Circulating CD133+VEGFR2+ and CD34+VEGFR2+ cells and arterial function in patients with beta-thalassaemia major

Arterial dysfunction has been documented in patients with beta-thalassaemia major. This study aimed to determine the quantity and proliferative capacity of circulating CD133+VEGFR2+ and CD34+VEGFR2+ cells in patients with beta-thalassaemia major and those after haematopoietic stem cell transplantation (HSCT), and their relationships with arterial function. Brachial arterial flow-mediated dilation (FMD), carotid arterial stiffness, the quantity of these circulating cells and their number of colony-forming units (CFUs) were determined in 17 transfusion-dependent thalassaemia patients, 14 patients after HSCT and 11 controls. Compared with controls, both patient groups had significantly lower FMD and greater arterial stiffness. Despite having increased CD133+VEGFR2+ and CD34+VEGFR2+ cells, transfusion-dependent patients had significantly reduced CFUs compared with controls (p = 0.002). There was a trend of increasing CFUs across the three groups with decreasing iron load (p = 0.011). The CFUs correlated with brachial FMD (p = 0.029) and arterial stiffness (p = 0.02), but not with serum ferritin level. Multiple linear regression showed that CFU was a significant determinant of FMD (p = 0.043) and arterial stiffness (p = 0.02) after adjustment of age, sex, body mass index, blood pressure and serum ferritin level. In conclusion, arterial dysfunction found in patients with beta-thalassaemia major before and after HSCT may be related to impaired proliferation of CD133+VEGFR2+ and CD34+VEGFR2+ cells

Zinc Coordination Is Required for and Regulates Transcription Activation by Epstein-Barr Nuclear Antigen 1

Epstein-Barr Nuclear Antigen 1 (EBNA1) is essential for Epstein-Barr virus to immortalize naïve B-cells. Upon binding a cluster of 20 cognate binding-sites termed the family of repeats, EBNA1 transactivates promoters for EBV genes that are required for immortalization. A small domain, termed UR1, that is 25 amino-acids in length, has been identified previously as essential for EBNA1 to activate transcription. In this study, we have elucidated how UR1 contributes to EBNA1's ability to transactivate. We show that zinc is necessary for EBNA1 to activate transcription, and that UR1 coordinates zinc through a pair of essential cysteines contained within it. UR1 dimerizes upon coordinating zinc, indicating that EBNA1 contains a second dimerization interface in its amino-terminus. There is a strong correlation between UR1-mediated dimerization and EBNA1's ability to transactivate cooperatively. Point mutants of EBNA1 that disrupt zinc coordination also prevent self-association, and do not activate transcription cooperatively. Further, we demonstrate that UR1 acts as a molecular sensor that regulates the ability of EBNA1 to activate transcription in response to changes in redox and oxygen partial pressure (pO2). Mild oxidative stress mimicking such environmental changes decreases EBNA1-dependent transcription in a lymphoblastoid cell-line. Coincident with a reduction in EBNA1-dependent transcription, reductions are observed in EBNA2 and LMP1 protein levels. Although these changes do not affect LCL survival, treated cells accumulate in G0/G1. These findings are discussed in the context of EBV latency in body compartments that differ strikingly in their pO2 and redox potential

Efficient estimation of the accuracy of the maximum likelihood method for ancestral state reconstruction

10.1007/s10878-009-9261-6Journal of Combinatorial Optimization214409-422JCOP

The emerging role of hypoxia, HIF-1 and HIF-2 in multiple myeloma

Hypoxia is an imbalance between oxygen supply and demand, which deprives cells or tissues of sufficient oxygen. It is well-established that hypoxia triggers adaptive responses, which contribute to short- and long-term pathologies such as inflammation, cardiovascular disease and cancer. Induced by both microenvironmental hypoxia and genetic mutations, the elevated expression of the hypoxia-inducible transcription factor-1 (HIF-1) and HIF-2 is a key feature of many human cancers and has been shown to promote cellular processes, which facilitate tumor progression. In this review, we discuss the emerging role of hypoxia and the HIFs in the pathogenesis of multiple myeloma (MM), an incurable hematological malignancy of BM PCs, which reside within the hypoxic BM microenvironment. The need for current and future therapeutic interventions to target HIF-1 and HIF-2 in myeloma will also be discussed.SK Martin, P Diamond, S Gronthos, DJ Peet and ACW Zannettin

The GHSG Approach to Treating Hodgkin's Lymphoma

Hodgkin's lymphoma (HL) is a relatively rare disease accounting for 15 % of all lymphoma. This disease has developed from an incurable disease to the adult malignancy with the most favorable prognosis. With current therapeutic approaches consisting of polychemo- and small-field radiotherapy, up to 80 % of all patients can be cured long term. In refractory or relapsed HL, intensified treatment including high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) is associated with progression-free survival (PFS) of 50 %. Evaluation of novel drugs in multiple relapsed or refractory cases, better treatment options for elderly patients and reducing treatment-related side effects are the main focus of current research. Recent clinical developments and future approaches in the treatment of HL will be discussed in this review