58 results on '"Yasuyuki Nagata"'
Search Results
2. Marked, Lasting Disease Regression and Concomitantly Induced Autoimmune Hemolytic Anemia and Hemophagocytic Lymphohistiocytosis in a Patient With Lung Adenocarcinoma and Autoantibodies Receiving Atezolizumab Plus Chemotherapy: A Case Report
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Yoshinari Endo, MD, Yusuke Inoue, MD, PhD, Masato Karayama, MD, PhD, Yasuyuki Nagata, MD. PhD, Hironao Hozumi, MD, PhD, Yuzo Suzuki, MD, PhD, Kazuki Furuhashi, MD, PhD, Noriyuki Enomoto, MD, PhD, Tomoyuki Fujisawa, MD, PhD, Yutaro Nakamura, MD, PhD, Naoki Inui, MD, PhD, and Takafumi Suda, MD, PhD
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Immune checkpoint inhibitors ,Lung cancer ,Autoimmune hemolytic anemia ,Hemophagocytic lymphohistiocytosis ,Case report ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Various immune-related adverse events can frequently occur, which may be life-threatening if programmed death 1 or its ligand is blocked. Here, we report a rare case of concomitant autoimmune hemolytic anemia and hemophagocytic lymphohistiocytosis caused by atezolizumab plus chemotherapy in a patient with lung adenocarcinoma and autoantibodies. Dramatic and lasting tumor regression in response to only one therapy cycle was achieved. Nevertheless, this case suggests that careful management is required when using immunotherapy in patients with autoantibodies.
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- 2022
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3. Recurrent Coronary Thrombus in a Patient with Chronic Immune Thrombocytopenia with Treatment Using Eltrombopag
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Terumori Satoh, Masao Saotome, Kenichiro Suwa, Hayato Ohtani, Yasuyuki Nagata, Takaaki Ono, and Yuichiro Maekawa
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Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Background. Eltrombopag, a nonpeptide thrombopoietin receptor agonist (TPO-RA), has been reported to be an effective therapy for chronic immune thrombocytopenia (ITP). However, a higher incidence of arterial and venous thromboembolic events was reported after using eltrombopag. Case Presentation. A 67-year-old man, treated with eltrombopag due to chronic ITP, was admitted due to acute coronary syndrome (ACS). Although coronary angiography revealed no occlusion, cardiac magnetic resonance imaging suggested a myocardial infarction in the territory of the left circumflex coronary artery. Three months after the ACS event, the obtuse marginal branches exhibited significant stenosis; hence, a percutaneous coronary intervention (PCI) was performed to implant a zotarolimus-eluting stent under the treatment of a dual antiplatelet therapy. However, stent thrombosis occurred 3 hours after PCI and required three other PCIs during the eltrombopag treatment. Conclusion. We present a case of an ITP patient, who experienced repeated coronary and stent thrombosis during the treatment with eltrombopag. We propose that the risk of ACS and consequent coronary stent thrombosis should be considered before the introduction of eltrombopag.
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- 2019
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4. Transcriptional repression of Cdc25B by IER5 inhibits the proliferation of leukemic progenitor cells through NF-YB and p300 in acute myeloid leukemia.
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Satoki Nakamura, Yasuyuki Nagata, Lin Tan, Tomonari Takemura, Kiyoshi Shibata, Michio Fujie, Shinya Fujisawa, Yasutaka Tanaka, Mitsuo Toda, Reiko Makita, Kenji Tsunekawa, Manabu Yamada, Mayumi Yamaoka, Junko Yamashita, Kazunori Ohnishi, and Mitsuji Yamashita
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Medicine ,Science - Abstract
The immediately-early response gene 5 (IER5) has been reported to be induced by γ-ray irradiation and to play a role in the induction of cell death caused by radiation. We previously identified IER5 as one of the 2,3,4-tribromo-3-methyl-1-phenylphospholane 1-oxide (TMPP)-induced transcriptional responses in AML cells, using microarrays that encompassed the entire human genome. However, the biochemical pathway and mechanisms of IER5 function in regulation of the cell cycle remain unclear. In this study, we investigated the involvement of IER5 in the cell cycle and in cell proliferation of acute myeloid leukemia (AML) cells. We found that the over-expression of IER5 in AML cell lines and in AML-derived ALDH(hi) (High Aldehyde Dehydrogenase activity)/CD34(+) cells inhibited their proliferation compared to control cells, through induction of G2/M cell cycle arrest and a decrease in Cdc25B expression. Moreover, the over-expression of IER5 reduced colony formation of AML-derived ALDH(hi)/CD34(+) cells due to a decrease in Cdc25B expression. In addition, over-expression of Cdc25B restored TMPP inhibitory effects on colony formation in IER5-suppressed AML-derived ALDH(hi)/CD34(+) cells. Furthermore, the IER5 reduced Cdc25B mRNA expression through direct binding to Cdc25B promoter and mediated its transcriptional attenuation through NF-YB and p300 transcriptinal factors. In summary, we found that transcriptional repression mediated by IER5 regulates Cdc25B expression levels via the release of NF-YB and p300 in AML-derived ALDH(hi)/CD34(+) cells, resulting in inhibition of AML progenitor cell proliferation through modulation of cell cycle. Thus, the induction of IER5 expression represents an attractive target for AML therapy.
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- 2011
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5. A Case Report of Difficult Diagnosis in the Patient with Systemic Mastocytosis
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Sayuri Sakamoto, Keisuke Kakizawa, Yujiro Ito, Yasuyuki Nagata, Yoshiaki Takahashi, Takeji Saito, Atsuto Yoshino, Akio Matsushita, Shigekazu Sasaki, Yutaka Oki, and Takafumi Suda
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General Medicine - Published
- 2021
6. Prognostic impact of the dosage of methotrexate combined with tacrolimus for graft-versus-host disease prophylaxis after cord blood transplantation
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Yasuyuki Nagata, Nami Sakamoto, Satoshi Dohtan, Shinichiro Oka, Hiroya Hirata, Katsumi Koyauchi, Takaaki Ono, Miwa Adachi, Kensuke Naito, Daisuke Yokota, Tomonari Takemura, and Masamitsu Takaba
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Adult ,Male ,musculoskeletal diseases ,medicine.medical_specialty ,Adolescent ,Graft vs Host Disease ,Gastroenterology ,Tacrolimus ,Leukocyte Count ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,immune system diseases ,Internal medicine ,medicine ,Humans ,Cumulative incidence ,skin and connective tissue diseases ,Survival rate ,Aged ,Neutrophil Engraftment ,Platelet Count ,business.industry ,Incidence (epidemiology) ,Graft Survival ,Hazard ratio ,Disease Management ,Retrospective cohort study ,Hematology ,Middle Aged ,medicine.disease ,Regimen ,Methotrexate ,Treatment Outcome ,Graft-versus-host disease ,030220 oncology & carcinogenesis ,Female ,Cord Blood Stem Cell Transplantation ,business ,Immunosuppressive Agents ,030215 immunology - Abstract
The optimal dosage of methotrexate (MTX) for graft-versus-host disease (GVHD) prophylaxis after cord blood transplantation (CBT) has not been well elucidated. Therefore, we conducted a retrospective study comparing a mini-MTX group (5 mg/m2 on day 1, 3 and 6) to a short-MTX group (10 mg/m2 on day 1 and 7 mg/m2 on day 3 and 6) after CBT. Sixty-three patients were classified as the mini-MTX group and 20 as the short-MTX group. The median time and cumulative incidence of neutrophil engraftment did not vary between the two groups. The cumulative incidence of grade 2–4 and grade 3–4 acute GVHD was similar in both groups. Overall survival in the mini-MTX group was significantly lower than in the short-MTX group (46.9% vs. 88.7% at 1 year, p
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- 2021
7. Expression of activated integrin β7 in multiple myeloma patients
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Masaki Ri, Shinsuke Iida, Naoki Hosen, Koichiro Minauchi, Shuji Ozaki, Shigeo Fuji, Shingen Nakamura, Hiroyuki Takamatsu, Ishikazu Mizuno, Yoichi Imai, Ichiro Hanamura, Hirohisa Nakamae, Eiju Negoro, Hiroshi Handa, Satoshi Yoshihara, Kenshi Suzuki, Yawara Kawano, Masahiro Kizaki, Rikio Suzuki, Junya Kuroda, Noriko Nishimura, Yasuyuki Nagata, Yoshimitsu Shimomura, Nobuhiko Uoshima, Hiroshi Kosugi, and Hiroshi Gomyo
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Male ,medicine.medical_specialty ,Integrin beta Chains ,Plasma Cells ,Integrin ,Bone Marrow Cells ,Immunotherapy, Adoptive ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,Internal medicine ,Humans ,Medicine ,Multiple myeloma ,Aged ,Hematology ,medicine.diagnostic_test ,biology ,business.industry ,Flow Cytometry ,medicine.disease ,Chimeric antigen receptor ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Female ,Bone marrow ,Car t cells ,Multiple Myeloma ,business ,030215 immunology - Abstract
Multiple myeloma (MM) is still extremely difficult to cure, and new therapeutic drugs are needed. We recently found that integrin β7 is constitutively activated in MM cells, and chimeric antigen receptor (CAR) T cells targeting activated integrin β7 have a significant anti-MM effect. In this study, we performed flow cytometry analysis of the expression of activated integrin β7 in bone marrow cells from 137 symptomatic MM patients. In 60/137 (44%) MM patients, activated integrin β7 was detected in most MM cells (> 80% of MM cells were in the positive gate). Activated integrin β7 was highly expressed in MM cells even in heavily treated patients. It also showed high expression in many CD38lo/−CD138−CD19+B cells, which reportedly include clonotypic B cells, in the bone marrow of MM patients. Taken together, these results suggest that CAR T-cell therapy targeting activated integrin β7 has the potential to benefit many patients with relapsed or refractory MM.
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- 2021
8. Final analysis of randomized phase II study optimizing melphalan, prednisolone, bortezomib in multiple myeloma (JCOG1105)
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Dai Maruyama, Shinsuke Iida, Ryunosuke Machida, Shigeru Kusumoto, Noriko Fukuhara, Nobuhiko Yamauchi, Kana Miyazaki, Makoto Yoshimitsu, Junya Kuroda, Norifumi Tsukamoto, Hideki Tsujimura, Kensuke Usuki, Takahiro Yamauchi, Takahiko Utsumi, Ishikazu Mizuno, Yasushi Takamatsu, Yasuyuki Nagata, Shuichi Ota, Eiichi Ohtsuka, Ichiro Hanamura, Yasuhiro Suzuki, Shinichiro Yoshida, Satoshi Yamasaki, Youko Suehiro, Yutaro Kamiyama, Suguru Fukuhara, Kunihiro Tsukasaki, and Hirokazu Nagai
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Bortezomib ,Cancer Research ,Clinical Trials, Phase II as Topic ,Oncology ,Prednisolone ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,General Medicine ,Multiple Myeloma ,Melphalan ,Randomized Controlled Trials as Topic - Published
- 2022
9. Polaprezinc for prevention of oral mucositis in patients receiving chemotherapy followed by hematopoietic stem cell transplantation: a multi-institutional randomized controlled trial
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Hisashi Tsurumi, Senji Kasahara, Yasuyuki Nagata, Hiroko Kato-Hayashi, Yoshinori Itoh, Michio Sawada, Masahito Shimizu, Koichi Ohata, Akio Suzuki, Hideki Hayashi, Takaaki Ono, Ryo Kobayashi, and Junichi Kitagawa
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Transplantation Conditioning ,Adolescent ,medicine.medical_treatment ,Antineoplastic Agents ,Hematopoietic stem cell transplantation ,Polaprezinc ,law.invention ,Oral mucositis ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Randomized controlled trial ,law ,Internal medicine ,Mucositis ,Organometallic Compounds ,Medicine ,Humans ,Chemotherapy ,Adverse effect ,Aged ,Stomatitis ,business.industry ,Incidence (epidemiology) ,Carnosine ,Middle Aged ,medicine.disease ,Anti-Ulcer Agents ,Transplantation ,Oncology ,Zinc Compounds ,030220 oncology & carcinogenesis ,Hematologic Neoplasms ,Female ,business ,Complication - Abstract
Oral mucositis is a common and distressing complication in patients receiving high-dose chemotherapy followed by hematopoietic stem cell transplantation (HSCT). We reported previously in a single-center retrospective analysis that zinc-L-carnosine (polaprezinc [PZ]) reduced the incidence of oral mucositis associated with HSCT. To verify the accuracy of the prophylactic effect of PZ against oral mucositis, we carried out a multi-institutional prospective randomized controlled study. Patients were randomly allocated to either the prevention group, in which PZ lozenge treatment was started before chemotherapy, or the control group, in which administration of PZ lozenges was initiated immediately after the onset of Grade 2 oral mucositis. Oral mucositis was evaluated daily from the start of chemotherapy to 35 days after transplantation. A total of 91 patients were enrolled, and 88 patients (47 in the control group and 41 in the prevention group) were eligible for data analysis. The incidence of Grade ≥2 but not Grade ≥3 oral mucositis was significantly reduced in the prevention group compared to the control group (44.7% in control group vs 22.0% in the prevention group, P = .025). There were no significant differences in the incidence rates of other adverse events or the rate of engraftment (95.6% vs 97.2%, P = .693) between the two groups. These findings suggest that PZ lozenge is effective for prophylaxis against Grade ≥2 oral mucositis associated with chemotherapy in patients undergoing HSCT without any influence on the HSCT outcome.
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- 2021
10. Effect of asymmetrical buttock pressure on forces exerted in buttock movement when using a reclining chair
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Kenichi Kobara, Yasuyuki Nagata, and Daisuke Fujita
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Orthodontics ,030506 rehabilitation ,Side inclination of the pelvis ,business.industry ,Shear force ,Reclining wheelchair ,Physical Therapy, Sports Therapy and Rehabilitation ,030229 sport sciences ,Sitting ,Body weight ,Buttocks pressure ,body regions ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Left buttock ,Medicine ,Original Article ,Back support ,Buttocks ,0305 other medical science ,business ,Reclining chair ,Right buttock - Abstract
[Purpose] To clarify the effect of asymmetrical buttock pressure on the shear forces exerted on a buttock. [Participants and Methods] Sixteen healthy adult males participated in this study. A cushion 0 or 2 cm high was placed on the left side of the seat for all participants. The 0- and 2-cm height conditions were called "without difference condition" and "difference condition", respectively. The back support was inclined at increasing angles, starting at the upright position, to a fully reclined position, and back to the upright position. [Results] With the "difference condition", the force on the left buttock was 147.4% body weight and that on the right buttock was 105.6% body weight. In contrast, with the "without difference condition", there was no significant difference in the force on the left buttock and right buttock in terms of percent body weight. [Conclusion] Our results suggest that asymmetrical buttock pressure while in the sitting position causes a difference in shear force exerted on the left and right buttocks when using a reclining chair.
