2 years for patients with HHV6-associated encephalitis/myelitis was significantly lower than that of CIPS (13.1% versus 29.2%; P = .049) or that of patients without HHV6-associated encephalitis/myelitis or CIPS (42.4%; P = .036), whereas there was no significant difference among the latter 2 groups (P = .889). The development of HHV6-associated encephalitis/myelitis but not CIPS was significantly associated with poor prognosis. Thus, transplant physicians should be aware that sensory nerve-related symptoms indicate early manifestations that might be correlated with reactivation of HHV6 or CIPS. Therefore, identification of HHV6 DNA is crucial for making a differential diagnosis and immediately starting appropriate treatments for each complication., (Copyright © 2018. Published by Elsevier Inc.)
- Published
- 2018
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11. Gastrointestinal Graft-versus-Host Disease Is a Risk Factor for Postengraftment Bloodstream Infection in Allogeneic Hematopoietic Stem Cell Transplant Recipients.
- Author
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Mori Y, Yoshimoto G, Nishida R, Sugio T, Miyawaki K, Shima T, Nagasaki Y, Miyake N, Harada Y, Kunisaki Y, Kamezaki K, Numata A, Kato K, Shiratsuchi M, Maeda T, Takenaka K, Iwasaki H, Shimono N, Akashi K, and Miyamoto T
- Subjects
- Adolescent, Adult, Aged, Bacteremia pathology, Female, Graft vs Host Disease mortality, Graft vs Host Disease pathology, Humans, Male, Middle Aged, Risk Factors, Young Adult, Bacteremia etiology, Gastrointestinal Tract pathology, Graft vs Host Disease complications, Hematopoietic Stem Cell Transplantation methods, Transplantation Conditioning methods, Transplantation, Homologous methods
- Abstract
Bloodstream infection (BSI) is a well-known cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Here, we conducted a retrospective study to assess the morbidity, etiology, risk factors, and outcomes of BSI in the postengraftment period (PE-BSI) after allo-HSCT. Forty-three of 316 patients (13.6%) developed 57 PE-BSI episodes, in which 62 pathogens were isolated: Gram-positive bacteria, gram-negative bacteria, and fungi, respectively, accounted for 54.8%, 35.5%, and 9.7% of the isolates. Multivariate analysis revealed methylprednisolone use for graft-versus-host disease (GVHD) prophylaxis (odds ratio [OR], 6.49; 95% confidence interval [CI], 1.49 to 28.2; P = .013) and acute gastrointestinal GVHD (GI-GVHD) (OR, 8.82; 95% CI, 3.99 to 19.5; P < .0001) as risk factors for developing PE-BSI. This finding suggested that GI-GVHD increases the risk of bacterial translocation and subsequent septicemia. Moreover, among patients with GI-GVHD, insufficient response to corticosteroids, presumably related to an intestinal dysbiosis, significantly correlated with this complication. Patients with PE-BSI presented worse outcome compared with those without (3-year overall survival, 47.0% versus 18.6%; P < .001). Close microbiologic monitoring for BSIs and minimizing intestinal dysbiosis may be crucial to break the vicious cycle between GI-GVHD and bacteremia and to improve transplant outcomes especially in patients who require additional immunosuppressants., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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12. Comparative Quantification of Chemotherapy-Induced Nausea and Emesis between the Common Terminology Criteria for Adverse Events and the Multinational Association of Supportive Care in Cancer Antiemesis Tool.
