Faculty Profiles - TAKAHASHI, Yoshiyuki

Defective Epstein-Barr virus in chronic active infection and haematological malignancy. Reviewed International journal

Yusuke Okuno, Takayuki Murata, Yoshitaka Sato, Hideki Muramatsu, Yoshinori Ito, Takahiro Watanabe, Tatsuya Okuno, Norihiro Murakami, Kenichi Yoshida, Akihisa Sawada, Masami Inoue, Keisei Kawa, Masao Seto, Koichi Ohshima, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Yohei Narita, Masahiro Yoshida, Fumi Goshima, Jun-Ichi Kawada, Tetsuya Nishida, Hitoshi Kiyoi, Seiichi Kato, Shigeo Nakamura, Satoko Morishima, Tetsushi Yoshikawa, Shigeyoshi Fujiwara, Norio Shimizu, Yasushi Isobe, Masaaki Noguchi, Atsushi Kikuta, Keiji Iwatsuki, Yoshiyuki Takahashi, Seiji Kojima, Seishi Ogawa, Hiroshi Kimura

Nature microbiology Vol. 4 ( 3 ) page： 404 - 413 2019.3

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

Epstein-Barr virus (EBV) infection is highly prevalent in humans and is implicated in various diseases, including cancer1,2. Chronic active EBV infection (CAEBV) is an intractable disease classified as a lymphoproliferative disorder in the 2016 World Health Organization lymphoma classification1,2. CAEBV is characterized by EBV-infected T/natural killer (NK) cells and recurrent/persistent infectious mononucleosis-like symptoms3. Here, we show that CAEBV originates from an EBV-infected lymphoid progenitor that acquires DDX3X and other mutations, causing clonal evolution comprising multiple cell lineages. Conspicuously, the EBV genome in CAEBV patients harboured frequent intragenic deletions (27/77) that were also common in various EBV-associated neoplastic disorders (28/61), including extranodal NK/T-cell lymphoma and EBV-positive diffuse large B-cell lymphoma, but were not detected in infectious mononucleosis or post-transplant lymphoproliferative disorders (0/47), which suggests a unique role of these mutations in neoplastic proliferation of EBV-infected cells. These deletions frequently affected BamHI A rightward transcript microRNA clusters (31 cases) and several genes that are essential for producing viral particles (20 cases). The deletions observed in our study are thought to reactivate the lytic cycle by upregulating the expression of two immediate early genes, BZLF1 and BRLF14-7, while averting viral production and subsequent cell lysis. In fact, the deletion of one of the essential genes, BALF5, resulted in upregulation of the lytic cycle and the promotion of lymphomagenesis in a xenograft model. Our findings highlight a pathogenic link between intragenic EBV deletions and EBV-associated neoplastic proliferations.

DOI： 10.1038/s41564-018-0334-0

Publisher Correction: Defective Epstein-Barr virus in chronic active infection and haematological malignancy. Reviewed International journal Open Access

Nature microbiology Vol. 4 ( 3 ) page： 544 - 544 2019.3

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

In the version of this Letter originally published, in the sentence beginning "The major driver role of DDX3X mutations...", the citation "Fig. 2a-f" should have been "Fig. 2". In addition, in the sentence beginning "Another finding of interest was the presence of identical driver mutations...", the citation "Fig. 3a,b and Fig. 4" should have been "Fig. 3". This has now been amended in all versions of the Letter.

DOI： 10.1038/s41564-019-0387-8

次世代シークエンス解析による発熱性好中球減少症の網羅的病原微生物検出

堀場千尋, 鳥居ゆか, 鈴木高子, 武内俊, 奥村俊彦, 川田潤一, 伊藤嘉規, 高橋義行, 嶋田繭子, 荻朋男

感染症学雑誌 Vol. 93 ( 臨増 ) page： 325 - 325 2019.3

がん診療拠点病院における整形外科 -その現状と課題- 小児がん拠点病院における整形外科診療小児がん治療後の整形外科的問題点と小児期の骨・軟部肉腫

西田佳弘, 内田広夫, 高橋義行, 石黒直樹

日本整形外科学会雑誌 Vol. 93 ( 2 ) page： S371 - S371 2019.3

Frequent intragenic microdeletions of elastin in familial supravalvular aortic stenosis. Reviewed International journal

Satoshi Hayano, Yusuke Okuno, Makiko Tsutsumi, Hidehito Inagaki, Yoshie Fukasawa, Hiroki Kurahashi, Seiji Kojima, Yoshiyuki Takahashi, Taichi Kato