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- 2021
11. Randomised phase II study to optimise melphalan, prednisolone, and bortezomib in untreated multiple myeloma (JCOG1105)
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Hirokazu Nagai, Gakuto Ogawa, Shinsuke Iida, Ishikazu Mizuno, Eiichi Ohtsuka, Takahiro Yamauchi, Dai Maruyama, Noriko Fukuhara, Koichiro Minauchi, Junya Kuroda, Shinichiro Yoshida, Youko Suehiro, Hideki Tsujimura, Yasuyuki Nagata, Kunihiro Tsukasaki, Satoshi Yamasaki, Sachiko Seo, Kana Miyazaki, Makoto Yoshimitsu, Akira Hangaishi, Norifumi Tsukamoto, Takahiko Utsumi, Yutaro Kamiyama, Ichiro Hanamura, and Yasushi Takamatsu
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Male ,Melphalan ,medicine.medical_specialty ,Prednisolone ,Phases of clinical research ,Neutropenia ,Gastroenterology ,Bortezomib ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,Prednisone ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,clinical studies ,Multiple myeloma ,Aged ,Aged, 80 and over ,business.industry ,Cumulative dose ,Haematological Malignancy ‐ Clinical ,eldery ,Hematology ,medicine.disease ,Survival Analysis ,multiple myeloma ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,business ,Research Paper ,030215 immunology ,medicine.drug - Abstract
Summary We conducted a randomised phase II study to determine the optimal dose and schedule of melphalan, prednisone, and bortezomib (MPB) (jRCTs031180097). Transplant‐ineligible untreated multiple myeloma patients were randomised to Arm A (twice weekly bortezomib in one six‐week cycle followed by eight five‐week cycles of four times once weekly bortezomib with melphalan and prednisolone on days 1–4) or Arm B (nine four‐week cycles of three times once weekly bortezomib with melphalan and prednisolone on days 1–4). The primary end‐point was complete response (CR) rate. Of 91 patients randomised to two arms, 88 were eligible. The median cumulative bortezomib doses were 45·8 and 35·1 mg/m2, CR rate was 18·6% [95% confidence interval (CI) 8·4–33·4] and 6·7% (95% CI 1·4–18·3), and the median progression‐free survival (PFS) was 2·5 and 1·4 years in Arms A and B [hazard ratio (HR) 1·93 (95% CI 1·09–3·42)], respectively. Frequent grade ≥3 haematologic toxicities in Arms A and B were neutropenia (64·4% vs. 28·3%) and thrombocytopenia (35·6% vs. 10·9%). Grade 2/3 peripheral neuropathy was observed in 24·4/2·2% in Arm A and 8·7/0% in Arm B. In conclusion, Arm A was the more promising regimen, suggesting that the twice weekly schedule of bortezomib in the first cycle and higher cumulative dose of both bortezomib and melphalan influences the efficacy of modified MPB.
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- 2020
12. An investigation into the effectiveness of a novel wheelchair seat-cover assembly for the reduction of forces exerted onto the buttocks
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Yasuyuki Nagata, Kenichi Kobara, Hisashi Takahashi, Daisuke Fujita, Tadanobu Suehiro, and Hiroshi Osaka
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030506 rehabilitation ,medicine.medical_treatment ,Posture ,Shear force ,Biomedical Engineering ,Physical Therapy, Sports Therapy and Rehabilitation ,03 medical and health sciences ,Speech and Hearing ,0302 clinical medicine ,Wheelchair ,Horizontal force ,medicine ,Humans ,Orthopedics and Sports Medicine ,Buttocks ,health care economics and organizations ,Reduction (orthopedic surgery) ,Pressure Ulcer ,Normal force ,business.industry ,Body Weight ,Rehabilitation ,Equipment Design ,Structural engineering ,body regions ,medicine.anatomical_structure ,Wheelchairs ,Cover (algebra) ,0305 other medical science ,business ,030217 neurology & neurosurgery ,Geology - Abstract
This purpose was to investigate developed seat-cover assemblies' effect on decreasing the fluctuation of the shear force exerted onto the buttocks as the factors causing decubitus ulcers when the back-support was inclined.The participants were 10 wheelchair users. The force plate was used to measure the horizontal force as the shear force. The back-support was inclined at increasing angles, starting from the upright position (IUP), then proceeding to a fully reclined position (FRP), and returning to the upright position (RUP). The experimental conditions were two conditions; the seat-cover assembly conditions and without the seat-cover assembly as the control conditions.The average values in the seat-cover assembly condition were 14.4 ± 3.3, 13.9 ± 2.3, and 17.3 ± 3.3% body weight in the IUP, FRP, and RUP, respectively. The average values in the control condition were 14.8 ± 2.6, 11.4 ± 1.7, and 24.0 ± 6.7% body weight in the IUP, FRP, and RUP, respectively. In the FUP and the RUP, there were significant differences between two conditions (These results suggested that the shear force exerted onto the buttocks may to be decreased by using novel seat-cover assembly.Implications for rehabilitationIt is possible to decrease the fluctuations in the shear force by moving the body up and down according the novel seat-cover assembly attached the back-support incline.Disabled, older individuals can be provided with a comfortable life on a reclining wheelchair while preventing decubitus ulcers.
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- 2020
13. Prospective evaluation of alternative donor from unrelated donor and cord blood in adult acute leukemia and myelodysplastic syndrome
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Tomoyuki Endo, Koichi Miyamura, Yachiyo Kuwatsuka, Masashi Sawa, Makoto Onizuka, Yoshiko Atsuta, Noriko Fukuhara, Hiroatsu Iida, Kotaro Miyao, Akio Kohno, Atsumi Yanagisawa, Shingo Kurahashi, Hisayuki Yokoyama, Tatsunori Goto, Seitaro Terakura, Masanobu Kasai, Mika Nakamae, Makoto Murata, Nobuhiro Kanemura, Yasuo Tomiya, Nobuharu Fujii, Hiroatsu Ago, Yasushi Onishi, Tomonori Kato, Tetsuya Nishida, Yuichiro Nawa, Yasuyuki Nagata, Ritsuro Suzuki, Satoshi Iyama, Nagoya Blood, Yukiyasu Ozawa, and Kazutaka Ozeki
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Transplantation ,medicine.medical_specialty ,Acute leukemia ,Multivariate analysis ,business.industry ,medicine.medical_treatment ,Phases of clinical research ,Hematology ,Hematopoietic stem cell transplantation ,Internal medicine ,Cord blood ,Medicine ,Stem cell ,business ,Prospective cohort study - Abstract
A prospectively registered observational study was conducted to assess the significance of allogeneic hematopoietic stem cell transplantation from highly HLA-matched unrelated donors (UD) and cord blood (CB) on outcomes in adult acute leukemia (AL) and myelodysplastic syndrome (MDS). Between 2007 and 2015, 231 transplant-eligible patients were registered for a phase 2 study of alternative donor transplantation. After registration, a sufficient time period was given to find appropriate UD. Patients received CB transplantation (CBT) if an appropriate UD was unavailable. In total, 119 patients received CBT (106 AL and 13 MDS) and 91 patients received UD transplantation (UDT) (86 AL and 5 MDS). The median age was 39 years in both groups. The primary objective was overall survival (OS); secondary objectives included cumulative incidences of non-relapse mortality (NRM) and relapse, and disease-free survival. Diagnosis, disease status at transplantation, refined disease risk index, and hematopoietic cell transplant-specific comorbidity index did not differ between UDT and CBT. In multivariate analyses, graft source was not a significant risk factor for all objectives. In adjusted analyses, UDT and CBT showed similar OS, NRM, and relapse in this prospective study. CB can be a comparable alternative stem cell source to UD by achieving a timely transplant.
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- 2020
14. Bortezomib, lenalidomide, and dexamethasone in transplant-eligible newly diagnosed multiple myeloma patients: a multicenter retrospective comparative analysis
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Masahiro Yokoyama, Shingo Yano, Yasuhito Terui, Kaichi Nishiwaki, Yuko Mishima, Noriko Nishimura, Nobuhiro Tsukada, Tadao Ishida, Kazuhito Suzuki, Kiyoshi Okazuka, Kenshi Suzuki, and Yasuyuki Nagata
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Adult ,Male ,medicine.medical_specialty ,Kaplan-Meier Estimate ,Gastroenterology ,Dexamethasone ,Bortezomib ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Lenalidomide ,Multiple myeloma ,Aged ,Retrospective Studies ,Hematology ,business.industry ,Hematopoietic Stem Cell Transplantation ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Survival Rate ,Regimen ,Treatment Outcome ,Tolerability ,Disease Progression ,Female ,Multiple Myeloma ,business ,medicine.drug - Abstract
The combination of bortezomib, lenalidomide, and dexamethasone (VRD) is used as induction treatment in multiple myeloma; however, the optimum schedule for this regimen remains controversial. In this retrospective study, we compared the efficacy and tolerability of twice-weekly VRD (twVRD) and modified VRD-lite in transplant-eligible myeloma patients. Fifty-five patients (median age 61 years) were included; 22 received twVRD (bortezomib [1.3 mg/m2 on days 1, 4, 8, and 11] and lenalidomide [25 mg/body on days 1–14] over 21-day cycles) and 33 received modified VRD-lite (bortezomib [1.3 mg/m2 on days 1, 8, 15, and 22) and lenalidomide [15 mg/body on days 2–7, 9–14, 16–21] over 28-day cycles). Overall response, very good partial response, and complete response rates after VRD were 96.4%, 45.5%, and 20.0%, respectively (median follow-up period, 17.7 months). The 1-year progression-free survival (PFS) and overall survival rates were 95.8% and 98.2%, respectively. The response rate and PFS were similar between the groups, regardless of cytogenetic risk and age. The incidence of peripheral neuropathy ≥ grade 2 and thrombocytopenia ≥ grade 3 was higher in the twVRD group (27.2% vs. 0.0%, P = 0.003 and 27.2% vs. 0.0%, P = 0.003). In conclusion, modified VRD-lite had similar efficacy with, but better tolerability than, twVRD in transplant-eligible patients.
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- 2019
15. Investigation of the effect of a 15-degree tilt-in-space on the fluctuation of shear forces exerted on the buttocks when the back support is reclined
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Yasuyuki Nagata, Hisashi Takahashi, Tadanobu Suehiro, Daisuke Fujita, Hiroshi Osaka, and Kenichi Kobara
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business.industry ,Shear force ,Physical Therapy, Sports Therapy and Rehabilitation ,Mechanics ,Space (mathematics) ,Degree (temperature) ,medicine.anatomical_structure ,Tilt (optics) ,Perpendicular ,medicine ,Original Article ,Back support ,Tilt-in-space ,Buttocks ,business ,Reclining - Abstract
[Purpose] This study aimed to investigate the effect of the combination of 15° tilt-in-space and recline angles on the fluctuation of shear forces exerted on the buttocks. [Participants and Methods] The participants were 11 healthy adult males. The parameters of the shear forces were the parallel and perpendicular forces exerted on the buttocks as measured by a force plate. The two conditions tested were T0R100-130 and T15R100-130. The tilt-in-space angles were set to 0° and 15° in the T0R100-130 and T15R100-130 conditions, respectively. The reclining angles were determined to be 100° to 130° in both conditions. [Results] Upon comparing the two conditions, the parallel and the perpendicular forces exerted on the buttocks in the T15R100-130 condition were significantly lower than those in the T0R100-130 condition in all positions of back support. Upon comparing the fluctuation values of the parallel and perpendicular forces, those applied in the T15R100-130 condition were significantly higher than those in the T0R100-130 condition. [Conclusion] These results suggest that the fluctuation of shear forces exerted on the buttocks could be decreased by using a combination of 15° tilt-in-space and reclining functions.
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- 2021
16. Cardiotoxicity of Carfilzomib in Two Japanese Patients with Relapsed Multiple Myeloma
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Yasuyuki Nagata, Makoto Sano, Yoshihisa Naruse, Tsuyoshi Urushida, Masao Saotome, Takaaki Ono, Takenori Ikoma, Hayato Ohtani, Yuichiro Maekawa, and Kenichiro Suwa
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Oncology ,Male ,medicine.medical_specialty ,Poor prognosis ,Case Report ,Antineoplastic Agents ,030204 cardiovascular system & hematology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Recurrence ,Internal medicine ,Internal Medicine ,medicine ,Humans ,In patient ,Multiple myeloma ,Heart Failure ,Cardiotoxicity ,carfilzomib ,cardiotoxity ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,Prognosis ,Carfilzomib ,multiple myeloma ,chemistry ,Hematological malignancy ,Heart failure ,Proteasome inhibitor ,030211 gastroenterology & hepatology ,Female ,business ,Oligopeptides ,Proteasome Inhibitors ,medicine.drug - Abstract
Although multiple myeloma (MM) had been an incurable hematological malignancy with a poor prognosis, recent advances in novel anti-neoplastic agents, including carfilzomib (a proteasome inhibitor), have improved the prognosis. We herein report two cases of congestive heart failure in patients treated with carfilzomib. Although there are some reports on the cardiotoxicity of carfilzomib, to our knowledge, this is the first report on the cardiac involvement of carfilzomib in Japanese MM patients. We review the critical points from our two cases, with the aim of avoiding carfilzomib-associated heart failure in MM patients.
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- 2019
17. A simple method to distinguish residual elotuzumab from monoclonal paraprotein in immunofixation assays for multiple myeloma patients
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Yasuyuki Nagata, Shurui Chen, Yotaro Tamai, Ryoko Kajiya, Yoshiki Akatsuka, Takeshi Ikeda, Takaaki Ono, Toru Kiguchi, Hiroyoshi Nishikawa, and Daisuke Sugiyama
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Immunofixation ,Monoclonal antibody ,medicine.medical_specialty ,medicine.drug_class ,Antibodies, Monoclonal, Humanized ,Gastroenterology ,03 medical and health sciences ,Immunofixation electrophoresis ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Signaling Lymphocytic Activation Molecule Family ,Internal medicine ,Biomarkers, Tumor ,Medicine ,Humans ,Elotuzumab ,Multiple myeloma ,Immunoassay ,Hematology ,biology ,integumentary system ,business.industry ,SLAMF7 ,medicine.disease ,Minimal residual disease ,Recombinant Proteins ,Myeloma Proteins ,030220 oncology & carcinogenesis ,Monoclonal ,biology.protein ,Therapeutic ,business ,Multiple Myeloma ,030215 immunology ,medicine.drug - Abstract
Negative immunofixation electrophoresis (IFE) of serum and/or urine is a diagnostic marker for determining a complete response (CR) after immunotherapy for multiple myeloma (MM). However, residual therapeutic antibodies such as elotuzumab (IgG-κ), can compromise IFE evaluation when the affected immunoglobulins belong to the same IgG-κ subclass. We thus sought to develop a simple and rapid method to treat patient serum before IFE to distinguish the residual elotuzumab. Serum samples from patients receiving elotuzumab were treated with a predetermined amount of soluble signaling lymphocyte activation molecule F7 (SLAMF7) protein and then subjected to conventional IFE testing. We tested our method in samples from 12 patients. The IgG-κ band in IFE disappeared or shifted after elotuzumab treatment in four patients with no bone marrow minimal residual disease and normalized free light chain, whereas seven patients with any sign of residual MM showed a remaining IgG-κ band after treatment. One-hour incubation of samples with 6-9 molar excess soluble SLAMF7 before IFE was sufficient to distinguish residual elotuzumab in 11 of 12 samples. This simple method does not require special reagents, can be performed in most clinical laboratories, and enables differentiation between patients with a CR and those requiring further treatment.
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- 2020
18. Success and limitations of plasma treatment in pregnant women with congenital thrombotic thrombocytopenic purpura
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Shigehiko Kaburagi, Koichi Kokame, Ayami Isonishi, Masanori Matsumoto, Yoshiyuki Ogawa, Yasuyuki Nagata, Yoshihiro Fujimura, Michiko Kajiwara, Satoshi Higasa, Kinta Hatakeyama, Toshiyuki Miyata, Masato Moriyama, Kazuya Sakai, Mutsuko Konno, and Tomoko Hara
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medicine.medical_specialty ,Thrombotic thrombocytopenic purpura ,ADAMTS13 Protein ,Congenital Thrombotic Thrombocytopenic Purpura ,030204 cardiovascular system & hematology ,03 medical and health sciences ,Plasma ,0302 clinical medicine ,Pregnancy ,medicine ,Humans ,Upshaw–Schulman syndrome ,Purpura, Thrombotic Thrombocytopenic ,business.industry ,Obstetrics ,Pregnancy Complications, Hematologic ,Hematology ,medicine.disease ,ADAMTS13 ,Gestation ,Female ,Fresh frozen plasma ,Pregnant Women ,Live birth ,business - Abstract
Background Congenital thrombotic thrombocytopenic purpura (cTTP), otherwise known as Upshaw-Schulman syndrome, is an extremely rare hereditary disease. Pregnancy is identified as a trigger for TTP episodes in patients with cTTP. Objectives To investigate the ideal management of pregnant patients with cTTP. Patients/methods We identified 21 patients with a reproductive history (38 pregnancies) in a Japanese cTTP registry. Fetal outcomes were compared between two groups: group 1 (n = 12), pregnancy after diagnosis of confirmed cTTP by ADAMTS13 gene analysis; and group 2 (n = 26), pregnancy before diagnosis of confirmed cTTP. Results In group 1, ADAMTS13 activity was closely monitored until delivery in most cases. Among 10 pregnancies in group 1, prophylactic fresh frozen plasma (FFP) infusions during pregnancy were performed to replenish ADAMTS13. In group 2, prophylactic FFP infusions were not administrated in 23 pregnancies and FFP test infusions were performed in only three pregnancies. The live birth rate of group 1 was significantly higher than that of group 2 (91.7% vs 50.0%, respectively, P = .027). The fetal survival rates of women without FFP infusions were dramatically decreased after 20 weeks of gestation. The FFP infusion dosage in group 1 was generally higher than 5 mL/kg/wk by 20 weeks of gestation. Conclusions Our results indicate that FFP infusions of more than 5 mL/kg/wk should be initiated as soon as patients become pregnant. However, even with these infusions, patients with repeated TTP episodes before pregnancy might have difficulty giving birth successfully. Recombinant ADAMTS13 products might be new treatment options for pregnant patients with cTTP.