- Author
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Uchida M, Nakamura T, Shima T, Yoshimoto G, Kato K, Hosohata K, Miyamoto T, and Akashi K
- Subjects
- Adult, Aged, Antiemetics therapeutic use, Female, Hospitals, Humans, Japan, Male, Middle Aged, Nausea prevention & control, Vomiting prevention & control, Young Adult, Antineoplastic Agents adverse effects, Hematologic Neoplasms drug therapy, Nausea chemically induced, Severity of Illness Index, Surveys and Questionnaires, Vomiting chemically induced
- Abstract
Chemotherapy-induced nausea and vomiting (CINV) are generally evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE). The Multinational Association for Supportive Care in Cancer (MASCC) developed the MASCC Antiemesis Tool (MAT) to facilitate recognition for CINV between patients and oncology specialists. In the present study, MAT and CTCAE were comparatively assessed in Japanese patients with hematological malignancies. A total of 61 patients were eligible for this study. The CTCAE data were collected from an electronic medical record system. The patients were asked to complete the Japanese version of MAT in the hospital, on the first and fourth days after the start of chemotherapy. The percentages of patients in whom nausea was completely controlled, with severity scores of zero, ranged from 70.5 to 82.0% for CTCAE and from 59.0 to 75.4% for MAT, during the first five days after the chemotherapy. The percentages of patients who had no vomiting ranged from 93.4 to 96.7% for CTCAE and from 90.2 to 98.4% for MAT. During the observation periods, the day-to-day response profiles of patients who received antiemetic treatment were comparable between CTCAE and MAT cohorts, and these two assessment tools showed good, positive correlations for nausea severity scores. The present study shows that the MAT is a useful tool for assessing the severity of CINV in patients with hematological malignancy, is comparable to CTCAE, and facilitates the identification of poor cancer care conditions by medical staff.
- Published
- 2018
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13. Recurrent Subcutaneous Sweet's Disease in a Myelofibrosis Patient Treated with Ruxolitinib before Allogeneic Stem Cell Transplantation.
- Author
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Sakoda T, Kanamitsu Y, Mori Y, Sasaki K, Yonemitsu E, Nagae K, Yoshimoto G, Kamezaki K, Kato K, Takenaka K, Miyamoto T, Furue M, Iwasaki H, and Akashi K
- Subjects
- Aged, Chronic Disease, Glucocorticoids therapeutic use, Hematopoietic Stem Cell Transplantation methods, Humans, Male, Nitriles, Pyrazoles adverse effects, Pyrimidines, Sweet Syndrome drug therapy, Primary Myelofibrosis complications, Primary Myelofibrosis drug therapy, Pyrazoles therapeutic use, Sweet Syndrome complications
- Abstract
Allogeneic hematopoietic stem cell transplantation (allo-SCT) has a curative potential for myelofibrosis (MF) patients; however, its association with a high therapy-related mortality (TRM) remains a big obstacle that needs to be overcome. Ruxolitinib (RUXO), a novel JAK1/2 inhibitor, can be used as a bridging therapy until allo-SCT can be performed to reduce TRM. We herein report a RUXO-treated MF patient who developed recurrent subcutaneous Sweet's disease (SSD) that was successfully treated by the administration of systemic glucocorticoids. We performed allo-SCT as previously scheduled, resulting in a good clinical course without deterioration of SSD. RUXO administration, as well as MF itself, might therefore sometimes cause this rare non-infectious event.
- Published
- 2017
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14. Phase I study of glasdegib (PF-04449913), an oral smoothened inhibitor, in Japanese patients with select hematologic malignancies.
- Author
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Minami Y, Minami H, Miyamoto T, Yoshimoto G, Kobayashi Y, Munakata W, Onishi Y, Kobayashi M, Ikuta M, Chan G, Woolfson A, Ono C, Shaik MN, Fujii Y, Zheng X, and Naoe T
- Subjects
- Administration, Oral, Aged, Aged, 80 and over, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacology, Benzimidazoles adverse effects, Benzimidazoles pharmacology, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Gene Expression Regulation, Neoplastic drug effects, Hematologic Neoplasms genetics, Humans, Japan, Male, Maximum Tolerated Dose, Middle Aged, Phenylurea Compounds adverse effects, Phenylurea Compounds pharmacology, Treatment Outcome, Antineoplastic Agents administration & dosage, Benzimidazoles administration & dosage, Hematologic Neoplasms drug therapy, Phenylurea Compounds administration & dosage, Zinc Finger Protein GLI1 genetics
- Abstract
