Methods for measuring proteasome activity: Current limitations and future developments

The proteasome has been validated as a therapeutic target, with proteasome inhibitors showing particular efficacy in the treatment of Multiple Myeloma. A wide range of methods have been developed to profile proteasome activity. These include the current method of choice fluorogenic peptide substrates, as well as bioluminescent imaging, immunological methods, and more recently, site-specific fluorescent probes. The aim of this review is to evaluate the currently available methods for profiling proteasome activity and their suitability for use in translational studies. Ongoing development of techniques for profiling proteasome activity will facilitate future research into proteasome-related pathologies, thus accelerating the development of more specific drug regimes. (C) 2010 Elsevier Ltd. All rights reserved.

Matching Well-Being to Merit:The Example of Punishment

In this paper, I explore our common-sense thinking about the relation between moral value, moral merit, and well-being. Starting from Ross’s observation that welfarist axiologies ignore our intuitions about desert, I focus on axiologies that take moral merit and well-being to be independent determinants of value. I distinguish three ways in which these axiologies can be formulated, and I then consider their application to the issue of punishment. The objection that they recommend penalties in circumstances in which intuitively we would judge them to be unjustified is examined, and I suggest that it can be met by incorporating temporal information into the way in which value, well-being and moral merit are linked.

Prognostic and Predictive Biomarkers in Resected Colon Cancer: Current Status and Future Perspectives for Integrating Genomics into Biomarker Discovery

The number of agents that are potentially effective in the adjuvant treatment of locally advanced resectable colon cancer is increasing. Consequently, it is important to ascertain which subgroups of patients will benefit from a specific treatment. Despite more than two decades of research into the molecular genetics of colon cancer, there is a lack of prognostic and predictive molecular biomarkers with proven utility in this setting. A secondary objective of the Pan European Trials in Adjuvant Colon Cancer-3 trial, which compared irinotecan in combination with 5-fluorouracil and leucovorin in the postoperative treatment of stage III and stage II colon cancer patients, was to undertake a translational research study to assess a panel of putative prognostic and predictive markers in a large colon cancer patient cohort. The Cancer and Leukemia Group B 89803 trial, in a similar design, also investigated the use of prognostic and predictive biomarkers in this setting. In this article, the authors, who are coinvestigators from these trials and performed similar investigations of biomarker discovery in the adjuvant treatment of colon cancer, review the current status of biomarker research in this field, drawing on their experiences and considering future strategies for biomarker discovery in the postgenomic era. The Oncologist 2010; 15: 390-404

Gene expression profiling in MDS and AML: potential and future avenues

Today, the classification systems for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) already incorporate cytogenetic and molecular genetic aberrations in an attempt to better reflect disease biology. However, in many MDS/AML patients no genetic aberrations have been identified yet, and even within some cytogenetically well-defined subclasses there is considerable clinical heterogeneity. Recent advances in genomics technologies such as gene expression profiling (GEP) provide powerful tools to further characterize myeloid malignancies at the molecular level, with the goal to refine the MDS/AML classification system, incorporating as yet unknown molecular genetic and epigenetic pathomechanisms, which are likely reflected by aberrant gene expression patterns. In this study, we provide a comprehensive review on how GEP has contributed to a refined molecular taxonomy of MDS and AML with regard to diagnosis, prediction of clinical outcome, discovery of novel subclasses and identification of novel therapeutic targets and novel drugs. As many challenges remain ahead, we discuss the pitfalls of this technology and its potential including future integrative studies with other genomics technologies, which will continue to improve our understanding of malignant transformation in myeloid malignancies and thereby contribute to individualized risk-adapted treatment strategies for MDS and AML patients. Leukemia (2011) 25, 909-920; doi:10.1038/leu.2011.48; published online 29 March 2011

Dartmouth Symposium on the Future of Computer Music Software: A Panel Discussion

Transcript of a Panel Discussion at the Dartmouth Symposium, chaired by Eric Lyon.

‘Transforming justice’: challenges for restorative justice in an era of punishment-based corrections

Scholars of restorative justice have long debated its theoretical relationship with formal criminal justice. This analysis critically examines the range of sociostructural conditions in contemporary society that have halted the spread of restorative policies in practice and prevented them from realizing their transformative potential as an alternative system of justice. These factors are attributed largely to a punitive penal culture that is characterized by policy-making based on penal populism, the governance of risk and a managerialist criminal justice agenda; and the widespread co-optation of restorative programs by the state. This broad argument is explored in the context of two particular case studies – recent developments in youth justice and in sexual offending respectively in England and Wales and elsewhere. This examination ultimately highlights challenges for restorative justice in the current risk-driven penal climate and advocates a need to re-evaluate its relationship with formal state justice.