Combination of panobinostat with ponatinib synergistically overcomes imatinib-resistant CML cells

The major mechanism of imatinib (IM) resistance of CML is the reactivation of ABL kinase either through BCR-ABL gene amplification or mutation. We investigated the cytotoxicity of a pan-ABL tyrosine kinase inhibitor, ponatinib, and a pan-histone deacetylase inhibitor, panobinostat, against IM-resistant CML cells in vitro. Two different IM-resistant cell lines, K562/IM-R1 and Ba/F3/T315I were evaluated in comparison with their respective, parental cell lines, K562 and Ba/F3. K562/IM-R1 overexpressed BCR-ABL due to gene amplification. Ba/F3/T315I was transfected with a BCR-ABL gene encoding T315I-mutated BCR-ABL. Ponatinib inhibited the growth of both K562/IM-R1 and Ba/F3/T315I as potently as it inhibited their parental cells with an IC50 of 2-30 nM. Panobinostat also similarly inhibited the growth of all of the cell lines with an IC50 of 40-51 nM. This was accompanied by reduced histone deacetylase activity, induced histone H3 acetylation, and an increased protein level of heat shock protein 70, which suggested disruption of heat shock protein 90 chaperone function for BCR-ABL and its degradation. Importantly, the combination of ponatinib with panobinostat showed synergistic growth inhibition and induced a higher level of apoptosis than the sum of the apoptosis induced by each agent alone in all of the cell lines. Ponatinib inhibited phosphorylation not only of BCR-ABL but also of downstream signal transducer and activator of transcription 5, protein kinase B, and ERK1/2 in both K562/IM-R1 and Ba/F3/T315I, and the addition of panobinostat to ponatinib further inhibited these phosphorylations. In conclusion, panobinostat enhanced the cytotoxicity of ponatinib towards IM-resistant CML cells including those with T315I-mutated BCR-ABL

Combination of panobinostat with ponatinib synergistically overcomes imatinib‐resistant CML

The major mechanism of imatinib (IM) resistance of CML is the reactivation of ABL kinase either through BCR-ABL gene amplification or mutation. We investigated the cytotoxicity of a pan-ABL tyrosine kinase inhibitor, ponatinib, and a pan-histone deacetylase inhibitor, panobinostat, against IM-resistant CML cells in vitro. Two different IM-resistant cell lines, K562/IM-R1 and Ba/F3/T315I were evaluated in comparison with their respective, parental cell lines, K562 and Ba/F3. K562/IM-R1 overexpressed BCR-ABL due to gene amplification. Ba/F3/T315I was transfected with a BCR-ABL gene encoding T315I-mutated BCR-ABL. Ponatinib inhibited the growth of both K562/IM-R1 and Ba/F3/T315I as potently as it inhibited their parental cells with an IC50 of 2-30 nM. Panobinostat also similarly inhibited the growth of all of the cell lines with an IC50 of 40-51 nM. This was accompanied by reduced histone deacetylase activity, induced histone H3 acetylation, and an increased protein level of heat shock protein 70, which suggested disruption of heat shock protein 90 chaperone function for BCR-ABL and its degradation. Importantly, the combination of ponatinib with panobinostat showed synergistic growth inhibition and induced a higher level of apoptosis than the sum of the apoptosis induced by each agent alone in all of the cell lines. Ponatinib inhibited phosphorylation not only of BCR-ABL but also of downstream signal transducer and activator of transcription 5, protein kinase B, and ERK1/2 in both K562/IM-R1 and Ba/F3/T315I, and the addition of panobinostat to ponatinib further inhibited these phosphorylations. In conclusion, panobinostat enhanced the cytotoxicity of ponatinib towards IM-resistant CML cells including those with T315I-mutated BCR-ABL

Group psychotherapy programs for the elementary school students in the lower and middle grades of elementary school with hyperactive tendency

