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- Ji, Zhenyu, et al.
(författare)
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Vemurafenib Synergizes with Nutlin-3 to Deplete Survivin and Suppresses Melanoma Viability and Tumor Growth
- 2013
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 19:16, s. 4383-4391
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: For patients with advanced melanoma, primary and secondary resistance to selective BRAF inhibition remains one of the most critically compelling challenges. One rationale argues that novel biologically informed strategies are needed to maximally cripple melanoma cells up front before compensatory mechanisms emerge. As p53 is uncommonly mutated in melanoma, restoration of its function represents an attractive adjunct to selective BRAF inhibition. Experimental Design: Thirty-seven BRAF(V600E)-mutated melanoma lines were subjected to synergy studies in vitro using a combination of vemurafenib and nutlin-3 (Nt-3). In addition, cellular responses and in vivo efficacy were also determined. We also analyzed changes in the levels of canonical apoptotic/survival factors in response to vemurafenib. Results: Dual targeting of BRAF(V600E) and Hdm2 with vemurafenib and Nt-3, respectively, synergistically induced apoptosis and suppressed melanoma viability in vitro and tumor growth in vivo. Suppression of p53 in melanoma cells abrogated Nt-3's effects fully and vemurafenib's effects partially. A survey of canonical survival factors revealed that both vemurafenib and Nt-3 independently attenuated levels of the antiapoptotic protein, survivin. Genetic depletion of survivin reproduces the cytotoxic effects of the combination strategy. Conclusion: These results show preclinical feasibility for overcoming primary vemurafenib resistance by restoring p53 function. Moreover, it identifies survivin as one downstream mediator of the observed synergism and a potential secondary target. (C)2013 AACR.
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| 2. |
- Tremblay, Christine, et al.
(författare)
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Proposed filterless architecture and control plane for emerging flexible coherent networks
- 2013
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Ingår i: ICTON 2013. - 9781479906833 ; , s. 1-1
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Konferensbidrag (refereegranskat)abstract
- Recent developments in coherent modem performance and digital signal processing (DSP) technologies have opened the opportunity for new agile network architectures [1, 2]. The filterless network concept has been proposed in [3] and it is shown that they are more cost-effective and reliable compared to active optical switching networks. Filterless optical networks use broadcast-and-select techniques in which passive non-filtered optical splitters and combiners are used for channel add-drop and fiber link interconnection. Furthermore, DSP-based coherent modems are complementary foundational technologies for flexible optical networking owing to their properties of dynamic impairment compensation, performance monitoring and tuneability. The resulting network architecture makes an attractive candidate solution for flexible optical networking [4]. In this talk, we review the recent progress in filterless optical network design and control [5]ￜ[7]. In the first part, filterless architectural solutions are proposed for different network topologies and compared to active photonic switching solutions. A cost and performance analysis of filterless network solutions with 1 + 1 optical layer protection is also presented. In the second part, we present a control plane for filterless optical networks and describe its main characteristics through a performance study. Our results show that passive filterless networks can be considered as a cost effective and simpler alternative to active optical switching networks whenever traffic loading is not approaching full network capacity.
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