Faculty Profiles - SONE, Hirohito

The Glasgow Prognostic Score as a pre-transplant risk assessment for allogeneic hematopoietic cell transplantation. Reviewed International journal

Yasuhiko Shibasaki, Tatsuya Suwabe, Takayuki Katagiri, Tomoyuki Tanaka, Hironori Kobayashi, Kyoko Fuse, Takashi Ushiki, Naoko Sato, Toshio Yano, Takashi Kuroha, Shigeo Hashimoto, Miwako Narita, Tatsuo Furukawa, Hirohito Sone, Masayoshi Masuko

Clinical transplantation 31 ( 11 ) 2017.11

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

Evaluation methods, such as scoring systems for predicting complications in advance, are necessary for determining the adaptation of allogeneic hematopoietic cell transplantation (HCT) and selecting appropriate conditioning regimens. The Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI), which is based on functions of main organs, is a useful tool for pre-transplant risk assessments and has been widely applied in determining treatment strategies for patients with hematological diseases. However, as allogeneic HCT is performed on patients with diverse backgrounds, another factor, which reinforces the HCT-CI, is required to evaluate pre-transplant risk assessments. The Glasgow Prognostic Score (GPS), which assesses the combined C-reactive protein and albumin, was reported to predict survival of patients with solid-organ malignancies independently of receiving chemo/radiotherapy and stages of cancer. In this study, we applied the GPS for pre-transplant risk assessments for allogeneic HCT. The GPS successfully stratified the patients into three risk groups of overall survival (OS) and non-relapse mortality (NRM). Moreover, the GPS could predict outcomes independently of the HCT-CI for OS and NRM in multivariate analysis. The GPS is considered to be a useful tool and reinforces the HCT-CI for determining adaptation of allogeneic HCT for patients with hematopoietic neoplasms.

DOI： 10.1111/ctr.13103

Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies. Reviewed International journal

Tomoyuki Tanaka, Yaeko Nakajima-Takagi, Kazumasa Aoyama, Shiro Tara, Motohiko Oshima, Atsunori Saraya, Shuhei Koide, Sha Si, Ichiro Manabe, Masashi Sanada, Manabu Nakayama, Masayoshi Masuko, Hirohito Sone, Haruhiko Koseki, Atsushi Iwama

The Journal of experimental medicine 214 ( 10 ) 2901 - 2913 2017.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ROCKEFELLER UNIV PRESS

Recurrent inactivating mutations have been identified in various hematological malignancies in the X-linked BCOR gene encoding BCL6 corepressor (BCOR); however, its tumor suppressor function remains largely uncharacterized. We generated mice missing Bcor exon 4, expressing a variant BCOR lacking the BCL6-binding domain. Although the deletion of exon 4 in male mice (BcorΔE4/y ) compromised the repopulating capacity of hematopoietic stem cells, BcorΔE4/y thymocytes had augmented proliferative capacity in culture and showed a strong propensity to induce acute T-cell lymphoblastic leukemia (T-ALL), mostly in a Notch-dependent manner. Myc, one of the critical NOTCH1 targets in T-ALL, was highly up-regulated in BcorΔE4/y T-ALL cells. Chromatin immunoprecipitation/DNA sequencing analysis revealed that BCOR was recruited to the Myc promoter and restrained its activation in thymocytes. BCOR also targeted other NOTCH1 targets and potentially antagonized their transcriptional activation. Bcl6-deficient thymocytes behaved in a manner similar to BcorΔE4/y thymocytes. Our results provide the first evidence of a tumor suppressor role for BCOR in the pathogenesis of T lymphocyte malignancies.

DOI： 10.1084/jem.20170167

Severe hypoglycaemia is a major predictor of incident diabetic retinopathy in Japanese patients with type 2 diabetes Reviewed

S. Tanaka, R. Kawasaki, S. Tanaka-Mizuno, S. Iimuro, S. Matsunaga, T. Moriya, S. Ishibashi, S. Katayama, Y. Ohashi, Y. Akanuma, H. Sone, H. Yamashita

DIABETES & METABOLISM 43 ( 5 ) 424 - 429 2017.10

Language：English Publishing type：Research paper (scientific journal) Publisher：MASSON EDITEUR

