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...

Combined cardiac stem cell delivery induces a moderate but significant improvement in myocardial infarct size and left ventricular function.

These results indicate that continuous support of calcium-gluconate during LVL is an effective means of reducing the incidence of citrate-related symptoms and improving subjective tolerance toward LVL, without affecting the technical performance or the number of CD34+ cells collected.

This study aims to assess the association of the preoperative neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) with tumor stage in colorectal cancer (CRC) patients. A retrospective study was performed in 336 CRC patients. Preoperative whole blood counts, serum levels of carcinoembryonic antigen (CEA), and clinicopathologic data were collected. The correlations between laboratory parameters and the tumor, node, and metastasis (TNM) stages were analyzed. The clinicopathologic TNM stages among CRC patients were 12.8 % at stage I, 32.4 % at stage II, 44.6 % at stage III, and 10.1 % at stage IV. NLR, PLR, and CEA levels were higher in CRC patients compared to healthy controls (all P < 0.0001). Both NLR and PLR showed an early elevation as compared to CEA, with a higher area under curve (AUC) value (0.71 vs. 0.62) in predicting the presence of the tumor with stage I/II. Accordingly, significant elevations of NLR (P = 0.0018) and PLR (P < 0.0001) were firstly detected in stage I and stage II, respectively. In addition, NLR exhibited a second phase elevation in stage IV, with a significant higher level in M1 subgroup compared to M0 subgroup (P = 0.022). While PLR showed a T stage-dependent increase (P = 0.0003) and was identified as an independent factor for the T grade development (P < 0.0001). Our data indicated that both neutrophil- and platelet-mediated inflammatory reactions are predominantly involved in the different stages of CRC development. Determination of pretreatment levels of NLR and PLR might provide useful information for the early diagnosis or the therapeutic choices in CRC patients.