Crosstalk between BCR/ABL oncoprotein and CXCR4 signaling through a Src family kinase in human leukemia cells

Stromal-derived factor (SDF)-1 and its G protein-coupled receptor, CXCR4, regulate stem/progenitor cell migration and retention in the marrow and are required for hematopoiesis. We show here an interaction between CXCR4 and the Src-related kinase, Lyn, in normal progenitors. We demonstrate that CXCR4-dependent stimulation of Lyn is associated with the activation of phosphatidylinositol 3-kinase (PI3-kinase). This chemokine signaling, which involves a Src-related kinase and PI3-kinase, appears to be a target for BCR/ABL, a fusion oncoprotein expressed only in leukemia cells. We show that the binding of phosphorylated BCR/ABL to Lyn results in the constitutive activation of Lyn and PI3-kinase, along with a total loss of responsiveness of these kinases to SDF-1 stimulation. Inhibition of BCR/ABL tyrosine kinase with STI571 restores Lyn responsiveness to SDF-1 signaling. Thus, BCR/ABL perturbs Lyn function through a tyrosine kinase-dependent mechanism. Accordingly, the blockade of Lyn tyrosine kinase inhibits both BCR/ABL-dependent and CXCR4-dependent cell movements. Our results demonstrate, for the first time, that Lyn-mediated pathological crosstalk exists between BCR/ABL and the CXCR4 pathway in leukemia cells, which disrupts chemokine signaling and chemotaxis, and increases the ability of immature cells to escape from the marrow. These results define a Src tyrosine kinases-dependent mechanism whereby BCR/ABL (and potentially other oncoproteins) dysregulates G protein-coupled receptor signaling and function of mammalian precursors.     

Bedside ultrasound in the diagnosis of uterine rupture following surgical abortion

Reports of uterine rupture following surgical abortion are rare but may result in hemorrhage, sepsis, and even death. In this unique case, we describe how a transabdominal pelvic ultrasound performed at the bedside by an emergency department physician identified uterine rupture with retained products of conception and led to an emergent laparotomy and hysterectomy. This case illustrates how bedside ultrasound may be used in patients presenting with abdominopelvic pain following surgical abortion to shorten the time to definitive treatment and ultimately lower the morbidity and mortality associated with a diagnosis of life-threatening uterine rupture.     

An overview of the endocrinology of skeletal muscle.

Endocrine regulation of the balance between skeletal muscle anabolism and catabolism has been investigated extensively. Factors determining whether hormones exert anabolic or catabolic influences are multifaceted and often unclear. Testosterone, growth hormone, insulin and insulin-like growth factor-I have complex anabolic effects, some of which have only recently been elucidated, and are important regulators of muscle remodeling, whereas glucocorticoids have direct catabolic effects and induce muscle protein loss. The effects of estrogen are poorly understood and warrant further study. We review recent literature and evaluate the hormones driving skeletal muscle anabolism and catabolism, which ultimately dictate the endocrinology and metabolism of skeletal muscle in humans. Understanding hormonal regulation of skeletal muscle remodeling might facilitate development of improved hormone-mediated therapies for muscle wasting conditions.