Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy with abnormal progenitor self-renewal and defective white blood cell differentiation. Its pathogenesis comprises subversion of transcriptional regulation, through mutation and by hijacking normal chromatin regulation. Kat2a is a histone acetyltransferase central to promoter activity, that we recently associated with stability of pluripotency networks, and identified as a genetic vulnerability in AML. Through combined chromatin profiling and single-cell transcriptomics of a conditional knockout mouse, we demonstrate that Kat2a contributes to leukemia propagation through preservation of leukemia stem-like cells. Kat2a loss impacts transcription factor binding and reduces transcriptional burst frequency in a subset of gene promoters, generating enhanced variability of transcript levels. Destabilization of target programs shifts leukemia cell fate out of self-renewal into differentiation. We propose that control of transcriptional variability is central to leukemia stem-like cell propagation, and establish a paradigm exploitable in different tumors and distinct stages of cancer evolution.
Adaptation of bone to functional challenges is complex but it is clear that more is not necessarily better and that even very low-magnitude mechanical signals can be anabolic. The development of effective biomechanical interventions in areas such as orthodontics, craniofacial repair, or osteoporosis will require the identification of the specific components of bone's mechanical environment that are anabolic, catabolic, or anti-catabolic.
Aortic stenosis the is most prevalent and life threatening form of valvular heart disease. It is primarily treated via open-heart surgical valve replacement with either a tissue or mechanical prosthetic heart valve (PHV), each prone to degradation and thrombosis, respectively. Polymeric PHVs may be optimized to eliminate these complications, and they may be more suitable for the new transcatheter aortic valve replacement (TAVR) procedure and in devices like the Total Artificial Heart. However, the development of polymer PHVs has been hampered by persistent in vivo calcification, degradation, and thrombosis. To address these issues, we have developed a novel surgically implantable polymer PHV comprised of a new thermoset polyolefin called xSIBS, in which key parameters were optimized for superior functionality via our Device Thrombogenicity Emulation (DTE) methodology. In this parametric study, we compared our homogeneous optimized polymer PHV to a prior composite polymer PHV and to a benchmark tissue valve. Our results show significantly improved hemodynamics and reduced thrombogenicity in the optimized polymer PHV compared to the other valves. These results indicate that our new design may not require anticoagulants and may be more durable than its predecessor, and validates the improvement, towards optimization, of this novel polymeric PHV design.
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