Ex Vivo Expansion of Phenotypic and Transcriptomic Chronic Myeloid Leukemia Stem Cells.

Despite decades of research, standard therapies remain ineffective for most leukemias, pushing toward an essential unmet need for targeted drug screens. Moreover, preclinical drug testing is an important consideration for success of clinical trials without affecting non-transformed stem cells. Using the transgenic chronic myeloid leukemia (CML) mouse model, we determine that leukemic stem cells (LSCs) are transcriptionally heterogenous with a preexistent drug-insensitive signature. To test targeting of potentially important pathways, we establish ex vivo expanded LSCs that have long-term engraftment and give rise to multilineage hematopoiesis. Expanded LSCs share transcriptomic signatures with primary LSCs including enrichment in Wnt, JAK-STAT, MAPK, mTOR and transforming growth factor ß signaling pathways. Drug testing on expanded LSCs show that transforming growth factor ß and Wnt inhibitors had significant effects on the viability of LSCs, but not leukemia-exposed healthy HSCs. This platform allows testing of multiple drugs at the same time to identify vulnerabilities of LSCs.

Severing of skull cap: A rare trauma attributed to transportation of bulldozer.

Bulldozer fatalities are usually due to accidental crushing of the body at the workplace. However, severance of the skull cap simulating a chopping injury to head is rare in the literature. Medico-legal investigation may be posed with different challenges when carrying out an autopsy of a victim with this devastating head injury. The police will seek an opinion about the type of weapon responsible for the injuries, the nature of injuries produced and manner of death. In the present case, the victim was hit at dusk by a protruding part of the bulldozer blade as he crossed in front of a bulldozer that was approaching his tractor from the opposite side of the road. His skull cap was severed and he died instantly. This report considers the circumstances of his death, its mechanisms and strategies for preventing such deaths.