Kinase inhibitor screening using artificial neural networks and engineered cardiac biowires.
Kinase inhibitor screening using artificial neural networks and engineered cardiac biowires.
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DOI：
10.1038/s41598-017-12048-5
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发表时间：
2017-09-18
影响因子：
4.6
通讯作者：
Radisic M
中科院分区：
文献类型：
--
作者：
Conant G;Ahadian S;Zhao Y;Radisic M
由于能够阻止细胞生长和增殖信号的激活，激酶抑制剂经常被用作癌症靶向药物。已经确定了一些上市的激酶抑制剂的心脏毒性作用，这些药物在临床试验中没有被检测到。我们假设，通过结合高通量二维(2D)筛选试验和基于高含量三维(3D)工程心脏组织(BiowireTM)的试验，并使用人类诱导多能干细胞来源的CMS(hiPSC-CMS)，可以建立更具预测性的对人类心肌的激酶抑制剂的心功能评估。GlaxoSmithKline公布的激酶抑制剂集的一部分(80)化合物在HiPSC-CM单层上进行测试，观察到对细胞存活率、钙瞬变和收缩频率的显著影响。然后使用人工神经网络模型以高效和公正的方式分析实验结果，以选择对细胞存活率和功能影响最小的激酶抑制剂。在3D生物线组织中对基于建模的特定感兴趣的抑制剂进行评估。与单层测试相比，三维生物导线平台消除了在检测钙离子瞬时幅度增强以及应用激酶抑制剂对细胞活力的急性有害影响方面的过度敏感性。
Kinase inhibitors are often used as cancer targeting agents for their ability to prevent the activation of cell growth and proliferation signals. Cardiotoxic effects have been identified for some marketed kinase inhibitors that were not detected during clinical trials. We hypothesize that more predictive cardiac functional assessments of kinase inhibitors on human myocardium can be established by combining a high-throughput two-dimensional (2D) screening assay and a high-content three-dimensional (3D) engineered cardiac tissue (BiowireTM) based assay, and using human induced pluripotent stem cell-derived CMs (hiPSC-CMs). A subset (80) of compounds from the GlaxoSmithKline published kinase inhibitor set were tested on hiPSC-CM monolayers and significant effects on cell viability, calcium transients, and contraction frequency were observed. Artificial neural network modelling was then used to analyze the experimental results in an efficient and unbiased manner to select for kinase inhibitors with minimal effects on cell viability and function. Inhibitors of specific interest based on the modeling were evaluated in the 3D Biowire tissues. The three-dimensional Biowire platform eliminated oversensitivity in detecting both Ca2+ transient amplitude enhancements as well as the acute detrimental effects on cell viability due to the kinase inhibitor application as compared to the monolayer testing.
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影响因子：
3.8
作者：
Cohen JD;Babiarz JE;Abrams RM;Guo L;Kameoka S;Chiao E;Taunton J;Kolaja KL
通讯作者：
Kolaja KL
影响因子：
3.7
作者：
Dranchak P;MacArthur R;Guha R;Zuercher WJ;Drewry DH;Auld DS;Inglese J
通讯作者：
Inglese J
影响因子：
21.3
作者：
D'Uva, Gabriele;Aharonov, Alla;Tzahor, Eldad
通讯作者：
Tzahor, Eldad
DOI：
10.1093/jnci/djs317
发表时间：
2012-09-05
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Bowles EJ;Wellman R;Feigelson HS;Onitilo AA;Freedman AN;Delate T;Allen LA;Nekhlyudov L;Goddard KA;Davis RL;Habel LA;Yood MU;McCarty C;Magid DJ;Wagner EH;Pharmacovigilance Study Team
通讯作者：
Pharmacovigilance Study Team
影响因子：
3.7
作者：
Jacob F;Yonis AY;Cuello F;Luther P;Schulze T;Eder A;Streichert T;Mannhardt I;Hirt MN;Schaaf S;Stenzig J;Force T;Eschenhagen T;Hansen A
通讯作者：
Hansen A