The nuclear export protein XPO1 is overexpressed in cancer, leading to the cytoplasmic mislocalization of multiple tumor suppressor proteins. Existing XPO1-targeting agents lack selectivity and have been associated with significant toxicity. Small molecule selective inhibitors of nuclear export (SINEs) were designed that specifically inhibit XPO1. Genetic experiments and X-ray structures demonstrate that SINE covalently bind to a cysteine residue in the cargo-binding groove of

Key Points Persistent CLL cells during ibrutinib therapy show evidence of biochemical activation, but inhibited BCR and no proliferation. Long lymphocytosis during ibrutinib therapy is not associated with adverse progression-free survival.

In England there is both top-down and bottom-up pressure to deliver a sustainable built environment. However, most new projects display few sustainability features. This paper presents 12 barriers to achieving sustainability in development schemes, drawn from qualitative research on five recently completed projects in England. The barriers that were identified by the stakeholders in the schemes include a lack of consideration of sustainability measures, real and perceived costs and inadequate expertise and powers. The paper concludes by suggesting some ways in which these barriers might be overcome. Copyright © 2006 John Wiley & Sons, Ltd and ERP Environment.

Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is overexpressed in CLL and is enriched proximal to genes upregulated or expressed in CLL with known functions in disease pathogenesis and progression. These genes, including key members of the B-cell receptor (BCR) signaling pathway, provide a rationale for this therapeutic approach to identify new targets in alternative types of cancer. Additionally, we describe PLX51107, a structurally distinct BET inhibitor with novel and pharmacologic properties that emulates or exceeds the efficacy of BCR signaling agents in preclinical models of CLL. Herein, the discovery of the involvement of BRD4 in the core CLL transcriptional program provides a compelling rationale for clinical investigation of PLX51107 as epigenetic therapy in CLL and application of BRD4 profiling in other cancers. To date, functional studies of BRD4 in CLL are lacking. Through integrated genomic, functional, and pharmacologic analyses, we uncover the existence of BRD4-regulated core CLL transcriptional programs and present preclinical proof-of-concept studies validating BET inhibition as an epigenetic approach to target BCR signaling in CLL. .

If we want to hear the voices of people who have ID then we need appropriate ways to do this. Qualitative methods are playing an increasing role in bringing the unknown about people who have ID into the known. The approach plays a valuable role in informing us about the experiences and lives of people who have ID. However, we have identified many methodological issues which will need to be further explored. At the same time, we need to develop methods to enable increased participation of people who have ID in some aspects of research. The participatory paradigm is more established in qualitative approaches as it lends itself to participation in generating research questions, developing interview questions, conducting interviews and even stages of the analysis. There are clearly areas that need to be addressed by trained researchers and the whole process will need some facilitation and support. Writing up for journals is one aspect that could be very problematic: so other forms of dissemination need to be explored.