Faculty Profiles - TORII Yuka

Papers - TORII Yuka

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Comprehensive pathogen detection in sera of Kawasaki disease patients by high-throughput sequencing: a retrospective exploratory study. International journal Open Access

Yuka Torii, Kazuhiro Horiba, Satoshi Hayano, Taichi Kato, Takako Suzuki, Jun-Ichi Kawada, Yoshiyuki Takahashi, Seiji Kojima, Yusuke Okuno, Tomoo Ogi, Yoshinori Ito

BMC pediatrics Vol. 20 ( 1 ) page： 482 - 482 2020.10

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Kawasaki disease (KD) is an idiopathic systemic vasculitis that predominantly damages coronary arteries in children. Various pathogens have been investigated as triggers for KD, but no definitive causative pathogen has been determined. As KD is diagnosed by symptoms, several days are needed for diagnosis. Therefore, at the time of diagnosis of KD, the pathogen of the trigger may already be diminished. The aim of this study was to explore comprehensive pathogens in the sera at the acute stage of KD using high-throughput sequencing (HTS). METHODS: Sera of 12 patients at an extremely early stage of KD and 12 controls were investigated. DNA and RNA sequences were read separately using HTS. Sequence data were imported into the home-brew meta-genomic analysis pipeline, PATHDET, to identify the pathogen sequences. RESULTS: No RNA virus reads were detected in any KD case except for that of equine infectious anemia, which is known as a contaminant of commercial reverse transcriptase. Concerning DNA viruses, human herpesvirus 6B (HHV-6B, two cases) and Anelloviridae (eight cases) were detected among KD cases as well as controls. Multiple bacterial reads were obtained from KD and controls. Bacteria of the genera Acinetobacter, Pseudomonas, Delfita, Roseomonas, and Rhodocyclaceae appeared to be more common in KD sera than in the controls. CONCLUSION: No single pathogen was identified in serum samples of patients at the acute phase of KD. With multiple bacteria detected in the serum samples, it is difficult to exclude the possibility of contamination; however, it is possible that these bacteria might stimulate the immune system and induce KD.

DOI： 10.1186/s12887-020-02380-7

Association between graft source and response to live-attenuated vaccination in pediatric hematopoietic stem cell transplantation recipients: a single-center retrospective study. International journal Open Access

Takako Suzuki, Jun-Ichi Kawada, Eri Nishikawa, Yuka Torii, Kazuhiro Horiba, Suguru Takeuchi, Toshihiko Okumura, Hideki Muramatsu, Yoshiyuki Takahashi, Yoshinori Ito

Bone marrow transplantation Vol. 55 ( 9 ) page： 1872 - 1874 2020.9

Viral DNA Loads in Various Blood Components of Patients With Epstein-Barr Virus-Positive T-Cell/Natural Killer Cell Lymphoproliferative Diseases. International journal

Jun-Ichi Kawada, Yasuko Kamiya, Akihisa Sawada, Keiji Iwatsuki, Koji Izutsu, Yuka Torii, Hiroshi Kimura, Yoshinori Ito

The Journal of infectious diseases Vol. 220 ( 8 ) page： 1307 - 1311 2019.10

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

To evaluate diagnostic values for Epstein-Barr virus (EBV) DNA loads in different blood components of patients with EBV-positive T-cell/natural killer cell lymphoproliferative diseases, EBV DNA loads were compared among disease categories in each blood component from 59 patients. Plasma viral loads were significantly higher in "active" disease in chronic active EBV infection. EBV DNA was not detected in the plasma from 7 patients in whom EBV DNA was detected in peripheral blood mononuclear cells and whole blood. Diagnostic cutoff values for whole blood EBV DNA loads of patients with chronic active EBV infection compared with those of infectious mononucleosis was 104.2 (15 800) IU/mL.

