Publications by authors named "Masahiko Fukatsu"

12 Publications

  • Page 1 of 1

Weight Loss Intervention before Cord Blood Transplantation in an Obese Patient with Acute Myeloid Leukemia: A Case Study.

Prog Rehabil Med 2021 19;6:20210018. Epub 2021 Mar 19.

Department of Hematology, Fukushima Medical University, Fukushima, Japan.

Background: A severely obese woman (39.8 kg/m) with relapsed acute myeloid leukemia was admitted to our hospital to undergo salvage chemotherapy followed by cord blood transplantation (CBT).

Case: During the salvage chemotherapy period, a 70-day weight loss program addressing diet and exercise was administered. After the 70-day intervention, the patient's body weight and body fat mass had decreased (8.6% and 15.0%, respectively) without any adverse events. The number of available cord blood units with total nucleated cells per body weight greater than 2 × 10/kg was zero at admission and two after weight loss; therefore, CBT could be performed.

Discussion: Considering this case, we suggest that a weight loss program combining exercise and nutrition therapy may help patients scheduled for hematopoietic stem cell transplantation by focusing on risk management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2490/prm.20210018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972948PMC
March 2021

Mutation Promoted IL-6 Production and Glycolysis Mediating PKM1 Stabilization in Macrophages.

Front Immunol 2020 8;11:589048. Epub 2021 Feb 8.

The Department of Hematology, Fukushima Medical University, Fukushima, Japan.

A substitution mutation of valine to phenylalanine at codon encoding position 617 of the Janus kinase 2 () gene ( ) has been detected in myeloid cells of some individuals with higher levels of proinflammatory cytokine production such as interleukin (IL)-6. However, the mechanisms by which mutation mediating those cytokines remain unclear. We, therefore, established -expressing murine macrophages ( macrophages) and found that the levels of p-STAT3 were markedly elevated in macrophages in association with an increase in IL-6 production. However, inhibition of STAT3 by C188-9 significantly decreased the production of IL-6. Furthermore, the mutation endowed macrophages with an elevated glycolytic phenotype in parallel with aberrant expression of PKM1. Interestingly, silencing of PKM1 inactivated STAT3 in parallel with reduced IL-6 production. In contrast, ectopic expression of PKM1 elevated IL-6 production STAT3 activation. Importantly, the mutation contributed to PKM1 protein stabilization blockade of lysosomal-dependent degradation chaperone-mediated autophagy (CMA), indicating that the mutation could protect PKM1 from CMA-mediated degradation, leading to activation of STAT3 and promoting IL-6 production.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.589048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897702PMC
February 2021

Dasatinib induces endothelial-to-mesenchymal transition in human vascular-endothelial cells: counteracted by cotreatment with bosutinib.

Int J Hematol 2021 Mar 3;113(3):441-455. Epub 2021 Jan 3.

Department of Hematology, Fukushima Medical University, Hikariga-oka 1, Fukushima, 960-1295, Japan.

Adverse vascular events have become a serious clinical problem in chronic myeloid leukemia (CML) patients who receive certain BCR/ABL1 tyrosine kinase inhibitors (TKIs). Studies have shown that endothelial-to-mesenchymal transition (EndMT) can contribute to various vascular diseases. We investigated the effects of TKIs on the development of EndMT in human vascular-endothelial cells (VECs). Exposure of VECs to dasatinib, but not to other TKIs, produced a significant increase in the formation of spindle-shaped cells. This effect was accompanied by a significant increase in expression of the EndMT inducer transforming growth factor-β (TGF-β) and mesenchymal markers vimentin, smooth muscle alpha-actin, and fibronectin, as well as a significant decrease in expression of vascular-endothelial markers CD31 and VE-cadherin attributable at least in part to activation of ERK signaling. Inhibitors of TGF-β and ERK partially attenuated dasatinib-induced EndMT. Interestingly, bosutinib efficiently counteracted dasatinib-induced EndMT and attenuated dasatinib-induced phosphorylation of ERK. Taken together, these results show that dasatinib induces EndMT, which might contribute to the development of vascular toxicity, such as the pulmonary hypertension observed in CML patients receiving dasatinib. Bosutinib could play a distinct role in protecting VECs from EndMT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-020-03034-1DOI Listing
March 2021

Assessment of dysplasia in bone marrow smear with convolutional neural network.