Aim. - Hypoglycaemia is a common complication in diabetes patients. However, its relationship with retinopathy has not been well documented in patients with type 2 diabetes (T2D). This study aimed to investigate the associations between hypoglycaemia and the incidence and progression of diabetic retinopathy (DR).
Methods. - In this longitudinal cohort study, which was part of the Japan Diabetes Complications Study (JDCS), adult patients with T2D were recruited at 59 diabetes clinics across Japan. Their history of hypoglycaemia was assessed by standardized self-reported questionnaires. Severe hypoglycaemia was defined as having at least one episode with coma requiring an outpatients visit or hospitalization. Adjusted hazard ratios (HRs) for incidence and progression of DR over 8 years of follow-up were determined.
Results. - Of 1221 patients without DR, 127 (10.4%) had experienced non-severe hypoglycaemia within the previous year, whereas 10 (0.8%) reported severe hypoglycaemia episodes. During the 8-year follow-up involving 8492 person-years, 329 patients developed DR. In 410 patients with prevalent DR, the adjusted HRs for incident DR were 4.35 (95% CI: 1.98-9.56; P < 0.01) and, for progression of DR, 2.29 (95% CI: 0.45-11.78; P = 0.32) with severe hypoglycaemia.
Conclusion. - Having a history of severe hypoglycaemia was one of the strongest predictors of incident DR in patients with T2D, with a fourfold increased risk. Identifying patients with greater risks of DR based on their history of hypoglycaemia may help to personalize risk evaluation in patients with diabetes. (C) 2017 Elsevier Masson SAS. All rights reserved.

DOI： 10.1016/j.diabet.2017.06.002

Comparative evaluation of torasemide and spironolactone on adverse cardiac remodeling in a rat model of dilated cardiomyopathy. Reviewed International journal

Somasundaram Arumugam, Remya Sreedhar, Vengadeshprabhu Karuppagounder, Meilei Harima, Masahiko Nakamura, Hiroshi Suzuki, Hirohito Sone, Kenichi Watanabe

Cardiovascular therapeutics 35 ( 5 ) 2017.10

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

BACKGROUND: Chronic heart failure (CHF) involves fluid retention and volume overload, leading to impaired cardiac function. In these conditions, diuretic agents are most commonly used to treat edema and thereby reducing the volume load on the failing heart. There are several other beneficial effects of diuretics apart from their action on urinary excretion. METHODS: To identify the effects of diuretic agents on adverse cardiac remodeling in CHF, this study was carried out, where we have compared the effects of torasemide and spironolactone in a rat model of dilated cardiomyopathy induced by porcine cardiac myosin-mediated experimental autoimmune myocarditis. RESULTS: Cardiac protein expression levels of inflammation, endoplasmic reticulum stress, and fibrosis markers were upregulated in the hearts of CHF rats, while treatment with either torasemide or spironolactone has downregulated their expression. The effect produced by spironolactone on cardiac fibrosis markers was comparably lesser than torasemide. Further, immunohistochemical analysis and histopathological studies have provided evidence to confirm the beneficial effects of these drugs on adverse cardiac remodeling in rats with CHF. CONCLUSION: Torasemide treatment has benefits against adverse cardiac remodeling in CHF rats, which was better than the protection offered by spironolactone.

DOI： 10.1111/1755-5922.12283

Comprehensive risk management for the prevention of cerebro-cardiovascular diseases in Japan Reviewed

Tamio Teramoto, Masayuki Yokode, Hiroyasu Iso, Akihiko Kitamura, Hiroki Shiomi, Tsuyoshi Kimura, Masayasu Matsumoto, Mami Iida, Jun Sasaki, Shigeru Inoue, Ryouichi Nagatomi, Tetsuo Shoji, Hidenori Arai, Hiromi Rakugi, Hirohito Sone, Shizuya Yamashita, Shigeru Mizyzaki

CLINICAL AND EXPERIMENTAL NEPHROLOGY 21 ( 5 ) 743 - 754 2017.10

Functional dissection of hematopoietic stem cell populations with a stemness-monitoring system based on NS-GFP transgene expression. Reviewed International journal

Mohamed A E Ali, Kyoko Fuse, Yuko Tadokoro, Takayuki Hoshii, Masaya Ueno, Masahiko Kobayashi, Naho Nomura, Ha Thi Vu, Hui Peng, Ahmed M Hegazy, Masayoshi Masuko, Hirohito Sone, Fumio Arai, Atsushi Tajima, Atsushi Hirao