DOI： 10.1093/infdis/jiz315

Metagenomic analysis using next-generation sequencing of pathogens in bronchoalveolar lavage fluid from pediatric patients with respiratory failure. International journal Open Access

Suguru Takeuchi, Jun-Ichi Kawada, Kazuhiro Horiba, Yusuke Okuno, Toshihiko Okumura, Takako Suzuki, Yuka Torii, Shinji Kawabe, Sho Wada, Takanari Ikeyama, Yoshinori Ito

Scientific reports Vol. 9 ( 1 ) page： 12909 - 12909 2019.9

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

Next-generation sequencing (NGS) has been applied in the field of infectious diseases. Bronchoalveolar lavage fluid (BALF) is considered a sterile type of specimen that is suitable for detecting pathogens of respiratory infections. The aim of this study was to comprehensively identify causative pathogens using NGS in BALF samples from immunocompetent pediatric patients with respiratory failure. Ten patients hospitalized with respiratory failure were included. BALF samples obtained in the acute phase were used to prepare DNA- and RNA-sequencing libraries. The libraries were sequenced on MiSeq, and the sequence data were analyzed using metagenome analysis tools. A mean of 2,041,216 total reads were sequenced for each library. Significant bacterial or viral sequencing reads were detected in eight of the 10 patients. Furthermore, candidate pathogens were detected in three patients in whom etiologic agents were not identified by conventional methods. The complete genome of enterovirus D68 was identified in two patients, and phylogenetic analysis suggested that both strains belong to subclade B3, which is an epidemic strain that has spread worldwide in recent years. Our results suggest that NGS can be applied for comprehensive molecular diagnostics as well as surveillance of pathogens in BALF from patients with respiratory infection.

DOI： 10.1038/s41598-019-49372-x

Serological screening of immunoglobulin M and immunoglobulin G during pregnancy for predicting congenital cytomegalovirus infection. International journal Open Access

Yuka Torii, Shigeru Yoshida, Yoichiro Yanase, Takashi Mitsui, Kazuhiro Horiba, Toshihiko Okumura, Suguru Takeuchi, Takako Suzuki, Jun-Ichi Kawada, Tomomi Kotani, Mamoru Yamashita, Yoshinori Ito

BMC pregnancy and childbirth Vol. 19 ( 1 ) page： 205 - 205 2019.6

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Cytomegalovirus (CMV) is one of the most frequent pathogens for congenital infections. Most cases of congenital CMV infection (cCMV) are asymptomatic at birth, but sensorineural hearing loss (SNHL) or neurodevelopmental delay can appear later in childhood. This prospective study examined the practicability of serological screening for anti-CMV immunoglobulin (Ig) G and anti-CMV IgM in pregnant women. METHODS: A total of 11,753 pregnant women were examined for CMV IgG and CMV IgM during the first or second trimester. When IgM was positive, IgG was reevaluated more than two weeks later. When IgG was negative, IgG was reevaluated in the second or third trimester. All neonates from mothers with positive/borderline IgM or IgG seroconversion underwent polymerase chain reaction assay for CMV using urine samples to diagnose cCMV. Levels of IgG and IgM were compared between mothers with and without cCMV. Receiver operating characteristic (ROC) curves for IgM titers were analyzed. RESULTS: Eight of 500 neonates (1.6%) born from mothers with positive IgG and positive IgM, and 3 of 13 neonates (23.1%) born from mothers with IgG seroconversion were diagnosed with cCMV. Neither IgM titers nor IgG titers differed significantly between cCMV and non-cCMV groups. The area under the ROC curve was 0.716 and the optimal cut-off for IgM was 7.28 index (sensitivity = 0.625, specificity = 0.965, positive predictive value = 0.238, negative predictive value = 0.993). Titers of IgG were not frequently elevated in pregnant women with positive IgM during the observation period, including in those with cCMV. All 11 cCMV cases were asymptomatic at birth and none had shown SNHL or developmental delay as of the last regular visit (mean age, 40 months). CONCLUSIONS: Seroconversion of CMV IgG and high-titer IgM during early pregnancy are predictors of cCMV. High IgM titer (> 7.28 index) is a predictor despite relatively low sensitivity. Levels of IgG had already plateaued at first evaluation in mothers with cCMV. Maternal screening offered insufficient positive predictive value for diagnosing cCMV, but allowed identifying asymptomatic cCMV cases in an early stage.