The hedgehog signaling pathway regulates multiple morphogenetic processes during embryogenesis. Aberrant activation of the hedgehog pathway signal transduction in adult tissues is associated with the pathogenesis of hematologic malignancies and solid tumors. We report findings from an open-label, multicenter phase I trial of the selective, small-molecule hedgehog signaling inhibitor glasdegib (PF-04449913) in Japanese patients with select advanced hematologic malignancies. Glasdegib was administered as once-daily oral doses (25, 50 and 100 mg) in 28-day cycles after a lead-in dose on Day -5. The primary objectives were to determine first-cycle dose-limiting toxicities, safety, vital signs and laboratory test abnormalities. Secondary objectives included evaluation of pharmacokinetics, pharmacodynamics and preliminary evidence of clinical activity of glasdegib. No dose-limiting toxicities were noted in the 13 patients in the present study. All patients experienced at least one treatment-emergent, all-causality adverse event. The most frequent treatment-related adverse events (observed in ≥3 patients) were dysgeusia (n = 9), muscle spasms (n = 5), alopecia, decreased appetite (n = 4 each), and increased blood creatinine phosphokinase, constipation and diarrhea (n = 3 each). Two deaths occurred during the study and were deemed not to be treatment-related due to disease progression. Glasdegib demonstrated dose-proportional pharmacokinetics, marked downregulation of the glioma-associated transcriptional regulator GLI1 expression in normal skin, and evidence of preliminary clinical activity, although data are limited. Glasdegib was safe and well tolerated across the dose levels tested. It is confirmed that the 100-mg dose is safe and tolerable in Japanese patients, and this dose level will be examined in the future clinical trial., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
- Published
- 2017
- Full Text
- View/download PDF
15. Mogamulizumab Treatment Prior to Allogeneic Hematopoietic Stem Cell Transplantation Induces Severe Acute Graft-versus-Host Disease.
- Author
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Sugio T, Kato K, Aoki T, Ohta T, Saito N, Yoshida S, Kawano I, Henzan H, Kadowaki M, Takase K, Muta T, Miyawaki K, Yamauchi T, Shima T, Takashima S, Mori Y, Yoshimoto G, Kamezaki K, Takenaka K, Iwasaki H, Ogawa R, Ohno Y, Eto T, Kamimura T, Miyamoto T, and Akashi K
- Subjects
- Acute Disease, Adult, Aged, Antibodies, Monoclonal, Humanized therapeutic use, Female, Graft vs Host Disease mortality, Hematopoietic Stem Cell Transplantation mortality, Humans, Leukemia-Lymphoma, Adult T-Cell mortality, Leukemia-Lymphoma, Adult T-Cell therapy, Male, Middle Aged, Remission Induction methods, Retrospective Studies, Survival Analysis, Transplantation, Homologous, Antibodies, Monoclonal, Humanized toxicity, Graft vs Host Disease chemically induced, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia-Lymphoma, Adult T-Cell complications, Leukemia-Lymphoma, Adult T-Cell drug therapy
- Abstract
Mogamulizumab (MOG), a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, has recently played an important role in the treatment of adult T cell leukemia/lymphoma (ATLL). Because CCR4 is expressed on normal regulatory T cells as well as on ATLL cells, MOG may accelerate graft-versus-host disease (GVHD) by eradicating regulatory T cells in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is limited information about its safety and efficacy in patients treated with MOG before allo-HSCT. In the present study, 25 patients with ATLL were treated with MOG before allo-HSCT, after which 18 patients (72%) achieved remission. The overall survival and progression-free survival at 1 year post-transplantation were 20.2% (95% CI, 6.0% to 40.3%) and 15.0% (95% CI, 4.3% to 32.0%), respectively. The cumulative incidence of acute GVHD was 64.0% (95% CI, 40.7% to 80.1%) for grade II-IV and 34.7% (95% CI, 15.8% to 54.4%) for grade III-IV. The cumulative incidence of transplantation-related mortality (TRM) was 49.0% (95% CI, 27.0% to 67.8%). Six of 7 patients with acute GVHD grade III-IV died from GVHD, which was the leading cause of death. In particular, a shorter interval from the last administration of MOG to allo-HSCT was associated with more severe GVHD. MOG use before allo-HSCT may decrease the ATLL burden; however, it is associated with an increase in TRM due to severe GVHD. Because MOG is a potent anti-ATLL agent, new treatment protocols should be developed to integrate MOG at suitable doses and timing of administration to minimize unwanted GVHD development., (Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
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16. Morphological Study of the Articular Disc and Capillary of the Retrodiscal Tissue in a Type 2 Spontaneous Diabetes Mellitus Rat Model.