Scientific reports 7 ( 1 ) 11442 - 11442 2017.9

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Hematopoietic stem cells (HSCs) in a steady state can be efficiently purified by selecting for a combination of several cell surface markers; however, such markers do not consistently reflect HSC activity. In this study, we successfully enriched HSCs with a unique stemness-monitoring system using a transgenic mouse in which green florescence protein (GFP) is driven by the promoter/enhancer region of the nucleostemin (NS) gene. We found that the phenotypically defined long-term (LT)-HSC population exhibited the highest level of NS-GFP intensity, whereas NS-GFP intensity was strongly downregulated during differentiation in vitro and in vivo. Within the LT-HSC population, NS-GFPhigh cells exhibited significantly higher repopulating capacity than NS-GFPlow cells. Gene expression analysis revealed that nine genes, including Vwf and Cdkn1c (p57), are highly expressed in NS-GFPhigh cells and may represent a signature of HSCs, i.e., a stemness signature. When LT-HSCs suffered from remarkable stress, such as transplantation or irradiation, NS-GFP intensity was downregulated. Finally, we found that high levels of NS-GFP identified HSC-like cells even among CD34+ cells, which have been considered progenitor cells without long-term reconstitution ability. Thus, high NS-GFP expression represents stem cell characteristics in hematopoietic cells, making this system useful for identifying previously uncharacterized HSCs.

DOI： 10.1038/s41598-017-11909-3

Successful 5-azacytidine treatment of myeloid sarcoma and leukemia cutis associated with myelodysplastic syndrome: A case report and literature review. Reviewed International journal

Takayuki Katagiri, Takashi Ushiki, Masayoshi Masuko, Tomoyuki Tanaka, Shukuko Miyakoshi, Kyoko Fuse, Yasuhiko Shibasaki, Jun Takizawa, Sadao Aoki, Hirohito Sone

Medicine 96 ( 36 ) e7975 2017.9

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

RATIONALE: Myeloid sarcoma (MS) and leukemia cutis (LC) are extramedullary tumors comprising myeloid blasts. They can occur de novo or concurrently with hematological disorders, usually acute myeloid leukemia (AML). AML chemotherapy is generally the initial therapy for MS and LC, and hematopoietic stem cell transplantation (HSCT) can be considered as additional therapy. However, treatment for older patients who are unable to continue intensive chemotherapy is not currently standardized. PATIENT CONCERNS: A 71-year-old Japanese woman was diagnosed with multiple MSs associated with myelodysplastic syndrome (MDS), using bone marrow aspiration and lymph node biopsy. DIAGNOSES: Additionally, LC was diagnosed by skin biopsy. Extramedullary MS and LC lesions were formed by massive infiltration of myeloblastic cells. INTERVENTIONS: Twenty courses of 5-azacytidine (5-Aza) were administrated as maintenance therapy after induction therapy with daunorubicin and cytarabine. OUTCOMES: Myeloblasts decreased in the bone marrow and the LC disappeared after induction therapy. The MSs completely disappeared, except for the palatine tonsil lesion, after 5-Aza maintenance therapy. 5-Aza treatment provided long-term partial response for more than 21 months. LESSONS: 5-Aza was well tolerated and may be a good option for the treatment of MS and LC associated with MDS, especially in older patients who cannot receive HSCT.

DOI： 10.1097/MD.0000000000007975

移植前予後予測モデルとしての同種造血細胞移植特異的Glasgow Prognostic Score(HCT specific Glasgow Prognostic Score as a new predictive tool for pre-transplant risk assessments)

Shibasaki Yasuhiko, Suwabe Tatsuya, Katagiri Takayuki, Tanaka Tomoyuki, Kobayashi Hironori, Fuse Kyoko, Ushiki Takashi, Narita Miwako, Sone Hirohito, Masuko Masayoshi

臨床血液 58 ( 9 ) 1547 - 1547 2017.9

Association between all-cause mortality and severity of depressive symptoms in patients with type 2 diabetes: Analysis from the Japan Diabetes Complications Study (JDCS). Reviewed International journal

Satoshi Matsunaga, Shiro Tanaka, Kazuya Fujihara, Chika Horikawa, Satoshi Iimuro, Masafumi Kitaoka, Asako Sato, Jiro Nakamura, Masakazu Haneda, Hitoshi Shimano, Yasuo Akanuma, Yasuo Ohashi, Hirohito Sone

