In this pilot study, the new method of implantation of an esophageal stent was found to be a safe and effective treatment for massive bleeding from esophageal varices in patients with liver cirrhosis. These initial clinical results will of course have to be confirmed in comparative studies including a large number of patients.

Members of theThe pathomechanisms underlying the disease primarily involve defects that prevent cell turnover because of apoptosis, rather than alterations in cell cycle regulation. 1,2 One of the hallmarks of B-CLL cells is the overexpression of the transmembrane glycoprotein CD23, 1-3 which undergoes spontaneous proteolysis, giving rise to soluble CD23 (sCD23) molecules. 4 The serum concentration of sCD23 can be several hundredfold higher than in healthy individuals and parallels the clinical stage of the disease. 5,6 Two isoforms of CD23 exist, CD23a and CD23b, which are expressed from 2 different promoters. 7 Expression of CD23a is restricted to B lymphocytes, whereas CD23b is found on a number of different hematopoietic cell types, predominantly after interleukin 4 (IL-4) treatment. 8 In B-CLL cells, selective expression of CD23a has been found to be concurrent to a state of cell survival, thereby providing a link between CD23a and the regulation of apoptosis. 9 CD23 is also closely associated with Epstein-Barr virus (EBV)-mediated B-cell immortalization, because a naturally occurring EBV mutant (P3HR1), carrying a deletion of the EBNA2 gene, has lost its ability to induce CD23 expression and to transform primary B cells in vitro. 10-12 EBNA2 activates the CD23a gene through a CBF1 repressor site located in the CD23a proximal promoter. [13][14][15] Several lines of evidence strongly suggest that EBNA2 mimics Notch signaling by acting as a transcriptional activator after binding and masking the repression domain of CBF1. [16][17][18][19] The Notch gene family encodes transmembrane receptors that modulate differentiation, proliferation, and apoptotic programs in response to extracellular ligands expressed on neighboring cells. 20,21 Ligand-mediated stimulation of Notch causes the proteolytic release of the intracellular domain (NotchIC), which then passes into the nucleus where it activates transcription of CBF1 responsive genes. [22][23][24][25] Deregulation of this pathway by overexpression of a constitutively activated form of Notch not only diverts cell fate decisions but is also tumorigenic. For example, truncation of Notch1 found in a subset of human T-cell leukemias leads to the expression of a ligand-independent oncogenic protein lacking the extracellular domain. 26 The truncated Notch proteins consist primarily of the intracellular domain and localize predominantly in the nucleus. Enforced expression of Notch1IC in bone marrow stem cells causes T-cell leukemia in mice, indicating a causative role for Notch1 in T-cell oncogenesis. 27 To elucidate the mechanisms leading to the up-regulation of CD23a in B-CLL cells, we analyzed the CD23a proximal promoter for sequence-specific DNA-protein interactions. By electrophoretic mobility shift assays (EMSAs), we detected a transcription factor For personal use only. on May 10, 2018. by guest www.bloodjournal.org From complex containing Notch2IC that binds to 5 different CBF1 responsive elements. Our data indicate that Notch2 is overexpressed in B-CLL cells, sug...

IntroductionMajor progress has been achieved in the past decade in understanding the biology of B-cell chronic lymphocytic leukemia (CLL), leading to new therapeutic concepts and a trend toward improved survival. However, the disease remains incurable, and many patients develop drug resistance. [1][2][3] Despite the long lifespan of CLL cells in vivo, these cells undergo rapid and spontaneous apoptosis in vitro but can be rescued by marrow stromal cells, [4][5][6] nurse-like cells, 7 and follicular dendritic cells. 8 There are also indications that the stromal cells mediate resistance to chemotherapy in CLL cells. 9 This point to the dependence of CLL cells on antiapoptotic stimuli that could be provided in vivo by marrow microenvironment 10,11 and may have a major effect on disease progression and response or resistance to therapy.Bone marrow microenvironment is a complex structure that comprises accessory cells (stromal cells, adipocytes, reticulum cells, endothelial cells, follicular dendritic cells, T cells, and macrophages), matrix proteins, and soluble factors, including growth factors and cytokines. 11,12 Bone marrow stromal cells (BMSCs) represent a major component of the marrow microenvironment. They originate from the mesenchymal stem cells and have hematopoietic supportive properties. They also produce matrix proteins, express integrin ligands, and release several cytokines and growth factors that are involved in the generation and maturation of normal and leukemic B cells. [11][12][13] Therefore, BMSCs could provide a suitable milieu for the development and survival of CLL cells. However, the antiapoptotic cascades and the molecular events that are activated upon the interaction between CLL cells and BMSCs are not fully identified.Several stimuli that are endogenously produced in the microenvironment were shown to activate the antiapoptotic phosphatidylinositol 3-kinase (PI3-K)/Akt pathway. These include cytokines and growth factors, 14 adhesion molecules and matrix proteins, 15 and involve receptors that are expressed on the surface of CLL cells, including the B-cell receptor, CD19, and CD5. [16][17][18] This strongly suggests that the PI3-K/Akt pathway might play a central role in the interaction between CLL cells and the bone marrow microenvironment. The PI3-K/Akt cascade contributes to the regulation of many cellular processes, including motility, proliferation, apoptosis, and tumorigenesis. 14,19 Class I of PI3-K family is the best characterized and comprises p110␣, p110␤, p110␥, and The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 11, 2018. by guest www.bloodjournal.org From p110␦ isotypes. 14,19 The first generation of pan-PI3-K inhibitors (LY294002 and wortmannin) provided substantial information on the molecular mechanism of action and ...

The use of a self-expanding stent to stop acute bleeding from esophageal varices is a new therapeutic method. The authors' initial experience, which involved no method-related mortality or complications, is encouraging. More data are necessary to confirm their results.