DOI： 10.1186/s12884-019-2360-1

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

Authorship：Lead author 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

Risk Factors for Viral Infections in Pediatric Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Narita, A; Ito, Y; Torii, Y; Kawada, JI; Miwata, S; Narita, K; Kitazawa, H; Hamada, M; Kataoka, S; Ichikawa, D; Ito, R; Murakami, N; Kojima, D; Suzuki, K; Nishikawa, E; Kawashima, N; Okuno, Y; Muramatsu, H; Hama, A; Kojima, S; Takahashi, Y

BONE MARROW TRANSPLANTATION Vol. 53 page： 588 - 589 2018.9

Congenital Cytomegalovirus Pneumonitis and Treatment Response Evaluation Using Viral Load during Ganciclovir Therapy: a Case Report Open Access

Lee-Yoshimoto Minsoo, Goishi Keiji, Torii Yuka, Ito Yoshinori, Ono Hiroya, Mori Tomoko, Kashiwa Naoyuki, Hosokawa Shinichi, Shichino Hiroyuki

Japanese Journal of Infectious Diseases Vol. 71 ( 4 ) page： 309 - 311 2018.7

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：National Institute of Infectious Diseases, Japanese Journal of Infectious Diseases Editorial Committee

<p>Cytomegalovirus (CMV) is the most common cause of congenital infection. Pneumonitis is considered to be a rare manifestation although congenital CMV infection presents with various non-specific findings. Ganciclovir and valganciclovir are beneficial for improving neurodevelopmental sequelae and hearing outcomes of congenital CMV infection; however, treatment response evaluation is not well reported. We report a female case of congenital CMV infection presenting with pneumonitis, meningoencephalitis, and chorioretinitis. She was treated with intravenous ganciclovir for 6 weeks, and clinical features improved. Measurement of the CMV genome load by real-time polymerase chain reaction assay was performed during treatment. After the administration of ganciclovir, the CMV genome was not detected in the blood and levels decreased gradually in the urine. Physicians should consider the possibility of congenital CMV infection in neonates who present with respiratory distress. Furthermore, measurement of the CMV genome load in blood and urine may be useful for evaluating treatment response.</p>

DOI： 10.7883/yoken.jjid.2017.577

Antitumor effects of duvelisib on Epstein-Barr virus-associated lymphoma cells. International journal Open Access

Jun-Ichi Kawada, Shotaro Ando, Yuka Torii, Takahiro Watanabe, Yoshitaka Sato, Yoshinori Ito, Hiroshi Kimura

Cancer medicine Vol. 7 ( 4 ) page： 1275 - 1284 2018.4

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

Epstein-Barr virus (EBV) is a ubiquitous oncogenic virus that is associated with B cell lymphomas, including Burkitt lymphoma and Hodgkin lymphoma. Previous studies have shown that the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is activated in EBV-associated lymphomas and can be a novel therapeutic target. An oral dual inhibitor of PI3Kγ and PI3Kδ, duvelisib, is in clinical trials for the treatment of lymphoid malignancies. In this study, we evaluated how duvelisib affects the activity of the PI3K/Akt signaling pathway and if it has antitumor effects in EBV-associated lymphoma cell lines. We found that the PI3K/Akt signaling pathway was activated in most of the B and T cell lymphoma cell lines tested. Additionally, duvelisib treatment inhibited cellular growth in the tested cell lines. Overall, B cell lines were more susceptible to duvelisib than T and NK cell lines in vitro regardless of EBV infection. However, the additional influence of duvelisib on the tumor microenvironment was not assessed. Duvelisib treatment induced both apoptosis and cell cycle arrest in EBV-positive and -negative B cell lines, but not in T cell lines. Furthermore, duvelisib treatment reduced the expression of EBV lytic genes (BZLF1 and gp350/220) in EBV-positive B cell lines, suggesting that duvelisib suppresses the lytic cycle of EBV induced by B cell receptor signaling. However, duvelisib did not induce a remarkable change in the expression of EBV latent genes. These results may indicate that there is therapeutic potential for duvelisib administration in the treatment of EBV-associated B cell lymphomas and other B cell malignancies.

