Getting out of a wheelchair: an uncommon insertion mutation in exon 19 of EGFR responsive to erlotinib.

BACKGROUND: Most patients with non-small cell lung cancer (NSCLC) present with advanced disease and have poor long-term prognosis. Advanced NSCLC that contains characteristic mutations in epidermal growth factor receptor (EGFR) are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs). EGFR exon 19 insertions mutations are rare, and response to TKIs is still unclear. CASE DESCRIPTION: A young Arab patient was diagnosed with metastatic disease of NSCLC harboring an exon 19 insertion of 18 nucleotides. The patient showed a very impressive clinical and radiological response within few weeks treatment with TKI agent. DISCUSSION AND EVALUATION: To our best knowledge, This case is the first case in Arab woman and one of few cases described in the literature with this rare mutation responding to TKIs. CONCLUSIONS: Treatment with TKIs should be the standard choice in patients with metastatic disease NSCLC.

Vascular cells.

Embryonic stem (ES) cells are cells derived from the inner cell mass of a blastocyst stage embryo. These self-renewing multipotent cells are able to differentiate to the three embryonic germ layers, the endoderm, ectoderm, and mesoderm, and are thus able to produce virtually all cell types. The ES cell capacity to generate various cell types has been studied extensively, and exploitation of ES cell characteristics allowed the production of several differentiated cell types of multiple tissues. Moreover, the process of ES cell differentiation provides a unique opportunity to observe early embryonic developmental events that are unattainable in the embryo itself. This chapter addresses the in vitro differentiation procedure of endothelial and vascular smooth muscle cells from human ES cells, with reference to similar studies performed in mouse and nonhuman primate ES cells, and provides several tools for the detailed characterization of differentiated cells.

Human embryonic stem cells for vascular development and repair.

Embryonic stem cells, derived from the inner cell mass of embryos in the blastocyst stage, are cells capable of perpetual self-renewal and long-term propagation and hold the potential to differentiate to progeny of the three embryonic germ layers. Since their derivation approximately two decades ago, exploration of mouse ES cells made major advances in ES cell differentiation research and in the successful development and propagation of various cell types. The subsequent derivation of ES cells from human embryos allows detailed study of early developmental events practically unreachable in early human embryos, and the potential derivation of a variety of adult cell types differentiated from the ES cells holds immense therapeutic promise. Recently, the study of ES cell-derived teratomas identified the partial presence of human ES cell-derived premature vessels within the teratoma, and a preliminary protocol for the in vitro derivation of a vascular progenitor was developed based on the study with the mouse ES cells. Furthermore, genetic profiling identified a pattern of expression of various endothelial and vascular smooth muscle cell genes that provide additional information on the degree of vascular development that ES cells undergo. Finally, the clinical application of ES cells in transplantation medicine is closer than ever following the affirmation that human ES cell-derived endothelial progenitors conferred increased neovascularization in transplanted engineered skeletal muscle. This review summarizes these recent advances in vascular development from human ES cells and their potential clinical applications.

New horizons for VEGF. Is there a role for nuclear localization?

Angiogenesis, or new blood vessel formation, is a physiological response of tissues to hypoxia or ischemia. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that is up-regulated by hypoxia. The mechanisms responsible for hypoxic induction of VEGF are still not completely understood, though both transcriptional and post-transcriptional mechanisms are involved. In recent years, we have investigated cis-regulatory sequences and trans-acting factors which mediate the hypoxia-induced increase in VEGF mRNA stability. In particular, we have identified a 40 bp sequence motif in the 3'-untranslated region of VEGF mRNA, which is critical for the increase in VEGF mRNA stability with hypoxia and have shown that the RNA-binding protein, HuR, binds to this region. By means of indirect immunofluorescence experiments using monoclonal antibodies against HuR, we demonstrated that HuR localizes to the nucleus under hypoxia. As HuR binds to VEGF mRNA and appears to mediate stabilization of VEGF mRNA, it was of interest to show whether a fraction of VEGF protein localizes similarly to the nucleus. Double-labeling immunofluorescence showed that VEGF protein colocalizes with HuR in discrete nuclear compartments and nuclear VEGF protein was increased in hypoxia. These results indicate that VEGF may have a nuclear function, especially during hypoxia.

A 40-bp RNA element that mediates stabilization of vascular endothelial growth factor mRNA by HuR.

VEGF is a critical mediator of hypoxia-induced angiogenesis in numerous physiological and pathophysiological conditions. The hypoxic induction of VEGF is due in large part to an increase in the stability of its mRNA. We recently demonstrated that the stabilization of VEGF mRNA by hypoxia is dependent upon the RNA-binding protein HuR. This report describes the identification of a 40-bp functional HuR binding site in the VEGF mRNA 3'-untranslated region. This element can confer HuR-mediated stabilization of a heterologous gene in vitro and in vivo. Furthermore, the element is sufficient to confer an increase in the hypoxic induction of a heterologous gene. Deletion of the HuR binding site within this 40-bp element as mapped by RNase T1 and lead footprinting uncouples a stabilizing sequence from a destabilizing sequence, thus providing a novel RNA-protein regulatory model that might be exploited to manipulate VEGF expression and hypoxia-induced angiogenesis.