The PAX-SIX-EYA-DACH network modulates GATA-FOG function in fly hematopoiesis and human erythropoiesis.

The GATA and PAX-SIX-EYA-DACH transcriptional networks (PSEDNs) are essential for proper development across taxa. Here, we demonstrate novel PSEDN roles in vivo in Drosophila hematopoiesis and in human erythropoiesis in vitro Using Drosophila genetics, we show that PSEDN members function with GATA to block lamellocyte differentiation and maintain the prohemocyte pool. Overexpression of human SIX1 stimulated erythroid differentiation of human erythroleukemia TF1 cells and primary hematopoietic stem-progenitor cells. Conversely, SIX1 knockout impaired erythropoiesis in both cell types. SIX1 stimulation of erythropoiesis required GATA1, as SIX1 overexpression failed to drive erythroid phenotypes and gene expression patterns in GATA1 knockout cells. SIX1 can associate with GATA1 and stimulate GATA1-mediated gene transcription, suggesting that SIX1-GATA1 physical interactions contribute to the observed functional interactions. In addition, both fly and human SIX proteins regulated GATA protein levels. Collectively, our findings demonstrate that SIX proteins enhance GATA function at multiple levels, and reveal evolutionarily conserved cooperation between the GATA and PSEDN networks that may regulate developmental processes beyond hematopoiesis.

Is Tranexamic Acid Associated With Mortality or Multiple Organ Failure Following Severe Injury?

BACKGROUND: Tranexamic acid (TXA) administration is recommended in severely injured trauma patients. We examined TXA administration, admission fibrinolysis phenotypes, and clinical outcomes following traumatic injury and hypothesized that TXA was associated with increased multiple organ failure (MOF). METHODS: Two-year, single-center, retrospective investigation. Inclusion criteria were age ≥ 18 years, Injury Severity Score (ISS) >16, admitted from scene of injury, thromboelastography within 30 min of arrival. Fibrinolysis was evaluated by lysis at 30 min (LY30) and fibrinolysis phenotypes were defined as: Shutdown: LY30 ≤ 0.8%, Physiologic: LY30 0.81-2.9%, Hyperfibrinolysis: LY30 ≥ 3.0%. Primary outcomes were 28-day mortality and MOF. The association of TXA with mortality and MOF was assessed among the entire study population and in each of the fibrinolysis phenotypes. RESULTS: Four hundred twenty patients: 144/420 Shutdown (34.2%), 96/420 Physiologic (22.9%), and 180/410 Hyperfibrinolysis (42.9%). There was no difference in 28-day mortality by TXA administration among the entire study population (P = 0.52). However, there was a significant increase in MOF in patients who received TXA (11/46, 23.9% vs 16/374, 4.3%; P < 0.001). TXA was associated MOF (OR: 3.2, 95% CI 1.2-8.9), after adjusting for confounding variables. There was no difference in MOF in patients who received TXA in the Physiologic (1/5, 20.0% vs 7/91, 7.7%; P = 0.33) group. There was a significant increase in MOF among patients who received TXA in the Shutdown (3/11, 27.3% vs 5/133, 3.8%; P = 0.001) and Hyperfibrinolysis (7/30, 23.3% vs 5/150, 3.3%; P = 0.001) groups. CONCLUSIONS: Administration of TXA following traumatic injury was associated with MOF in the fibrinolysis shutdown and hyperfibrinolysis phenotypes and warrants continued evaluation.