要約 1.想定されるグループの特徴 2.プログラム各論 3.プログラム立案の視点についての総括本稿の目的は，多動傾向を伴う広汎性発達障害の小学校低・中学年児童のための集団心理療法プログラムについて報告することであった。関心や気持ちを他児と共有するための活動として，プログラム「僕も！それいいね！質問したい！ゲーム」，「名探偵ゲーム」を報告した。他者に注目し協力するための活動として，プログラム「オオカミから王様を守ろう！」，「カッパ山にいこう！」を報告した。自己表現し受け入れられることを促すための活動として，プログラム「あべこベジェスチャークイズ」を報告した。じっくりと活動に取り組むことや気持ちを落ち着かせるための活動としてプログラム「グニャグニャいったんもめん」を報告した。最後にプログラムの立案の視点を他児への注目や協力を促す工夫他児との関心や気持ちの共有を促す工夫，自己表現と被受容体験の重要性，各プログラムのつなぎ方の工夫，年間を通したプログラム立案という5点から考察した。The purpose of this study was to report group psychotherapy programs for the elementary school students in the lower and middle grades with pervasive developmental disorders and hyperactive tendency. The games were as below: \u22Me too! That\u27s nice! I want to ask a question! game\u22 and \u22Great detective game\u22 to share their concern and feelings with others, \u22Let\u27s defend the king from the wolf!\u22 and \u22Let\u27s go to the kappa mountain!\u22 to pay attention to others and cooperate with them, \u22Reversed gesture quiz\u22 to improve the skill for self-expression and the attitude to be accepted comfortably by others, and \u22Body stretching game\u22 to work on the activity deliberately and make feelings settle down. Conclusively, important aspects for planning the programs were discussed from the viewpoints as below: procedure to facilitate children\u27s attention to others which could derive cooperative behavior with other children, the way to facilitate the skills to share their concern and feelings with others, importance of self-expression and the opportunities to be accepted by others, the way to connect each programs effectively, and the way for planning programs through one year

The application of Dohsa-hou to the mothers who have the child with physically handicapped

要約 Ⅰ.問題 Ⅱ.本研究の目的 Ⅲ.活動の概要 Ⅳ.事例経過 Ⅴ.考察 Ⅵ.今後の課題 引用文献本稿では，肢体不自由の子どもを持つ親の会のメンバーからの相談に基づいた健康動作法の実践（生涯発達支援部門）について報告し同時にその意義を考えることを目的とする。来談者は、肢体不自由の子どもを持つ保護者（母親） 9名である。参加者は主として成人した肢体不自由の子どもを持ち， 日常生活における介護，家事，仕事の疲労などから身体の痛みや硬さなどの訴えが主なもので、あった。来談者は，動作法については子どもへの実践によってリラクセイション効果なとさについては知っているため動作法を受ける ことを希望しそれに基づいて月約2回の割合で3年間継続した。その健康動作法の実施の結果，身体的な不具合と身体・生活の不安の軽減などが本稿では，肢体不自由の子どもを持つ親の会のメンバーからの相談に基づいた健康動作法の実践（生涯発達支援部門）について報告し同時にその意義を考えることを目的とする。来談者は、肢体不自由の子どもを持つ保護者（母親） 9名である。参加者は主として成人した肢体不自由の子どもを持ち， 日常生活における介護，家事，仕事の疲労などから身体の痛みや硬さなどの訴えが主なもので、あった。来談者は，動作法については子どもへの実践によってリラクセイション効果などついては知っているため動作法を受けることを希望しそれに基づいて月約2回の割合で3年間継続した。その健康動作法の実施の結果，身体的な不具合と身体・生活の不安の軽減などが実感され，日常生活において肢体不自由を持つ子どもに対しての介助や世話にもゆとりが感じられるようになったなどの感想が述べられるようになった。これらのことから健康動作法を実施することは，肢体不自由の子どもを持つ親の日常を支えることにつながることが示唆された。The purpose of this study is to discuss the effects of Dohsa-hou to the mothers who had the son or daughter with physically handicapped causing cerebral palsy. Their child became to be adult who had continued to undergo Dohsa-hou therapy. They, however, had stiffness at any parts of body and they needed supports from the parents in daily life. The parents, especially mothers were hard to take care of their child, so they felt tired and had stiffness at their body like as the son and daughter. They knew very well the effect of Dohsa-hou, because they had own experience of Dousa-hou practice to their child. So, they applied the Dousa-hou to the Center, Kyushu University. They had been taken Dohsa-hou therapy twice a month for 3 years. Each session is 1 hour. The results of the therapy were the following. The clients described and reported that their stiffness and pain ant the body has been weakened and their anxiety of body or the behaviors of daily life have been reduced. And then, they reported that they felt easy and relaxed to take care of the child in daily life. These clients reports and descriptions suggest that Dohsa-hou could be effective as the support method for the parents who should be take care of their child with physically handicapped