DOI： 10.1002/cam4.1311

Comprehensive detection of pathogens in immunocompromised children with bloodstream infections by next-generation sequencing. International journal Open Access

Kazuhiro Horiba, Jun-Ichi Kawada, Yusuke Okuno, Nobuyuki Tetsuka, Takako Suzuki, Shotaro Ando, Yasuko Kamiya, Yuka Torii, Tetsuya Yagi, Yoshiyuki Takahashi, Yoshinori Ito

Scientific reports Vol. 8 ( 1 ) page： 3784 - 3784 2018.2

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

Bloodstream infection (BSI) is a severe complication in immunocompromised patients. Next-generation sequencing (NGS) allows us to analyze comprehensively and quantitatively all microorganisms present in a clinical sample. Thirty-five pediatric patients (12 with BSI and 23 with suspected BSI/negative blood culture) were enrolled. Plasma/serum samples were used for sequencing and the results were compared with those from blood culture. Sequencing reads of bacteria isolated in blood culture were identified by NGS in all plasma/serum samples at disease onset. Bacteria isolated in blood culture were identical to the dominant bacteria by NGS in 8 of 12 patients. Bacterial reads per million reads of the sequence depth (BR) > 200 and relative importance values of the dominant bacteria (P1) > 0.5 were employed to determine causative pathogens. Causative pathogens were detected using these criteria in 7 of 12 patients with BSI. Additionally, causative bacteria were detected in the plasma/serum at 7 days before disease onset in two patients with catheter-related BSI. Causative pathogens, including virus, were identified in three patients with suspected BSI. Lastly, a total of 62 resistance genes were detected by NGS. In conclusion, NGS is a new method to identify causative microorganisms in BSI and may predict BSI in some patients.

DOI： 10.1038/s41598-018-22133-y

Comprehensive detection of viruses in pediatric patients with acute liver failure using next-generation sequencing. International journal

Takako Suzuki, Jun-Ichi Kawada, Yusuke Okuno, Satoshi Hayano, Kazuhiro Horiba, Yuka Torii, Yoshiyuki Takahashi, Syuichiro Umetsu, Tsuyoshi Sogo, Ayano Inui, Yoshinori Ito

Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology Vol. 96 page： 67 - 72 2017.11

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Pediatric acute liver failure (PALF) is a rare and severe syndrome that frequently requires liver transplantation. Viruses are one of the most frequent causes of this disease, however, pathogenic viruses are not determined in many patients. Recently next-generation sequencing (NGS) has been applied to comprehensively detect pathogens of infectious diseases of unknown etiology. OBJECTIVES: To evaluate an NGS-based approach for detecting pathogenic viruses in patients with PALF or acute hepatitis of unknown etiology. STUDY DESIGN: To detect virus-derived DNA and RNA sequences existing in sera/plasma from patients, both DNA and RNA sequencing were performed. First, we validated the ability of NGS to detect viral pathogens in clinical serum/plasma samples, and compared different commercial RNA library preparation methods Then, serum/plasma of fourteen patients with PALF or acute hepatitis of unknown etiology were evaluated using NGS. RESULTS: Among three RNA library preparation methods, Ovation RNA-Seq System V2 had the highest sensitivity to detect RNA viral sequences. Among fourteen patients, sequence reads of torque teno virus, adeno-associated virus, and stealth virus were found in the sera of one patient each, however, the pathophysiological role of these three viruses was not clarified. Significant virus reads were not detected in the remaining 11 patients. CONCLUSIONS: This finding might be due to low virus titer in blood at the time of referral or a non-infectious cause might be more frequent. These results suggest an NGS-based approach has potential to detect viral pathogens in clinical samples and would contribute to clarification of the etiology of PALF.

