Deriving a preference-based measure for cancer using the EORTC QLQ-C30 : a confirmatory versus exploratory approach

Background: To derive preference-based measures from various condition-specific descriptive health-related quality of life (HRQOL) measures. A general 2-stage method is evolved: 1) an item from each domain of the HRQOL measure is selected to form a health state classification system (HSCS); 2) a sample of health states is valued and an algorithm derived for estimating the utility of all possible health states. The aim of this analysis was to determine whether confirmatory or exploratory factor analysis (CFA, EFA) should be used to derive a cancer-specific utility measure from the EORTC QLQ-C30. Methods: Data were collected with the QLQ-C30v3 from 356 patients receiving palliative radiotherapy for recurrent or metastatic cancer (various primary sites). The dimensional structure of the QLQ-C30 was tested with EFA and CFA, the latter based on a conceptual model (the established domain structure of the QLQ-C30: physical, role, emotional, social and cognitive functioning, plus several symptoms) and clinical considerations (views of both patients and clinicians about issues relevant to HRQOL in cancer). The dimensions determined by each method were then subjected to item response theory, including Rasch analysis. Results: CFA results generally supported the proposed conceptual model, with residual correlations requiring only minor adjustments (namely, introduction of two cross-loadings) to improve model fit (increment χ2(2) = 77.78, p 75% observation at lowest score), 6 exhibited misfit to the Rasch model (fit residual > 2.5), none exhibited disordered item response thresholds, 4 exhibited DIF by gender or cancer site. Upon inspection of the remaining items, three were considered relatively less clinically important than the remaining nine. Conclusions: CFA appears more appropriate than EFA, given the well-established structure of the QLQ-C30 and its clinical relevance. Further, the confirmatory approach produced more interpretable results than the exploratory approach. Other aspects of the general method remain largely the same. The revised method will be applied to a large number of data sets as part of the international and interdisciplinary project to develop a multi-attribute utility instrument for cancer (MAUCa)

PP2A inhibition overcomes acquired resistance to HER2 targeted therapy

Background: HER2 targeted therapies including trastuzumab and more recently lapatinib have significantly improved the prognosis for HER2 positive breast cancer patients. However, resistance to these agents is a significant clinical problem. Although several mechanisms have been proposed for resistance to trastuzumab, the mechanisms of lapatinib resistance remain largely unknown. In this study we generated new models of acquired resistance to HER2 targeted therapy and investigated mechanisms of resistance using phospho-proteomic profiling. Results: Long-term continuous exposure of SKBR3 cells to low dose lapatinib established a cell line, SKBR3-L, which is resistant to both lapatinib and trastuzumab. Phospho-proteomic profiling and immunoblotting revealed significant alterations in phospho-proteins involved in key signaling pathways and molecular events. In particular, phosphorylation of eukaryotic elongation factor 2 (eEF2), which inactivates eEF2, was significantly decreased in SKBR3-L cells compared to the parental SKBR3 cells. SKBR3-L cells exhibited significantly increased activity of protein phosphatase 2A (PP2A), a phosphatase that dephosphorylates eEF2. SKBR3-L cells showed increased sensitivity to PP2A inhibition, with okadaic acid, compared to SKBR3 cells. PP2A inhibition significantly enhanced response to lapatinib in both the SKBR3 and SKBR3-L cells. Furthermore, treatment of SKBR3 parental cells with the PP2A activator, FTY720, decreased sensitivity to lapatinib. The alteration in eEF2 phosphorylation, PP2A activity and sensitivity to okadaic acid were also observed in a second HER2 positive cell line model of acquired lapatinib resistance, HCC1954-L. Conclusions: Our data suggests that decreased eEF2 phosphorylation, mediated by increased PP2A activity, contributes to resistance to HER2 inhibition and may provide novel targets for therapeutic intervention in HER2 positive breast cancer which is resistant to HER2 targeted therapies