- Author
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Uemura M, Toda I, Kawashima W, Yoshimoto G, Fang YR, Xu YJ, Liu Y, Zhang L, and Takemura A
- Subjects
- Animals, Male, Rats, Rats, Wistar, Temporomandibular Joint blood supply, Capillaries pathology, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2 pathology, Temporomandibular Joint pathology
- Abstract
The objective of this study was to evaluate morphological changes at the articular disc of the temporomandibular joint and capillary of the retrodiscal tissue in a rat model for type 2 spontaneous diabetes mellitus (DM) (i.e., Goto-Kakizaki [GK] rats) compared to normal Wistar rats. A total of 20 experimental rats were used in this study; the rats were categorized into the normal (n = 10 male 8-week-old Wistar rats) and DM (n = 10 male 8-week-old GK rats) groups. Hematoxylin-eosin stained specimens were obtained from 5 rats from each group. Image analyses of the hematoxylin-eosin stained specimens were conducted using light micrographs, which allowed comparisons of the thickness of the anterior, central, and posterior parts of the articular disc. Afterwards, the microvascular corrosion cast specimens were obtained from 5 rats from each group. The diameter of the capillary of the retrodiscal tissue was determined by analyzing scanning electron micrographs of the microvascular corrosion cast specimens. Student's t-test was used to test for statistical significant differences between the 2 groups. Differences were considered significant when p < 0.01. We found that the thickness of the anterior, central, and posterior parts of the articular disc, and the diameter of the capillary of the retrodiscal tissue was significantly lower in the DM vs. normal group. Therefore, we consider that DM-associated the hyperglycemia causes atrophy of the articular disc and microangiopathy of the capillary of the retrodiscal tissue in GK rats.
- Published
- 2016
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17. Light Chain Deposition Disease in an Older Adult Patient Successfully Treated with Long-term Administration of Bortezomib, Melphalan and Prednisone.
- Author
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Hiyamuta H, Yamada S, Matsukuma Y, Tsuchimoto A, Nakano T, Taniguchi M, Masutani K, Yoshimoto G, Muta T, Akashi K, Kitazono T, and Tsuruya K
- Subjects
- Aged, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Bortezomib administration & dosage, Female, Humans, Liver Function Tests, Melphalan administration & dosage, Prednisone administration & dosage, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Paraproteinemias drug therapy
- Abstract
A 70-year-old woman was admitted to our hospital because of fatigue and renal dysfunction and was diagnosed with light chain deposition disease (LCDD) with multiple organ involvement (kidney, thyroid gland, heart and eyes). After chemotherapy with bortezomib, cyclophosphamide and dexamethasone, hepatobiliary enzyme levels increased abruptly. A liver biopsy showed light chain deposition in Disse spaces. After two years of treatment with bortezomib, melphalan and prednisone (VMP) administered at shorter intervals relative to regular cycles, the patient showed a hematological and organ response. This case indicates that a relatively low dose intensity VMP regimen is preferable for elderly patients with LCDD with multiple organ involvement.
- Published
- 2016
- Full Text
- View/download PDF
18. Ascites Retention during Mogamulizumab Treatment in a Patient with Adult T-cell Leukemia/lymphoma.
- Author
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Shima T, Kamezaki K, Higashioka K, Takashima S, Yoshimoto G, Kato K, Muta T, Takenaka K, Iwasaki H, Miyamoto T, and Akashi K
- Subjects
- Aged, Antibodies, Monoclonal, Humanized pharmacokinetics, Antibodies, Monoclonal, Humanized therapeutic use, Female, Humans, Leukemia-Lymphoma, Adult T-Cell pathology, Antibodies, Monoclonal, Humanized adverse effects, Ascites chemically induced, Leukemia-Lymphoma, Adult T-Cell drug therapy
- Abstract
A 74-year-old woman with refractory adult T-cell leukemia/lymphoma (ATLL) received three courses of mogamulizumab. Despite obtaining complete remission, she thereafter presented with progressive ascites. An analysis of the ascites and laboratory tests revealed no evidence of ATLL invasion, infectious disease, or liver cirrhosis. The mogamulizumab concentrations were maintained in the ascites at approximately 10-15% of that in the plasma. Mogamulizumab was considered to be a plausible pathogenesis of her ascites. To the best of our knowledge, this is the first report suggesting mogamulizumab-induced ascites.