Sci Rep 2020 09 7;10(1):14734. Epub 2020 Sep 7.

Department of Hemato-Oncology, International Medical Center, Saitama Medical University, Saitama, Japan.

In this study, we developed the world's first artificial intelligence (AI) system that assesses the dysplasia of blood cells on bone marrow smears and presents the result of AI prediction for one of the most representative dysplasia-decreased granules (DG). We photographed field images from the bone marrow smears from patients with myelodysplastic syndrome (MDS) or non-MDS diseases and cropped each cell using an originally developed cell detector. Two morphologists labelled each cell. The degree of dysplasia was evaluated on a four-point scale: 0-3 (e.g., neutrophil with severely decreased granules were labelled DG3). We then constructed the classifier from the dataset of labelled images. The detector and classifier were based on a deep neural network pre-trained with natural images. We obtained 1797 labelled images, and the morphologists determined 134 DGs (DG1: 46, DG2: 77, DG3: 11). Subsequently, we performed a five-fold cross-validation to evaluate the performance of the classifier. For DG1-3 labelled by morphologists, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 91.0%, 97.7%, 76.3%, 99.3%, and 97.2%, respectively. When DG1 was excluded in the process, the sensitivity, specificity, PPV, NPV, and accuracy were 85.2%, 98.9%, 80.6%, and 99.2% and 98.2%, respectively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-71752-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477564PMC
September 2020

Optimal timing of apheresis for the efficient mobilization of peripheral blood progenitor cells recruited by high-dose granulocyte colony-stimulating factor in healthy donors.

Transfus Apher Sci 2020 Jun 5;59(3):102737. Epub 2020 Feb 5.

Department of Hematology, Fukushima Medical University, Fukushima, Japan.

Predictors of peripheral blood stem cell (PBSC) yield can potentially improve the comfort, safety, and efficacy of CD34+ cell collection from donors treated with recombinant human granulocyte colony-stimulating factor (G-CSF). We investigated 181 apheresis procedures on 109 healthy allogeneic donors to identify factors correlating with efficient PBSC collection. Apheresis started on Day 4 or 5 and continued up to Day 6 of G-CSF administration. CD34+ cell yields on Days 4 and 5 were comparable, and significantly higher than on Day 6. This suggests that starting apheresis on Day 4 rather than Day 5 may be preferable, to reduce G-CSF exposure and optimize yield, even if multi-day collection is required. More CD34+ cells were collected from male and cytomegalovirus (CMV)-seronegative donors than from female and CMV-seropositive donors, respectively. The yields of CD34+ cells were similarly high in both male and female donors aged 20-29 years; yields decreased in female donors in their thirties, and were comparably low in both male and female donors in their forties and thereafter. These findings should guide decision-making about when to begin apheresis, and encourage careful consideration of donor factors such as gender, age, and CMV serostatus when collecting PBSCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.transci.2020.102737DOI Listing
June 2020

Circulating intranuclear proteins may play a role in development of disseminated intravascular coagulation in individuals with acute leukemia.

Int J Hematol 2020 Mar 17;111(3):378-387. Epub 2019 Dec 17.

Department of Hematology, Fukushima Medical University, Hikarigaoka-1, Fukushima, Fukushima, 960-1295, Japan.

Intranuclear proteins, including high mobility group box 1 (HMGB1) and histone H3, released from inflammatory cells activate platelets and the coagulation systems, leading to development of disseminated intravascular coagulation (DIC) in individuals with sepsis. These observations prompted us to hypothesize that HMGB1 and histone H3 liberated from leukemia cells undergoing apoptosis after chemotherapy might play a role in development of DIC. To test this hypothesis, we prospectively measured plasma levels of coagulation markers and intranuclear proteins in patients with newly diagnosed acute leukemia (n = 17) before and after chemotherapy. Ten of 17 patients were diagnosed with DIC at the time of diagnosis of leukemia. Serum levels of HMGB1 and histone H3 were significantly higher in patients with DIC than in non-DIC patients. Of note, seven patients developed DIC or experienced exacerbation of coagulopathy after administration of anti-leukemic agents. Intriguingly, an increase in levels of HMGB1 and histone H3 were detected in five of seven patients. These findings suggest that intranuclear proteins spontaneously released from leukemia cells may play a role in development of leukemia-related DIC. Additionally, remission induction chemotherapy causes apoptosis of leukemia cells, leading to forced release of intranuclear proteins, which may exacerbate coagulopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-019-02798-5DOI Listing
March 2020

