Publications by authors named "Hiroshi Ohkawara"

54 Publications

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

Diagnosis and treatment of disseminated intravascular coagulation in COVID-19 patients: a scoping review.

Int J Hematol 2021 Mar 7;113(3):320-329. Epub 2021 Feb 7.

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

Background: Disseminated intravascular coagulation (DIC) is noted in severe cases of coronavirus disease 2019 (COVID-19). Recently, a number of studies evaluating the diagnosis and treatment of DIC in COVID-19 patients have been reported.

Objective: The aim of this study is to identify existing gaps where further research is needed on the diagnosis and treatment of DIC complicated by COVID-19.

Methods: We used the PRISMA Extension for Scoping Reviews. MEDLINE, CENTRAL, WHO-ICTRP, ClinicalTrial.gov and PROSPERO were searched from their inception to 6 October 2020.

Results: Seven studies were selected; five were already published and two are ongoing. DIC was diagnosed using the International Society on Thrombosis and Hemostasis (ISTH) DIC score (n = 4) and the sepsis-induced coagulopathy (SIC) DIC score (n = 5). Seven studies examined the effectiveness of low molecular weight heparin (LMWH); of these, four studies used a prophylactic dose and five used a therapeutic dose of LMWH. A prophylactic dose of unfractionated heparin (UFH) was investigated in two studies.

Conclusion: Studies on DIC diagnostic criteria and anticoagulants were limited to the ISTH or SIC scores and heparinoids, particularly LMWH. Further studies are needed to compare these with other available DIC scoring systems and anticoagulants.
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http://dx.doi.org/10.1007/s12185-021-03084-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868079PMC
March 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.
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http://dx.doi.org/10.1007/s12185-020-03034-1DOI Listing
March 2021

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

Integral role of receptor for advanced glycation end products (RAGE) in nondiabetic atherosclerosis.

Fukushima J Med Sci 2019 ;65(3):109-121

Department of Cardiology and Hematology, Fukushima Medical University.

An advanced glycation end products (AGE)/a receptor for AGE (RAGE) axis plays a central role in the pathogenesis of diabetic vascular remodeling. This study was conducted to clarify the role of RAGE in nondiabetic atherosclerosis. We used the aortic and coronary atherosclerotic lesions of Watanabe heritable hyperlipidemic (WHHL) rabbits prone to myocardial infarction (WHHLMI) at 1 to 14 months. Immunohistochemistry demonstrated the significant expression of RAGE as early as at 1 month with the stronger expression at 3 and 7 months, which was remarkably diminished at 14 months. RAGE expression was concordant with AGE accumulation. The major original sources of RAGE expression were macrophages and smooth muscle cells in addition to endothelial cells, and RAGE expression was distributed in the areas of phospholipid products, a component of oxidized LDL and nitrotyrosine. The concentrations of serum AGE did not alter significantly with aging. These findings suggested the expression of RAGE was induced by hyperlipidemia and oxidative stress independent of diabetes in WHHLMI rabbits. Additionally, our in vitro study showed that silencing of RAGE tended to attenuate oxidized-LDL-triggered PAI-1 expression in human cultured macrophages, as well as oxidized-LDL-induced tissue factor expression in peritoneal macrophages, suggesting a possible role of RAGE in prothrombogenic molecular regulation. In conclusion, the present study provides in vivo evidence that RAGE plays an integral role in the initiation and progression of nondiabetic atherosclerosis, suggesting that RAGE may be a novel target for treating not only diabetic but also nondiabetic vascular complications.
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http://dx.doi.org/10.5387/fms.2019-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012590PMC
May 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.
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http://dx.doi.org/10.1007/s12185-019-02798-5DOI Listing
March 2020

Intestinal Behçet disease associated with myelodysplastic syndrome accompanying trisomy 8 successfully treated with abdominal surgery followed by hematopoietic stem cell transplantation: A case report.

Medicine (Baltimore) 2019 Nov;98(46):e17979

Department of Rheumatology.

Rationale: Intestinal Behçet disease (BD) with myelodysplastic syndrome (MDS) is a rare condition that is resistant to various immunosuppressive therapies. Several cases in which hematopoietic stem cell transplantation (HSCT) was effective for intestinal BD with MDS accompanying trisomy 8 have been reported.