- Published
- 2016
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19. The ordered acquisition of Class II and Class I mutations directs formation of human t(8;21) acute myelogenous leukemia stem cell.
- Author
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Shima T, Miyamoto T, Kikushige Y, Yuda J, Tochigi T, Yoshimoto G, Kato K, Takenaka K, Iwasaki H, Mizuno S, Goto N, and Akashi K
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Cell Proliferation, Cell Survival, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic metabolism, Cell Transformation, Neoplastic pathology, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, Core Binding Factor Alpha 2 Subunit metabolism, Female, Hematopoietic Stem Cells pathology, Humans, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-kit metabolism, RUNX1 Translocation Partner 1 Protein, Signal Transduction, Transcription Factors metabolism, Translocation, Genetic, Core Binding Factor Alpha 2 Subunit genetics, Gene Expression Regulation, Leukemic, Hematopoietic Stem Cells metabolism, Leukemia, Myeloid, Acute genetics, Mutation, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins c-kit genetics, Transcription Factors genetics
- Abstract
The cellular properties of leukemia stem cells (LSCs) are achieved at least through Class I and Class II mutations that generate signals for enhanced proliferation and impaired differentiation, respectively. Here we show that in t(8;21) acute myelogenous leukemia (AML), hematopoietic stem cells (HSCs) transform into LSCs via definitively-ordered acquisition of Class II (AML1/ETO) and then Class I (c-KIT mutant) abnormalities. Six t(8;21) AML patients with c-KIT mutants maintaining > 3 years of complete remission were analyzed. At diagnosis, all single LSCs had both AML1/ETO and c-KIT mutations. However, in remission, 16 out of 1,728 CD34(+)CD38(-) HSCs and 89 out of 7,187 single HSC-derived myeloerythroid colonies from these patients had AML1/ETO, whose breakpoints were identical to those found in LSCs. These cells had wild-type c-KIT, which expressed AML1/ETO at a low level, and could differentiate into mature blood cells, suggesting that they may be the persistent preleukemic stem cells. Microarray analysis suggested that mutated c-KIT signaling provides LSCs with enhanced survival and proliferation. Thus, in t(8;21) AML, the acquisition of AML1/ETO is not sufficient, and the subsequent upregulation of AML1/ETO and the additional c-KIT mutant signaling are critical steps for transformation into LSCs., (Copyright © 2014 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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20. Monitoring of minimal residual disease (MRD) is useful to predict prognosis of adult patients with Ph-negative ALL: results of a prospective study (ALL MRD2002 Study).
- Author
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Nagafuji K, Miyamoto T, Eto T, Kamimura T, Taniguchi S, Okamura T, Ohtsuka E, Yoshida T, Higuchi M, Yoshimoto G, Fujisaki T, Abe Y, Takamatsu Y, Yokota S, Akashi K, and Harada M
- Subjects
- Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols, Combined Modality Therapy, DNA, Neoplasm genetics, Female, Follow-Up Studies, Hematopoietic Stem Cell Transplantation, Humans, Male, Middle Aged, Neoplasm, Residual genetics, Neoplasm, Residual therapy, Polymerase Chain Reaction, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Prognosis, Prospective Studies, Remission Induction, Risk Factors, Survival Rate, Transplantation, Homologous, Young Adult, Biomarkers, Tumor genetics, Gene Expression Profiling, Neoplasm, Residual mortality, Philadelphia Chromosome, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality
- Abstract
Background: Allogeneic hematopoietic stem cell transplantation (HSCT) for patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1) is much more intensive than multi-agent combined chemotherapy, although allogeneic HSCT is associated with increased morbidity and mortality when compared with such chemotherapy. Minimal residual disease (MRD) status has been proven to be a strong prognostic factor for adult patients with Ph-negative ALL., Methods: We investigated whether MRD status in adult patients with ALL is useful to decide clinical indications for allogeneic HSCT. We prospectively monitored MRD after induction and consolidation therapy in adult patients with Ph-negative ALL., Results: Of 110 adult ALL patients enrolled between July 2002 and August 2008, 101 were eligible, including 59 Ph-negative patients. MRD status was assessed in 43 patients by the detection of major rearrangements in TCR and Ig and the presence of chimeric mRNA. Thirty-nine patients achieved CR1, and their probabilities of 3-year overall survival and disease-free survival (DFS) were 74% and 56%, respectively. Patients who were MRD-negative after induction therapy (n = 26) had a significantly better 3-year DFS compared with those who were MRD-positive (n = 13; 69% vs. 31%, p = 0.004). All of 3 patients who were MRD-positive following consolidation chemotherapy and did not undergo allogeneic HSCT, relapsed and died within 3 years after CR., Conclusions: These results indicate that MRD monitoring is useful for determining the clinical indications for allogeneic HSCT in the treatment of ALL in CR1.