DOI： 10.1016/j.jcv.2017.10.001

Metabolome analysis reveals the association between the kynurenine pathway and human herpesvirus 6 encephalopathy in immunocompetent children

Yuka Torii, Yoshihiko Kawano, Hajime Sato, Tamaki Fujimori, Kazunori Sasaki, Jun-ichi Kawada, Osamu Takikawa, Chai K. Lim, Gilles J. Guillemin, Yoshiaki Ohashi, Yoshinori Ito

METABOLOMICS Vol. 13 ( 11 ) 2017.11

Authorship：Lead author Language：Japanese Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Introduction Human herpesvirus 6 (HHV-6) is the second most common causative pathogen of acute encephalopathy in immunocompetent children in Japan. Identification of biomarkers associated the pathophysiology is desirable to monitor disease severity, progression, and prognosis.Objectives To investigate potential biomarkers for HHV-6 encephalopathy, serum metabolome profiling was analyzed and candidate metabolites were investigated the function in the diseases.Methods Pediatric patients with HHV-6 encephalopathy (n = 8), febrile seizure (n = 20), and febrile infection without febrile seizure (n = 7) were enrolled in this study, and serum metabolites were identified and quantified. For further analysis, serum samples of HHV-6 infected patients were analyzed by absolute quantification assay for kynurenine (KYN) and quinolinic acid (QUIN) in a total of 38 patients with or without encephalopathy. An in vitro blood-brain barrier (BBB) model was used to evaluate the effect of KYN and QUIN on BBB integrity because BBB damage induces brain edema.Results Metabolome profiling identified 159 metabolites in serum samples. The levels of KYN and QUIN, which belong to the tryptophan-KYN pathway, were significantly higher in the HHV-6 encephalopathy group than the other two groups. When quantified in the larger patient group, remarkably high levels of KYN and QUIN were observed exclusively in the encephalopathy group. Trans-endothelial electrical resistance of the BBB model was significantly decreased after QUIN treatment in culture.Conclusion Metabolome analysis revealed that KYN and QUIN may be associated with the pathophysiology of HHV-6 encephalopathy. In particular, QUIN may damage BBB integrity.

DOI： 10.1007/s11306-017-1268-x

Epstein-Barr virus infection-induced inflammasome activation in human monocytes. International journal Open Access

Yuka Torii, Jun-Ichi Kawada, Takayuki Murata, Hironori Yoshiyama, Hiroshi Kimura, Yoshinori Ito

PloS one Vol. 12 ( 4 ) page： e0175053 2017.4

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

Inflammasomes are cytoplasmic sensors that regulate the activity of caspase-1 and the secretion of interleukin-1β (IL-1β) or interleukin-18 (IL-18) in response to foreign molecules, including viral pathogens. They are considered to be an important link between the innate and adaptive immune responses. However, the mechanism by which inflammasome activation occurs during primary Epstein-Barr virus (EBV) infection remains unknown. Human B lymphocytes and epithelial cells are major targets of EBV, although it can also infect a variety of other cell types. In this study, we found that EBV could infect primary human monocytes and the monocyte cell line, THP-1, inducing inflammasome activation. We incubated cell-free EBV with THP-1 cells or primary human monocytes, then confirmed EBV infection using confocal microscopy and flow cytometry. Lytic and latent EBV genes were detected by real-time RT-PCR in EBV-infected monocytes. EBV infection of THP-1 cells and primary human monocytes induced caspase-dependent IL-1β production, while EBV infection of B-cell or T-cell lines did not induce IL-1β production. To identify the sensor molecule responsible for inflammasome activation during EBV infection, we examined the mRNA and the protein levels of NLR family pyrin domain-containing 3 (NLRP3), absent in melanoma 2 (AIM2), and interferon-inducible protein 16 (IFI16). Increased AIM2 levels were observed in EBV-infected THP-1 cells and primary human monocytes, whereas levels of IFI16 and NLRP3 did not show remarkable change. Furthermore, knockdown of AIM2 by small interfering RNA attenuated caspase-1 activation. Taken together, our results suggest that EBV infection of human monocytes induces caspase-1-dependent IL-1β production, and that AIM2, acting as an inflammasome, is involved in this response.