Patient Concerns: We report an 18-year-old female with a 7-year history of BD. Colonoscopy demonstrated a huge ulcer in the cecum. Chromosomal examination revealed a karyotype of trisomy 8 in 87% of cells. Bone marrow examination revealed dysplastic cells in multilineages.

Diagnoses: A diagnosis of intestinal BD associated with MDS accompanying trisomy 8 was made.

Interventions: The patient underwent ileocecal resection due to microperforations of ileocecal ulcers; she then underwent allogeneic peripheral blood stem cell transplantation (PBSCT) with her mother as a donor.

Outcomes: After the PBSCT, the patient's symptoms due to BD (fever, oral aphthae, abdominal pain, and genital ulcers) completely disappeared, with no severe adverse events.

Lessons: The present case demonstrates that HSCT including PBSCT might be an effective new therapeutic option for refractory intestinal BD with MDS when immunosuppressive therapy has achieved insufficient efficacy.
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http://dx.doi.org/10.1097/MD.0000000000017979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867715PMC
November 2019

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

Distinct Forms of Esophageal Lesions After Radiofrequency and Cryoballoon Pulmonary Vein Isolation.

JACC Clin Electrophysiol 2018 Dec;4(12):1642-1643

Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan; Department of Arrhythmia and Cardiac Pacing, Fukushima Medical University, Fukushima, Japan.

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http://dx.doi.org/10.1016/j.jacep.2018.08.006DOI Listing
December 2018

Predicting factors of transmural thermal injury after cryoballoon pulmonary vein isolation.

J Interv Card Electrophysiol 2019 Mar 19;54(2):101-108. Epub 2018 Sep 19.

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

Purpose: Transmural thermal injury (TTI), such as esophageal erosion/ulcer and periesophageal nerve injury leading to gastric hypomotility, is not rare complications associated with pulmonary vein isolation (PVI). However, the mechanism and predicting factors of TTI have not yet been fully elucidated with second-generation cryoballoon (CB) PVI.

Methods: One hundred ten consecutive patients, who underwent CB PVI for atrial fibrillation and received esophagogastroduodenoscopy 2 days later, were investigated. The relationships between TTI and both clinical and anatomical parameters were examined. We measured the following parameters based on the computed tomography data: the angle of the left atrial (LA) posterior wall to the descending aorta (Ao) (LA-Ao angle); the branching angle of the left inferior pulmonary vein (LIPV) to the coronal plane (LIPV angle); and the minimum distance between the LA posterior wall and descending Ao enclosing the esophagus (LA-Ao distance).

Results: TTIs occurred in 19 patients (esophageal erosion in 2 and gastric hypomotility in 17). The patients with TTI were significantly older than those without TTI. In the anatomical parameters, the LIPV angle was larger and the LA-Ao distance was shorter in the TTI (+) group compared to the TTI (-) group. With the multivariate logistic regression analysis, the age (odds ratio [OR] 2.148, P = 0.022) and LA-Ao distance (OR 0.430, P = 0.013) were independent predictors of TTI.

Conclusions: The occurrence of TTI in CB PVI was associated with aging, suggesting compromised periesophageal circulation, and the anatomical proximities between the LA and the descending Ao, which enclose the esophagus.
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http://dx.doi.org/10.1007/s10840-018-0454-8DOI Listing
March 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.
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http://dx.doi.org/10.11406/rinketsu.59.1012DOI Listing
July 2019

Lenalidomide as a Beneficial Treatment Option for Renal Impairment Caused by Light Chain Deposition Disease.

Intern Med 2018 Dec 10;57(24):3651-3657. Epub 2018 Aug 10.

Department of Hematology, Fukushima Medical University, Japan.