Journal of psychosomatic research 99 34 - 39 2017.8

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

OBJECTIVE: The aims of this study are to confirm whether the excess mortality caused by depressive symptoms is independent of severe hypoglycemia in patients with type 2 diabetes mellitus (T2DM) and to evaluate the association between all-cause mortality and degrees of severity of depressive symptoms in Japanese patients with T2DM. METHODS: A total of 1160 Japanese patients with T2DM were eligible for this analysis. Participants were followed prospectively for 3years and their depressive states were evaluated at baseline by the Center for Epidemiologic Studies Depression Scale (CES-D). Cox proportional hazards model was used to evaluate the relative risk of all-cause mortality and was adjusted by possible confounding factors, including severe hypoglycemia, all of which are known as risk factors for both depression and mortality. RESULTS: After adjustment for severe hypoglycemia, each 5-point increase in the CES-D score was significantly associated with excess all-cause mortality (hazard ratio 1.69 [95% CI 1.26-2.17]). The spline curve of HRs for mortality according to total CES-D scores showed that mortality risk was slightly increased at lower scores but was sharply elevated at higher scores. CONCLUSION: A high score on the CES-D at baseline was significantly associated with all-cause mortality in patients with T2DM after adjusting for confounders including severe hypoglycemia. However, only a small effect on mortality risk was found at relatively lower levels of depressive symptoms in this population. Further research is needed to confirm this relationship between the severity of depressive symptoms and mortality in patients with T2DM.

DOI： 10.1016/j.jpsychores.2017.05.020

Elovl6 Deficiency Improves Glycemic Control in Diabetic db/db Mice by Expanding beta-Cell Mass and Increasing Insulin Secretory Capacity Reviewed International journal

Hui Zhao, Takashi Matsuzaka, Yuta Nakano, Kaori Motomura, Nie Tang, Tomotaka Yokoo, Yuka Okajima, Song-iee Han, Yoshinori Takeuchi, Yuichi Aita, Hitoshi Iwasaki, Shigeru Yatoh, Hiroaki Suzuki, Motohiro Sekiya, Naoya Yahagi, Yoshimi Nakagawa, Hirohito Sone, Nobuhiro Yamada, Hitoshi Shimano

DIABETES 66 ( 7 ) 1833 - 1846 2017.7

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER DIABETES ASSOC

Dysfunctional fatty acid (FA) metabolism plays an important role in the pathogenesis of beta-cell dysfunction and loss of beta-cell mass in type 2 diabetes (T2D). Elovl6 is a microsomal enzyme that is responsible for converting C16 saturated and monounsaturated FAs into C18 species. We previously showed that Elovl6 played a critical role in the development of obesity-induced insulin resistance by modifying FA composition. To further define its role in T2D development, we assessed the effects of Elovl6 deletion in leptin receptor-deficient C57BL/KsJ db/db mice, a model of T2D. The db/db; Elovl6(-/-) mice had a markedly increased beta-cell mass with increased proliferation and decreased apoptosis, an adaptive increase in insulin, and improved glycemic control. db/db islets were characterized by a prominent elevation of oleate (C18: 1n-9), cell stress, and inflammation, which was completely suppressed by Elovl6 deletion. As a mechanistic ex vivo experiment, isolated islets from Elovl6(-/-) mice exhibited reduced susceptibility to palmitate-induced inflammation, endoplasmic reticulum stress, and beta-cell apoptosis. In contrast, oleate-treated islets resulted in impaired glucose-stimulated insulin secretion with suppressed related genes irrespective of the Elovl6 gene. Taken together, Elovl6 is a fundamental factor linking dysregulated lipid metabolism to beta-cell dysfunction, islet inflammation, and beta-cell apoptosis in T2D, highlighting oleate as the potential culprit of beta-cell lipotoxicity.

DOI： 10.2337/db16-1277

Clinicopathological features of cryptococcal lymphadenitis and a review of literature. Reviewed

Elovl6 Deficiency Improves Glycemic Control in Diabetic db/db Mice by Expanding β-Cell Mass and Increasing Insulin Secretory Capacity

Zhao, Hui, Matsuzaka, Takashi, Nakano, Yuta, Motomura, Kaori, Tang, Nie, Yokoo, Tomotaka, Okajima, Yuka, Han, Song-Iee, Takeuchi, Yoshinori, Aita, Yuichi, Iwasaki, Hitoshi, Yatoh, Shigeru, Suzuki, Hiroaki, Sekiya, Motohiro, Yahagi, Naoya, Nakagawa, Yoshimi, Sone, Hirohito, Yamada, Nobuhiro, Shimano, Hitoshi

Diabetes 66 ( 7 ) 1833 - 1846 2017.7

Impact of Obesity and Metabolic Phenotypes on Coronary Artery Disease (CAD) According to Glucose Tolerance Status Reviewed