DOI： 10.1371/journal.pone.0175053

Analysis of circulating human and viral microRNAs in patients with congenital cytomegalovirus infection Open Access

Kawano, Y; Kawada, J; Kamiya, Y; Suzuki, M; Torii, Y; Kimura, H; Ito, Y

JOURNAL OF PERINATOLOGY Vol. 36 ( 12 ) page： 1101 - 1105 2016.12

Authorship：Lead author Language：English Publisher：Journal of Perinatology

Objective:Cytomegalovirus (CMV) is the most common cause of congenital infection and can cause neurodevelopmental disabilities, although a majority of patients are asymptomatic. Biomarkers associated with disease severity would be desirable to distinguish asymptomatic from mildly symptomatic patients who may benefit from antiviral treatment. MicroRNAs (miRNAs) are noncoding RNAs that may have the potential to serve as biomarkers.Study Design:Thirteen infants with congenital CMV infection were enrolled, and plasma levels of 11 human- and 3 CMV-encoded miRNAs were quantitated by real-time PCR. Plasma levels of miRNAs and their associations with clinical features were evaluated.Results:The levels of miR-183-5p and miR-210-3p were significantly higher in patients with congenital CMV infection than in control infants, whereas no significant associations between levels of miRNAs and clinical features of congenital CMV infection were observed.Conclusion:Plasma miRNAs could be associated with the pathogenesis of congenital CMV infection and could be used as disease biomarkers.

DOI： 10.1038/jp.2016.157

Primary psoas abscess caused by group A streptococcus in a child: Case report with microbiologic findings. International journal

Yasuko Kamiya, Tadao Hasegawa, Yasuhiko Takegami, Kazuhiro Horiba, Shotaro Ando, Yuka Torii, Hiroyuki Kidokoro, Taichi Kato, Jun Natsume, Jun-Ich Kawada, Yoshinori Ito

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy Vol. 22 ( 12 ) page： 811 - 814 2016.12

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

Primary abscess of the iliopsoas muscle in children is uncommon, especially due to Streptococcus pyogenes (group A streptococcus: GAS), which causes a variety of diseases ranging from pharyngitis to invasive life-threatening infection. We present primary iliopsoas abscess in a nine-year-old boy presenting with fever, mild disturbance of consciousness, limp, and pain in the right loin. Magnetic resonance imaging and isolation of GAS from both blood and abscess samples led us to the confirmative diagnosis. The patient recovered after treatment comprising drainage and intravenous antibiotics. The CovRS system is one of the best-characterized systems with two-component signal transduction in the GAS, and mutations in covRS induce overproduction of various virulence factors that play a crucial role in invasive GAS infection. RopB, also known as a GAS regulator, influences the expression of multiple regulatory networks to coregulate virulence factor expression in GAS. In the present case, sequence analysis revealed the isolated GAS as emm type 6 with alterations in covS, whereas the covR and ropB genes were intact. The covS alterations might have influenced the virulence of the strain causing this severe GAS infection.

DOI： 10.1016/j.jiac.2016.06.011

Tofacitinib induces G1 cell-cycle arrest and inhibits tumor growth in Epstein-Barr virus-associated T and natural killer cell lymphoma cells. International journal Open Access

Shotaro Ando, Jun-Ichi Kawada, Takahiro Watanabe, Michio Suzuki, Yoshitaka Sato, Yuka Torii, Masato Asai, Fumi Goshima, Takayuki Murata, Norio Shimizu, Yoshinori Ito, Hiroshi Kimura

Oncotarget Vol. 7 ( 47 ) page： 76793 - 76805 2016.11

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

Epstein-Barr virus (EBV) infects not only B cells, but also T cells and natural killer (NK) cells, and is associated with T or NK cell lymphoma. These lymphoid malignancies are refractory to conventional chemotherapy. We examined the activation of the JAK3/STAT5 pathway in EBV-positive and -negative B, T and NK cell lines and in cell samples from patients with EBV-associated T cell lymphoma. We then evaluated the antitumor effects of the selective JAK3 inhibitor, tofacitinib, against these cell lines in vitro and in a murine xenograft model. We found that all EBV-positive T and NK cell lines and patient samples tested displayed activation of the JAK3/STAT5 pathway. Treatment of these cell lines with tofacitinib reduced the levels of phospho-STAT5, suppressed proliferation, induced G1 cell-cycle arrest and decreased EBV LMP1 and EBNA1 expression. An EBV-negative NK cell line was also sensitive to tofacitinib, whereas an EBV-infected NK cell line was more sensitive to tofacitinib than its parental line. Tofacitinib significantly inhibited the growth of established tumors in NOG mice. These findings suggest that tofacitinib may represent a useful therapeutic agent for patients with EBV-associated T and NK cell lymphoma.