Light chain deposition disease (LCDD) is a rare systemic disorder caused by the deposition of light chain immunoglobulins, which often results in renal impairment associated with either nephrotic syndrome or asymptomatic proteinuria. B-cell neoplasms, such as multiple myeloma and lymphoproliferative disorders, are well-known underlying diseases in LCDD. Some chemotherapy regimens have been reported, but both evidence-based treatment and management for LCDD have yet to be established. We herein report three cases of LCDD treated with lenalidomide-based therapy, resulting in hematologic responses accompanied by a significant reduction in proteinuria and improvement in the renal function. We recommend lenalidomide-based therapy for renal impairment caused by LCDD.
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http://dx.doi.org/10.2169/internalmedicine.1018-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355407PMC
December 2018

Cytoprotective and pro-angiogenic functions of thrombomodulin are preserved in the C loop of the fifth epidermal growth factor-like domain.

Haematologica 2018 10 14;103(10):1730-1740. Epub 2018 Jun 14.

Department of Hematology, Fukushima Medical University, Japan

We previously found that the fifth epidermal growth factor-like domain of thrombomodulin (TME5) exerts cytoprotective and pro-angiogenic functions G-protein coupled receptor 15 (GPR15). TME5 is comprised of three S-S bonds that divide it into three loops: A (TME5A), B (TME5B), and C (TME5C). Herein we identified the minimum structure of TME5 that produces favorable effects in vascular endothelial cells (ECs). We found that TME5C, composed of 19 amino acids, but not TME5A or TME5B, stimulated the proliferation of human umbilical vein endothelial cells (HUVECs) and human hepatic sinusoidal endothelial cells (HHSECs). Matrigel plug assays showed that TME5C stimulates angiogenesis. In addition, TME5C counteracted calcineurin inhibitor-induced apoptosis and vascular permeability in HUVECs and HHSECs. Western blot analysis indicated that exposure of either HUVECs or HHSECs to TME5C increased the levels of anti-apoptotic myeloid cell leukemia-1 protein in association with the activation of signal transduction pathways, including extracellular signal-regulated kinase, AKT, and mitogen-activated protein kinase p38. Importantly, TME5C did not affect the coagulation pathway The cytoprotective function of TME5C was mediated by cell surface-expressed GPR15, as TME5C was not able to protect vascular ECs isolated from knock-out (KO) mice. Strikingly, TME5C successfully ameliorated sinusoidal obstruction syndrome in a murine model by counteracting the reduction of sinusoidal EC numbers. Taken together, the cytoprotective and pro-angiogenetic functions of TM are preserved in TME5C. The use of TME5C may be a promising treatment strategy to prevent or treat lethal complications, such as sinusoidal obstruction syndrome, whose pathogenesis is based on endothelial insults.
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http://dx.doi.org/10.3324/haematol.2017.184481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165823PMC
October 2018

Defibrotide Stimulates Angiogenesis and Protects Endothelial Cells from Calcineurin Inhibitor-Induced Apoptosis via Upregulation of AKT/Bcl-xL.

Thromb Haemost 2018 01 5;118(1):161-173. Epub 2018 Jan 5.

Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.

Sinusoidal obstruction syndrome is a life-threatening complication that can occur after haematopoietic stem cell transplantation. Defibrotide (DF) has been approved for the treatment of individuals with severe sinusoidal obstruction syndrome following haematopoietic stem cell transplantation in the European Union and the United States. However, the precise mechanisms by which DF protects endothelial cells remain to be elucidated. In this study, we found that DF stimulated angiogenesis in vitro and in vivo as assessed by vascular tube formation, scratch-wound repair and Matrigel plug assays. These effects were associated with an activation of pro-survival signalling pathways, including AKT (protein kinase B), ERK (extracellular signal-regulated kinases) and p38. More importantly, DF alleviated calcineurin inhibitor-induced growth inhibition and apoptosis of human umbilical vein endothelial cells and human hepatic sinusoidal endothelial cells in parallel with upregulation of anti-apoptotic protein B-cell lymphoma-extra-large (Bcl-xL), which was mediated by AKT (protein kinase B). Notably, these effects were abrogated when Bcl-xL was depleted by small interfering RNA (ribonucleic acid). In addition, DF counteracted calcineurin inhibitor-induced activation of nuclear factor-κB and Janus kinase 2 (JAK2)/Signal Transducer and Activator of Transcription 3 (STAT3) signalling and production of cytokines in vascular endothelial cell-derived EA.hy926 cells. Taken together, DF has pro-angiogenic, anti-apoptotic and anti-inflammatory effects on endothelial cells. DF is a potentially useful agent to prevent the development of, and treat individuals with, endothelial cell injury-related complications after haematopoietic stem cell transplantation.
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http://dx.doi.org/10.1160/TH17-04-0275DOI Listing
January 2018

Hmga2 collaborates with V617F in the development of myeloproliferative neoplasms.