Majorizing measures for the optimizer

The theory of majorizing measures, extensively developed by Fernique, Talagrand and many others, provides one of the most general frameworks for controlling the behavior of stochastic processes. In particular, it can be applied to derive quantitative bounds on the expected suprema and the degree of continuity of sample paths for many processes. One of the crowning achievements of the theory is Talagrand’s tight alternative characterization of the suprema of Gaussian processes in terms of majorizing measures. The proof of this theorem was difficult, and thus considerable effort was put into the task of developing both shorter and easier to understand proofs. A major reason for this difficulty was considered to be theory of majorizing measures itself, which had the reputation of being opaque and mysterious. As a consequence, most recent treatments of the theory (including by Talagrand himself) have eschewed the use of majorizing measures in favor of a purely combinatorial approach (the generic chaining) where objects based on sequences of partitions provide roughly matching upper and lower bounds on the desired expected supremum. In this paper, we return to majorizing measures as a primary object of study, and give a viewpoint that we think is very natural and clarifying from an optimization perspective. As our main contribution, we give an algorithmic proof of the majorizing measures theorem based on two parts: - We make the simple (but apparently new) observation that finding the best majorizing measure can be cast as a convex program. This also allows for efficiently computing the measure using off-the-shelf methods from convex optimization. - We obtain tree-based upper and lower bound certificates by rounding, in a series of steps, the primal and dual solutions to this convex program. While duality has conceptually been part of the theory since its beginnings, as far as we are aware no explicit link to convex optimization has been previously made.<p

A demonstration of a service oriented virtual environment for complex system analysis

Distributed virtual simulation is increasingly in demand within the automotive industry. A distributed and networked approach to system level design and simulation stands to benefit from a unifying relational oriented modeling and simulation framework. This will permit innovative use of existing independent simulations for increased concurrency in design and verification and validation. This paper demonstrates an analysis of the vehicle as a complex system through the combination of a relational framework, high level syntax and semantics for representing models and distributed simulation. This promises to provide a rigorous, traceable and agile approach to conceptual vehicle design and analysis

Convergence calls: multimedia storytelling at British news websites

This article uses qualitative interviews with senior editors and managers from a selection of the UK's national online news providers to describe and analyse their current experimentation with multimedia and video storytelling. The results show that, in a period of declining newspaper readership and TV news viewing, editors are keen to embrace new technologies, which are seen as being part of the future of news. At the same time, text is still reported to be the cornerstone for news websites, leading to changes in the grammar and function of news video when used online. The economic rationale for convergence is examined and the article investigates the partnerships sites have entered into in order to be able to serve their audience with video content. In-house video is complementing syndicated content, and the authors examine the resulting developments in newsroom training and recruitment practices. The article provides journalism and interactive media scholars with case studies on the changes taking place in newsrooms as a result of the shift towards multimedia, multiplatform news consumption

Phosphate steering by Flap Endonuclease 1 promotes 5´-flap specificity and incision to prevent genome instability

DNA replication and repair enzyme Flap Endonuclease 1 (FEN1) is vital for genome integrity, and FEN1 mutations arise in multiple cancers. FEN1 precisely cleaves single-stranded (ss) 50-flaps one nucleotide into duplex (ds) DNA. Yet, how FEN1 selects for but does not incise the ss 50-flap was enigmatic. Here we combine crystallographic, biochemical and genetic analyses to show that two dsDNA binding sites set the 50polarity and to reveal unexpected control of the DNA phosphodiester backbone by electrostatic interactions. Via ‘phosphate steering’, basic residues energetically steer an inverted ss 50-flap through a gateway over FEN1’s active site and shift dsDNA for catalysis. Mutations of these residues cause an 18,000-fold reduction in catalytic rate in vitro and large-scale trinucleotide (GAA)n repeat expansions in vivo, implying failed phosphate-steering promotes an unanticipated lagging-strand template-switch mechanism during replication. Thus, phosphate steering is an unappreciated FEN1 function that enforces 50-flap specificity and catalysis, preventing genomic instability

Phosphate steering by Flap Endonuclease 1 promotes 5´-flap specificity and incision to prevent genome instability

DNA replication and repair enzyme Flap Endonuclease 1 (FEN1) is vital for genome integrity, and FEN1 mutations arise in multiple cancers. FEN1 precisely cleaves single-stranded (ss) 50-flaps one nucleotide into duplex (ds) DNA. Yet, how FEN1 selects for but does not incise the ss 50-flap was enigmatic. Here we combine crystallographic, biochemical and genetic analyses to show that two dsDNA binding sites set the 50polarity and to reveal unexpected control of the DNA phosphodiester backbone by electrostatic interactions. Via ‘phosphate steering’, basic residues energetically steer an inverted ss 50-flap through a gateway over FEN1’s active site and shift dsDNA for catalysis. Mutations of these residues cause an 18,000-fold reduction in catalytic rate in vitro and large-scale trinucleotide (GAA)n repeat expansions in vivo, implying failed phosphate-steering promotes an unanticipated lagging-strand template-switch mechanism during replication. Thus, phosphate steering is an unappreciated FEN1 function that enforces 50-flap specificity and catalysis, preventing genomic instability