DOI： 10.18632/oncotarget.12529

Identification of Viruses in Cases of Pediatric Acute Encephalitis and Encephalopathy Using Next-Generation Sequencing. International journal Open Access

Jun-Ichi Kawada, Yusuke Okuno, Yuka Torii, Ryo Okada, Satoshi Hayano, Shotaro Ando, Yasuko Kamiya, Seiji Kojima, Yoshinori Ito

Scientific reports Vol. 6 page： 33452 - 33452 2016.9

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

Acute encephalitis/encephalopathy is a severe neurological syndrome that is occasionally associated with viral infection. Comprehensive virus detection assays are desirable because viral pathogens have not been identified in many cases. We evaluated the utility of next-generation sequencing (NGS) for detecting viruses in clinical samples of encephalitis/encephalopathy patients. We first determined the sensitivity and quantitative performance of NGS by comparing the NGS-determined number of sequences of human herpesvirus-6 (HHV-6) in clinical serum samples with the HHV-6 load measured using real-time PCR. HHV-6 was measured as it occasionally causes neurologic disorders in children. The sensitivity of NGS for detection of HHV-6 sequences was equivalent to that of real-time PCR, and the number of HHV-6 reads was significantly correlated with HHV-6 load. Next, we investigated the ability of NGS to detect viral sequences in 18 pediatric patients with acute encephalitis/encephalopathy of unknown etiology. A large number of Coxsackievirus A9 and mumps viral sequences were detected in the cerebrospinal fluid of 2 and 1 patients, respectively. In addition, Torque teno virus and Pepper mild mottle viral sequences were detected in the sera of one patient each. These data indicate that NGS is useful for detection of causative viruses in patients with pediatric encephalitis/encephalopathy.

DOI： 10.1038/srep33452

Quantitative metabolome profiling reveals the involvement of the kynurenine pathway in influenza-associated encephalopathy

Yuka Torii, Yoshihiko Kawano, Hajime Sato, Kazunori Sasaki, Tamaki Fujimori, Jun-ichi Kawada, Osamu Takikawa, Chai K. Lim, Gilles J. Guillemin, Yoshiaki Ohashi, Yoshinori Ito

METABOLOMICS Vol. 12 ( 5 ) 2016.5

Authorship：Lead author Language：Japanese Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Introduction Influenza-associated encephalopathy is a serious complication of influenza and is the most common form of acute encephalitis/encephalopathy in Japan. The number of reports from other countries is increasing, reflecting international recognition and concern.Objectives Identification of a specific biomarker could provide important clues about the pathophysiology of influenza-associated encephalopathy.Methods During the 2009-2011 flu seasons, 34 pediatric patients hospitalized with influenza complications, including influenza-associated encephalopathy, were enrolled in the study. Serum samples were collected during the acute and convalescent phases of disease. Patients were classified into encephalopathy (n = 12) and non-encephalopathy (n = 22) groups. Serum metabolites were identified and quantified by capillary electrophoresis coupled with time-of-flight mass spectrometry. Quantified data were evaluated for comparative analysis. Subsequently, a total of 55 patients with or without encephalopathy were enrolled for absolute quantification of serum kynurenine and quinolinic acid.Results Based on m/z values and migration times, 136 metabolites were identified in serum samples. During the acute phase of disease, three metabolites (succinic acid, undecanoic acid, and kynurenine) were significantly higher, and two other metabolites (decanoic acid and cystine) were significantly lower, in the encephalopathy group compared to the non-encephalopathy group (p = 0.012, 0.022, 0.044, 0.038, 0.046, respectively). In a larger patient group, serum kynurenine and its downstream product in tryptophan metabolism, quinolinic acid, a known neurotoxin, were significantly higher in the encephalopathy than the non-encephalopathy without febrile seizure group.Conclusion Comprehensive metabolite profiles revealed five metabolites as potential biomarkers for influenza-associated encephalopathy; the tryptophan-kynurenine metabolic process could be associated with its pathophysiology.