Blood Adv 2017 Jun 14;1(15):1001-1015. Epub 2017 Jun 14.

Department of Cardiovascular Medicine, and.

High-mobility group AT-hook 2 () is crucial for the self-renewal of fetal hematopoietic stem cells (HSCs) but is downregulated in adult HSCs via repression by and the polycomb-recessive complex 2 (PRC2) including EZH2. The messenger RNA (mRNA) level is often elevated in patients with myelofibrosis that exhibits an advanced myeloproliferative neoplasm (MPN) subtype, and deletion of promotes the progression of severe myelofibrosis in mice with upregulation of several oncogenes such as . However, the direct role of in the pathogenesis of MPNs remains unknown. To clarify the impact of on MPNs carrying the driver mutation, we generated Δ/ mice overexpressing Hmga2 due to deletion of the 3' untranslated region. Compared with mice, Δ/ mice exhibited more severe leukocytosis, anemia and splenomegaly, and shortened survival, whereas severity of myelofibrosis was comparable. Δ/ cells showed a greater repopulating ability that reproduced the severe MPN compared with cells in serial bone marrow transplants, indicating that Hmga2 promotes MPN progression at the HSC level. Hmga2 also enhanced apoptosis of erythroblasts that may worsen anemia. Relative to hematopoietic stem and progenitor cells (HSPCs), over 30% of genes upregulated in Δ/ HSPCs overlapped with those derepressed by loss in / HSPCs, suggesting that Hmga2 may facilitate upregulation of Ezh2 targets. Correspondingly, deletion of ameliorated anemia and splenomegaly in / mice, and suppression and PRC2 mutations correlated with the elevated mRNA levels in patients with MPNs, especially myelofibrosis. These findings suggest the crucial role of HMGA2 in MPN progression.
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http://dx.doi.org/10.1182/bloodadvances.2017004457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728313PMC
June 2017

Anatomical predisposing factors of transmural thermal injury after pulmonary vein isolation.

Europace 2018 07;20(7):1122-1128

Department of Cardiovascular Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima, Japan.

Aims: Transmural thermal injury (TTI), such as oesophageal erosion/ulcer and perioesophageal nerve injury leading to gastric hypomotility, is an important complication associated with pulmonary vein isolation (PVI). However, a predictor of TTI concerning anatomical structures surrounding the oesophagus has not yet been fully elucidated. Therefore, we sought to identify the predisposing factors of TTI after PVI.

Methods And Results: Consecutive 110 patients, who underwent PVI for atrial fibrillation, received oesophagogastroduodenoscopy 2 days later, were investigated. The relationships between TTI and clinical and anatomical parameters were examined. Based on the computed tomography data, we measured the angle of the left atrial (LA) posterior wall to the descending aorta (Ao) (LA-Ao angle), the branching angle of the left inferior pulmonary vein (LIPV) to the coronal plane (LIPV angle), and the minimum distance between the LA posterior wall and descending Ao enclosing the oesophagus (LA-Ao distance). Transmural thermal injuries occurred in 21 patients (oesophageal erosion in 5 and gastric hypomotility in 16). Age, gender, body mass index, LA diameter, and LA volume index in echocardiography were not associated with TTI. However, the LIPV angle was larger and the LA-Ao distance was shorter in the TTI (+) group compared to the TTI (-) group. With multivariate logistic regression analysis, the LIPV angle [odds ratio (OR): 2.144, P = 0.0031] and LA-Ao distance (OR: 0.392, P = 0.0229) were independent predictors of TTI.

