A major obstacle to curing chronic myeloid leukemia (CML) is residual disease maintained by tyrosine kinase inhibitor (TKI)-persistent leukemic stem cells (LSC). These are BCR-ABL1 kinase independent, refractory to apoptosis, and serve as a reservoir to drive relapse or TKI resistance. We demonstrate that Polycomb Repressive Complex 2 is misregulated in chronic phase CML LSCs. This is associated with extensive reprogramming of H3K27me3 targets in LSCs, thus sensitizing them to apoptosis upon treatment with an EZH2-specifi c inhibitor (EZH2i). EZH2i does not impair normal hematopoietic stem cell survival. Strikingly, treatment of primary CML cells with either EZH2i or TKI alone caused signifi cant upregulation of H3K27me3 targets, and combined treatment further potentiated these effects and resulted in signifi cant loss of LSCs compared to TKI alone, in vitro , and in long-term bone marrow murine xenografts. Our fi ndings point to a promising epigenetic-based therapeutic strategy to more effectively target LSCs in patients with CML receiving TKIs. SIGNIFICANCE:In CML, TKI-persistent LSCs remain an obstacle to cure, and approaches to eradicate them remain a signifi cant unmet clinical need. We demonstrate that EZH2 and H3K27me3 reprogramming is important for LSC survival, but renders LSCs sensitive to the combined effects of EZH2i and TKI. This represents a novel approach to more effectively target LSCs in patients receiving TKI treatment. Cancer Discov; 6(11); 1248-57.

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McSig" is a multimodal teaching and learning environment for visually-impaired students to learn character shapes, handwriting and signatures collaboratively with their teachers. It combines haptic and audio output to realize the teacher's pen input in parallel non-visual modalities. McSig is intended for teaching visually-impaired children how to handwrite characters (and from that signatures), something that is very difficult without visual feedback. We conducted an evaluation with eight visually-impaired children with a pre-test to assess their current skills with a set of character shapes, a training phase using McSig and then a post-test of the same character shapes to see if there were any improvements. The children could all use McSig and we saw significant improvements in the character shapes drawn, particularly by the completely blind children (many of whom could draw almost none of the characters before the test). In particular, the blind participants all expressed enjoyment and excitement about the system and using a computer to learn to handwrite.

The automated simulator equipped students with useful skills for examining cows. In addition, a simulator that does not need the presence of an instructor will increase the availability of training for students and be a more sustainable option for institutions.