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Nakagusuku, Japan

Sawada S.,University of Ryukyus | Ishikawa C.,University of Ryukyus | Tanji H.,University of Ryukyus | Nakachi S.,University of Ryukyus | And 15 more authors.
Blood | Year: 2010

Caveolin-1 is implicated in the regulation of signal pathways. Adult T-cell leukemia (ATL) is a T-cell malignancy causatively associated with human T-cell leukemia virus type 1 (HTLV-1). To determine the role of caveolin-1 in leukemogenesis, we examined caveolin-1 expression levels in HTLV-1-infected T-cell lines and ATL cells. These cells expressed high levels of caveolin-1 compared with uninfected T-cell lines and normal peripheral blood mononuclear cells (PBMCs). Caveolin-1-positive ATL cells were detected in ATL lymph nodes and skin lesions, and caveolin-1 was also detected in the plasma of patients with ATL. Infection of a human T-cell line, an epithelial cell line, and normal PBMCs with HTLV-1 induced caveolin-1 expression. The viral protein Tax transcriptionally activated caveolin-1 gene through nuclear factor-κB and cAMP response element binding protein signal pathways. HTLV-1-infected T-cell lines, and ATL cells are known to be resistant to transforming growth factor β (TGF-β)-induced growth inhibition. Caveolin-1 was colocalized with TGF-β type I receptor in HTLV-1-infected T-cell lines and suppressed TGF-β signaling. Caveolin-1 knockdown in an HTLV-1-infected T-cell line exhibited susceptibility to TGF-β. Thus, we describe a new function for Tax, repression of TGF-β signaling through caveolin-1 expression, which may play a critical role in ATL leukemogenesis. © 2010 by The American Society of Hematology.

Ishida T.,Nagoya City University | Jo T.,Red Cross | Suzushima H.,Kumamoto Shinto General Hospital | Uozumi K.,Kagoshima University | And 16 more authors.
British Journal of Haematology | Year: 2015

This multicentre, randomized, phase II study was conducted to examine whether the addition of mogamulizumab, a humanized anti-CC chemokine receptor 4 antibody, to mLSG15, a dose-intensified chemotherapy, further increases efficacy without compromising safety of patients with newly diagnosed aggressive adult T-cell leukaemia-lymphoma (ATL). Patients were assigned 1:1 to receive mLSG15 plus mogamulizumab or mLSG15 alone. The primary endpoint was the complete response rate (%CR); secondary endpoints included the overall response rate (ORR) and safety. The %CR and ORR in the mLSG15-plus-mogamulizumab arm (n = 29) were 52% [95% confidence interval (CI), 33-71%] and 86%, respectively; the corresponding values in the mLSG15 arm (n = 24) were 33% (95% CI, 16-55%) and 75%, respectively. Grade ≥ 3 treatment-emergent adverse events, including anaemia, thrombocytopenia, lymphopenia, leucopenia and decreased appetite, were observed more frequently (≥10% difference) in the mLSG15-plus-mogamulizumab arm. Several adverse events, including skin disorders, cytomegalovirus infection, pyrexia, hyperglycaemia and interstitial lung disease, were observed only in the mLSG15-plus-mogamulizumab arm. Although the combination strategy showed a potentially less favourable safety profile, a higher %CR was achieved, providing the basis for further investigation of this novel treatment for newly diagnosed aggressive ATL. This study was registered at ClinicalTrials.gov, identifier: NCT01173887. © 2015 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.

Tamaki K.,University of Ryukyus | Kinjo T.,University of Ryukyus | Aoyama H.,University of Ryukyus | Tomoyose T.,University of Ryukyus | And 13 more authors.
Journal of Infection and Chemotherapy | Year: 2015

We report a case of fatal pneumonia and viremia due to human parainfluenza virus type 1 (HPIV-1) in a 65-year-old male patient with adult T-cell leukemia-lymphoma (ATL) treated with mogamulizumab, a brand-new therapeutic agent for ATL. To our knowledge, this is the first report describing viremia due to HPIV-1. After administering mogamulizumab, lymphocyte count in the blood was drastically decreased and the patient suffered from complicated infections including gram-negative bacterial sepsis, cytomegalovirus antigenemia and aspergillosis. Although these infections were successfully controlled by broad spectrum antimicrobial therapy, patchy ground-grass opacities in the both lungs were gradually worsened. He finally died due to acute respiratory failure. Since findings of the chest CT was consistent with typical patterns of viral pneumonia, we screened major respiratory viruses in the peripheral blood with multiplex PCR, and it turned out that RNA of HPIV-1 was positive. Although ATL cells were not detected in the autopsied lungs and a variety of other tissues, cytoplasmic inclusion bodies, which are commonly observed in RNA viral infection, were abundantly observed in the autopsied lung tissue. These findings suggest that mogamulizumab accomplished complete remission of ATL, while the chemotherapy-induced prolonged lymphopenia caused fatal pneumonia and viremia due to HPIV-1. As it has been well recognized that community respiratory viruses including HPIV-1 often cause fatal pneumonia in patients with leukemia, but also there is no specific treatment for HPIV-1, we have to enforce standard precautions especially when we treat leukemic patients with intensively immunosuppressive agents such as mogamulizumab. © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases.

Kagawa T.,Tokai University | Oka A.,Tokai University | Kobayashi Y.,Mie University | Hiasa Y.,Ehime University | And 20 more authors.
Human Mutation | Year: 2015

Sequences of long-interspersed elements (LINE-1, L1) make up ∼17% of the human genome. De novo insertions of retrotransposition-active L1s can result in genetic diseases. It has been recently shown that the homozygous inactivation of two adjacent genes SLCO1B1 and SLCO1B3 encoding organic anion transporting polypeptides OATP1B1 and OATP1B3 causes a benign recessive disease presenting with conjugated hyperbilirubinemia, Rotor syndrome. Here, we examined SLCO1B1 and SLCO1B3 genes in six Japanese diagnosed with Rotor syndrome on the basis of laboratory data and laparoscopy. All six Japanese patients were homozygous for the c.1738C>T nonsense mutation in SLCO1B1 and homozygous for the insertion of a ∼6.1-kbp L1 retrotransposon in intron 5 of SLCO1B3, which altogether make up a Japanese-specific haplotype. RNA analysis revealed that the L1 insertion induced deleterious splicing resulting in SLCO1B3 transcripts lacking exon 5 or exons 5-7 and containing premature stop codons. The expression of OATP1B1 and OATP1B3 proteins was not detected in liver tissues. This is the first documented case of a population-specific polymorphic intronic L1 transposon insertion contributing to molecular etiology of recessive genetic disease. © 2014 WILEY PERIODICALS, INC.

Shibata D.,University of Ryukyus | Arakaki S.,University of Ryukyus | Maeshiro T.,University of Ryukyus | Sakugawa H.,Heartlife Hospital | And 4 more authors.
Acta Hepatologica Japonica | Year: 2014

A 23-year-old woman with adult growth hormone deficiency (AGHD) presented for liver dysfunction. She was not obese with BMI at 22.5, merely a social drinker. Abdominal computed tomography (CT) scans showed fatty liver. Histopathology of the liver revealed pericellular fibrosis, marked large-cell steatosis, and ballooning degeneration, consistent with NASH (Brunt score: Grade 1, Stage 1). Her serum insulin like growth factor-1 (IGF-was low. She was diagnosed as having NASH accompanied by AGHD. Liver dysfunction was gradually im­proved with growth hormone-replacement therapy. © 2014 The Japan Society of Hepatology.

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