Conclusion: The anatomical proximities of the LA posterior wall, LIPV, and descending Ao surrounding the oesophagus are strongly associated with the prevalence of TTI.
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http://dx.doi.org/10.1093/europace/eux185DOI Listing
July 2018

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

The BCR/ABL tyrosine kinase inhibitor, nilotinib, stimulates expression of IL-1β in vascular endothelium in association with downregulation of miR-3p.

Leuk Res 2017 07 5;58:83-90. Epub 2017 May 5.

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

BCR/ABL tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis for in dividuals with chronic myeloid leukemia (CML). However, many patients treated with TKIs suffer from TKI-related complications. In particular, vascular events such as peripheral artery occlusive disease have become aserious clinical problem for patients who receive the TKI, nilotinib. At present, the molecular mechanisms by which TKIs cause vascular endothelial cell insults remain unknown.This study explored the effects of the TKIs, imatinib, nilotinib and dasatinib, on vascular endothelial cells in vitro, and found that only nilotinib induced expression of interleukin-1β (IL-1β) by vascular endothelial cells. Nilotinib-induced IL-1β expression stimulated the adhesion of monocytes to vascular endothelial cells in association with an increase in levels of adhesion molecules. MicroRNA database searching identified miR-3121-3p binding sites in the 3'-UTR of the IL-1β gene. Exposure of endothelial cells to nilotinib caused downregulation of miR-3121-3p in these cells. Importantly, forced-expression of miR-3121-3p counteracted nilotinib-induced expression of IL-1β. Importantly, serum levels if IL-1β were significantly elevated in CML patients receiving nilotinib (n=14) compared to those receiving other TKIs (n=16) (3.76±1.22pg/ml vs 0.27±0.77pg/ml, p<0.05). Taken together, our data suggest that nilotinib decreases levels of miR-3121-3p resulting in an increase in expression of IL-1β and adhesion molecules in vascular endothelial cells. The miR-3121-3p/IL-1β axis could be a potential target to prevent vascular events in CML patients with high risk of vascular events.
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http://dx.doi.org/10.1016/j.leukres.2017.05.005DOI Listing
July 2017

Autocrine and Paracrine Interactions between Multiple Myeloma Cells and Bone Marrow Stromal Cells by Growth Arrest-specific Gene 6 Cross-talk with Interleukin-6.

J Biol Chem 2017 03 31;292(10):4280-4292. Epub 2017 Jan 31.

Cardiovascular Medicine and.

The pathogenesis of multiple myeloma (MM) has not yet been fully elucidated. Our microarray analysis and immunohistochemistry revealed significant up-regulation of growth arrest-specific gene 6 (Gas6), a vitamin K-dependent protein with a structural homology with protein S, in bone marrow (BM) cells of MM patients. ELISA showed that the serum levels of soluble Gas6 were significantly increased in the MM patients when compared with healthy controls. Gas6 was overexpressed in the human CD138-positive MM cell line RPMI-8226. Exogenous Gas6 suppressed apoptosis induced by serum deprivation and enhanced cell proliferation of the MM cells. The conditional medium from the human BM stromal cell line HS-5 induced cell proliferation and anti-apoptosis of the MM cells with extracellular signal-regulated kinase, Akt, and nuclear factor-κB phosphorylation, which were reversed by the neutralizing antibody to Gas6 or IL-6. The TAM family receptor Mer, which has been identified as a Gas6 receptor, was overexpressed in BM cells of MM patients. The knockdown of Mer by siRNA inhibited cell proliferation, anti-apoptosis, and up-regulation of intercellular cell adhesion molecule-1 (ICAM-1) in MM cells stimulated by an HS-5 cell-conditioned medium. Furthermore, the Gas6-neutralizing antibody reduced the up-regulation of IL-6 and ICAM-1 induced by a HS-5 cell-conditioned medium in MM cells. The present study provides new evidence that autocrine and paracrine stimulation of Gas6 in concert with IL-6 contributes to the pathogenesis of MM, suggesting that Gas6-Mer-related signaling pathways may be a promising novel target for treating MM.
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http://dx.doi.org/10.1074/jbc.M116.733030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354500PMC
March 2017

MEMBRANE TYPE 1-MATRIX METALLOPROTEINASE (MT1-MMP) IDENTIFIED AS A MULTIFUNCTIONAL REGULATOR OF VASCULAR RESPONSES.

