IntroductionB-cell chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and is characterized by the accumulation of mature, monoclonal B lymphocytes in the blood, bone marrow, and secondary lymphoid organs. 1 The expansion of CLL malignant B cells appears to result mainly from a decrease in apoptosis. 2 Clinically, CLL is a very heterogeneous disease with overall survival raging from a few years to decades. Prognostic indicators include immunoglobulin heavy chain variable region (IgV H ) mutation status, cytogenetic abnormalities, clinical stage, lymphocyte doubling time, leukocyte counts, serum lactate dehydrogenase and ␤2 microglobulin levels, and ZAP-70 and CD38 expression. 3 Despite significant advances CLL is still an incurable disease, 1 and the identification of new therapeutic strategies is warranted. Characterization of the molecular mechanisms that regulate leukemia cell viability may provide novel insights into the biology of this malignancy and reveal prognostic markers and therapeutic targets. In particular, specific inhibition of signaling elements essential for leukemia cell survival offers great promise for the design of more efficient and selective therapies.The ubiquitous serine/threonine protein kinase CK2, a tetramer consisting of 2 catalytic (␣ and/or ␣Ј) and 2 regulatory ␤ subunits, is highly pleiotropic and intervenes laterally on many signaling pathways. 4,5 CK2 can drive tumorigenesis by different mechanisms, playing a global antiapoptotic role, enhancing multidrug resistance, activating the chaperone machinery that protects the oncokinome, and sustaining neo-vascularization. 6 Overexpression of CK2 has been consistently observed in human cancers, including lung, 7 kidney, 8 head and neck, 9 prostate, 10 and breast. 11 Importantly, inhibition of CK2 activity, using specific pharmacologic inhibitors or silencing the catalytic subunit, has been shown to decrease the survival of multiple myeloma, 12 acute myeloid leukemia, 13 and T-cell acute lymphoblastic leukemia 14 cells. In CLL, the genes that code for CK2␣ (CSNK2A1) and CK2␤ (CSNK2B) were identified as a part of a poor prognosis cluster associated with shorter treatment-free survival. 15 Primary CLL cells display constitutive activation of PI3K kinase activity, 16 which appears to be critical for CLL cell survival. 17,18 PTEN, the main negative regulator of PI3K signaling pathway, can be phosphorylated by CK2 at the C terminus, leading to PTEN functional inactivation and concomitant increased protein stability. 19 We recently showed that CK2 overexpression/hyperactivation in primary T-cell acute lymphoblastic leukemia cells induces PTEN nondeletional posttranslational inactivation by phosphorylation and consequent PI3K pathway hyperactivation. 14 However, the relative expression and functional impact of CK2 in CLL remains to be established.In the current study, we demonstrate that CK2 plays a critical role in the maintenance of CLL cell viability. Primary CLL cells displayed significantly higher CK2 expre...

The objective of this paper is to assess the chronological variations in the available transfer capability (ATC) caused by uncertainties associated with hourly load fluctuations and equipment unavailabilities. The system states resulting from these uncertainties are generated using the Monte Carlo method with sequential simulation (MCMSS). The ATC for each generated state is evaluated through a linear dc optimal power flow (OPF). The test results, with a modified version of the IEEE Reliability Test System, demonstrate that the time-dependent uncertainties have a significant impact on the ATC. These effects have been assessed through statistical indexes such as expected values, box plot, and percentiles.Index Terms-Available transfer capability (ATC), composite system, linear programming, Monte Carlo method (MCM), power system reliability.

Several papers have recognized the effect of uncertainties in voltage stability analysis through probabilistic methods. In these papers, the unstable states are generally identified by the unsolvability of the power flow equations or by violations in the voltage stability margin limit. However, voltage stability problems may also be associated with a loss in voltage controllability, when a voltage control action has an effect which is contrary to what is usually expected. The main aim of this paper is to include unstable states caused by unsolvability and voltage controllability loss in the voltage stability probabilistic assessment. This goal is achieved through the combination of three techniques: the Monte Carlo Simulation Method, the nonlinear optimal power flow and the D' matrix method. These three techniques permit the inclusion of a new issue in the computation of voltage instability risk: the unstable states stemming from controllability loss. Index Terms-Composite systems, interior point method, MonteCarlo simulation, optimal power flow, probabilistic methods, sensitivity analysis, voltage stability.

Chronic lymphocytic leukemia (CLL) remains an incurable malignancy, urging for the identifcation of new molecular targets for therapeutic intervention. CLL cells rely on overexpression and hyperactivation of the ubiquitous serine/threonine protein kinase CK2 for their viability in vitro. CIGB-300 is a cell-permeable selective CK2 inhibitor peptide undergoing clinical trials for several cancers. Here, we show that CIGB-300 promotes activation of the tumor suppressor PTEN and abrogates PI3K-mediated downstream signaling in CLL cells. In accordance, CIGB-300 decreases the viability and proliferation of CLL cell lines, promotes apoptosis of primary leukemia cells and displays antitumor efcacy in a xenograft mouse model of human CLL. Our studies provide pre-clinical support for the testing and possible inclusion of CK2 inhibitors in the clinical arsenal against CLL.

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