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- 2020
19. Influence of Different Postures on the Autonomic Nerve Activity of Children with Severe Motor and Intellectual Disabilities
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Daisuke Fujita, Yasuyuki Nagata, Akina Hirata, Takuya Ujikawa, and Kenichi Kobara
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business.industry ,Medicine ,Physical Therapy, Sports Therapy and Rehabilitation ,business - Published
- 2018
20. Genomic Analysis of NPM1 Mutation and KMT2A(MLL)-Rearrangement/Amplification in Japanese Patients with Acute Myeloid Leukemia: Hematologic Malignancies (HM)-Screen-Japan 01
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Naoko Hosono, Takaaki Ono, Takeshi Kondo, Tsutomu Kobayashi, Akihiko Gotoh, Kentaro Fukushima, Kensuke Usuki, SungGi Chi, Kenji Ishitsuka, Seiichiro Katagiri, Kazuhito Yamamoto, Yukinori Nakamura, Kaoru Yamamoto, Makoto Yoshimitsu, Takahiro Yamauchi, Suguru Fukuhara, Hiroto Horiguchi, Nobuhiko Yamauchi, Yoshikazu Utsu, Hirohiko Shibayama, Koji Izutsu, Junya Kuroda, Makoto Nakamura, Junichiro Yuda, Takanobu Morishita, Yasuyuki Nagata, Reiki Ogasawara, Nobuyuki Aotsuka, Yoshimasa Kamoda, Motoki Eguchi, Yosuke Minami, Naoto Takahashi, Kensuke Kojima, Masamitsu Yanada, Satoshi Iyama, and Naohito Fujishima
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biology ,business.industry ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Mll rearrangement ,Biochemistry ,NPM1 Mutation ,KMT2A ,Cancer research ,biology.protein ,Medicine ,business - Abstract
Background and Methods: NPM1 mutation and KMT2A(MLL)-rearrangement/amplification are present in approximately 27% and 8.5% patients with acute myeloid leukemia (AML), respectively (data from cBioPortal). Although they have different clinical features and prognostic impact, recent studies suggest that the MLL co-factor, menin, plays a key role in maintaining self-renewal of immature leukemic cells by upregulating transcription of HOXA and MEIS (Gundry et al.). However, the real-world epidemiology of these mutations and co-existing gene alterations have not been thoroughly investigated in Japan. We launched an actionable mutation profiling multicenter study entitled Hematologic Malignancies (HM)-SCREEN-Japan 01 (UMIN000035233). In this study, a comprehensive genomic assay was performed by Foundation One Heme (F1H) panel for patients with relapsed/refractory (R/R) AML as well as patients with newly-diagnosed (ND) AML who are ineligible for standard chemotherapy. Paraffin-embedded bone marrow samples were gathered from 17 Japanese faculties and the F1H reports were returned to the patients. Results: One-hundred-eighty-two patients were recruited in this study and the F1H report was successfully returned in 177 patients (97.3%). Median age of 68 patients with ND-AML was 73 [63-79] years and those of 109 patients with R/R-AML was 50 [40-68.5] years. Median turn-around time was 13 days (minimum 8 days).We found 32 patients (18.1%) with NPM1 mutation and 23 patients (13.0%) of KMT2A(MLL)-rearrangement/amplification out of the 177 patients. These two alterations were mutually exclusive in this study. The median age of patients with NPM1 mutation (NPM1 mt.) and KMT2A-rearrangement (KMT2A-r) were 56.5 [43.5-73.8] and 62 [45-71] years, respectively. Three quarters or more patients were R/R-AML in both groups. WT1 expression levels were much higher in patients with NPM1 mt. than the other group (6,000 [77-110,000] vs. 93 [34-5,800] copies/mcgRNA). The major amino acid alteration of NPM1 was a frameshift mutation at the 288 th histidine (W288fs*12). Patterns of KMT2A(MLL)-rearrangement included MLL fusion (e.g., MLL-MLLT3) and partial tandem duplication (PTD) in ten patients each. MLL amplification was observed in three patients. Frequently co-occurring mutations with NPM1 mt. included FLT3 (56.3%), DNMT3A (46.9%), TET2 (34.4%), WT1 (18.8%), IDH1 (18.8%), and IDH2 (15.6%). Those with KMT2A-r included FLT3 (39.1%), TP53 (26.1%), PTPN11 (21.7%), DNMT3A (17.4%), and IDH2 (17.4%). Mutations of RAS pathway-related genes (e.g., KRAS, NRAS, PTPN11, and NF1) were observed in five patients with NPM1 mt. (15.6%) and 11 patients (47.8%) with KMT2A-r. None of the six patients with TP53 mutation had NPM1 mutation. The prognostic impact of each genes is currently being analyzed. Conclusions: Approximately three in ten patients with AML had NPM1 mutation and/or KMT2A(MLL)-rearrangement/amplification. No single patient had both the alterations. FLT3 and DNA methylation-associated genes (e.g., DNMT3A and TET2) were frequently seen in patients with NPM1 mt. In contrast, TP53 and RAS pathway-related gene alterations (e.g., NRAS, KRAS, PTPT11 and NF1) were relatively dominant in patients with KMT2A-r. TP53 mutation seemed unlikely to occur along with NPM1 mutation. Figure 1 Figure 1. Disclosures Shibayama: Celgene: Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Avvie: Honoraria, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Essentia Pharma Japan: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria; Fujimoto: Honoraria; Nippon Shinyaku: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Otsuka: Honoraria; Mundi Pharma: Honoraria. Yamauchi: Otsuka: Research Funding; Ono Pharmaceutical: Honoraria; Pfizer: Honoraria, Research Funding; Chugai: Honoraria; Abbie: Research Funding; Astellas: Research Funding; Daiichi Sankyo: Research Funding; Solasia Pharma: Research Funding. Kondo: Otsuka Pharmaceutical: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Sanwa Kagaku Kenkyusho CO.,LTD: Consultancy; Astellas Pharma Inc.: Consultancy, Honoraria; Abbvie: Honoraria. Yamamoto: Bristol-Myers Squibb/Celgene: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Eisai: Honoraria, Research Funding; IQIVA/Incyte: Research Funding; IQIVA/HUYA: Honoraria; HUYA: Consultancy; Janssen: Honoraria; Kyowa Kirin: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria, Research Funding; MSD: Honoraria; Mundipharma: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria; Solasia Pharma: Research Funding; SymBio: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Yakult: Honoraria, Research Funding; Zenyaku: Honoraria, Research Funding; Micron: Honoraria; IQIVA/Genmab: Research Funding; ADC Therapeutics: Honoraria; AbbVie: Honoraria, Research Funding. Kuroda: Fujimoto Pharmaceutical: Current Employment, Honoraria, Research Funding; Taiho Pharmaceutical: Research Funding; Asahi Kasei: Research Funding; Shionogi: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sysmex: Research Funding; Eisai: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; MSD: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Bristol-MyersSquibb: Consultancy, Honoraria, Research Funding; Janssen Pharmaceutical K.K: Consultancy. Usuki: Astellas: Research Funding, Speakers Bureau; Abbvie: Research Funding; Gilead: Research Funding; Symbio: Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding, Speakers Bureau; Sumitomo Dainippon: Research Funding; Otsuka: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Brisol-Myers Squibb: Research Funding, Speakers Bureau; Ono: Research Funding, Speakers Bureau; Janssen: Research Funding; Celgene: Research Funding, Speakers Bureau; Takeda: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Mundipharma: Research Funding; Astellas-Amgen-Biopharma: Research Funding; Nippon shinyaku: Research Funding, Speakers Bureau; Kyowa Kirin: Research Funding, Speakers Bureau; Pfizer: Research Funding; Alexion: Speakers Bureau; Eisai: Speakers Bureau; MSD: Speakers Bureau; PharmaEssentia: Speakers Bureau; Yakult: Speakers Bureau. Yoshimitsu: Novartis: Honoraria; Takeda: Honoraria; Sanofi: Honoraria. Ishitsuka: Kyowa Kirin: Other: Personal fees, Research Funding; Daiichi Sankyo: Consultancy, Other: Personal fees; Ono Pharmaceutical: Other: Personal fees, Research Funding; Celgene: Honoraria, Other: Personal fees; Chugai Pharmaceutical: Honoraria, Other: Personal fees, Research Funding; BMS: Other; Takeda: Other: Personal fees, Research Funding; Mundipharma: Other: Personal fees; Taiho Pharmaceuticals: Other: Personal fees, Research Funding; Janssen Pharmaceuticals: Other: Personal fees; Novartis: Other: Personal fees; Pfizer: Other: Personal fees; Astellas Pharma: Other: Personal fees, Research Funding; Genzyme: Other: Personal fees; Sumitomo Dainippon Pharma: Other: Personal fees, Research Funding; Eisai: Other: Personal fees, Research Funding; Mochida: Other: Personal fees, Research Funding; Shire: Other; Otsuka Pharmaceutical: Other: Personal fees; Teijin Pharma: Research Funding; MSD: Research Funding; Asahi kasei: Research Funding; Eli Lilly: Research Funding; Huya Japan: Other: Personal fees. Ono: DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Mundipharma K.K.: Honoraria; Celgene: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Janssen Pharmaceutical K.K: Honoraria; Eisai Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding. Fujishima: Pfizer: Speakers Bureau. Takahashi: Toyamakagaku: Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Research Funding; Eizai: Research Funding; Asahikasei: Research Funding; Kyowahakko-Kirin: Research Funding; Ono: Research Funding. Iyama: Alexion Pharmaceuticals: Honoraria, Research Funding; Astellas: Honoraria; CSL Behring: Honoraria; Daiichi Sankyo: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; MSD: Research Funding; Nippon Shinyaku: Honoraria; Novartis: Honoraria; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; SymBio Pharmaceuticals: Research Funding. Izutsu: Symbio: Honoraria; Takeda: Honoraria, Research Funding; Solasia: Research Funding; Pfizer: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MSD: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Huya Biosciences: Research Funding; Genmab: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Eisai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; Yakult: Research Funding; Allergan Japan: Honoraria; AbbVie: Honoraria. Minami: Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Pfizer Japan Inc.: Honoraria; Takeda: Honoraria; Astellas: Honoraria; Ono: Research Funding; CMIC: Research Funding.