Fukushima J Med Sci 2015 11;61(2):91-100. Epub 2015 Sep 11.

Department of Cardiology and Hematology, Fukushima Medical University.

Membrane type 1-matrix metalloproteinase (MT1-MMP) functions as a signaling molecules in addition to a transmembrane metalloprotease, which degrades interstitial collagens and extracellular matrix components. This review focuses on the multifunctional roles of MT1-MMP as a signaling molecule in vascular responses to pro-atherosclerotic stimuli in the pathogenesis of cardiovascular diseases. First, the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1)-MT1-MMP signaling axis contributes to endothelial dysfunction, which is mediated via small GTP-binding protein RhoA and Rac1 activation. Second, MT1-MMP plays a crucial role in reactive oxygen species (ROS) generation through the activation of receptor for advanced glycation end products (AGEs) in smooth muscle cells, indicating that MT1-MMP may be a therapeutic target for diabetic vascular complications. Third, MT1-MMP is involved in RhoA/Rac1 activation and Ca(2+) signaling in the mechanism of thrombin-stimulated endothelial dysfunction and oxidant stress. Fourth, the inhibition of the MT1-MMP/Akt signaling pathway may be an attractive strategy for treating endothelial disordered hemostasis in the development of vascular diseases linked to TNF-α-induced inflammation. Fifth, MT1-MMP through RAGE induced RhoA/Rac1 activation and tissue factor protein upregulation through NF-κB phosphorylation in endothelial cells stimulated by high-mobility group box-1, which plays a key role in the systemic inflammation. These findings suggest that the MT1-MMP-mediated signaling axis may be a promising target for treating atherosclerosis and subsequent cardiovascular diseases.
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http://dx.doi.org/10.5387/fms.2015-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131593PMC
August 2017

CD4+ T cells in aged or thymectomized recipients of allogeneic stem cell transplantations.

Biol Res 2015 Jul 26;48:41. Epub 2015 Jul 26.

Department of Cardiology and Hematology, School of Medicine, Fukushima Medical University, Fukushima, Japan.

Background: CD4+CD25highFOXP3+ regulatory T (Treg) cells, which include thymus-derived and peripherally induced cells, play a central role in immune regulation, and are therefore crucial to prevent graft-versus-host disease (GVHD). The increasing use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for elderly patients with thymus regression, and our case of allo-HSCT shortly after total thymectomy, raised questions about the activity of thymus-derived Treg cells and peripherally induced Treg cells, which are otherwise indistinguishable.

Results: We found that despite pre-transplant thymectomy or older age, both naïve and effector Treg cells, as well as naïve and effector conventional T cells, proliferated in allo-HSCT recipients. Higher proportions of total Treg cells 1 month post allo-HSCT, and naïve Treg cells 1 year post allo-HSCT, appeared in patients achieving complete chimera without developing significant chronic GVHD, including our thymectomized patient, compared with patients who developed chronic GVHD.

Conclusions: Treg cells that modulate human allogeneic immunity may arise peripherally as well as in the thymus of allo-HSCT recipients.
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http://dx.doi.org/10.1186/s40659-015-0033-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4514962PMC
July 2015

Persistent complete remission of acute leukemic-phase CCR4-positive gamma-delta peripheral T-cell lymphoma by autologous stem cell transplantation with mogamulizumab.

Int J Hematol 2015 Oct 15;102(4):498-505. Epub 2015 May 15.

