Inhibition of constitutively active Jak-Stat pathway suppresses cell growth of human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cell leukemia cells

BACKGROUND: Human T-cell leukemia virus type 1 (HTLV-1), the etiologic agent for adult T-cell leukemia (ATL), induces cytokine-independent proliferation of T-cells, associated with the acquisition of constitutive activation of Janus kinases (Jak) and signal transducers and activators of transcription (Stat) proteins. Our purposes in this study were to determine whether activation of Jak-Stat pathway is responsible for the proliferation and survival of ATL cells, and to explore mechanisms by which inhibition of Jak-Stat pathway kills ATL cells. RESULTS: Constitutive activation of Stat3 and Stat5 was observed in HTLV-1-infected T-cell lines and primary ATL cells, but not in HTLV-1-negative T-cell lines. Using AG490, a Jak-specific inhibitor, we demonstrated that the activation of Stat3 and Stat5 was mediated by the constitutive phosphorylation of Jak proteins. AG490 inhibited the growth of HTLV-1-infected T-cell lines and primary ATL cells by inducing G(1 )cell-cycle arrest mediated by altering the expression of cyclin D2, Cdk4, p53, p21, Pim-1 and c-Myc, and by apoptosis mediated by the reduced expression of c-IAP2, XIAP, survivin and Bcl-2. Importantly, AG490 did not inhibit the growth of normal peripheral blood mononuclear cells. CONCLUSION: Our results indicate that activation of Jak-Stat pathway is responsible for the proliferation and survival of ATL cells. Inhibition of this pathway may provide a new approach for the treatment of ATL

Human T-cell leukemia virus type I infects human lung epithelial cells and induces gene expression of cytokines, chemokines and cell adhesion molecules

<p>Abstract</p> <p>Background</p> <p>Human T-cell leukemia virus type I (HTLV-I) is associated with pulmonary diseases, characterized by bronchoalveolar lymphocytosis, which correlates with HTLV-I proviral DNA in carriers. HTLV-I Tax seems to be involved in the development of such pulmonary diseases through the local production of inflammatory cytokines and chemokines in T cells. However, little is known about induction of these genes by HTLV-I infection in lung epithelial cells.</p> <p>Results</p> <p>We tested infection of lung epithelial cells by HTLV-I by coculture studies in which A549 alveolar and NCI-H292 tracheal epithelial cell lines were cocultured with MT-2, an HTLV-I-infected T-cell line. Changes in the expression of several cellular genes were assessed by reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay and flow cytometry. Coculture with MT-2 cells resulted in infection of lung epithelial cells as confirmed by detection of proviral DNA, HTLV-I Tax expression and HTLV-I p19 in the latter cells. Infection was associated with induction of mRNA expression of various cytokines, chemokines and cell adhesion molecule. NF-κB and AP-1 were also activated in HTLV-I-infected lung epithelial cells. <it>In vivo </it>studies showed Tax protein in lung epithelial cells of mice bearing Tax and patients with HTLV-I-related pulmonary diseases.</p> <p>Conclusion</p> <p>Our results suggest that HTLV-I infects lung epithelial cells, with subsequent production of cytokines, chemokines and cell adhesion molecules through induction of NF-κB and AP-1. These changes can contribute to the clinical features of HTLV-I-related pulmonary diseases.</p

Retraction: NF-κB activation by Helicobacter pylori requires Akt-mediated phosphorylation of p65

Article retracte

海水濃度が温浴時の体温変動に及ぼす影響

本研究は，温浴時の海水濃度条件の違いが体温変動，心拍数および主観的温度感覚に及ばす影響を検討するために，38．5℃に設定された水温条件下で15分間入浴および60分間安静の温浴実験をおこなった。海水濃度条件は0％，1％，3．5％，7％の4種類とした。被験者は年齢18～21歳の健康な男子大学生8名であった。被験者の平均の年齢，身長，体重および体脂肪率はそれぞれ19．8±1．0歳，169．2±5．Ocm，57．1±3．1kgおよび14．0±2．6％であった。直腸温は，全条件とも入浴直後から一過性に上昇傾向を示し，出浴後は潜熱現象を示した。海水濃度を比較すると，7＞3．5＞1＞0％の順に有意な上昇傾向を示した。平均皮膚温は，全条件とも入浴直後から10分間は一過性に上昇傾向を示した。その後，入浴10～20分の間はわずかに上昇し，出浴後は10分前後に急速に下降傾向を示し，それ以降はゆるやかな低下を示した。海水濃度を比較すると，7％膿度が他濃度より入浴時の上昇度が高く，またその影響で出浴後の温度低下度も他濃度より低い傾向を示した。平均体温は，全条件とも入浴直後から一過性に上昇傾向を，また出浴直後から急速に下降傾向を示し，その後の回復期にはゆるやかな低下を示した。以上の結果から7％までの海水濃度温浴では，直腸温および皮膚温ともに成分濃度依存性の体温上昇反応が示唆された。The purpose of the present study was to compare thermal responses of the body between bathing in warm sea water and further to examine effects of concentration of chemical components in sea water affect thermal responses of the body when bathing in warm sea water. The thermal responses were based on the examination of taking rectal, skin, and mean body temperatures in bathing and recovery on land. Eight healthy men were the subjects in this experiment, and they were in average 19.8±1.0 in age, 169.2±5.0cms in height, 57.1±3.1kgs in weight, and 14.0±2.6% in fat. The subjects bathed in sea water and fresh water for 15 minutes and took recovery on land for 60 minutes respectively. The experiment was tested under water temperature at 38.5℃ during bathing. The conditions of concentration of chemical components in sea water were 7, 3.5, 1, 0%. For all the subjects, the rectal temperature increased during bathing and decreased gradually during recovery on land. Bathing in sea water statistically showed significant increases of rectal temperature at 15 minutes during bathing. It was constantly higher at 7> 3.5 > 1 > 0%. The mean skin temperature showed a continuous increase during bathing and showed a rapid decrease during 5 minutes in recovery on land, and a gradual decrease after then. No statistically significant differences were detected in the mean skin temperature between 7, 3.5, 1 and 0%. The mean body temperature also showed a continuous increase during bathing and showed a rapid decrease during the 10 minutes in recovery on land, and a gradual decrease after then. In bathing in sea water the mean body temperature statistically showed significant increases during bathing

Relationship between nerve fiber layer defect and the presence of epiretinal membrane in a Japanese population: The JPHC-NEXT Eye Study

The study subjects were residents of Chikusei city, Japan, aged 40 years or older who attended annual health check-up programs and participated in the JPHC-NEXT Eye Study which performed non-mydriatic fundus photography of both eyes. The relationship of glaucomatous fundus changes such as optic disc cupping (cup to disc ratio ≥ 0.7) and retinal nerve fiber layer defect (NFLD) with the presence of epiretinal membrane (ERM) were examined cross-sectionally. A total of 1990 persons gave consent to participate in this study in 2013. The overall prevalence of ERM was 12.9%. Of these, 1755 had fundus photographs of sufficient quality and no history of intraocular surgery (mean age: 62.3 ± 10.0 years). After adjusting for age, sex and refractive error, NFLD was positively associated with the presence of ERM (odds ratio [OR]: 2.48; 95% confidence interval [CI]: 1.24, 4.96; P = 0.010), but optic disc cupping was not (OR: 1.33; CI: 0.71, 2.48; P = 0.37). The results did not necessarily suggest an association between glaucoma and ERM, but indicated an association between NFLD and ERM