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Drug combination therapies are commonly used for the treatment of cancers to increase therapeutic efficacy, reduce toxicity, and decrease the incidence of drug resistance. Although drug combination therapies were originally devised primarily by empirical methods, the increased understanding of drug mechanisms and the pathways they modulate provides a unique opportunity to design combinations that are based on mechanistic rationale. We have identified protein kinase CK2 as a promising therapeutic target for combination therapy, because CK2 regulates not just one but many oncogenic pathways and processes that play important roles in drug resistance, including DNA repair, epidermal growth factor receptor signaling, PI3K/AKT/mTOR signaling, Hsp90 machinery activity, hypoxia, and interleukin-6 expression. In this article, we show that CX-4945, a clinical stage selective small molecule inhibitor of CK2, blocks the DNA repair response induced by gemcitabine and cisplatin and synergizes with these agents in models of ovarian cancer. Mechanistic studies show that the enhanced activity is a result of inactivation of XRCC1 and MDC1, two mediator/adaptor proteins that are essential for DNA repair and that require phosphorylation by CK2 for their function. These data position CK2 as a valid pharmacologic target for intelligent drug combinations and support the evaluation of CX-4945 in combination with gemcitabine and platinum-based chemotherapeutics in the clinical setting. Mol Cancer Ther; 11(4); 994–1005. ©2012 AACR.

PDF file - 148K, The effects of CK2, MDC1 or XRCC1 depletion by siRNA on Gamma-H2AX levels induced by cisplatin or gemcitabine.

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PDF file - 97K, Quantified western blots for Gamma-H2AX and cleaved PARP levels normalized to �eta-actin levels from cisplatin or gemcitabine combinations with CX-4945.

PDF file - 1.0MB, The global role of CK2 in DNA repair and cancer therapies that potentially rely on CK2 mediated repair mechanisms.

Supplementary Methods and Materials from Anticancer Activity of CX-3543: A Direct Inhibitor of rRNA Biogenesis

The battery management system (BMS) is the main safeguard of a battery system for electric propulsion and machine electrification. It is tasked to ensure reliable and safe operation of battery cells connected to provide high currents at high voltage levels. In addition to effectively monitoring all the electrical parameters of a battery pack system, such as the voltage, current, and temperature, the BMS is also used to improve the battery performance with proper safety measures within the system. With growing acceptance of lithium-ion batteries, major industry sectors such as the automotive, renewable energy, manufacturing, construction, and even some in the mining industry have brought forward the mass transition from fossil fuel dependency to electric powered machinery and redefined the world of energy storage. Hence, the functional safety considerations, which are those relating to automatic protection, in battery management for battery pack technologies are particularly important to ensure that the overall electrical system, regardless of whether it is for electric transportation or stationary energy storage, is in accordance with high standards of safety, reliability, and quality. If the system or product fails to meet functional and other safety requirements on account of faulty design or a sequence of failure events, then the environment, people, and property could be endangered. This paper analyzed the details of BMS for electric transportation and large-scale energy storage systems, particularly in areas concerned with hazardous environment. The analysis covers the aspect of functional safety that applies to BMS and is in accordance with the relevant industrial standards. A comprehensive evaluation of the components, architecture, risk reduction techniques, and failure mode analysis applicable to BMS operation was also presented. The article further provided recommendations on safety design and performance optimization in relation to the overall BMS integration.