A critical role of the Gas6-Mer axis in endothelial dysfunction contributing to TA-TMA associated with GVHD.

Blood Adv 2019 07;3(14):2128-2143

Department of Hematology, Fukushima Medical University, Fukushima, Japan.

Endothelial dysfunction in the early phases of hematopoietic stem cell transplantation (HSCT) contributes to a common pathology between transplant-associated thrombotic microangiopathy (TA-TMA) and graft-versus-host disease (GVHD), which are serious complications of HSCT. Growth arrest-specific (Gas) 6 structurally belongs to the family of plasma vitamin K-dependent proteins working as a cofactor for activated protein C, and has growth factor-like properties through its interaction with receptor tyrosine kinases of the TAM family: Tyro3, Axl, and Mer. Serum Gas6 levels were significantly increased in HSCT patients with grade II to IV acute GVHD (aGVHD), and Gas6 and Mer expression levels were upregulated in aGVHD lesions of the large intestine and skin. The increased serum Gas6 levels were also correlated with elevated lactate dehydrogenase, d-dimer, and plasmin inhibitor complex values in HSCT patients with aGVHD. In human umbilical vein endothelial cells (ECs), exogenous Gas6 or the exposure of sera isolated from patients with grade III aGVHD to ECs induced the downregulation of thrombomodulin and the upregulation of PAI-1, as well as the upregulation of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, which were inhibited by UNC2250, a selective Mer tyrosine kinase inhibitor. In mouse HSCT models, we observed hepatic GVHD with hepatocellular apoptosis, necrosis, and fibrosis, as well as TA-TMA, which is characterized pathologically by thrombosis formation in the microvasculature of the liver and kidney. Of note, intravenous administration of UNC2250 markedly suppressed GVHD and TA-TMA in these mouse HSCT models. Our findings suggest that the Gas6-Mer axis is a promising target for TA-TMA after GVHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2019000222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650735PMC
July 2019

[Airway obstruction due to localized tracheal lesion of extranodal NK/T-cell lymphoma, nasal type].

Rinsho Ketsueki 2018;59(8):1012-1015

Department of Hematology, Fukushima Medical University.

A 76-year-old man presented with a tracheal tumor associated with severe respiratory obstruction. A tracheotomy was performed due to respiratory failure. F-fluorodeoxyglucose (FDG) -positron emission tomography/computed tomography revealed an abnormal accumulation of FDG (maximum standardized uptake value: 16) in the trachea. A histopathological examination of the tracheal biopsy revealed extranodal NK/T-cell lymphoma, nasal type (ENKL). He was treated with concurrent radiotherapy (50 Gy) for the tracheal tumor and three courses of two-thirds dose ofdexamethasone, etoposide, ifosfamide, and carboplatin. Although the tumor responded remarkably well to this therapy, the patient died of an ENKL recurrence in the lungs and liver 11 months post therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11406/rinketsu.59.1012DOI Listing
July 2019

Steroid-resistant autoimmune myelofibrosis in a patient with autoimmune hepatitis and Evans syndrome complicated with increased expression of TGF-β in the bone marrow: a case report.

Int J Hematol 2017 Nov 5;106(5):718-724. Epub 2017 Jun 5.

Department of Hematology, Fukushima Medical University, 1 Hikariga-oka, Fukushima, Fukushima, 960-1295, Japan.