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

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), frequently shows a poor outcome. Especially, expressions of CC chemokine receptor 4 (CCR4) and γδ T-cell receptor (TCR) are associated with worse prognosis in PTCL-NOS. We here report successful treatment with autologous peripheral blood stem cell transplantation (auto-PBSCT) combined with anti-CCR4 antibody mogamulizumab for a very rare case of CCR4+γδTCR+ PTCL-NOS that coexisted with Hodgkin's lymphoma. PTCL-NOS in this patient progressed to leukemic phase, whereas Hodgkin's lymphoma disappeared with standard chemotherapies within 4 years of the initial diagnosis. Leukemic-phase PTCL-NOS was refractory to several chemotherapies. However, auto-PBSCT following high-dose chemotherapy combined with pre- and post-transplant mogamulizumab, which is a humanized monoclonal antibody to CCR4, provided persistent complete remission of PTCL-NOS, despite residual γδTCR+ in the transplanted stem cell product, suggesting a purging effect of mogamulizumab. At 15 months after transplantation, we also found markedly fewer effector regulatory T cells, which may have contributed to prolonged remission. This case suggests that autologous stem cell transplantation combined with mogamulizumab may have a potential to cure T-cell neoplasms that express CCR4 including leukemic-phase PTCL-NOS.
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http://dx.doi.org/10.1007/s12185-015-1805-1DOI Listing
October 2015

Receptor for advanced glycation end products - membrane type1 matrix metalloproteinase axis regulates tissue factor expression via RhoA and Rac1 activation in high-mobility group box-1 stimulated endothelial cells.

PLoS One 2014 9;9(12):e114429. Epub 2014 Dec 9.

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

Background: Atherosclerosis is understood to be a blood vessel inflammation. High-mobility group box-1 (HMGB-1) plays a key role in the systemic inflammation. Tissue factor (TF) is known to lead to inflammation which promotes thrombus formation. Membrane type1 matrix metalloprotease (MT1-MMP) associates with advanced glycation endproducts (AGE) triggered-TF protein expression and phosphorylation of NF-κB. However, it is still unclear about the correlation of MT1-MMP and HMBG-1-mediated TF expression. In this study, we investigated the molecular mechanisms of TF expression in response to HMGB-1 stimulation and the involvement of MT1-MMP in endothelial cells.

Methods And Results: Pull-down assays and Western blotting revealed that HMGB-1 induced RhoA/Rac1 activation and NF-kB phosphorylation in cultured human aortic endothelial cells. HMGB-1 increased the activity of MT1-MMP, and inhibition of RAGE or MT1-MMP by siRNA suppressed HMGB-1-induced TF upregulation as well as HMGB-1-triggered RhoA/Rac1 activation and NF-kB phosphorylation.

Conclusions: The present study showed that RAGE/MT1-MMP axis modified HMBG-1-mediated TF expression through RhoA and Rac1 activation and NF-κB phosphorylation in endothelial cells. These results suggested that MT1-MMP was involved in vascular inflammation and might be a good target for treating atherosclerosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0114429PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260861PMC
September 2015

Severe immune thrombocytopenia possibly elicited by the anti-influenza viral agent peramivir.

Intern Med 2014 15;53(20):2369-71. Epub 2014 Oct 15.

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

A 44-year-old man whose platelet count had been at the lower limit of the normal range for years visited the urgent care department of our hospital for treatment of a high fever and severe fatigue. The influenza A virus was detected, and the patient therefore received the intravenous antiviral agent, peramivir. One week later, he developed systemic petechial rashes. A peripheral blood examination showed a markedly decreased platelet count (3.0×10(9) cells/L), and the bone marrow findings were compatible with a diagnosis of immune thrombocytopenia (ITP). Furthermore, a drug-induced lymphocyte-stimulating test was positive for peramivir. The thrombocytopenia slowly responded to treatment with oral prednisolone. This case suggests that neuraminidase inhibitors, including peramivir, can elicit or worsen ITP.
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http://dx.doi.org/10.2169/internalmedicine.53.2330DOI Listing
June 2015

Dysregulation of the MIRLET7/HMGA2 axis with methylation of the CDKN2A promoter in myeloproliferative neoplasms.

Br J Haematol 2015 Feb 19;168(3):338-49. Epub 2014 Sep 19.