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- 2021
21. Topic: AS04-MDS Biology and Pathogenesis/AS04b-Clonal diversity & evolution
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Satoru Miyano, A. Kondo-Takaori, Hidehiro Itonaga, Makoto Onizuka, Yasushi Miyazaki, Kazuma Ohyashiki, Jurjen Jansen, Yusuke Shiozawa, T Haferlach, Yoshiko Atsuta, Luca Malcovati, June Takeda, S. Kasahara, Yasuyuki Nagata, Tetsuichi Yoshizato, Yuichi Shiraishi, Toru Kiguchi, Masashi Sanada, Magnus Tobiasson, J. Maciejewski, Mario Cazzola, Y. Iijima-Yamashita, Elli Papaemmanuil, Yasuhito Nannya, F. Matsuda, Maria Creignou, R. Saiki, Kenichi Yoshida, Carmelo Gurnari, Hisashi Tsurumi, Y. Momozawa, Chantana Polprasert, Masahiro Nakagawa, Hideki Makishima, Yoshinobu Kanda, Eva Hellström-Lindberg, Austin G. Kulasekararaj, Seishi Ogawa, and Y. Kamatani
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Pathogenesis ,Cancer Research ,Oncology ,Evolutionary biology ,Hematology ,Biology ,Clonal diversity - Published
- 2021
22. Genetic Features of AML with MLL-Rearrangement and NPM1 Mutation: An Interim-Analysis of HM-Screen-Japan 01
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Akihiko Gotoh, Satoshi Iyama, Naohito Fujishima, Suguru Fukuhara, Koji Izutsu, Ken-ichi Miyamoto, Seiichiro Katagiri, Naoko Hosono, Junya Kuroda, Takaaki Ono, Hiroto Horiguchi, Takeshi Kondo, Makoto Nakamura, Kentaro Fukushima, Yoshikazu Utsu, Makoto Yoshimitsu, Kenji Ishitsuka, Kazuhito Yamamoto, Yosuke Minami, Kazuto Togitani, Takanobu Morishita, Kanenari Takemura, Hirohiko Shibayama, Takahiro Yamauchi, SungGi Chi, Kensuke Kojima, Yasuyuki Nagata, Yukinori Nakamura, Nobuyuki Aotsuka, Naoto Takahashi, Motohito Okabe, Kensuke Usuki, Yoshimasa Kamoda, Kaoru Yamamoto, Tsutomu Kobayashi, Reiki Ogasawara, and Masamitsu Yanada
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Genetics ,NPM1 Mutation ,Immunology ,Cell Biology ,Hematology ,Mll rearrangement ,Biology ,Interim analysis ,Biochemistry - Abstract
Background: Acute myeloid leukemias with KMT2A (formerly known as MLL-1) fusion genes (MLL-AML) and those with NPM1 mutations (NPM1-AML) are distinct subtypes as defined by the WHO classification. Although they have different clinical features and prognostic impact , recent studies suggest that the MLL1 co-factor, menin, plays a key role in maintaining self-renewal of immature leukemic cells by upregulating transcription of HOXA and MEIS (Gundry et al.). New targeted strategies for these AML subtypes are expected as preliminary data suggest that menin-MLL1 inhibition may inhibit malignancy. In addition to classical chromosomal analysis and prefixed fusion gene screening, next-generation sequencing (NGS) should help in identifying the precise prevalence of these alterations and understanding the relationship with other pathological mutations. We launched the HM-SCREEN-JAPAN01 study (UMIN000035233) in which gene alterations are analyzed by FoundationOne Heme® in patients with AML who are relapsed/refractory to, or ineligible for standard therapies. Aiming for 200 registrations, recruitment has reached approximately 100. The interim results are described here. Methods: HM-SCREEN-JAPAN01 is an observational study and conducted by 17 participating institutions. The eligibility criteria are as follows: 1) histological diagnosis of AML must be made by bone marrow testing; 2) one of the following conditions must be fulfilled: i) a patient with newly diagnosed AML and is ineligible for standard treatment, or ii) a patient with AML who has relapsed or is refractory to prior therapy; 3) sufficient amount of bone marrow sample must be available; 4) age at registration must be 20 or more; and 5) written informed consent must be taken. All samples were analyzed by FoundationOne Heme®. Results:Nine patients (9.9%) with MLL-AML and seventeen patients (18.7%) with NPM1-AML were found among 91 available cases (either one found in 28.6%). No patients demonstrated MLL-rearrangement and NPM1-mutation simultaneously. Median age of patients with MLL-AML (42-68 y) was a decade less than that of patients with NPM1-AML (55-74 y), and the majority of cases had a clinical relapse or were refractory to prior therapies. Translocations involving chromosome 11q23.3 (e.g. t(9;11)(p21.3;q23.3)) were found in 5 of 8 patients (62.5%) with MLL-AML (data not available due to insufficient cell count in one case) and no chromosomal abnormalities were detected in 10 of 16 patients (62.5%) with NPM1-AML (chromosomal analysis was not performed in one case). In patients with MLL-AML (see Figure), FLT3 mutations were found in 3 of 9 cases (33.3%), all of which were point mutations within the tyrosine kinase domain (FLT3-TKD). PTPN11 mutations were also found simultaneously in these three cases. Co-existing NRAS and TP53 mutations with high allele-frequency (32-50%) were also seen in two different cases. A targetable mutation of IDH2 was seen in one patient (11.1%) who had an FLT3 mutation with low allele-frequency (2%). In patients with NPM1-AML (see Figure), allele-frequency of mutated NPM1 ranged from 10 to 44%. Relatively common co-existing mutations were TET2 (7 of 17; 41.2%), DNMT3A (9 of 17; 52.9%), and FLT3 (9 of 17; 52.9%). Unlike in MLL-AML patients, all FLT3 alterations were internal tandem duplication (FLT-ITD) with one case of dual FLT3-ITD and -TKD mutation. IDH1 and IDH2 mutations were found in two (11.8%) and four (23.5%) separate cases, respectively. A rare fusion gene ETV6-NTRK3 (one of primary targets of NTRK inhibitors) was detected in one patient (5.9%) who had IDH1 mutation with moderate allele-frequency (17%). Conclusion: MLL-rearrangements and NPM1-mutations were found in approximately a quarter of the 91 AML patient (mostly relapsed or refractory) bone marrow samples analyzed. These alterations appeared to be mutually exclusive. FLT3 alterations were seen in a third of the MLL-AML cases and half of the NPM1-AML cases, seemingly more frequent than that previously reported. Interestingly, FLT3-TKDs were dominant in MLL-AML cases, whereas NPM1-AML cases carried FLT3-ITD. IDH1 and IDH2 mutations commonly co-existed in both groups. This HM-SCREEN-Japan01 study is now recruiting patients, and a further understanding of genomic distribution and correlation is expected. Figure Disclosures Yamauchi: Otsuka:Research Funding;Astellas:Research Funding;Daiichi Sankyo:Research Funding;Chugai:Honoraria;Pfizer:Honoraria, Research Funding;Abbie:Research Funding;Solasia Pharma:Research Funding;Ono Pharmaceutical:Honoraria.Shibayama:AstraZeneca:Honoraria, Membership on an entity's Board of Directors or advisory committees;Sanofi:Honoraria;Pfizer:Honoraria;Fujimoto:Honoraria;Janssen:Honoraria, Research Funding;Teijin:Research Funding;Novartis:Honoraria, Research Funding;Takeda:Honoraria, Research Funding;Nippon Shinyaku:Honoraria, Research Funding;Daiichi Sankyo:Honoraria;Chugai:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Sumitomo Dainippon:Honoraria, Research Funding;Merck Sharp & Dohme:Research Funding;Shionogi:Research Funding;Astellas:Research Funding;Taiho:Research Funding;Otsuka:Honoraria;Bristol-Myers Squibb:Honoraria;Celgene:Membership on an entity's Board of Directors or advisory committees, Research Funding;Eisai:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;AbbVie:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Kyowa Kirin:Honoraria;Ono:Honoraria, Research Funding;Mundi Pharma:Honoraria.Yamamoto:Stemline Therapeutics:Consultancy;Meiji Seika Pharma:Consultancy, Honoraria;MSD:Consultancy, Honoraria, Research Funding;Chugai:Consultancy, Honoraria, Research Funding;Eisai:Consultancy, Honoraria, Research Funding;Daiichi Sankyo:Consultancy;IQIVA/HUYA:Honoraria;HUYA:Consultancy;IQIVA/Incyte:Research Funding;Mundipharma:Consultancy, Honoraria, Research Funding;Kyowa Kirin:Honoraria;Mochida:Honoraria;Gilead Sciences:Research Funding;Solasia Pharma:Research Funding;Nippon Shinyaku:Honoraria, Research Funding;Novartis:Honoraria, Research Funding;Ono:Consultancy, Honoraria, Research Funding;Aichi Cancer Center:Current Employment;AbbVie:Consultancy, Honoraria, Research Funding;Astra-Zeneca:Consultancy, Research Funding;Bayer:Research Funding;Bristol-Myers Squibb:Honoraria;Celgene:Consultancy, Honoraria, Research Funding;Zenyaku:Research Funding;Takeda:Consultancy, Honoraria, Research Funding;Yakult:Research Funding;SymBio:Research Funding;Pfizer:Honoraria;Otsuka:Consultancy, Honoraria, Research Funding;Sanofi:Honoraria;Sumitomo Dainippon:Honoraria;Janssen:Honoraria.Fujishima:Pfizer:Speakers Bureau.Takahashi:Pfizer Japan Inc.:Honoraria, Research Funding;Novartis Pharma KK:Honoraria, Research Funding;Bristol-Myers Squibb Company:Honoraria.Usuki:Alexion:Speakers Bureau;Pfizer:Research Funding;Nippon Boehringer Ingelheim:Research Funding;Mundipharma:Research Funding;Astellas-Amgen-Biopharma:Research Funding;Nippon shinyaku:Research Funding, Speakers Bureau;Eisai:Speakers Bureau;MSD:Speakers Bureau;Takeda:Speakers Bureau;PharmaEssentia:Speakers Bureau;Yakult:Speakers Bureau;Symbio:Research Funding, Speakers Bureau;Daiichi Sankyo:Research Funding, Speakers Bureau;Sumitomo Dainippon:Research Funding;Otsuka:Research Funding, Speakers Bureau;Novartis:Research Funding, Speakers Bureau;Brisol-Myers Squibb:Research Funding, Speakers Bureau;Kyowa Kirin:Research Funding, Speakers Bureau;Ono:Research Funding, Speakers Bureau;Janssen:Research Funding;Celgene:Research Funding, Speakers Bureau;Takeda:Research Funding;Astellas:Research Funding, Speakers Bureau;Abbvie:Research Funding;Gilead:Research Funding.Ono:Celgene:Honoraria, Research Funding;Kyowa Kirin Co., Ltd.:Honoraria, Research Funding;Chugai Pharmaceutical Co., Ltd.:Honoraria, Research Funding;Novartis Pharma KK:Honoraria;Mundipharma K.K.:Honoraria;TAIHO PHARMACEUTICAL CO., LTD.:Research Funding;Eisai Co., Ltd.:Honoraria;Otsuka Pharmaceutical Co., Ltd.:Honoraria;Astellas Pharma Inc.:Honoraria;Bristol-Myers Squibb Company:Honoraria;Pfizer Japan Inc.:Honoraria;Takeda Pharmaceutical Company Limited.:Honoraria;ONO PHARMACEUTICAL CO., LTD.:Honoraria, Research Funding;DAIICHI SANKYO COMPANY, LIMITED.:Honoraria;Janssen Pharmaceutical K.K:Honoraria.Kuroda:Daiichi Sankyo:Honoraria, Research Funding;Pfizer:Honoraria, Research Funding;Sysmex:Research Funding;Janssen Pharmaceutical K.K:Consultancy;Eisai:Honoraria, Research Funding;Sanofi:Consultancy, Honoraria, Research Funding;Kyowa Kirin:Honoraria, Research Funding;Otsuka Pharmaceutical:Honoraria, Research Funding;Ono Pharmaceutical:Honoraria, Research Funding;Abbvie:Consultancy, Honoraria;MSD:Research Funding;Celgene:Consultancy, Honoraria, Research Funding;Dainippon Sumitomo Pharma:Honoraria, Research Funding;Chugai Pharmaceutical:Honoraria, Research Funding;Takeda:Honoraria, Research Funding;Bristol-MyersSquibb:Consultancy, Honoraria, Research Funding;Astellas Pharma:Honoraria, Research Funding;Fujimoto Pharmaceutical:Honoraria, Research Funding;Taiho Pharmaceutical:Research Funding;Asahi Kasei:Research Funding;Shionogi:Research Funding;Nippon Shinyaku:Honoraria, Research Funding.Ishitsuka:Celgene:Other: Personal Fees;Kyowa Hakko Kirin:Other: Personal fees, Research Funding;BMS:Other: Personal fees;Chugai Pharmaceutical:Other: Personal fees, Research Funding;Takeda:Other: Personal fees, Research Funding;mundiharma:Other: Personal fees;Taiho Pharmaceuticals:Other: Personal fees, Research Funding;Janssen Pharmaceuticals:Other: Personal fees;Novartis:Other: Personal fees;Pfizer:Other: Personal fees;Astellas Pharma:Other, Research Funding;Genzyme:Other;Sumitomo Dainippon Pharma:Other, Research Funding;Eisai:Other, Research Funding;Mochida:Other, Research Funding;Shire:Other;Otsuka Pharmaceutical:Other;Ono Pharmaceutical:Other, Research Funding;Teijin Pharma:Research Funding;MSD:Research Funding;Asahi kasei:Research Funding;Eli Lilly:Research Funding;Daiichi Sankyo:Other;Huya Japan:Other.Minami:Bristol-Myers Squibb Company:Honoraria;Novartis Pharma KK:Honoraria;Pfizer Japan Inc.:Honoraria;Takeda:Honoraria.
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- 2020
23. Bortezomib, lenalidomide, and dexamethasone in transplant-eligible newly diagnosed multiple myeloma: A multicenter retrospective comparative analysis
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Shingo Yano, Yuko Mishima, Tadao Ishida, Nobuhiro Tsukada, Kenshi Suzuki, Masahiro Yokoyama, Yasuhito Terui, Noriko Nishimura, Yasuyuki Nagata, Kaichi Nishiwaki, Kazuhito Suzuki, and Kiyoshi Okaduka
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Hematology ,Newly diagnosed ,medicine.disease ,Internal medicine ,Bortezomib/lenalidomide ,Medicine ,business ,Dexamethasone ,Multiple myeloma ,medicine.drug - Published
- 2019
24. [Sarcoidosis-lymphoma syndrome showing abnormal FDG uptake in lymph nodes and muscles upon post-chemotherapy PET/CT imaging]
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Kotaro, Nakano, Yujiro, Ito, Fumisato, Takagi, Satoshi, Uchiyama, Akari, Yoda, Nami, Sakamoto, Masamitsu, Takaba, Miwa, Adachi, Tomonari, Takemura, Yasuyuki, Nagata, and Takaaki, Ono
- Subjects
Sarcoidosis ,Fluorodeoxyglucose F18 ,Positron Emission Tomography Computed Tomography ,Positron-Emission Tomography ,Humans ,Female ,Lymph Nodes ,Lymphoma, Large B-Cell, Diffuse ,Radiopharmaceuticals ,Muscle, Skeletal ,Aged - Abstract
A 65-year-old woman was diagnosed with rheumatoid arthritis in 2010 and was treated with methotrexate (MTX). In 2012, she was diagnosed with sarcoidosis and underwent a follow-up therapy for mild peripheral neuropathy due to neurosarcoidosis. In 2018, she experienced primary splenic diffuse large B-cell lymphoma (DLBCL) and was diagnosed with sarcoidosis-lymphoma syndrome (SLS). MTX was discontinued, and six cycles of rituximab were administered combined with chemotherapy. Positron emission tomography combined with computed tomography performed 18 weeks after the last cycle of chemotherapy showed new abnormal fluoro-2-deoxy-D-glucose (FDG) uptake in the mediastinal and hilar lymph nodes and skeletal muscles. Sarcoidosis was suspected because of increased serum angiotensin-converting enzyme levels and magnetic resonance imaging findings in the lower limb muscles. However, pathological findings of DLBCL and sarcoidosis were not confirmed in the hilar lymph node biopsy. Therefore, malignant lymphoma can be distinguished from sarcoidosis using abnormal FDG uptake after chemotherapy for SLS.
- Published
- 2019
25. Recurrent Coronary Thrombus in a Patient with Chronic Immune Thrombocytopenia with Treatment Using Eltrombopag
- Author
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Hayato Ohtani, Masao Saotome, Takaaki Ono, Yasuyuki Nagata, Terumori Satoh, Yuichiro Maekawa, and Kenichiro Suwa
- Subjects
medicine.medical_specialty ,Acute coronary syndrome ,lcsh:Diseases of the circulatory (Cardiovascular) system ,medicine.medical_treatment ,Eltrombopag ,Case Report ,030204 cardiovascular system & hematology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Coronary stent ,Medicine ,030212 general & internal medicine ,Myocardial infarction ,cardiovascular diseases ,business.industry ,Stent ,Percutaneous coronary intervention ,medicine.disease ,Thrombosis ,chemistry ,lcsh:RC666-701 ,Conventional PCI ,Cardiology ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background. Eltrombopag, a nonpeptide thrombopoietin receptor agonist (TPO-RA), has been reported to be an effective therapy for chronic immune thrombocytopenia (ITP). However, a higher incidence of arterial and venous thromboembolic events was reported after using eltrombopag.Case Presentation. A 67-year-old man, treated with eltrombopag due to chronic ITP, was admitted due to acute coronary syndrome (ACS). Although coronary angiography revealed no occlusion, cardiac magnetic resonance imaging suggested a myocardial infarction in the territory of the left circumflex coronary artery. Three months after the ACS event, the obtuse marginal branches exhibited significant stenosis; hence, a percutaneous coronary intervention (PCI) was performed to implant a zotarolimus-eluting stent under the treatment of a dual antiplatelet therapy. However, stent thrombosis occurred 3 hours after PCI and required three other PCIs during the eltrombopag treatment.Conclusion. We present a case of an ITP patient, who experienced repeated coronary and stent thrombosis during the treatment with eltrombopag. We propose that the risk of ACS and consequent coronary stent thrombosis should be considered before the introduction of eltrombopag.