- Published
- 2013
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21. Engulfment of hematopoietic stem cells caused by down-regulation of CD47 is critical in the pathogenesis of hemophagocytic lymphohistiocytosis.
- Author
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Kuriyama T, Takenaka K, Kohno K, Yamauchi T, Daitoku S, Yoshimoto G, Kikushige Y, Kishimoto J, Abe Y, Harada N, Miyamoto T, Iwasaki H, Teshima T, and Akashi K
- Subjects
- ADP-ribosyl Cyclase 1 metabolism, Adolescent, Adult, Aged, Antigens, CD34 metabolism, Antigens, Differentiation genetics, CD47 Antigen genetics, Cell Line, Cytokines pharmacology, Humans, Inflammation Mediators pharmacology, Macrophage Activation immunology, Macrophages metabolism, Middle Aged, Models, Biological, Mutation, RNA Interference, Receptors, Immunologic genetics, Young Adult, CD47 Antigen metabolism, Cytophagocytosis immunology, Down-Regulation drug effects, Hematopoietic Stem Cells metabolism, Lymphohistiocytosis, Hemophagocytic etiology
- Abstract
Hemophagocytic lymphohistiocytosis (HLH) is characterized by deregulated engulfment of hematopoietic stem cells (HSCs) by BM macrophages, which are activated presumably by systemic inflammatory hypercytokinemia. In the present study, we show that the pathogenesis of HLH involves impairment of the antiphagocytic system operated by an interaction between surface CD47 and signal regulatory protein α (SIRPA). In HLH patients, changes in expression levels and HLH-specific polymorphism of SIRPA were not found. In contrast, the expression of surface CD47 was down-regulated specifically in HSCs in association with exacerbation of HLH, but not in healthy subjects. The number of BM HSCs in HLH patients was reduced to approximately 20% of that of healthy controls and macrophages from normal donors aggressively engulfed HSCs purified from HLH patients, but not those from healthy controls in vitro. Furthermore, in response to inflammatory cytokines, normal HSCs, but not progenitors or mature blood cells, down-regulated CD47 sufficiently to be engulfed by macrophages. The expression of prophagocytic calreticulin was kept suppressed at the HSC stage in both HLH patients and healthy controls, even in the presence of inflammatory cytokines. These data suggest that the CD47-SIRPA antiphagocytic system plays a key role in the maintenance of HSCs and that its disruption by HSC-specific CD47 down-regulation might be critical for HLH development.
- Published
- 2012
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22. Self-renewing hematopoietic stem cell is the primary target in pathogenesis of human chronic lymphocytic leukemia.
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Kikushige Y, Ishikawa F, Miyamoto T, Shima T, Urata S, Yoshimoto G, Mori Y, Iino T, Yamauchi T, Eto T, Niiro H, Iwasaki H, Takenaka K, and Akashi K
- Subjects
- Animals, Antigens, CD immunology, B-Lymphocytes immunology, Cell Lineage, Humans, Immunophenotyping, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Mice, Transplantation, Heterologous, Hematopoietic Stem Cells cytology, Leukemia, Lymphocytic, Chronic, B-Cell pathology
- Abstract
We report here that in chronic lymphocytic leukemia (CLL), the propensity to generate clonal B cells has been acquired already at the hematopoietic stem cell (HSC) stage. HSCs purified from patients with CLL displayed lymphoid-lineage gene priming and produced a high number of polyclonal B cell progenitors. Strikingly, their maturation into B cells was restricted always to mono- or oligo-clones with CLL-like phenotype in xenogeneic recipients. These B cell clones were independent of the original CLL clones because they had their own immunoglobulin VDJ genes. Furthermore, they used preferentially VH genes frequently used in human CLL, presumably reflecting the role of B cell receptor signaling in clonal selection. These data suggest that HSCs can be involved in leukemogenesis even in mature lymphoid tumors., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
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23. FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD-specific STAT5 activation.
