• Molecular profiling was used to optimize an ex vivo modulation protocol with dmPGE 2 for UCB transplantation.• Pulse treatment of UCB with dmPGE 2 is safe and may lead to accelerated UCB engraftment and preferential cord chimerism.Umbilical cord blood (UCB) is a valuable source of hematopoietic stem cells (HSCs) for use in allogeneic transplantation. Key advantages of UCB are rapid availability and less stringent requirements for HLA matching. However, UCB contains an inherently limited HSC count, which is associated with delayed time to engraftment, high graft failure rates, and early mortality. 16,16-Dimethyl prostaglandin E 2 (dmPGE 2 ) was previously identified to be a critical regulator of HSC homeostasis, and we hypothesized that brief ex vivo modulation with dmPGE 2 could improve patient outcomes by increasing the "effective dose" of HSCs. Molecular profiling approaches were used to determine the optimal ex vivo modulation conditions (temperature, time, concentration, and media) for use in the clinical setting. A phase 1 trial was performed to evaluate the safety and therapeutic potential of ex vivo modulation of a single UCB unit using dmPGE 2 before reduced-intensity, double UCB transplantation. Results from this study demonstrated clear safety with durable, multilineage engraftment of dmPGE 2 -treated UCB units. We observed encouraging trends in efficacy, with accelerated neutrophil recovery (17.5 vs 21 days, P 5 .045), coupled with preferential, long-term engraftment of the dmPGE 2 -treated UCB unit in 10 of 12 treated participants. This study was registered at www. clinicaltrials.gov as #NCT00890500. (Blood. 2013;122(17):3074-3081)

Genetic efficiency in higher organisms depends on mechanisms to create multiple functions from single genes. To investigate this question for an enzyme family, we chose aminoacyl tRNA synthetases (AARSs). They are exceptional in their progressive and accretive proliferation of noncatalytic domains as the Tree of Life is ascended. Here we report discovery of a large number of natural catalytic nulls (CNs) for each human AARS. Splicing events retain noncatalytic domains while ablating the catalytic domain (CD) to create CNs with diverse functions. Each synthetase is converted into several new signaling proteins with biological activities ‘orthogonal’ to that of the catalytic parent. We suggest that splice variants with non-enzymatic functions may be more general, as evidenced by recent findings of other catalytically inactive splice-variant enzymes.

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Background: Autoantibodies (anti-Jo-1) to cytoplasmic histidyl-tRNA synthetase (HisRS) are associated with inflammatory myositis. Results: HisRS and two splice variants (SVs) cross-react with anti-Jo-1 antibodies and are secreted; at least one SV transcript is up-regulated in dermatomyositis. Conclusion: Secreted HisRS SVs contain major epitopes of anti-Jo-1 autoantibodies. Significance: Secreted HisRS and its SVs share epitopes for potential extracellular anti-Jo-1 antibody binding.

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