Kazuya Fujihara, Satoru Kodama, Masahiko Yamamoto, Satoshi Matsunaga, Yasuhiro Matsubayashi, Masahiro Ishizawa, Mieko Koishi, Chie Ito, Nauta Yamanaka, Kiminori Kato, Hirohito Sone

DIABETES 66 A406 - A406 2017.6

Advanced Glycation End Products Induce Brain-Derived Neurotrophic Factor Release from Human Platelets through the Src Family Kinases Activation Reviewed

Kazuo Furukawa, Ichiro Fuse, Yuriko Iwakura, Hidekazu Sotoyama, Osamu Hanyu, Hiroyuki Nawa, Nobuyuki Takei, Hirohito Sone

DIABETES 66 A123 - A123 2017.6

Kawamoto K, Miyoshi H, Suzuki T, Muto R, Yamada K, Yanagida E, Koshino M, Sasaki Y, Takizawa J, Sone H, Sugita Y, Seto M, Ohshima K

Journal of clinical and experimental hematopathology : JCEH 57 ( 1 ) 26 - 30 2017.6

Language：English Publishing type：Research paper (scientific journal)

Cryptococcosis is an invasive fungal infection in immunocompromised patients. The clinicopathological characteristics of cryptococcal lymphadenitis are not well known. We analyzed three cases of cryptococcal lymphadenitis and compared their characteristics with those in previous reports. Two patients were human immunodeficiency virus (HIV) carriers, and one patient was a human T-cell leukemia virus type-1 (HTLV-1) carrier. The age of the HTLV-1 carrier with cryptococcosis was much higher than that of the HIV-1 carriers. CD4-positive cell counts in peripheral blood were 5.8/μL (Case 1) and 79.9/μL (Case 2) in the HIV carriers and 3285/μL in the HTLV-1 carrier (Case 3). According to flow cytometric analysis of the lymph nodes of Cases 1, 2, and 3, 50.0%, 87.1%, and 85.9%, respectively, of the T-cells were CD3; 9.8%, 16.3%, and 75.8%, respectively, were CD4; and 35.5%, 77.3%, and 10.2%, respectively, were CD8. Cryptococcus neoformans was detected in tissue culture in all patients. Although gelatinous lesions and numerous fungal cocci were observed in the two HIV patients, the granuloma formation was small. Gelatinous formation and granuloma formation were observed in the HTLV-1 carrier. Necrosis was observed in all cases. In previous reports, granuloma formation, epithelioid cells, and necrotic lesions were observed in most cases. Most of the patients were also immunosuppressed. However, no HTLV-1 carrier was detected. In conclusion, lymphadenopathy in a HTLV-1 carrier may suggest the presence of cryptococcal lymphadenitis. The frequency of cryptococcosis in HTVL-1 carriers may increase with increase in the long-term survival rate of HTLV-1 carriers.

DOI： 10.3960/jslrt.17011

Impact of glucose tolerance status on the development of coronary artery disease among working-age men. Reviewed

Fujihara K, Igarashi R, Yamamoto M, Ishizawa M, Matsubayasi Y, Matsunaga S, Kato K, Ito C, Koishi M, Yamanaka N, Kodama S, Sone H

DIABETES & METABOLISM 43 ( 3 ) 261 - 264 2017.6

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：MASSON EDITEUR

Aims. To examine the impact of glucose tolerance status on the development of coronary artery disease (CAD) in working-age men in Japan.
Methods. This population-based retrospective cohort study included 111,621 men aged 31-60 years [63,558 with normal glucose tolerance (NGT); 37,126 with prediabetes; 10,937 with diabetes]. The Cox proportional-hazards regression model was used to identify variables related to the incidence of CAD.
Results. Multivariate analysis showed that, compared with NGT, diabetes increased the risk of CAD by 17.3 times (95% CI: 6.36-47.0) at ages 31-40 years, by 2.74 times (95% CI: 1.85-4.05) at ages 41-50 years and by 2.47 times (95% CI: 1.69-3.59) at ages 51-60 years. The HRs for CAD in men with diabetes aged 31-40 equaled that of men with NGT aged 51-60 [18.2 (7.15-46.4) and 19.4 (8.28-45.4), respectively].
Conclusion. The impact of diabetes on CAD was markedly greater in men aged 31-40 years compared with those aged 41-60 years. (C) 2016 Elsevier Masson SAS. All rights reserved.

DOI： 10.1016/j.diabet.2016.09.001