- Published
- 2019
26. Prospective Evaluation of Alternative Donor from Unrelated Volunteer Donor and Cord Blood in Adult Acute Leukemia and Myelodysplastic Syndrome: No Difference between Unrelated Donor and Cord Blood
- Author
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Yachiyo Kuwatsuka, Kazutaka Ozeki, Tomoyuki Endo, Koichi Miyamura, Yasuyuki Nagata, Yasuo Tomiya, Nobuharu Fujii, Yoshiko Atsuta, Satoshi Iyama, Hiroatsu Iida, Mika Nakamae, Masanobu Kasai, Kotaro Miyao, Akio Kohno, Makoto Murata, Tatsunori Goto, Tomonori Kato, Yuichiro Nawa, Hisayuki Yokoyama, Shingo Kurahashi, Ritsuro Suzuki, Seitaro Terakura, Makoto Onizuka, Tetsuya Nishida, Noriko Fukuhara, Nobuhiro Kanemura, Hiroatsu Ago, Atsumi Yanagisawa, Yasushi Onishi, Masashi Sawa, and Yukiyasu Ozawa
- Subjects
medicine.medical_specialty ,Acute leukemia ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Comorbidity ,Tacrolimus ,Transplantation ,Graft-versus-host disease ,Internal medicine ,Cord blood ,medicine ,Methotrexate ,business ,medicine.drug - Abstract
Background: Among HLA-well-matched unrelated donor (UD) and umbilical cord blood (CB), HLA-8/8 allele-matched UD transplantation (UDT) showed superior overall survival (OS) to 7/8 allele-matched UDT and CBT, while a similar OS has been demonstrated between the HLA-7/8 allele-matched UDT and the CBT. However, a fair comparison between UDT and CBT is difficult, because graft availability and time required for donor-search is completely different. Once patients relapsed during UD-search period, most of those patients would choose immediate CBT. This means that patients who maintained CR in UD group may have more favorable characteristics, because those patients have been longer in remission and selected as a group of patients who maintained CR. Thus we thought that the factor of "donor-search duration" is important upon conducting a comparative study between UDT and CBT. We planned a clinical study that also taken "donor-search duration" into consideration to compare CBT outcomes with HLA well-matched UDT in a prospective trial setting. Purpose: The purpose of the current study is to compare the transplant outcomes of HLA-well-matched UDT with those of CBT in a prospective trial. Patients and Methods: From 2007 to 2015, 231 patients were provisionally registered for a single-arm phase 2 study of CBT (manuscript submitted). All provisionally registered patients were subjects of current study (Figure 1). After provisional registration, we attempted to find appropriate UD within a decent time period. After approximately 180 days of donor-search, patients received CBT if an appropriate UD was not available. In total, 91 patients received UDT, and 119 patients received CBT. Six patients withdrew and three died before transplantation. Twelve patients did not receive either UDT or CBT, but five received HLA-mismatched SCT from family donor (seven chose not to receive allogeneic SCT). Of 119 CBT recipients, 62 patients were eligible and registered to a phase 2 clinical trial reported elsewhere. Herein we analyzed transplant outcomes of 91 UDT and 119 CBT (UDT group; 49 AML, 37 ALL, 5 MDS: CBT group; 68 AML, 38 ALL, 13 MDS). Risk factors were analyzed by cox proportional hazard model, and survival estimates were depicted by Kaplan-Meier estimation and tested by log-rank test. Results: Patient age was median 39 yrs in both UDT and CBT (p=0.80). Patient body weight was median 59kg (37-90kg) in UDT, and median 55kg (35-90kg) in CBT (p=0.10). Sixty-six of 91 (72.5%) in UDT and 114 of 119 (95.8%) in CBT received myeloablative conditioning. More than 90% of patients received Tacrolimus and short-term methotrexate as GVHD prophylaxis in both UDT and CBT. Days from provisional registration to transplant were median 126 days (range, 77-261 days) in UDT, and median 99 days (8-286 days) in CBT (p Conclusion: Taken donor-search period into consideration, OS after UDT and CBT were similar in a prospective clinical study. CB may be the comparable alternative donor source to UDT. Disclosures Terakura: Novartis: Honoraria; Astellas Pharma Inc.: Honoraria; Amgen Astellas BioPharma K.K.: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Yakult Honsha, Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria. Nishida:Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; MSD K.K.: Consultancy, Honoraria; Amgen Astellas BioPharma K.K.: Honoraria. Sawa:Mundi Pharma: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Sanofi: Honoraria; Astellas Pharma Inc.: Honoraria; Ono Pharmaceutical Co., Ltd: Honoraria; Otsuka Pharmaceutical: Honoraria; Kyowa-Hakko Kirin: Honoraria; Novartis: Honoraria; Shire: Honoraria; Eisai: Honoraria; Mochida: Honoraria; Pfizer Japan Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Nippon Shinyaku: Honoraria; MSD: Honoraria; Asahi-Kasei: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Miyao:Bristol-Myers Squibb: Honoraria; Celgene Corporation: Honoraria; Novartis: Honoraria. Ozawa:Pfizer Japan Inc.: Honoraria; Kyowa-Hakko Kirin: Honoraria; Astellas Pharma Inc.: Honoraria; Novartis: Honoraria. Goto:Celgene Co., Ltd.: Honoraria; JCR Pharmaceuticals Co., Ltd.: Honoraria; Novartis Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria. Onishi:Sumitomo Dainippon Pharma: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; ONO PHARMACEUTICAL CO., LTD.: Honoraria; Nippon Shinyaku: Honoraria; Kyowa-Hakko Kirin: Honoraria; Pfizer Japan Inc.: Honoraria; Astellas Pharma Inc.: Honoraria; Celgene: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Novartis Pharma: Honoraria; Takeda Pharmaceutical Co., Ltd.: Research Funding; MSD: Honoraria, Research Funding. Fukuhara:Janssen Pharma: Honoraria; Eisai: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; AbbVie: Research Funding; Celgene Corporation: Honoraria, Research Funding; Zenyaku: Honoraria; Bayer: Research Funding; Nippon Shinkyaku: Honoraria; Kyowa-Hakko Kirin: Honoraria; Mochida: Honoraria; Mundi: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Gilead: Research Funding; Solasia Pharma: Research Funding. Fujii:Novartis Pharma Co., Ltd.: Honoraria; Kyowa-Hakko Kirin Co., Ltd.: Honoraria. Iida:Chugai Pharmaceutical Co., Ltd.: Research Funding. Endo:Ono: Research Funding. Onizuka:Sumitomo Dainippon Pharma: Research Funding; Astellas: Research Funding; Novartis: Research Funding; pfizer: Research Funding; Chugai Pharma: Research Funding; Bristol-Myers Squibb: Research Funding. Iyama:Otsuka Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Factory: Honoraria; Astellas Pharma: Honoraria; Daiichi Sankyo: Honoraria; Allexion Pharma: Honoraria; CSL Behring: Honoraria. Nakamae:Japan Blood Products Organization: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Nippon Shinyaku: Honoraria; Bristol-Myers Squibb: Honoraria; Shire Japan KK.: Honoraria; Pfizer Japan Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma Inc.: Research Funding; Alexion: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Honoraria. Nagata:Janssen Pharmaceutical K.K.: Honoraria; Bristol-Myers Squibb K.K.: Honoraria; Ono Pharmaceutical Co., Ltd: Honoraria; Novartis Pharma K.K.: Honoraria; Celgene K.K.: Honoraria; Takeda Pharmaceutical Co., Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kurahashi:Novartis Pharma Co., Ltd.: Honoraria; Bristol-Myers Squibb, Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd: Honoraria. Suzuki:Celgene: Honoraria; Eisai: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical Co.,Ltd.: Honoraria; Meiji Seika: Honoraria; Merck Sharp & Dohme: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; ONO Pharmaceutical Co., Ltd.: Honoraria; Janssen: Honoraria; AbbVie: Honoraria. Atsuta:Mochida Pharmaceutical Co. Ltd: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Janssen Paharmaceutical K.K.: Honoraria. Miyamura:Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical: Honoraria; Takeda Pharmaceutical: Honoraria; Kyowa-Hakko Kirin Co., Ltd: Honoraria; CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Astellas Pharma Inc.: Honoraria; Celgene: Honoraria. Murata:Bristol-Myers Squibb, Ltd.: Honoraria; Kyowa-Hakko Kirin Co., Ltd.: Honoraria; Celgene Co., Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Consultancy, Honoraria; GSK Co., Ltd.: Consultancy; Astellas Pharma Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; JCR Pharmaceuticals Co., Ltd.: Honoraria; Novartis Pharma Co., Ltd.: Honoraria; MSD Co., Ltd.: Honoraria.
- Published
- 2019
27. Palmitic acid, verified by lipid profiling using secondary ion mass spectrometry, demonstrates anti-multiple myeloma activity
- Author
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Mitsutoshi Setou, Yasuyuki Nagata, Itsuko Ishizaki, Amir Hossen, Yoshimi Ide, Kazunori Ohnishi, Takuya Miyayama, and Michihiko Waki
- Subjects
Male ,Cancer Research ,Programmed cell death ,Cell Survival ,Plasma Cells ,Palmitic Acid ,Spectrometry, Mass, Secondary Ion ,Peripheral blood mononuclear cell ,Mass spectrometry imaging ,Palmitic acid ,Membrane Lipids ,chemistry.chemical_compound ,Cell Line, Tumor ,medicine ,Humans ,Viability assay ,Enzyme Inhibitors ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Fatty acid ,Hematology ,medicine.anatomical_structure ,Oncology ,chemistry ,Biochemistry ,Apoptosis ,Female ,Bone marrow ,Multiple Myeloma - Abstract
Recent studies indicate that lipid metabolic changes affect the survival of multiple myeloma (MM) cells. Time-of-flight secondary ion mass spectrometry (TOF-SIMS), an imaging mass spectrometry technique, is used to visualize the subcellular distribution of biomolecules including lipids. We therefore applied this method to human clinical specimens to analyze the membrane fatty acid composition and determine candidate molecules for MM therapies. We isolated MM cells and normal plasma cells (PCs) from bone marrow aspirates of MM patients and healthy volunteers, respectively, and these separated cells were analyzed by TOF-SIMS. Multiple ions including fatty acids were detected and their ion counts were estimated. In MM cells, the mean intensity of palmitic acid was significantly lower than the mean intensity in PCs. In a cell death assay, palmitic acid reduced U266 cell viability dose-dependently at doses between 50 and 1000 μM. The percentage of apoptotic cells increased from 24 h after palmitic acid administration. In contrast, palmitic acid had no effect on the viability of normal peripheral blood mononuclear cells (PBMCs). The results of this study indicated that palmitic acid is a potential candidate for novel therapeutic agents that specifically attack MM cells.
- Published
- 2015
28. Decreased level of phosphatidylcholine (16:0/20:4) in multiple myeloma cells compared to plasma cells: a single-cell MALDI–IMS approach
- Author
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Mitsutoshi Setou, Shogo Tajima, Kazunori Ohnishi, Hana Fukano, Shiro Takei, Yoshimi Ide, Gustavo A. Romero-Perez, Amir Hossen, Ikuko Yao, Yasuyuki Nagata, and Michihiko Waki
- Subjects
Plasma Cells ,Cell ,Cell Separation ,Biochemistry ,Mass spectrometry imaging ,Analytical Chemistry ,chemistry.chemical_compound ,Cell Line, Tumor ,Phosphatidylcholine ,Tumor Cells, Cultured ,medicine ,Humans ,Cells, Cultured ,Multiple myeloma ,Chemistry ,Cell sorting ,medicine.disease ,Molecular biology ,Haematopoiesis ,medicine.anatomical_structure ,Cell culture ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Phosphatidylcholines ,Bone marrow ,Single-Cell Analysis ,Multiple Myeloma - Abstract
Lipid metabolic changes under diseased conditions, particularly in solid tumors, are attracting increased attention. However, in non-solid tumors, including most hematopoietic tumors, lipid analyses are scarce. Multiple myeloma (MM) is a plasma cell disorder arising from bone marrow, and the lipid status of MM cells has not been reported yet. In this study, we analyzed flow cytometry-sorted single MM cells and normal plasma cells (NPCs) using matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS), a two-dimensional label-free mass spectrometry technique for biomolecular analysis, to obtain specific lipid information. We isolated 1.31-5.77% of MM cells and 0.03-0.24% of NPCs using fluorescence-activated cell sorting (FACS). Analysis of purified cells using MALDI-IMS at the single-cell level revealed that the peak intensity and ion signals of phosphatidylcholine [PC (16:0/20:4) + H](+) at m/z 782.5 were significantly decreased in MM cells compared to NPCs. By examining particular cell populations rather than cell mixtures, our method can become a suitable tool for the analysis of rare cell populations at the single-cell level and advance the understanding of MM progression.
- Published
- 2015
29. Single-cell time-of-flight secondary ion mass spectrometry reveals that human breast cancer stem cells have significantly lower content of palmitoleic acid compared to their counterpart non-stem cancer cells
- Author
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Yoshimi Ide, Fumiyoshi Yamazaki, Nobuya Kurabe, Takahiro Hayasaka, Takeshi Kondo, Michihiko Waki, Yasuyuki Nagata, Norihiko Shiiya, Mitsutoshi Setou, Hiroyuki Ogura, Koji Ikegami, Noritaka Masaki, Eiji Sugiyama, Takanori Hiraide, Noriaki Sanada, Yumiko Taki, Dan Nicolaescu, Kiyoshi Shibata, and Itsuko Ishizaki
- Subjects
Adult ,Spectrometry, Mass, Electrospray Ionization ,Spectrometry, Mass, Secondary Ion ,Breast Neoplasms ,Mass spectrometry ,Biochemistry ,Mass spectrometry imaging ,Fatty Acids, Monounsaturated ,chemistry.chemical_compound ,Tandem Mass Spectrometry ,Cancer stem cell ,Phosphatidylcholine ,Humans ,Palmitoleic acid ,CD24 Antigen ,Lipid metabolism ,General Medicine ,Middle Aged ,Flow Cytometry ,Hyaluronan Receptors ,chemistry ,Cancer cell ,Neoplastic Stem Cells ,Phosphatidylcholines ,Female ,Single-Cell Analysis ,Stem cell ,Chromatography, Liquid - Abstract
Lipids comprise the primary component of cell membranes. Imaging mass spectrometry is increasingly being used to visualize membranous lipids in clinical specimens, and it has revealed that abnormal lipid metabolism is related to the development of diseases. To characterize cell populations which are rare and sparsely localized in tissues, we conducted time-of-flight secondary ion mass spectrometry (TOF-SIMS) analyses of individual cells sorted by fluorescence activated cell sorting (FACS) and applied the method to analyze breast cancer stem cells (CSCs). TOF-SIMS analyses visualized phosphoric acids and four fatty acid (FA) species in the sorted CD45 − /CD44 + /CD24 − CSCs, and these ions are suspected to have originated from membranous phospholipids as they were uniformly detected from the locus where the cells attached. Integrated ion intensity of palmitoleic acids [FA(16:1)] normalized by phosphoric acid signals were decreased significantly in CSCs as compared to that of CD45 − /CD44 − /CD24 + non-stem cancer cells (NSCCs). This finding was supported by liquid chromatography coupled electrospray ionization-tandem mass spectrometry analysis, which revealed phosphatidylcholine (PC)(16:0/16:1) to be less abundant and PC(16:0/16:0) to be more abundant in CSCs as compared to NSCCs. Therefore, our novel method successfully provided lipid composition analysis of individual cells classified by the expression of a complex combination of cell-surface markers. The lipid compositions of CSCs originating from the heterogeneous cellular populations of clinical specimens were successfully characterized by this method.
- Published
- 2014
30. Single cell lipidomics of SKBR-3 breast cancer cells by using time-of-flight secondary-ion mass spectrometry
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Takeshi Kondo, Itsuko Ishizaki, Yoshimi Ide, Hiroyuki Ogura, Takahiro Hayasaka, Noriaki Sanada, Mitsutoshi Setou, Noritaka Masaki, Kiyoshi Shibata, Yasuyuki Nagata, Michihiko Waki, Koji Ikegami, and Fumiyoshi Yamazaki
- Subjects
chemistry.chemical_classification ,Cell ,Fatty acid ,Cancer ,Surfaces and Interfaces ,General Chemistry ,Condensed Matter Physics ,medicine.disease ,Mass spectrometry ,Surfaces, Coatings and Films ,chemistry.chemical_compound ,medicine.anatomical_structure ,Breast cancer ,chemistry ,Single-cell analysis ,Biochemistry ,Lipidomics ,Materials Chemistry ,medicine ,Phosphocholine - Abstract
Breast cancer is the most common cancer among women worldwide. The molecular characterization of breast tumor cells by using single-cell lipidomics remains relatively unexplored. Here, we introduce a time-of-flight secondary-ion mass spectrometry (TOF-SIMS) approach to visualize the lipids in individual breast cancer cells. The SKBR-3 breast cancer cell line was cultured and dispersed into individual cells. After attachment to a substrate, the cells were rinsed with ammonium acetate and were analyzed using TOF-SIMS. The instrument was operated with Bi32+ as the primary ion. The distributions of ions, including positively charged phosphocholine, and negatively charged phosphates and fatty acids, were simultaneously visualized. These ions were distributed predominantly at the cell attachment sites. The signal intensities of fatty acid ions were determined from the mass spectra at the regions-of-interest. The results of fatty acid analyses on breast cancer cells were consistent with those of our previous study in which prominent expression of stearoyl-CoA desaturase 1 in breast cancer cells was demonstrated. Static TOF-SIMS was shown to be an effective method for determining the lipid molecular signature of the plasma membrane of individual breast cancer cells. Copyright © 2014 John Wiley & Sons, Ltd.