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

Overexpression of high mobility group AT-hook 2 (Hmga2), which is negatively regulated by MIRLET7 micro RNAs through 3'-untranslated region (3'UTR), causes proliferative haematopoiesis mimicking myeloproliferative neoplasms (MPNs) and contributes to progression of myelofibrosis in mice. Thus, we investigated HMGA2 mRNA expression in 66 patients with MPNs including 23 polycythaemia vera (PV), 33 essential thrombocythaemia (ET) and 10 primary myelofibrosis (PMF). HMGA2 mRNA expression, especially variant 1 with 3'UTR that contains MIRLET7-specific sites, rather than variant 2 lacking 3'UTR, is frequently deregulated due to decreased MIRLET7 expression in granulocytes from over 20% of PV and ET, and in either granulocytes or CD34(+) cells from 100% of PMF. Patients with deregulated HMGA2 mRNA expression were significantly more likely to show splenomegaly, high serum lactate dehydrogenase values, and methylation of the CDKN2A promoter compared with other patients without deregulation of HMGA2. A histone deacetylase inhibitor, panobinostat, significantly increased MIRLET7 expression and reduced variant 1 of HMGA2 mRNA expression, but not variant 2, in both U937 cells and PMF-derived CD34(+) cells. Moreover, both panobinostat and small interfering RNA of HMGA2 demethylated the CDKN2A promoter in U937 cells. In conclusion, the frequently dysregulated MIRLET7/HMGA2 axis could be a therapeutic target in MPNs.
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http://dx.doi.org/10.1111/bjh.13129DOI Listing
February 2015

Membrane type 1-matrix metalloproteinase/Akt signaling axis modulates TNF-α-induced procoagulant activity and apoptosis in endothelial cells.

PLoS One 2014 27;9(8):e105697. Epub 2014 Aug 27.

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

Membrane type 1-matrix metalloproteinase (MT1-MMP) functions as a signaling molecule in addition to a proteolytic enzyme. Our hypothesis was that MT1-MMP cooperates with protein kinase B (Akt) in tumor necrosis factor (TNF)-α-induced signaling pathways of vascular responses, including tissue factor (TF) procoagulant activity and endothelial apoptosis, in cultured human aortic endothelial cells (ECs). TNF-α (10 ng/mL) induced a decrease in Akt phosphorylation within 60 minutes in ECs. A chemical inhibitor of MMP, TIMP-2 and selective small interfering RNA (siRNA)-mediated suppression of MT1-MMP reversed TNF-α-triggered transient decrease of Akt phosphorylation within 60 minutes, suggesting that MT1-MMP may be a key regulator of Akt phosphorylation in TNF-α-stimulated ECs. In the downstream events, TNF-α increased TF antigen and activity, and suppressed the expression of thrombomodulin (TM) antigen. Inhibition of Akt markedly enhanced TNF-α-induced expression of TF antigen and activity, and further reduced the expression of TM antigen. Silencing of MT1-MMP by siRNA also reversed the changed expression of TF and TM induced by TNF-α. Moreover, TNF-α induced apoptosis of ECs through Akt- and forkhead box protein O1 (FoxO1)-dependent signaling pathway and nuclear factor-kB (NF-kB) activation. Knockdown of MT1-MMP by siRNA reversed apoptosis of ECs by inhibiting TNF-α-induced Akt-dependent regulation of FoxO1 in TNF-α-stimulated ECs. Immunoprecipitation demonstrated that TNF-α induced the changes in the associations between the cytoplasmic fraction of MT1-MMP and Akt in ECs. In conclusion, we show new evidence that MT1-MMP/Akt signaling axis is a key modifier for TNF-α-induced signaling pathways for modulation of procoagulant activity and apoptosis of ECs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0105697PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4146507PMC
May 2015

Pleural solitary fibrous tumor complicated with autoimmune hemolytic anemia.

Intern Med 2014 15;53(14):1549-52. Epub 2014 Jul 15.

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

We herein report a 74-year-old woman who presented with autoimmune hemolytic anemia (AIHA) associated with pleural solitary fibrous tumor (SFT). Her AIHA was initially treated with 1 mg/kg daily of oral prednisolone (PSL) for 2 months, which had a limited effect. However, after surgical tumor resection, the patient showed remarkable improvement of AIHA with normalizations of serum lactate dehydrogenase and bilirubin levels, and we were able to rapidly reduce the PSL dosage. This is the first description of a case of AIHA caused by SFT.
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http://dx.doi.org/10.2169/internalmedicine.53.2121DOI Listing
June 2015
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