We here report a 47-year-old female with autoimmune myelofibrosis (AIMF) associated with liver damage caused by autoimmune hepatitis and Evans syndrome. Bone marrow biopsy revealed hypocellular marrow with grade 2 reticulin fibrosis and increased levels of B lymphocytes (CD20), T lymphocytes (CD3, CD8), and plasma cells (CD138). Immunohistochemical analysis revealed increased expression of transforming growth factor-β (TGF-β) in infiltrating lymphocytes and macrophages in the bone marrow. She was initially treated with oral prednisolone (PSL) for 2 months, which had a limited effect. However, after treatment with rituximab, the patient's pancytopenia showed improvement, allowing us to rapidly reduce the PSL dosage. The present case suggests the possibility that increased expression of TGF-β in infiltrating lymphocytes and macrophages of bone marrow may contribute to the pathogenesis of AIMF. Prednisolone combined with rituximab may thus be an effective option for steroid-refractory cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-017-2268-3DOI Listing
November 2017

A possible role of low regulatory T cells in anti-acetylcholine receptor antibody positive myasthenia gravis after bone marrow transplantation.

BMC Neurol 2017 May 15;17(1):93. Epub 2017 May 15.

Department of Neurology, Fukushima Medical University, 1 Hikariga-oka, Fukushima, Fukushima, 960-1295, Japan.

Background: Chronic graft-versus-host disease (GVHD) appears several months following allogenic hematopoietic stem cell transplantation (HSCT) and is clinically analogous to autoimmune disorder. Polymyositis is a common neuromuscular disorder in chronic GVHD, but myasthenia gravis (MG) is extremely rare. Hence, its pathophysiology and treatment have not been elucidated.

Case Presentation: A 63-year-old man with a history of chronic GVHD presented with ptosis, dropped head, and dyspnea on exertion, which had worsened over the previous several months. He showed progressive decrement of compound muscle action potential in the deltoid muscle evoked by 3-Hz repetitive nerve stimulation, a positive edrophonium test, and elevated levels of serum anti-acetylcholine receptor antibodies, which suggested a diagnosis of generalized MG. No thymoma was found. Flow cytometric analysis revealed a remarkable depletion of peripheral Tregs (CD4CD25FOXP3 cells, 0.24% of the total lymphocytes). Administration of prednisolone and tacrolimus was insufficient to alleviate his symptoms; however, the use of rituximab successfully improved his condition.

Conclusions: Myasthenic symptoms appeared in the process of tapering prednisolone for the treatment of chronic GVHD, supporting the diagnosis of MG associated with chronic GVHD. The present case proposes a possibility that reduction of Tregs might contribute to the pathogenesis of MG underlying chronic GVHD. Immunotherapy with rituximab is beneficial for treatment of refractory MG and GVHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12883-017-0881-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433011PMC
May 2017

Subgroup differences in 'brain-type' transferrin and α-synuclein in Parkinson's disease and multiple system atrophy.

J Biochem 2016 Aug 11;160(2):87-91. Epub 2016 Mar 11.

Bixochemistry;

Two transferrin (Tf) glycan-isoforms were previously found in cerebrospinal fluid (CSF); one appears to be derived from serum (Tf-2) and the other from choroid plexus, a CSF-producing tissue (Tf-1). To analyse metabolic differences associated with the two isoforms, their ratio (Tf-2/Tf-1) was defined as the Tf index. Here we report that Tf indices of patients with tauopathies including Alzheimer's disease (2.29 + 0.64) were similar to those of neurological controls (2.07 + 0.87) (P = 0.147). In contrast, Tf indices with Parkinson's disease (PD, 3.38 ± 1.87) and multiple system atrophy (MSA, 3.15 ± 1.72) were higher than those of the controls (2.07 ± 0.87), the P-values being < 0.001 and 0.024, respectively. Tf indices of PD and MSA did not appear to be normally distributed. Indeed, detrended normal Quantile-Quantile plot analysis revealed the presence of an independent subgroup showing higher Tf indices in PD and MSA. The subgroup of PD showed higher levels of CSF α-synuclein (38.3 ± 17.8 ng/ml) than the rest (25.3 ± 11.3 ng/ml, P = 0.012). These results suggest that PD (and MSA) includes two subgroups, which show different metabolism of CSF transferrin and α-synuclein.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jb/mvw015DOI Listing
August 2016