DOI： 10.1007/s11306-016-1011-z

Correlation of rabbit antithymocyte globulin serum levels and clinical outcomes in children who received hematopoietic stem cell transplantation from an alternative donor. International journal Open Access

Shaimaa Elmahdi, Hideki Muramatsu, Atsushi Narita, Yuka Torii, Olfat Ismael, Nozomu Kawashima, Yusuke Okuno, Yuko Sekiya, Yinyan Xu, Xinan Wang, Asahito Hama, Yoshinori Ito, Yoshiyuki Takahashi, Seiji Kojima

Pediatric transplantation Vol. 20 ( 1 ) page： 105 - 113 2016.2

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

We analyzed the correlation between rabbit ATG (rATG) serum levels and clinical outcomes in 37 children who received rATG at a total dose of 10 or 15 mg/kg during HSCT conditioning from an alternative donor. Fourteen patients had advanced malignant diseases, 13 had severe AA, and 10 had inherited disorders. Complete engraftment was achieved in all patients, and no rejection occurred. The cumulative incidence of grades II-IV acute GVHD and extensive chronic GVHD was 27% (95% CI, 12.5-39.6%) and 8.1% (95% CI, 0-23.1%), respectively. Multivariate analysis identified lower rATG levels at week 4 as an independent risk factor in the development of grades II-IV acute GVHD (p = 0.037). Serious infections were not observed in any patient following HSCT. No correlation was found between EBV reactivation and rATG levels at week 2 and week 4 after HSCT. Furthermore, no correlation was found between relapse and rATG levels two and four wk post-transplantation. The probability of five-yr OS among patients was 70.3% (95% CI, 59.8-79.2%). Our results suggest that targeted rATG administration may protect patients from severe acute GVHD without increasing the risk of EBV reactivation or relapse.

DOI： 10.1111/petr.12620

Fulminant adenovirus hepatitis after hematopoietic stem cell transplant: Retrospective real-time PCR analysis for adenovirus DNA in two cases. International journal

Nozomu Kawashima, Hideki Muramatsu, Yusuke Okuno, Yuka Torii, Jun-ichi Kawada, Atsushi Narita, Koji Nakanishi, Asahito Hama, Aya Kitamura, Naoya Asai, Shigeo Nakamura, Yoshiyuki Takahashi, Yoshinori Ito, Seiji Kojima

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy Vol. 21 ( 12 ) page： 857 - 863 2015.12

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Viral infection is one of the major causes of mortality in patients undergoing hematopoietic stem cell transplant (HSCT). Systemic infection of adenovirus (AdV) has emerged as a not uncommon viral infection with significant morbidity and mortality as with cytomegalovirus and Epstein-Barr virus infection. Routine surveillance for these viruses has become a clinical practice and subsequent preemptive therapy improves patients' outcomes; however, the effectiveness of preemptive therapy for AdV has not been fully investigated in patients with a lethal form of AdV infection. METHODS: Sequential AdV loads were retrospectively analyzed in children with fulminant AdV hepatitis after HSCT. RESULTS: The AdV DNA became detectable (1 × 10(4) copies/mL) as early as 2 weeks after HSCT. These levels reached >1 × 10(8) copies/mL at the onset of fulminant hepatitis. However, we determined that γ-glutamyltransferase levels were elevated to >100 IU/L at least 2 weeks before the diagnosis of hepatitis. CONCLUSIONS: Our observation raises the possibility that elevated γ-glutamyltransferase could be a sentinel marker for AdV hepatitis, which prompts elaborated monitoring of AdV load and targeted treatment.

DOI： 10.1016/j.jiac.2015.08.018

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