- Published
- 2014
31. Glutaraldehyde fixation method for single-cell lipid analysis by time-of-flight secondary ion-mass spectrometry
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Itsuko Ishizaki, Noriaki Sanada, Kazunori Ohnishi, Yasuyuki Nagata, Michihiko Waki, Mitsutoshi Setou, Yoshimi Ide, and Amir Hossen
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Chromatography ,Chemistry ,Lipid metabolism ,Surfaces and Interfaces ,General Chemistry ,Condensed Matter Physics ,Mass spectrometry ,Surfaces, Coatings and Films ,Secondary ion mass spectrometry ,chemistry.chemical_compound ,Membrane ,Single-cell analysis ,Materials Chemistry ,Glutaraldehyde ,Ammonium acetate ,Fixation (histology) - Abstract
Lipid metabolism has attracted much attention in tumor biology studies. Recently, time-of-flight secondary ion-mass spectrometry (TOF-SIMS) imaging has enabled in situ lipid analysis of biological specimens with a submicrometer spatial resolution for analyses of tumor cells. In clinical settings, sample preservation is important, and specimens are often obtained from patients at different times; these samples must be preserved prior to measurement, and preservation techniques commonly involve chemical fixation with aldehydes. However, the influence of sample preservation on TOF-SIMS analysis of fatty acids has not been reported. Thus, we examined the influence of glutaraldehyde fixation on TOF-SIMS analyses by using the multiple myeloma cell line U266. We prepared two indium-tin-oxide-coated glass slides on which cells were attached. One slide was fixed with 0.25% glutaraldehyde and rinsed in ammonium acetate buffer, whereas the other was left untreated. The specimens were subjected to TOF-SIMS analyses in negative-ion mode, and signals in the mass range of m/z 0–1850 were monitored. Both fixed and unfixed cells exhibited intense ion peaks corresponding to phosphoric acids and five types of fatty acids, putatively derived from membrane phospholipids. These ions were localized at the cell attachment site. We statistically compared the mean intensity of fatty acids between fixed and unfixed cells and found that both showed equivalent signals. Glutaraldehyde fixation was thus shown to be an effective method for preparing samples for single-cell lipid analysis by TOF-SIMS. Copyright © 2014 John Wiley & Sons, Ltd.
- Published
- 2014
32. Serum IgM levels independently predict immune response to influenza vaccine in long-term survivors vaccinated at1 year after undergoing allogeneic hematopoietic stem cell transplantation
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Takaaki Ono, Miwa Adachi, Yasuyuki Nagata, Tomohiro Yagyu, and Yusuke Fukatsu
- Subjects
Adult ,Male ,Time Factors ,Survival ,Influenza vaccine ,medicine.medical_treatment ,Graft vs Host Disease ,chemical and pharmacologic phenomena ,Hematopoietic stem cell transplantation ,Virus ,03 medical and health sciences ,Immunocompromised Host ,0302 clinical medicine ,Immune system ,Predictive Value of Tests ,medicine ,Humans ,business.industry ,Vaccination ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,medicine.disease ,Allografts ,Transplantation ,Calcineurin ,Pneumonia ,surgical procedures, operative ,Immunoglobulin M ,Influenza Vaccines ,030220 oncology & carcinogenesis ,Immunology ,Multivariate Analysis ,Female ,business ,030215 immunology - Abstract
Influenza virus infection can cause fatal complications (e.g., pneumonia) in immunodeficient long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The immune response to the vaccine improves if it is administered at >1 year after allo-HSCT, although the response may vary according to the patient’s immune status. We sought to identify predictors of immune response to trivalent inactivated influenza vaccine (TIV) among patients vaccinated at >1 year after allo-HSCT. We included 27 allo-HSCT recipients, with a median interval of 4.3 years (range 1.0–10.1 years) from transplantation to vaccination. Nineteen patients achieved a response to TIV, although a low immune response to TIV was significantly associated with calcineurin inhibitor treatment, and moderate chronic graft-versus-host disease and IgM levels of
- Published
- 2016
33. Recovery of Kidney Function by Rituximab-based Therapy in a Patient with Waldenström's Macroglobulinemia-related Nephropathy Presenting Cast Nephropathy and Interstitial Lymphocytic Infiltration
- Author
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Kazuyuki Shigeno, Yukitoshi Sakao, Sayaka Ishigaki, Tomoyuki Fujikura, Yoshihide Fujigaki, Hideo Yasuda, Yasuyuki Nagata, Masafumi Ono, Akihiko Kato, Hiroyuki Suzuki, Satoki Nakamura, Masashi Miwa, and Kazunori Ohnishi
- Subjects
Male ,Melphalan ,medicine.medical_specialty ,Prednisolone ,medicine.medical_treatment ,Renal function ,urologic and male genital diseases ,Gastroenterology ,Nephropathy ,Antibodies, Monoclonal, Murine-Derived ,Renal Dialysis ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Internal Medicine ,medicine ,Humans ,Lymphocytes ,Cyclophosphamide ,medicine.diagnostic_test ,business.industry ,Macroglobulinemia ,General Medicine ,Middle Aged ,medicine.disease ,Vincristine ,Creatinine ,Immunology ,Kidney Diseases ,Rituximab ,Renal biopsy ,Hemodialysis ,Waldenstrom Macroglobulinemia ,business ,medicine.drug - Abstract
A 60-year-old man with Waldenström's macroglobulinemia (WM) was admitted to our hospital for evaluation of rapid progressive renal deterioration despite 3 cycles of oral melphalan and prednisolone (MP) therapy. Renal biopsy just before introducing hemodialysis revealed cast nephropathy and severe tubulo-interstitial infiltration of B lymphocytes. After 6 cycles of rituximab, cyclophosphamide, vincristine and prednisolone (R-COP) therapy, his renal function improved enough to discontinue hemodialysis. This is a rare case of WM-related renal involvement caused by both monoclonal protein and tumor infiltration and, to our knowledge, the second report on improved renal function by rituximab-based therapy.
- Published
- 2012
34. JmjC-domain containing histone demethylase 1B-mediated p15 Ink4b suppression promotes the proliferation of leukemic progenitor cells through modulation of cell cycle progression in acute myeloid leukemia
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Yasuyuki Nagata, Tomonari Takemura, Tomohiro Yagyu, Aya Asahina, Lin Tan, Satoki Nakamura, Shinya Fujisawa, Kiyoshi Shibata, Kazunori Ohnishi, and Daisuke Yokota
- Subjects
Cancer Research ,Myeloid ,Cell growth ,CD34 ,Myeloid leukemia ,Biology ,Cell cycle ,Molecular biology ,medicine.anatomical_structure ,Cell culture ,hemic and lymphatic diseases ,medicine ,Progenitor cell ,Molecular Biology ,G1 phase - Abstract
The histone demethylase JHDM1B has been implicated in cell cycle regulation and tumorigenesis. In addition, it has been reported that JHDM1B is highly expressed in various human tumors, including leukemias. However, it is not clearly understood how JHDM1B contributes to acute myeloid leukemia (AML) cell proliferation. In this study, we investigated the cellular and molecular function of JHDM1B in AML cells. In AML cell lines and AML-derived ALDH(hi) (high aldehyde dehydrogenase activity)/CD34(+) cells, the levels of JHDM1B mRNA were significantly higher than in normal ALDH(hi) /CD34(+) cells. Reduction of JHDM1B expression in AML cells inhibited cell proliferation compared to control cells, through induction of G1 cell cycle arrest, an increase in the p15(Ink4b) mRNA and protein expression. JHDM1B mRNA was overexpressed in all 133 AML clinical specimens tested (n = 22, 57, 34, and 20 for M1, 2, 4, and 5 subtypes respectively). Compared to normal ALDH(hi) /CD34(+) cells, JHDM1B gene expression was 1.57- to 1.87-fold higher in AML-derived ALDH(hi) /CD34(+) cells. Moreover, the JHDM1B protein was more strongly expressed in AML-derived ALDH(hi) /CD34(+) cells from compared to normal ALDH(hi) /CD34(+) cells. In addition, depletion of JHDM1B reduced colony formation of AML-derived ALDH(hi) /CD34(+) cells due to induction of p15(Ink4b) expression through direct binding to p15(Ink4b) promoter and loss of demethylation of H3K36me2. In summary, we found that JHDM1B mRNA is predominantly expressed in AML-derived ALDH(hi) /CD34(+) cells, and that aberrant expression of JHDM1B induces AML cell proliferation through modulation of cell cycle progression. Thus, inhibition of JHDM1B expression represents an attractive target for AML therapy.
- Published
- 2011
35. Small GTPase RAB45-mediated p38 activation in apoptosis of chronic myeloid leukemia progenitor cells
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Isao Hirano, Tomonari Takemura, Kazunori Ohnishi, Satoki Nakamura, Kazuyuki Shigeno, Michio Fujie, Shinya Fujisawa, Daisuke Yokota, Kiyoshi Shibata, Yasuyuki Nagata, and Lin Tan
- Subjects
Cancer Research ,Programmed cell death ,Blotting, Western ,Apoptosis ,Genes, abl ,Biology ,p38 Mitogen-Activated Protein Kinases ,Membrane Potentials ,Cell Line, Tumor ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Survivin ,medicine ,Humans ,Immunoprecipitation ,RNA, Messenger ,Phosphorylation ,Progenitor cell ,neoplasms ,Cell Proliferation ,DNA Primers ,ABL ,Base Sequence ,Caspase 3 ,Reverse Transcriptase Polymerase Chain Reaction ,Cell Cycle ,General Medicine ,medicine.disease ,XIAP ,Enzyme Activation ,Neoplastic Stem Cells ,Cancer research ,RNA Interference ,ras Guanine Nucleotide Exchange Factors ,Signal transduction ,Stem cell ,Chronic myelogenous leukemia - Abstract
Chronic myelogenous leukemia (CML) is characterized by a reciprocal chromosomal translocation (9;22) that generates the Bcr-Abl fusion gene. BCR-ABL transforming activity is mediated by critical downstream signaling pathways that are aberrantly activated by tyrosine kinases. However, the mechanisms of BCR-ABL anti-apoptotic effects and the signaling pathways by which BCR-ABL influences apoptosis in BCR-ABL-expressing cells are poorly defined. In this study, we found that treatment with ABL kinase inhibitors or depletion of BCR-ABL induced the expression of RAB45 messenger RNA and protein and induced apoptosis via reduction of mitochondrial membrane potential and p38 activation in CML cell lines and BCR-ABL + progenitor cells from CML patients. Overexpressed RAB45 induced the activation of caspases-3 and -9 and reduced the expression of Survivin, XIAP, c-IAP1 and c-IAP2 in CML cells. Moreover, in colony-forming cells derived from CML-aldehyde dehydrogenase hi / CD34 + cells, treatment with ABL kinase inhibitors induced RAB45 expression and reduced mitochondrial membrane potential, resulting in inhibited colony formation of Bcr-Abl + progenitor cells. The overexpression of RAB45 significantly decreased colony numbers and induced apoptosis through the activation of caspases-3 and -9. Furthermore, the overexpression of RAB45 increased the phosphorylation levels of p38, resulting in the induction of apoptosis and inhibition of proliferation of CML progenitor cells. Our results identify a new signaling molecule involved in BCR-ABL modulation of apoptosis and suggest that RAB45 induction strategies may have therapeutic utility in patients with CML.
- Published
- 2011
36. Down-regulation of Thanatos-associated protein 11 by BCR-ABL promotes CML cell proliferation through c-Myc expression
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Tomonari Takemura, Kiyoshi Shibata, Daisuke Yokota, Kazunori Ohnishi, Yasuyuki Nagata, Isao Hirano, Satoki Nakamura, Shinya Fujisawa, Lin Tan, and Kazuyuki Shigeno
- Subjects
Male ,Cancer Research ,Cell ,Fusion Proteins, bcr-abl ,Genes, myc ,Down-Regulation ,HL-60 Cells ,Piperazines ,Cyclin D1 ,Cell Line, Tumor ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,medicine ,Humans ,Protein Kinase Inhibitors ,neoplasms ,Protein kinase B ,Cell Proliferation ,ABL ,Cell growth ,Chemistry ,Hematopoietic Stem Cells ,medicine.disease ,Cell biology ,Repressor Proteins ,Pyrimidines ,medicine.anatomical_structure ,Oncology ,Cell culture ,Benzamides ,Imatinib Mesylate ,Cancer research ,Signal transduction ,K562 Cells ,Chronic myelogenous leukemia - Abstract
Bcr-Abl activates various signaling pathways in chronic myelogenous leukemia (CML) cells. The proliferation of Bcr-Abl transformed cells is promoted by c-Myc through the activation of Akt, JAK2 and NF-κB. However, the mechanism by which c-Myc regulates CML cell proliferation is unclear. In our study, we investigated the role of Thanatos-associated protein 11 (THAP11), which inhibits c-Myc transcription, in CML cell lines and in hematopoietic progenitor cells derived from CML patients. The induction of THAP11 expression by Abl kinase inhibitors in CML cell lines and in CML-derived hematopoietic progenitor cells resulted in the suppression of c-Myc. In addition, over-expression of THAP11 inhibited CML cell proliferation. In colony forming cells derived from CML-aldehyde dehydrogenase (ALDH)(hi) /CD34(+) cells, treatment with Abl kinase inhibitors and siRNA depletion of Bcr-Abl induced THAP11 expression and reduced c-Myc expression, resulting in inhibited colony formation. Moreover, overexpression of THAP11 significantly decreased the colony numbers, and also inhibited the expression of c-myc target genes such as Cyclin D1, ODC and induced the expression of p21(Cip1) . The depletion of THAP11 inhibited JAK2 or STAT5 inactivation-mediated c-Myc reduction in ALDH(hi) /CD34(+) CML cells. Thus, the induced THAP11 might be one of transcriptional regulators of c-Myc expression in CML cell. Therefore, the induction of THAP11 has a potential possibility as a target for the inhibition of CML cell proliferation.
- Published
- 2011
37. Bcr-Abl-mediated Raf kinase inhibitor protein suppression promotes chronic myeloid leukemia progenitor cells proliferation
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Yasuyuki Nagata, Satoki Nakamura, Kazunori Ohnishi, Isao Hirano, Michio Fujie, Tomohiro Yagyu, Kiyoshi Shibata, Daisuke Yokota, Shinya Fujisawa, Lin Tan, and Tomonari Takemura
- Subjects
MAPK/ERK pathway ,Chemistry ,hemic and lymphatic diseases ,Cancer research ,CD34 ,SKP2 ,FOXM1 ,Myeloid leukemia ,Progenitor cell ,Cell cycle ,Signal transduction ,neoplasms ,Cell biology - Abstract
The Ras/Raf-1/MEK/ERK pathway is constitutively activated in Bcr-Abl transformed cells, and Ras activity enhances the oncogenic ability of Bcr-Abl. On the hand, Raf kinase inhibitor protein (RKIP) inhibits activation of MEK by Raf-1 and its downstream signal transduction, resulting in blocking the MAP kinase pathway. Moreover, Raf-1 has been reported to regulate cell cycle progression. However, the mechanism by which Bcr-Abl promotes the cell cycle progression through Raf-1 is not completely understood. In the present study, we found that the expression of RKIP was suppressed in CML cells, and investigated the interaction between RKIP and Bcr-Abl in CML cells. In aldehyde dehydrogenase (ALDH)hi/CD34+ cells derived from CML patients, the inhibition of Bcr-Abl induced RKIP expression and reduced the phosphorylated-FOXM1 (pFOXM1) status, resulting in inhibited colony formation of Bcr-Abl+ progenitor cells. Moreover, overexpression of RKIP significantly decreased the colony numbers, reduced the pFOXM1 status, and reduced pFOXM-1 target genes such as Skp2, Cdc25B and KIS, and induced the expression of p27Kip1a and p21Cip1. Thus, Bcr-Abl represses the expression of RKIP, and continuously activates FOXM1, resulting in the proliferation of CML progenitor cells through the cell cycle modulation.
