cmos scaling-moores-law forever-lundstrom.pdf

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ed immune cells in which the Syk/SLP-76 sig- naling pathway is activated be responsible for the separation of the blood and lymphatic net- works? If so, then the absence of these signal- ing molecules in SLP-76– or Syk-deficient animals might result in fusion of the peripher- al lymphatic vessels with blood vessels result- ing in the vascular malformations observed in the knockout mice. Although Abtahian et al. argue to the con- trary, another possibility is that the bone mar- row–derived cells they used to rescue the lethally irradiated wild-type mice included lymphatic endothelial progenitor cells ( 6 ). These circulating cells differentiate into endothelial cells expressing lymphatic markers in vitro (see the figure, step 5). They may be important for lymphatic development as well as for postnatal lymphangiogenesis under physio- logical or pathological conditions. Could sig- naling through the SLP-76/Syk pathway trig- ger the early differentiation of a multipotent bone marrow stem cell into a more differentiat- ed lymphatic endothelial progenitor cell? Because SLP-76 or Syk could not be detected in the endothelial cells of the lethally irradiated wild-type mice, the expression of these mole- cules may be down-regulated before lymphatic endothelial progenitor cells become incorpo- rated into the developing lymphatic vessels. The careful functional studies of Abtahian et al . have broad implications. First, the iden- tification of SLP-76 and Syk during the sep- aration of the blood and lymphatic systems implicates these molecules in AVMs. The new findings may help to elucidate other pro- teins involved in various congenital AVM syndromes, thus speeding development of improved treatment strategies. Second, the Abtahian et al . work focuses attention on early events in the development of lymphatic vessels and the part played by cells derived from bone marrow. It is becoming clear that multiple molecules are necessary to ensure proper differentiation and patterning of lym- phatic endothelial cells into a functional lym- phatic system. By expanding the roster of molecules, many more targets for therapeutic intervention will emerge beyond VEGFR-3 and its ligands, yielding more possibilities for new treatments for lymphedema. Third, the new work may offer fresh insights into the dysregulation of both the vascular and lym- phatic systems during tumor formation, specifically through the SLP-76/Syk path- way. Syk expression is lower in breast tumors than in normal mammary tissue and corre- lates with an increase in metastases and a poor prognosis ( 7, 8 ). Could reduced Syk expression lead to abnormalities in the devel- oping tumor vasculature, hence boosting metastasis? Could mutations in SLP-76, Syk, or other pathway components also explain the finding that blood-filled vessels associated with some tumors bear lymphatic markers ( 9 )? Blood vessels and lymphatic vessels present metastatic tumor cells with two major routes for dispersal. Thus, strategies to selec- tively eradicate these vessels may provide a potent weapon against cancer. Increased
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