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Yoshimoto G, Miyamoto T, Jabbarzadeh-Tabrizi S, Iino T, Rocnik JL, Kikushige Y, Mori Y, Shima T, Iwasaki H, Takenaka K, Nagafuji K, Mizuno S, Niiro H, Gilliland GD, and Akashi K
- Subjects
- Apoptosis drug effects, Blotting, Western, Cell Survival, Enzyme Activation physiology, Flow Cytometry, Humans, Leukemia, Myeloid, Acute metabolism, Myeloid Cell Leukemia Sequence 1 Protein, Polymerase Chain Reaction, Proto-Oncogene Proteins c-bcl-2 metabolism, Reverse Transcriptase Polymerase Chain Reaction, Tandem Repeat Sequences, Up-Regulation, fms-Like Tyrosine Kinase 3 metabolism, Gene Expression Regulation, Neoplastic genetics, Leukemia, Myeloid, Acute genetics, Neoplastic Stem Cells metabolism, Proto-Oncogene Proteins c-bcl-2 genetics, STAT5 Transcription Factor metabolism, fms-Like Tyrosine Kinase 3 genetics
- Abstract
Myeloid cell leukemia-1 (MCL-1) is an essential survival factor for hematopoiesis. In humans, hematopoietic stem cells (HSCs) express MCL-1 at the highest level in response to FMS-like tyrosine kinase-3 (FLT3) signaling. We here show that this FLT3-dependent stem cell maintenance system also plays a critical role in survival of leukemic stem cells (LSCs) in acute myeloid leukemia (AML). The CD34(+)CD38(-) LSC fraction expresses high levels of FLT3 as well as MCL-1, even compared with normal HSCs. Treatment with FLT3 ligand induced further MCL-1 up-regulation in LSCs in all AML cases tested. Interestingly, the group of samples expressing the highest levels of MCL-1 constituted AML with FLT3-internal tandem duplications (ITD). In FLT3-ITD AML cell lines, cells expressed a high level of MCL-1, and an inhibition of MCL-1 induced their apoptotic cell death. A tyrosine kinase inhibitor suppressed MCL-1 expression, and induced apoptosis that was reversed by the enforced MCL-1 expression. Finally, transduction of FLT3-ITD into HSCs strongly activated MCL-1 expression through its signal transducer and activator of transcription 5 (STAT5)-docking domains. This effect was completely abrogated when STAT5 activation was blocked. Thus, the acquisition of FLT3-ITD ensures LSC survival by up-regulating MCL-1 via constitutive STAT5 activation that is independent of wild-type FLT3 signaling.
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- 2009
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24. Identification of the human eosinophil lineage-committed progenitor: revision of phenotypic definition of the human common myeloid progenitor.