International journal of cardiology Vol. 274 page： 290 - 295 2019.1

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

BACKGROUND: Supravalvular aortic stenosis (SVAS) is a congenital heart disease affecting approximately 1:25,000 live births. SVAS may occur sporadically, be inherited in an autosomal dominant manner, or be associated with Williams-Beuren syndrome, a complex developmental disorder caused by a microdeletion of chromosome 7q11.23. ELN on 7q11.23, which encodes elastin, is the only known gene to be recurrently mutated in less than half of SVAS patients. METHODS: Whole-exome sequencing (WES) was performed for seven familial SVAS families to identify other causative gene mutations of SVAS. RESULTS: Three truncating mutations and three intragenic deletions affecting ELN were identified, yielding a diagnostic efficiency of 6/7 (85%). The deletions, which explained 3/7 of the present cohort, spanned 1-29 exons, which might be missed in the course of mutational analysis targeting point mutations. The presence of such deletions was validated by both WES-based copy number estimation and multiplex ligation-dependent probe amplification analyses, and their pathogenicity was reinforced by co-segregation with clinical presentations. CONCLUSIONS: The majority of familial SVAS patients appear to carry ELN mutations, which strongly indicates that elastin is the most important causative gene for SVAS. The frequency of intragenic deletions highlights the need for quantitative tests to analyze ELN for efficient genetic diagnosis of SVAS.

DOI： 10.1016/j.ijcard.2018.09.032

Planetary-scale streak structure reproduced in high-resolution simulations of the Venus atmosphere with a low-stability layer Reviewed Open Access

Hiroki Kashimura, Norihiko Sugimoto, Masahiro Takagi, Yoshihisa Matsuda, Wataru Ohfuchi, Takeshi Enomoto, Kensuke Nakajima, Masaki Ishiwatari, Takao M. Sato, George L. Hashimoto, Takehiko Satoh, Yoshiyuki O. Takahashi, Yoshi-Yuki Hayashi

NATURE COMMUNICATIONS Vol. 10 ( 1 ) page： 23 2019.1

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

Cloud patterns are important clues for revealing the atmospheric circulation of Venus. Recently, a planetary-scale streak structure has been discovered in middle- and lower-cloud images of Venus' night-side taken by IR2, the 2-mu m camera, on board the Akatsuki orbiter. However, its formation mechanism has not been investigated. Here we succeed, for the first time, in reproducing the patterns of the observed streak structure, as regions of strong downward flows that develop in high-resolution global simulations of the Venus atmosphere. The streaks are formed in both hemispheres with equatorial symmetry, which is caused by equatorial Rossby-like and Kelvin-like waves with zonal wavenumber one. The low-stability layer that has been suggested by past observations is essential for reproducing the streak structure. The streaks of downward flow result from the interaction of the meridionally tilted phase lines of the Rossby-like waves and the characteristics of baroclinic instability produced around the low-stability layer.

DOI： 10.1038/s41467-018-07919-y

Investigation of appropriate semi-quantitative index for assessment of esophageal and breast cancer treatment response in Japanese patients using 18F-FDG PET/CT findings. Reviewed

Tsuchitani T, Takahashi Y, Maeda Y, Oda M, Enoki T, Kotoura N, Kitajima K

Hellenic journal of nuclear medicine Vol. 22 ( 1 ) page： 20 - 24 2019.1

A novel CUL4B splice site variant in a young male exhibiting less pronounced features. Reviewed International journal

Yuji Nakamura, Yusuke Okuno, Hideki Muramatsu, Tomoko Kawai, Kazuhito Satou, Daisuke Ieda, Ikumi Hori, Kei Ohashi, Yutaka Negishi, Ayako Hattori, Yoshiyuki Takahashi, Seiji Kojima, Shinji Saitoh

Human genome variation Vol. 6 page： 43 - 43 2019

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

Patients with variants in CUL4B exhibit syndromic intellectual disability (MIM #300354). A seven-year-old boy presented with intellectual disability, a history of seizure, characteristic facial features, and short stature. Whole-exome sequencing detected a c.974+3A>G variant in CUL4B, which was subsequently confirmed to disrupt mRNA splicing. The current patient showed less pronounced phenotypic features compared with the previously reported cases. This report, therefore, provides evidence of genotype-phenotype correlations in CUL4B-related disorders.

DOI： 10.1038/s41439-019-0074-6

[LOCALIZED AMYLOIDOSIS OF THE RENAL SINUS: A CASE REPORT]. Open Access

Ohashi T, Tanaka J, Asai K, Shimada S, Takahashi Y, Furukawa T

Nihon Hinyokika Gakkai zasshi. The japanese journal of urology Vol. 110 ( 3 ) page： 191 - 195 2019

Ureteral dilatation detected in magnetic resonance imaging predicts vesicoureteral reflux in children with urinary tract infection. Reviewed International journal Open Access

Norihiro Murakami, Jun-Ichi Kawada, Azumi Watanabe, Toshinao Arakawa, Takamasa Kano, Takako Suzuki, Ryo Tanaka, Daiei Kojima, Yoshihiko Kawano, Shin Hoshino, Hideki Muramatsu, Yoshiyuki Takahashi, Yoshiaki Sato, Masashi Koyama, Jun Natsume

