BCR-ABL is a fusion oncogene expressed in human leukemia cells with a (9;22) translocation known as the Philadelphia (Ph) chromosome. 2,3 Depending on the specific breakpoint, Bcr-Abl proteins exist in p190, p210, or p230 forms that are associated with different clinical syndromes. p210-Bcr-Abl is found in nearly all cases of chronic myelogenous leukemia (CML) and some patients with Ph ϩ acute lymphoid leukemia (ALL). p190-Bcr-Abl is almost exclusively found in ALL. Retroviral transduction of murine bone marrow cells with p210 or p190 forms can yield either myeloid or B-lymphoid tumors in recipient mice, depending on the experimental model used. 4 The Abl tyrosine kinase inhibitor imatinib (Gleevec, STI-571) has been shown to elicit remarkable clinical responses with minimal toxicity in CML and Ph ϩ ALL patients. Unfortunately, resistance eventually develops and is usually associated with mutations or amplifications of BCR-ABL. 5,6 Targeting multiple signaling steps therefore may generate more lasting remissions in patients with ABL-dependent leukemias. Expression of v-Abl or Bcr-Abl activates many of the same signaling intermediates including the small G proteins Ras and Rac, tyrosine kinases of the Janus kinase family, protein kinase C, and phosphoinositide 3-kinase (PI3K). 7,8 It is important to note that signaling components downstream of ABL oncogenes have been defined in diverse cell systems. However, it is becoming evident that many of the effects of v-ABL and BCR-ABL are cell-context specific and may not have functional significance in the transformation of primary cells. For example, signal transducer and activator of transcription 5 was shown to be dispensable for v-ABL-or BCR-ABL-mediated transformation and leukemogenesis even though it is phosphorylated in human CML cells and is required for conversion of hematopoietic cell lines to growth factor-independence. 9,10 Thus, it is critical that the contribution of specific signaling components to ABL-mediated disease be confirmed in direct transformation assays done in hematopoietic cell types representative of their natural target cells.The PI3K family of enzymes phosphorylates inositol phospholipids, thereby promoting membrane association of certain cytoplasmic proteins that specifically bind to PI3K lipid products. 11,12 There are many subtypes of PI3K with distinct functions in cells. Class I A PI3Ks, the subgroup that functions downstream of activated tyrosine kinases, are heterodimers composed of a catalytic subunit and a regulatory subunit. Signaling through class I A PI3K promotes cell proliferation and survival in many cell types and is strongly associated with transformation and metastasis. 13 There are 3 catalytic subunit isoforms (p110␣, p110␤, and p110␦) and 5 regulatory subunit isoforms (p85␣, p55␣, p50␣, p85␤, and p55␥; the first 3 are transcriptional variants of a single gene, Pik3r1). 11 We and others have shown that the predominant class I A regulatory isoform expressed in murine B cells, p85␣, is required for B-cell proliferation trigg...

IntroductionHemorrhage is one of the leading causes of death in trauma victims. Historically, paramedics have not had access to medications that specifically target the reversal of trauma-induced coagulopathies. The California Prehospital Antifibrinolytic Therapy (Cal-PAT) study seeks to evaluate the safety and efficacy of tranexamic acid (TXA) use in the civilian prehospital setting in cases of traumatic hemorrhagic shock.MethodsThe Cal-PAT study is a multi-centered, prospective, observational cohort study with a retrospective comparison. From March 2015 to July 2017, patients ≥ 18 years-old who sustained blunt or penetrating trauma with signs of hemorrhagic shock identified by first responders in the prehospital setting were considered for TXA treatment. A control group was formed of patients seen in the five years prior to data collection cessation (June 2012 to July 2017) at each receiving center who were not administered TXA. Control group patients were selected through propensity score matching based on gender, age, Injury Severity Scores, and mechanism of injury. The primary outcome assessed was mortality recorded at 24 hours, 48 hours, and 28 days. Additional variables assessed included total blood products transfused, the hospital and intensive care unit length of stay, systolic blood pressure taken prior to TXA administration, Glasgow Coma Score observed prior to TXA administration, and the incidence of known adverse events associated with TXA administration.ResultsWe included 724 patients in the final analysis, with 362 patients in the TXA group and 362 in the control group. Reduced mortality was noted at 28 days in the TXA group in comparison to the control group (3.6% vs. 8.3% for TXA and control, respectively, odds ratio [OR]=0.41 with 95% confidence interval [CI] [0.21 to 0.8]). This mortality difference was greatest in severely injured patients with ISS >15 (6% vs 14.5% for TXA and control, respectively, OR=0.37 with 95% CI [0.17 to 0.8]). Furthermore, a significant reduction in total blood product transfused was observed after TXA administration in the total cohort as well as in severely injured patients. No significant increase in known adverse events following TXA administration were observed.ConclusionFindings from the Cal-PAT study suggest that TXA use in the civilian prehospital setting may safely improve survival outcomes in patients who have sustained traumatic injury with signs of hemorrhagic shock.

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