- Author
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Mori Y, Iwasaki H, Kohno K, Yoshimoto G, Kikushige Y, Okeda A, Uike N, Niiro H, Takenaka K, Nagafuji K, Miyamoto T, Harada M, Takatsu K, and Akashi K
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Basophils cytology, Basophils metabolism, Cell Separation methods, Cells, Cultured, Eosinophil Peroxidase metabolism, Eosinophils metabolism, Female, Gene Expression, Granulocyte-Macrophage Progenitor Cells cytology, Granulocyte-Macrophage Progenitor Cells metabolism, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Humans, Male, Megakaryocyte-Erythroid Progenitor Cells cytology, Megakaryocyte-Erythroid Progenitor Cells metabolism, Middle Aged, Myeloid Progenitor Cells metabolism, Neutrophils cytology, Neutrophils metabolism, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors genetics, Antigens, CD metabolism, Cell Lineage, Eosinophils cytology, Interleukin-5 Receptor alpha Subunit metabolism, Myeloid Progenitor Cells cytology
- Abstract
To establish effective therapeutic strategies for eosinophil-related disorders, it is critical to understand the developmental pathway of human eosinophils. In mouse hematopoiesis, eosinophils originate from the eosinophil lineage-committed progenitor (EoP) that has been purified downstream of the granulocyte/macrophage progenitor (GMP). We show that the EoP is also isolatable in human adult bone marrow. The previously defined human common myeloid progenitor (hCMP) population (Manz, M.G., T. Miyamoto, K. Akashi, and I.L. Weissman. 2002. Proc. Natl. Acad. Sci. USA. 99:11872-11877) was composed of the interleukin 5 receptor alpha chain(+) (IL-5Ralpha(+)) and IL-5Ralpha(-) fractions, and the former was the hEoP. The IL-5Ralpha(+)CD34(+)CD38(+)IL-3Ralpha(+)CD45RA(-) hEoPs gave rise exclusively to pure eosinophil colonies but never differentiated into basophils or neutrophils. The IL-5Ralpha(-) hCMP generated the hEoP together with the hGMP or the human megakaryocyte/erythrocyte progenitor (hMEP), whereas hGMPs or hMEPs never differentiated into eosinophils. Importantly, the number of hEoPs increased up to 20% of the conventional hCMP population in the bone marrow of patients with eosinophilia, suggesting that the hEoP stage is involved in eosinophil differentiation and expansion in vivo. Accordingly, the phenotypic definition of hCMP should be revised to exclude the hEoP; an "IL-5Ralpha-negative" criterion should be added to define more homogenous hCMP. The newly identified hEoP is a powerful tool in studying pathogenesis of eosinophilia and could be a therapeutic target for a variety of eosinophil-related disorders.
- Published
- 2009
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25. Development of functional human blood and immune systems in NOD/SCID/IL2 receptor {gamma} chain(null) mice.
- Author
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Ishikawa F, Yasukawa M, Lyons B, Yoshida S, Miyamoto T, Yoshimoto G, Watanabe T, Akashi K, Shultz LD, and Harada M
- Subjects
- ADP-ribosyl Cyclase immunology, ADP-ribosyl Cyclase 1, Animals, Antigens, CD immunology, Antigens, CD34 immunology, Bone Marrow Cells cytology, Bone Marrow Cells immunology, Disease Models, Animal, Hematopoietic Stem Cell Transplantation, Humans, Infant, Newborn, Membrane Glycoproteins, Mice, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Receptors, Interleukin-2 deficiency, Receptors, Interleukin-2 genetics, Spleen cytology, Spleen immunology, Transplantation, Heterologous immunology, Cord Blood Stem Cell Transplantation, Immune System immunology, Receptors, Interleukin-2 immunology, Receptors, Interleukin-2 physiology
- Abstract
Here we report that a new nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse line harboring a complete null mutation of the common cytokine receptor gamma chain (NOD/SCID/interleukin 2 receptor [IL2r] gamma(null)) efficiently supports development of functional human hemato-lymphopoiesis. Purified human (h) CD34(+) or hCD34(+)hCD38(-) cord blood (CB) cells were transplanted into NOD/SCID/IL2rgamma(null) newborns via a facial vein. In all recipients injected with 10(5) hCD34(+) or 2 x 10(4) hCD34(+)hCD38(-) CB cells, human hematopoietic cells were reconstituted at approximately 70% of chimerisms. A high percentage of the human hematopoietic cell chimerism persisted for more than 24 weeks after transplantation, and hCD34(+) bone marrow grafts of primary recipients could reconstitute hematopoiesis in secondary NOD/SCID/IL2rgamma(null) recipients, suggesting that this system can support self-renewal of human hematopoietic stem cells. hCD34(+)hCD38(-) CB cells differentiated into mature blood cells, including myelomonocytes, dendritic cells, erythrocytes, platelets, and lymphocytes. Differentiation into each lineage occurred via developmental intermediates such as common lymphoid progenitors and common myeloid progenitors, recapitulating the steady-state human hematopoiesis. B cells underwent normal class switching, and produced antigen-specific immunoglobulins (Igs). T cells displayed the human leukocyte antigen (HLA)-dependent cytotoxic function. Furthermore, human IgA-secreting B cells were found in the intestinal mucosa, suggesting reconstitution of human mucosal immunity. Thus, the NOD/SCID/IL2rgamma(null) newborn system might be an important experimental model to study the human hemato-lymphoid system.
- Published
- 2005
- Full Text
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