PloS one Vol. 13 ( 12 ) page： e0209595 2018.12

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

OBJECTIVE: Urinary tract infection (UTI), one of the most common bacterial infections occurring during infancy and early childhood, is frequently associated with vesicoureteral reflux (VUR). Although several guidelines recommend performing ultrasonography as a screening test, its utility is not adequate and appropriate screening tests are strongly desirable. In this study, we evaluate the use of magnetic resonance imaging (MRI) as a screening test for VUR in children with UTI. METHODS: We prospectively studied 108 patients with suspected UTI between April 2014 and March 2016. UTI was diagnosed on the basis of diffusion-weighted MRI (DW-MRI) and urine culture findings. We measured ureteral dilatation using MRI in 96 patients with UTI and assessed the relationship between ureteral dilatation in MRI and VUR in 46 patients who underwent voiding cystourethrography (VCUG). RESULTS: Among 108 patients, 88 and 8 were diagnosed with upper and lower UTI, respectively. Among 46 patients who underwent VCUG, 23 had VUR (14 low grade and 9 high grade). Patients with ureteral dilatation detected on MRI had VUR more frequently than those without ureteral dilatation (any grades VUR, 71% vs. 32%; P = 0.02; high-grade VUR, 38% vs. 2%, P = 0.007). Overall, ureteral dilatation findings on MRI achieved sensitivity 65.2% and specificity 73.9% as a screening test for VUR. In addition, DW-MRI achieved sensitivity 100% and specificity 81.8% in the diagnosis of upper UTI. CONCLUSION: These findings suggested that MRI is a valuable tool for screening of VUR as well as diagnosis of upper UTI.

DOI： 10.1371/journal.pone.0209595

Identification of potential pathogenic viruses in patients with acute myocarditis using next-generation sequencing. Reviewed International journal

Suguru Takeuchi, Jun-Ichi Kawada, Yusuke Okuno, Kazuhiro Horiba, Takako Suzuki, Yuka Torii, Kazushi Yasuda, Atsushi Numaguchi, Taichi Kato, Yoshiyuki Takahashi, Yoshinori Ito

Journal of medical virology Vol. 90 ( 12 ) page： 1814 - 1821 2018.12

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

Myocarditis is an inflammatory disease of the myocardium and leads to cardiac dysfunction and heart failure. Although viral infections are considered to be the most common etiology of myocarditis, the identification of the causative virus is still challenging. Recently, next-generation sequencing (NGS) has been applied in the diagnosis of infectious diseases. The aim of the current study was to comprehensively analyze potential pathogenic microorganisms using NGS in the sera of patients with myocarditis. Twelve pediatric and five adult patients hospitalized for acute myocarditis were included. Serum samples in the acute phase were obtained and analyzed using NGS to detect pathogen-derived DNA and RNA. Viral sequence reads were detected in 7 (41%) of the 17 myocarditis patients by NGS. Among these patients, detection of Epstein-Barr virus, human parvovirus B19, torque teno virus, and respiratory syncytial virus reads by NGS was consistent with polymerase chain reaction or antigen test results in one patient each. A large number of human pegivirus reads were detected from one patient by RNA sequencing; however, its pathogenicity to human is unknown. Conversely, the number of detected virus-derived reads was small in most cases, and the pathophysiological role of these viruses remains to be clarified. No significant bacterial or fungal reads other than normal bacterial flora was detected. These data indicate that comprehensive detection of virus-derived DNA and RNA using NGS can be useful for the identification of potential pathogenic viruses in myocarditis.

DOI： 10.1002/jmv.25263

Reduction of stratum corneum ceramides in Neu-Laxova syndrome caused by phosphoglycerate dehydrogenase deficiency. Reviewed International journal Open Access

Takuya Takeichi, Yusuke Okuno, Akane Kawamoto, Takeshi Inoue, Eiko Nagamoto, Chiaki Murase, Eri Shimizu, Kenichi Tanaka, Yuichi Kageshita, Satoshi Fukushima, Michihiro Kono, Junko Ishikawa, Hironobu Ihn, Yoshiyuki Takahashi, Masashi Akiyama

Journal of lipid research Vol. 59 ( 12 ) page： 2413 - 2420 2018.12

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

Neu-Laxova syndrome (NLS) is a very rare autosomal recessive congenital disorder characterized by disturbed development of the central nervous system and the skin and caused by mutations in any of the three genes involved in de novo l-serine biosynthesis: PHGDH, PSAT1, and PSPH l-Serine is essential for the biosynthesis of phosphatidylserine and sphingolipids. The extracellular lipid of the stratum corneum, of which sphingolipid constitutes a significant part, plays a primary role in skin barrier function. Here, we describe a Japanese NLS pedigree with a previously unreported nonsense mutation in PHGDH and a unique inversion of chromosome 1. In addition, the levels of 11 major ceramide classes in the tape-stripped stratum corneum of the NLS patient's skin were assessed by LC/MS. Notably, lower amounts of ceramides of all classes were found in the patient's stratum corneum than in those of controls. This is the first report to demonstrate the reduction of ceramides in the stratum corneum of an NLS patient due to PHGDH mutations. The clinical findings and a detailed analysis of ceramides from the stratum corneum in the family extend the spectrum of clinical anomalies and give us a clue to the pathomechanisms of ichthyosis in NLS patients with phosphoglycerate dehydrogenase deficiency.

DOI： 10.1194/jlr.P087536