15 research outputs found

    Lenalidomide in the context of complex karyotype or interrupted treatment: case reviews of del(5q)MDS patients with unexpected responses

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    Lenalidomide has particular activity in patients with transfusion-dependent del(5q) myelodysplastic syndromes (MDS), but mechanistic information is limited regarding the relationship between erythroid and cytogenetic responses. We reviewed medical records from three distinct subgroups of del(5q) MDS patients who had unexpected effects with lenalidomide treatment: 1. two patients with complex karyotypes who achieved both cytogenetic remissions and transfusion independence; 2. two patients with 5q- syndrome who took lenalidomide for less than 12 weeks but remained transfusion independent for 15+ months still displaying del(5q) metaphases after 6 and 12 months; and 3. one patient who was a non-responder on lenalidomide during treatment but became transfusion independent for 13+ months after discontinuation. All but the latter patient in this series had reduction of affected metaphases, suggesting that erythroid responses might be mediated by result from partial or complete suppression of the malignant clone, either directly or indirectly through modulation of the bone marrow microenvironment. These clinical observations illustrate the heterogeneity of del(5q)MDS pathogenesis and the diversity of lenalidomide responses within this patient subset

    Satellite-based terrestrial production efficiency modeling

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    Production efficiency models (PEMs) are based on the theory of light use efficiency (LUE) which states that a relatively constant relationship exists between photosynthetic carbon uptake and radiation receipt at the canopy level. Challenges remain however in the application of the PEM methodology to global net primary productivity (NPP) monitoring. The objectives of this review are as follows: 1) to describe the general functioning of six PEMs (CASA; GLO-PEM; TURC; C-Fix; MOD17; and BEAMS) identified in the literature; 2) to review each model to determine potential improvements to the general PEM methodology; 3) to review the related literature on satellite-based gross primary productivity (GPP) and NPP modeling for additional possibilities for improvement; and 4) based on this review, propose items for coordinated research

    Simulation Modeling to Compare High-Throughput, Low-Iteration Optimization Strategies for Metabolic Engineering

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    Increasing the final titer of a multi-gene metabolic pathway can be viewed as a multivariate optimization problem. While numerous multivariate optimization algorithms exist, few are specifically designed to accommodate the constraints posed by genetic engineering workflows. We present a strategy for optimizing expression levels across an arbitrary number of genes that requires few design-build-test iterations. We compare the performance of several optimization algorithms on a series of simulated expression landscapes. We show that optimal experimental design parameters depend on the degree of landscape ruggedness. This work provides a theoretical framework for designing and executing numerical optimization on multi-gene systems

    The Conduct of Hostilities and International Humanitarian Law: Challenges of 21st Century Warfare International Law Association Study Group on the Conduct of Hostilities in the 21st Century

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    Armed conflicts evolve dynamically and the way wars are fought has changed significantly over time. The majority of contemporary armed conflicts involve a multitude of different actors with varying military capabilities. This asymmetry creates an incentive for the inferior party to use war tactics which violate rules of international humanitarian law in order to make up for disadvantages in matters relating to materiel, resources and fighting capacity. This links in with the observation that today’s armed conflicts (“new wars”) are often characterized not only by the objective to gain territory or military victory in the classical sense, but are rather often (also) about achieving independence, identity, ethnic cleansing, or spreading terror and gaining publicity. This being said, the traditional objectives of defeating enemy forces and gaining or maintaining control over territory are still highly relevant, including for non-State parties. For example, for the so-called Islamic State (IS) territorial control is a strategic priority. For State parties engaged in conflict with such groups, the objective is often to contain the threat posed by such tactics, regain and hold territories that such groups may have captured, degrade their ability to mount effective operations and ultimately to defeat them, which includes but is often not limited to a traditional military victory, whereby one side is forced to submit by superior force. Although international humanitarian law has already adapted in certain ways, for example, by providing rules for non-international armed conflicts (NIAC), one needs to keep in mind that IHL was originally designed to deal with interstate wars. What is more, in modern asymmetric armed conflicts the conduct of hostilities increasingly seems to take place in parallel with law enforcement operations. Thus, the central question is the extent to which the rules governing the conduct of hostilities need to be clarified, both in terms of their scope of application and their substantive aspects. Although some sub-aspects of this issue have been examined before, what is still missing is a coherent and more principled approach to the challenges of 21st century warfare. The central focus of the SG lies on the actual rules governing the conduct of hostilities, taking into account the three main areas highlighted above. In this context, it was not the aim of the SG to comprehensively deal with all of the various issues arising in relation to the conduct of hostilities, but to focus on selected issues where the SG felt that there is a need and/or potential for further clarification. Whereas API’s scope of application is limited by virtue of Article 49(3) API, the SG agreed that today it is widely accepted that the customary law rules governing the conduct of hostilities are applicable in all domains of warfare, i.e., land, air, sea as well as outer-space and cyber-space. Therefore, the SG decided to focus on three main issues related to the rules governing the conduct of hostilities: I. The meaning and interpretation of the term “Military Objectives;” II. “The Principle of Proportionality;” and III. “Precautions.
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