- Published
- 2011
38. Low IP-10/CXCL10 Levels are Associated with Good Responses to Lenalidomide Plus Low-Dose Dexamethasone for Relapsed and/or Refractory Multiple Myeloma
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Tomonari Takemura, Akari Yoda, Takaaki Ono, Kotaro Nakano, Masamitsu Takaba, Yujiro Ito, Miwa Adachi, Fumisato Takagi, Nami Sakamoto, Yasuyuki Nagata, and Satoshi Uchiyama
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Ip 10 cxcl10 ,business.industry ,Low dose ,Refractory Multiple Myeloma ,Hematology ,Internal medicine ,medicine ,business ,Dexamethasone ,Lenalidomide ,medicine.drug - Published
- 2018
39. Influence of strength and asymmetry of the coupling between a cavity and a transmission line on measurement of complex permittivity
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Hitoshi Shimasaki, Masaaki Ikeda, Masahiro Akiyama, Yasuyuki Nagata, and Kazuaki Nishida
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Physics ,Permittivity ,Condensed matter physics ,media_common.quotation_subject ,Perturbation (astronomy) ,Relative permittivity ,Resonant cavity ,Condensed Matter Physics ,Asymmetry ,Atomic and Molecular Physics, and Optics ,Electronic, Optical and Magnetic Materials ,Transmission line ,Strong coupling ,Electrical and Electronic Engineering ,Microwave ,media_common - Abstract
Influence of the strength and the asymmetry of input-output ports on the measurement of complex permittivity by the resonant cavity perturbation method was investigated experimentally.We adopted the |S21| as the criterion of the strength, and the difference between S11 and S22 as the criterion of the asymmetry. When the coupling is symmetric, the real part of permittivity can be evaluated in strong coupling state up to −3 dB of coupling. The imaginary part of permittivity can be evaluated up to −14 dB of coupling. Imaginary part of the relative permittivity e″r was calculated using the conventional equation, which is based on the complete symmetry of the coupling of input-output ports. For the measurement of high-Q materials, calculated e″r is strongly affected by the asymmetry in the strongly coupled region. For the measurement of lossy materials, the inevitable asymmetry and the strong coupling allow enough exact evaluation of e″r. © 2010 Wiley Periodicals, Inc. Microwave Opt Technol Lett 52: 706–709, 2010; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.24988
- Published
- 2010
40. Intravascular large B-cell lymphoma manifesting as cholecystitis: report of an Asian variant showing gain of chromosome 18 with concurrent deletion of chromosome 6q
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Shogo, Tajima, Michihiko, Waki, Hiroyuki, Yamazaki, Yasuyuki, Nagata, Hana, Fukano, Md Amir, Hossen, Shoji, Hoshi, and Takahiro, Takeuchi
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Chromosome Aberrations ,Male ,Asian People ,Cholecystitis ,Abnormal Karyotype ,Humans ,Chromosomes, Human, Pair 6 ,Case Report ,Lymphoma, Large B-Cell, Diffuse ,Chromosomes, Human, Pair 18 ,Immunohistochemistry ,In Situ Hybridization ,Aged - Abstract
Intravascular large B-cell lymphoma (IVLBCL), which involves the lumen of small vessels, is a rare variant of extranodal diffuse large B-cell lymphomas. Herein, we present a case of IVLBCL manifesting as cholecystitis in a 77-year-old Japanese man. He presented with fever, fatigue, and weight loss. Physical examination revealed tenderness of the right upper quadrant. The white blood cell count and C-reactive protein levels were elevated. Computed tomography revealed gallbladder thickening and pericholecystic fluid collection; these observations were consistent with the diagnosis of cholecystitis. Serum soluble interleukin-2 receptor levels were highly elevated, and gallium scintigraphy revealed an abnormal accumulation in the spleen, implying lymphoma. Consequently, G-banding analysis of the patient’s bone marrow aspirates revealed the presence of different abnormal clones, including those with gain of chromosome 18 and deletion of chromosome 6q. As cholecystectomy was necessary, a concurrent splenectomy was performed to diagnose the disease definitively. Histopathologically, atypical large lymphoid cells were observed to be localized in the vasculature in both the spleen and gallbladder; the atypical cells expressed high levels of CD20, CD5, and CD10, immunohistochemically. These findings were consistent with IVLBCL. The patient underwent post-operative treatment with rituximab, cyclophosphamide, adriamycin, vincristine, and prednisolone. However, a pancreatic fistula developed during chemotherapy, causing left pleural effusion and peritoneal effusion; the patient developed sepsis from multidrug-resistant microorganisms, and subsequently died of multi-organ failure 6 months after the diagnosis. No obvious recurrence of the tumor was found during autopsy. We discuss the characteristic karyotype and immunohistochemical status observed in this case.
- Published
- 2014
41. Acquired factor X deficiency developed four years after autologous transplantation in a patient with multiple myeloma associated with systemic AL amyloidosis
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Tomonari, Takemura, Yusuke, Fukatsu, Yasuyuki, Nagata, Aya, Asahina, Daisuke, Yokota, Isao, Hirano, Tomohiro, Yagyu, Takaaki, Ono, Akira, Katsumi, and Kazunori, Ohnishi
- Subjects
Treatment Outcome ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Female ,Immunoglobulin Light-chain Amyloidosis ,Amyloidosis ,Multiple Myeloma ,Factor X Deficiency ,Transplantation, Autologous ,Aged - Abstract
We describe a case of acquired factor X deficiency after high-dose melphalan with autologous stem cell transplantation (HDM/ASCT) for multiple myeloma (MM) with systemic AL amyloidosis. A 68-year-old woman with renal amyloidosis was diagnosed as having MM in 2007. She achieved a partial response after VAD (vincristine, adriamycin, dexamethasone) therapy and HDM/ASCT. In December 2011, coagulation tests revealed a prolonged prothrombin time (PT) of 17.6 sec and she was administered vitamin K. In January 2012, she received low anterior resection with colostomy for rectal cancer. She received fresh frozen plasma (FFP) infusion but the perioperative bleeding tendency persisted. In February 2012, she was referred from surgery for colostomy closure. She showed no progression of MM and had prolonged PT, corrected by mixing with normal plasma. Factor X activity was markedly decreased. She was diagnosed as having an acquired factor X deficiency and was given FFP infusion for colostomy closure. Although acquired factor X deficiency after HDM/ASCT for MM with systemic AL amyloidosis is rare, we should be aware of the possibility of this disease in MM patients with a bleeding tendency.
- Published
- 2014
42. Abstract P6-07-05: Single-cell TOF-SIMS reveals that human breast cancer stem cells have significantly lower content of palmitoleic acid compared to their counterpart non-stem cancer cells
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Noriaki Sanada, Itsuko Ishizaki, Yasuyuki Nagata, Michihiko Waki, Mitsutoshi Setou, Norihiko Shiiya, Yuko Hosokawa, Hiroyuki Ogura, Yumiko Taki, Ryoichi Matsunuma, and Yoshimi Ide
- Subjects
chemistry.chemical_classification ,Cancer Research ,biology ,Cell ,CD44 ,Fatty acid ,Mass spectrometry ,chemistry.chemical_compound ,medicine.anatomical_structure ,Oncology ,Biochemistry ,Single-cell analysis ,chemistry ,Cancer stem cell ,Cancer cell ,medicine ,biology.protein ,Palmitoleic acid - Abstract
Background Distinguishing individual cancers according to their biochemical heterogeneity have provided much useful information to clinical site. Recently, the cancer stem cell (CSC) theory has been accepted as a concept that explains the mechanism of cancer recurrence and resistance to treatment. To characterize such particular cell populations in heterogeneous tissues, we conducted combination of fluorescence activated cell sorting (FACS) and time-of-flight secondary-ion mass spectrometry (TOF-SIMS) and applied the method to analyses of breast CSCs. TOF-SIMS, which enables to visualize the composition of molecules with mass over 100 Da that were obtained in specimen, has been employed to analyze surface of industrial materials and biomaterials. This method is thus suitable for performing single cell analysis of membranous lipids. Methods Breast cancer specimens surgically resected from two patients were enzymatically dispersed into cells. They were labeled with fluorescence-conjugated antibodies of CD45, CD44, and CD24. The cells of CD45-CD44+ CD24- were sorted as CSCs with FACS as well as CD45-CD44- CD24+ cells as non-stem cancer cells (NSCCs). TOF-SIMS analysis and fatty acid analysis was performed according to our previous study published in Surface and Interface Analysis (1). The surface of the sorted cells was analyzed by a PHI TRIFT V (ULVAC-PHI Inc., Kanagawa, Japan) TOF-SIMS instrument. Primary ion beam is irradiated to the surface of the samples and, secondary ions derived from samples are calculated by time-of-flight with the information of the place where the molecular ions were ejected. Negative secondary ions were obtained with a mass range of m/z 0–1850. Mass spectra were analyzed by WinCadenceN software (ULVAC-PHI Inc.) to obtain ion counts and ion images. Integrated ion intensities of FA were normalized using phosphoric acid intensity. The Welch’s t-test was used to compare the normalized ion counts with P-value < 0.05 taken as statistically significant. Results FACS analyses successfully collected CD45-/CD44+/CD24- CSCs and CD45-/CD44-/CD24+ non-stem cancer cells (NSCCs) in both two cases, which were corresponding to o.33% and 0.74% of all cells in case 1, and 0.14% and 1.14% in case 2. TOF-SIMS analyses visualized phosphoric acids and four fatty acid (FA) species in the sorted CSCs and NSCCs. These ions probably came from membranous phosphopolipids and they were uniformly detected from the locus where the cell attached. Integrated ion intensity of palmitoleic acids [FA(16:1)] of CSCs normalized by phosphoric acids signals were significantly decreased than that of CD45-/CD44-/CD24+ NSCCs as a counterpart. Therefore, our novel method successfully provided lipid composition analysis of individual cells classified with complicated combination of marker expressions in clinical specimens composed of heterogeneous cellular populations, and characterized lipid composition of CSCs. Reference 1. Nagata Y, Ishizaki I, Waki M, Ide Y, Hossen A, Ohnishi K, et al. Glutaraldehyde Fixation Method for Single-Cell Lipid Analysis by Time-of-Flight Secondary Ion-Mass Spectrometry. Surface and interface analysis : SIA. 2014:DOI: 10.1002/sia/5522. Citation Format: Yoshimi Ide, Michihiko Waki, Itsuko Ishizaki, Yasuyuki Nagata, Yumiko Taki, Yuko Hosokawa, Ryoichi Matsunuma, Hiroyuki Ogura, Norihiko Shiiya, Noriaki Sanada, Mitsutoshi Setou. Single-cell TOF-SIMS reveals that human breast cancer stem cells have significantly lower content of palmitoleic acid compared to their counterpart non-stem cancer cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-07-05.
- Published
- 2015
43. JmjC-domain containing histone demethylase 1B-mediated p15(Ink4b) suppression promotes the proliferation of leukemic progenitor cells through modulation of cell cycle progression in acute myeloid leukemia
- Author
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Satoki, Nakamura, Lin, Tan, Yasuyuki, Nagata, Tomonari, Takemura, Aya, Asahina, Daisuke, Yokota, Tomohiro, Yagyu, Kiyoshi, Shibata, Shinya, Fujisawa, and Kazunori, Ohnishi
- Subjects
Adult ,Jumonji Domain-Containing Histone Demethylases ,F-Box Proteins ,Cell Cycle ,Antigens, CD34 ,Oxidoreductases, N-Demethylating ,Aldehyde Dehydrogenase ,Middle Aged ,Leukemia, Myeloid, Acute ,Cell Line, Tumor ,Neoplastic Stem Cells ,Humans ,Protein Kinase Inhibitors ,Aged ,Cell Proliferation ,Cyclin-Dependent Kinase Inhibitor p15 - Abstract
The histone demethylase JHDM1B has been implicated in cell cycle regulation and tumorigenesis. In addition, it has been reported that JHDM1B is highly expressed in various human tumors, including leukemias. However, it is not clearly understood how JHDM1B contributes to acute myeloid leukemia (AML) cell proliferation. In this study, we investigated the cellular and molecular function of JHDM1B in AML cells. In AML cell lines and AML-derived ALDH(hi) (high aldehyde dehydrogenase activity)/CD34(+) cells, the levels of JHDM1B mRNA were significantly higher than in normal ALDH(hi) /CD34(+) cells. Reduction of JHDM1B expression in AML cells inhibited cell proliferation compared to control cells, through induction of G1 cell cycle arrest, an increase in the p15(Ink4b) mRNA and protein expression. JHDM1B mRNA was overexpressed in all 133 AML clinical specimens tested (n = 22, 57, 34, and 20 for M1, 2, 4, and 5 subtypes respectively). Compared to normal ALDH(hi) /CD34(+) cells, JHDM1B gene expression was 1.57- to 1.87-fold higher in AML-derived ALDH(hi) /CD34(+) cells. Moreover, the JHDM1B protein was more strongly expressed in AML-derived ALDH(hi) /CD34(+) cells from compared to normal ALDH(hi) /CD34(+) cells. In addition, depletion of JHDM1B reduced colony formation of AML-derived ALDH(hi) /CD34(+) cells due to induction of p15(Ink4b) expression through direct binding to p15(Ink4b) promoter and loss of demethylation of H3K36me2. In summary, we found that JHDM1B mRNA is predominantly expressed in AML-derived ALDH(hi) /CD34(+) cells, and that aberrant expression of JHDM1B induces AML cell proliferation through modulation of cell cycle progression. Thus, inhibition of JHDM1B expression represents an attractive target for AML therapy.
- Published
- 2011
44. Vision Robot Positioning Applications for Assembly
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Yoshihiro Kuroki and Yasuyuki Nagata
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Computer science ,business.industry ,Machine vision ,Robot ,Computer vision ,Artificial intelligence ,business ,Mobile robot navigation ,Robot control - Published
- 1991
45. Palmitic acid as an anti-multiple myeloma molecule was sorted out from lipid profiling by secondary ion mass spectrometry
- Author
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Yasuyuki Nagata, Amir Hossen, Michihiko Waki, Mitsutoshi Setou, Kazunori Ohnishi, Itsuko Ishizaki, and Yoshimi Ide
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Cancer Research ,business.industry ,Hematology ,medicine.disease ,Palmitic acid ,Secondary ion mass spectrometry ,chemistry.chemical_compound ,Oncology ,chemistry ,Biochemistry ,Molecule ,Medicine ,Lipid profiling ,business ,Multiple myeloma - Published
- 2015
46. Palmitic Acid, As Verified Using Lipid Profiling By Secondary Ion Mass Spectrometry, Demonstrates Anti-Tumor Activity Against Multiple Myeloma
- Author
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Yasuyuki Nagata, Mitsutoshi Setou, Michihiko Waki, Amir Hossen, Yoshimi Ide, Itsuko Ishizaki, and Kazunori Ohnishi
- Subjects
chemistry.chemical_classification ,Linoleic acid ,Immunology ,Fatty acid ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Palmitic acid ,chemistry.chemical_compound ,Oleic acid ,chemistry ,Palmitoleic acid ,Propidium iodide ,Viability assay ,Stearic acid - Abstract
Introduction Many recent studies have examined lipid metabolic changes in multiple myeloma (MM). Changes in lipid metabolism affect the survival of MM cells. Developments in imaging mass spectrometry (IMS) have facilitated research on the lipid profiles of tumors. Time-of-flight secondary ion mass spectrometry (TOF-SIMS) is an IMS technique that uses a focused ion beam as the primary source for ionization. TOF-SIMS imaging is used to analyze the surface of specimens at sub-micrometer resolution, enabling analyses of the subcellular distribution of molecules in individual cells. TOF-SIMS analysis has enabled the detection of multiple fatty acid groups from single cells. Therefore, we applied this method to human clinical specimens to analyze the membrane fatty acid composition and determine candidate molecules for MM therapies. Using the different lipid profiles for MM cells and normal plasma cells (PCs), we conducted a cytocidal assay with MM cell lines supplemented with the fatty acids screened out by the profiles to assess lipotoxicity against MM. The molecules demonstrating distinct differences among cell types (i.e., MM and PC) were considered candidates for which supplementation leads to imbalanced lipid metabolism and cell death in a tumor-specific manner. We further evaluated the induction of apoptosis. Methods Primary patient MM cells and normal PCs were isolated from the bone marrow aspirates of two patients and two healthy volunteers using fluorescence-activated cell sorting. These separated cells were analyzed with PHI TRIFT V (ULVAC-PHI, Inc.). Analyses were performed in negative ion mode, and signals in the mass range of m/z 0 to 1850 were monitored. We performed pairwise comparisons of mean signal intensities for five types of fatty acids between MM cells and PCs. MM cell lines (U266 and RPMI-8226) were treated with 0–1000 µM of palmitic acid, palmitoleic acid, linoleic acid, oleic acid, and stearic acid. The number of viable cells in suspension at 72 hours after treatment was determined by the trypan blue exclusion test. HS-5, a human bone marrow stromal cell line, was used in the co-culture experiment. Healthy volunteers’ normal peripheral blood mononuclear cells (PBMCs) were purified by Ficoll-Hypaque density-gradient centrifugation. The distribution of apoptotic and necrotic cells were analyzed by measuring AnnexinV binding and propidium iodide uptake. Results The amounts of MM cells and PCs relative to the total nucleated cells were 3.38%, 35.9% for MM cells, 0.0368% and 0.246% for PCs. Multiple ions, including phosphoric acid, and five species of fatty acids (palmitoleic acid, palmitic acid, linoleic acid, oleic acid, and stearic acid) were detected. The mean signal intensities of palmitoleic acid and palmitic acid of MM cells were significantly lower than those of normal PCs (P = .00081 and .0018, respectively). These results were replicated in a second pairwise comparison. We did not observe statistically significant differences in intensities for linoleic acid, oleic acid, or stearic acid. In the cytocidal assay, palmitic acid reduced U266 cell viability dose-dependently for doses of 50–1000 μM. High concentrations of the other fatty acids also reduced cell viability; however, the effect on cell death was not observed at the low dose of 50–100 µM, as it was for palmitic acid. Even in co-culture experiments, palmitic acid decreased the viability of MM cells. Moreover, the proportions of both apoptotic and necrotic cells increased and the proportion of viable cells decreased 24 hours after palmitic acid treatment in MM cells. Palmitic acid also reduced the viability of RPMI-8226 cell lines. Meanwhile, cell viabilities of normal PBMCs were not affected by palmitic acid, even at 100–500 µM. Conclusion We applied the single-cell TOF-SIMS lipid analysis effectively to a very small population of cells. Significantly smaller intensities of palmitoleic acid and palmitic acid were observed in MM cells compared to normal cells. We also demonstrated an inhibitory effect of palmitic acid on the survival of MM cells. Palmitic acid is a potential candidate for novel therapeutic agents that specifically attack MM and should be considered in future studies of MM in a lipid biology framework. Disclosures No relevant conflicts of interest to declare.
- Published
- 2014
47. Induction of CABLES1 by the TKI Inhibits the Cell Cycle Progression and Induces Apoptosis In CML Cell
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Yasuyuki Nagata, Takaaki Ono, Isao Hirano, Daisuke Yokota, Satoki Nakamura, Kazuyuki Shigeno, Shinya Fujisawa, Kazunori Ohnishi, and Tomonari Takemura
- Subjects
ABL ,biology ,Cell growth ,Immunology ,Cell Biology ,Hematology ,Cell cycle ,Biochemistry ,Molecular biology ,Haematopoiesis ,Cyclin-dependent kinase ,hemic and lymphatic diseases ,biology.protein ,Cancer research ,Stem cell ,Progenitor cell ,neoplasms ,K562 cells - Abstract
Abstract 1199 [Background and Aims] CABLES1 (cyclin-dependent kinase (CDK)-5 and ABL enzyme 1) is a regulator of cell proliferation, apoptosis, and cell cycle, and it has been reported to be lost in a variety cancers. It has been also reported that knockout of the Cable1 gene has minimal to no effect on hematopoietic stem cells. However, we found that the expression of Cables1 gene and CABLES1 protein was suppressed in CML cells, and its function is little known in CML. In this study, we have investigated the function of CABLES1 in CML cell proliferation. [Methods] The cells used in this study were human CML cell lines, K562, Meg01 and SHG3 cells. Primary CML cells (ALDHhi cells) were obtained from the bone marrow of CML (CP) patients (n=12). Human normal ALDHhi cells were isolated from bone marrow of healthy volunteers after obtaining informed consents. For analysis of Cables1 mRNA expression, quantitative RT-PCR was performed in all cell lines treated with Abl kinase inhibitors (STI571, AMN107, and BMS354825). For cell survival analysis and the levels of p53 and some CDKIs in CML cells, MTT assays, western blot and cell cycle analysis were performed in all cell lines transfected with Cables1 shRNA or cDNA. For colony analysis, the colonies of CFU-GEMM, CFU-GM, and BFU-E were counted in CML stem/progenitor cells transfected with Cables1 cDNA or shiRNA, or treated with Abl kinase inhibitors. [Results] In CML cell lines, the expressions of Cables1 mRNA and CABLES1 protein were significantly increased by treatment with Abl kinase inhibitors or transfection with Bcr-Abl shRNA. In CML cells transfected with the Cables1 cDNA, it is shown that CML cell proliferation was inhibited, and the phosphorylation levels of p53, and the expression of BAX and p21 protein were markedly increased compared to the untransfected cells. In addition, the overexpression of CABLES1 induced G1 cell cycle arrest and reduced the DiOC6 fluorescence, indicating breakdown of the mitochondrial membrane potential in CML cells. On the other hand, the changes of p73 and p27 protein expression were not detected. Moreover, in CML cells transfected with Cables1 shRNA, the inhibition of CML cell proliferation by the Abl kinase inhibitors were weakened. In CML stem/progenitor cells (ALDHhi cells) obtained from patients with CML, the expression of Cables1 mRNA was suppressed, and the transfection with Bcr-Abl shRNA or treatment with Abl kinase inhibitors increased the expression of Cables1 mRNA and CABLES1 protein, and decreased the counts of CFU-GEMM, CFU-GM and BFU-E. [Conclusion] Our results demonstrated that the Bcr-Abl suppressed the expression of CABLES1, and the depletion of CABLES1 promotes cell cycle progression and p53-dependent apoptosis. Moreover, the induction of CABLES1 expression has the potentiality to eradicate CML stem/progenitor cells. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2010
48. Regulation of c-Myc Expression through the Depletion of THAP11 and Fbw7 by Bcr-Abl Promotes CML Cell Proliferation
- Author
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Kazunori Ohnishi, Daisuke Yokota, Satoki Nakamura, Kazuyuki Shigeno, Isao Hirano, Takaaki Ono, Yasuyuki Nagata, Shinya Fujisawa, and Tomonari Takemura
- Subjects
ABL ,Cell growth ,Immunology ,Cell Biology ,Hematology ,Transfection ,Biology ,Biochemistry ,Molecular biology ,Cell culture ,hemic and lymphatic diseases ,Progenitor cell ,Signal transduction ,neoplasms ,Protein kinase B ,K562 cells - Abstract
Abstract 4463 [Background and Aims] In various signaling pathways activated by Bcr-Abl, c-Myc promotes the Bcr-Abl transformed cell proliferation through activated Akt, Jak2 and NF-κB. We have previously shown that Bcr-Abl represses the expression of THAP11 and continuously expressed c-Myc, resulting in the proliferation of CML cells. However, the mechanism of c-Myc regulation is unclear in CML cell proliferation. In the present study, we investigated the mechanism of c-Myc transcription regulation in the Bcr-Abl+ progenitor cells derived from CML patients. [Methods] The cells used in this study were human CML cell lines, K562, Meg01 and SHG3 cells. Primary CML cells (ALDHhi cells) were obtained from the bone marrow of CML (CP) patients (n=12). Human normal ALDHhi cells were isolated from bone marrow of healthy volunteers after obtaining informed consents. For analysis of THAP11 mRNA expression, quantitative RT-PCR was performed in all cell lines treated with Abl kinase inhibitors (STI571, AMN107, and BMS354825). For cell survival analysis and the levels of c-Myc, Fbw7 and some CDKIs in CML cells, MTT assays, western blot and cell cycle analysis were performed in all cell lines transfected with THAP11 siRNA or cDNA. For colony analysis, the colonies of CFU-GEMM, CFU-GM, and BFU-E were counted in CML stem/progenitor cells transfected with THAP11 siRNA or cDNA, or treated with Abl kinase inhibitors. [Results] In CML cell lines, the expressions of THAP11 mRNA and protein were significantly increased by treatment with Abl kinase inhibitors or transfection with Bcr-Abl siRNA. In CML cells transfected with the THAP11 cDNA, it is shown that CML cell proliferation was inhibited, and the expression of c-Myc protein was decreased compared to the untransfected cells. In addition, the inhibition of Bcr-Abl by the Abl kinase inhibitors or depletion of Bcr-Abl induced the expression of Fbw7 in CML cells. In CML stem/progenitor cells (ALDHhi cells) obtained from patients with CML, the expression of THAP11 mRNA was suppressed, and the transfection with Bcr-Abl siRNA or treatment with Abl kinase inhibitors increased the expression of THAP11 and Fbw7. In CFU-GEMM, CFU-GM, and BFU-E, treatment with the Abl kinase inhibitors and depletion of Bcr-Abl induced the THAP11 and Fbw7 expression and reduced the c-Myc expression, and inhibited colony formation of Bcr-Abl+ progenitor cells. [Conclusion] In CML cells, we found that the depletion of THAP11 and Fbw7 expression. We showed that Bcr-Abl induced the expression of c-Myc by depletion of THAP11 and also inhibited the degradation of c-Myc by depletion of Fbw7. This study showed that Bcr-Abl promoted the CML cell proliferation through the THAP11 and Fbw7 mediated-c-Myc aberrant expression. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2010
49. Activation of Raf-1 through the Depletion of RKIP by Bcr-Abl Promotes CML Cell Proliferation
- Author
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Takaaki Ono, Tomonari Takemura, Yasuyuki Nagata, Kazunori Ohnishi, Isao Hirano, Satoki Nakamura, Shinya Fujisawa, Daisuke Yokota, and Kazuyuki Shigeno
- Subjects
ABL ,Cell growth ,Kinase ,Immunology ,Cell Biology ,Hematology ,Transfection ,Cell cycle ,Biology ,Biochemistry ,Cell culture ,hemic and lymphatic diseases ,Cancer research ,Progenitor cell ,neoplasms ,K562 cells - Abstract
Abstract 5105 [Background and Aims] RKIP (Raf kinase inhibitor protein) regulates cell proliferation, apoptosis, and cell cycle through the inhibition of Raf-1, and it has been reported that the suppression of the RKIP expression promotes the proliferation of tumor cells. However, its function is little known in CML. We found that the expression of RKIP gene and protein was suppressed in CML cells. In this study, we have investigated the expression and the function of the RKIP in CML cell proliferation. [Methods] The cells used in this study were human CML cell lines, K562, Meg01, and SHG3 cells. Primary CML cells (ALDHhicells) were obtained from the bone marrow of CML (CP) patients (n=12). Human normal ALDHhi cells were isolated from bone marrow of healthy volunteers after obtaining informed consents. For analysis of RKIP mRNA expression, quantitative RT-PCR was performed in all cell lines treated with Abl kinase inhibitors (STI571, AMN107, and BMS354825). For proliferation analysis and the levels of Erk1/2 phosphorylation in CML cells, MTT assays, western blot and cell cycle analysis were performed in all cell lines transfected with Bcr-Abl, RKIP siRNA, or RKIP cDNA respectively. For colony analysis, the colonies of CFU-GEMM, CFU-GM, and BFU-E were counted in CML stem/progenitor cells transfected with RKIP siRNA or treated with Abl kinase inhibitors. [Results] In CML cell lines treated with Abl kinase inhibitors or transfection with Bcr-Abl siRNA, the expressions of RKIP mRNA and protein were significantly increased more than untreated cells. Moreover, in CML cells transfected with the RKIP siRNA, the cell proliferation inhibition by treatment of the Abl kinase inhibitors was weakened compared to RKIP siRNA-untransfected cells, and the phosphorylation levels of Erk1/2 and Raf-1 were markedly increased compared to theRKIP siRNA-untransfected cells. On the other hands, the overexpression of RKIP induced G1 cell cycle arrest through p27 and p21 accumulation, decreased the phosphorylation levels of ERK1/2 and Raf-1, and inhibited the proliferation in CML cells. In CML stem/progenitor cells obtained from patients with CML, the expression of RKIP mRNA was suppressed in 10/10 (100 %) of CML. The transfection with Bcr-Abl siRNA or treatment with Abl kinase inhibitors increased the expression of RKIP mRNA and protein, and the overexpression of RKIP decreased the counts of CFU-GEMM, CFU-GM and BFU-E. [Conclusion] Our results demonstrated that the Bcr-Abl suppressed the expression of RKIP, the depletion of RKIP induced Raf-1 activation, and induced the proliferation of CML cells through ERK1/2 phosphorylation. Moreover, in CML, the induction of RKIP expression inhibited the proliferation of CML stem/progenitor cells. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2010
50. Bcr-Abl Mediated-Depletion of Dual-Specificity MAP Kinase Phosphatase, DUSP1, Expression Promotes the Cell Proliferation
- Author
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Tomonari Takemura, Kazuyuki Shigeno, Takaaki Ono, Satoki Nakamura, Daisuke Yokota, Shinya Fujisawa, Isao Hirano, Kazunori Ohnishi, and Yasuyuki Nagata
- Subjects
ABL ,Cell growth ,Kinase ,Immunology ,Cell Biology ,Hematology ,Transfection ,Cell cycle ,Biology ,Biochemistry ,Molecular biology ,Cell culture ,hemic and lymphatic diseases ,Cancer research ,Progenitor cell ,neoplasms ,K562 cells - Abstract
Abstract 3381 [Background and Aims] MAPK pathways control the cellular processes such as proliferation, differentiation and apoptosis. Abnormal MAPK signaling plays a key role in the development and progression of cancers. The dual-specificity MAPK phosphatases (DUSPs) act as negative regulators of MAPK activity in normal tissues. DUSP1 (dual-specificity MAPK phosphatase-1) is able to inactivate the ERK, p38, and JNK in resulting the cell cycle and apoptosis, and it has been reported to be lost in a variety advanced cancers. However, its function is little known in CML cells. In this study, we have investigated the function of DUSP1 in CML cell proliferation. [Methods] The cells used in this study were human CML cell lines, K562, Meg01 and SHG3 cells. Primary CML cells (ALDHhi cells) were obtained from the bone marrow of CML (CP) patients (n=12). Human normal ALDHhi cells were isolated from bone marrow of healthy volunteers after obtaining informed consents. For analysis of DUSP1 mRNA expression, quantitative RT-PCR was performed in all cell lines treated with Abl kinase inhibitors (STI571, AMN107, and BMS354825). For cell survival analysis and the levels of p-ERK1/2, p-p38, and p-ATF2 in CML cells, MTT assays, western blot and cell cycle analysis were performed in all cell lines transfected with DUSP1 shRNA or cDNA. For colony analysis, the colonies of CFU-GEMM, CFU-GM, and BFU-E were counted in CML stem/progenitor cells transfected with DUSP1 cDNA or shiRNA, or treated with Abl kinase inhibitors. [Results] In CML cell lines, the expressions of DUSP1 mRNA and protein were significantly increased by treatment with Abl kinase inhibitors or transfection with Bcr-Abl shRNA. In CML cells treated with Abl kinase inhibitors or transfection with Bcr-Abl shRNA, CML cell proliferation was inhibited, and the phosphorylation levels of p-ERK1/2, p-p38, and p-ATF2 were markedly decreased compared to the untreated cells. In addition, the overexpression of DUSP1 induced G1 cell cycle arrest indicating down regulation of cyclin D1 expression in CML cells. Moreover, in CML cells transfected with DUSP1 shRNA, the inhibition of CML cell proliferation by the Abl kinase inhibitors were weakened. In CML stem/progenitor cells (ALDHhi cells) obtained from patients with CML, the expression of DUSP1 mRNA was suppressed, and the transfection with Bcr-Abl shRNA or treatment with Abl kinase inhibitors increased the expression of DUSP1 mRNA and protein, and decreased the counts of CFU-GEMM, CFU-GM and BFU-E. [Conclusion] Our results demonstrated that the expression of DUSP1 was suppressed by Bcr-Abl in CML cells, and the depletion of DUSP1 promotes cell cycle progression through the induction of cyclin D1 expression, and stimulates CML cell proliferation through the continuous phosphorylation of ERK1/2, p38, and ATF2. Moreover, the induction of DUSP1 expression inhibited the proliferation of CML stem/progenitor cells. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2010
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