Genetic Susceptibility to Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the West and is an incurable malignancy. No firmly established evidence exists for environmental risk factors in the etiology of CLL. However, CLL is estimated to have one of the highest familial risks for a hematologic malignancy; this along with other evidence strongly supports an inherited genetic component. In the past 5 years, genome-wide association studies (GWAS) have provided the foundation for new avenues in the investigation of pathogenesis of this disease with 22 susceptibility loci currently identified. We review here the advances made in identifying these loci, the potential to translate these findings into clinical practice, and future directions needed to advance our understanding of the genetic susceptibility of CLL. (C) 2013 Elsevier Inc. All rights reserved

Mirroring and switching authoritative personae: A ventriloquial analysis of shareholder engagement on carbon emissions

We examine how the authority of investors to speak about climate change with corporations is established. Leveraging the ‘communication as constitutive of organizations’ (CCO) perspective, we analyse who speaks on behalf of whom (or what) in shareholder engagement on corporate carbon emissions. Based on access to private dialogues between an engager acting on behalf of a pool of investors with twenty utility corporations, we identify how three authoritative personae—that of diplomat, advocate and coach—convey climate change concerns. We find that the mirroring of these authoritative personae by corporations may lead to deliberation, evasion, or rejection of the suggested courses of action. We theorise how relational authority is communicatively constituted in shareholder engagement through a process of mirroring and switching between authoritative personae. Our framework contributes to the study of CCO and relational authority by highlighting how meta-figures are used by external actors in an attempt to author appropriate corporate actions. We discuss the implications of our framework for the role of shareholder engagement in current attempts at greening financial capitalism

The Impact of Sustainable Investing: A Multidisciplinary Review

We conduct a multidisciplinary review of how sustainable investing impacts the environment and society. Our review starts from the insight that shareholders can create impact not only through (1) portfolio screening and (2) shareholder engagement (two impact strategies most used by mainstream shareholders) but also through (3) field building (an impact strategy most used by shareholders at the periphery of the financial sector). Based on this framework of three impact strategies, we integrate insights from four disciplines (management, finance, sociology, and ethics/sustainability) to reconstruct how each impact strategy influences corporate sustainability. We identify 15 impact mechanisms through which the impact strategies produce three types of impact: portfolio screening and shareholder engagement mostly create direct impact on companies, while field building creates indirect impact via other shareholders and indirect impact via the institutional context. Our review suggests that shareholder impact emerges gradually as different types of shareholders build on each other's efforts, which we use to outline a research agenda on shareholder impact as a distributed process

Reliability of the Q Force; a mobile instrument for measuring isometric quadriceps muscle strength

BACKGROUND: The ability to generate muscle strength is a pre-requisite for all human movement. Decreased quadriceps muscle strength is frequently observed in older adults and is associated with a decreased performance and activity limitations. To quantify the quadriceps muscle strength and to monitor changes over time, instruments and procedures with a sufficient reliability are needed. The Q Force is an innovative mobile muscle strength measurement instrument suitable to measure in various degrees of extension. Measurements between 110 and 130° extension present the highest values and the most significant increase after training. The objective of this study is to determine the test-retest reliability of muscle strength measurements by the Q Force in older adults in 110° extension. METHODS: Forty-one healthy older adults, 13 males and 28 females were included in the study. Mean (SD) age was 81.9 (4.89) years. Isometric muscle strength of the Quadriceps muscle was assessed with the Q Force at 110° of knee extension. Participants were measured at two sessions with a three to eight day interval between sessions. To determine relative reliability, the intraclass correlation coefficient (ICC) was calculated. To determine absolute reliability, Bland and Altman Limits of Agreement (LOA) were calculated and t-tests were performed. RESULTS: Relative reliability of the Q Force is good to excellent as all ICC coefficients are higher than 0.75. Generally a large 95 % LOA, reflecting only moderate absolute reliability, is found as exemplified for the peak torque left leg of -18.6 N to 33.8 N and the right leg of -9.2 N to 26.4 N was between 15.7 and 23.6 Newton representing 25.2 % to 39.9 % of the size of the mean. Small systematic differences in mean were found between measurement session 1 and 2. CONCLUSION: The present study shows that the Q Force has excellent relative test-retest reliability, but limited absolute test-retest reliability. Since the Q Force is relatively cheap and mobile it is suitable for application in various clinical settings, however, its capability to detect changes in muscle force over time is limited but comparable to existing instruments

Relationship of blood monocytes with chronic lymphocytic leukemia aggressiveness and outcomes: a multi‐institutional study

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134120/1/ajh24376.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134120/2/ajh24376_am.pd

Relationship of blood monocytes with chronic lymphocytic leukemia aggressiveness and outcomes: a multi‐institutional study

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134120/1/ajh24376.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134120/2/ajh24376_am.pd

Discovery and implementation of transcriptional biomarkers of synthetic LXR agonists in peripheral blood cells

<p>Abstract</p> <p>Background</p> <p>LXRs (Liver X Receptor α and β) are nuclear receptors that act as ligand-activated transcription factors. LXR activation causes upregulation of genes involved in reverse cholesterol transport (RCT), including ABCA1 and ABCG1 transporters, in macrophage and intestine. Anti-atherosclerotic effects of synthetic LXR agonists in murine models suggest clinical utility for such compounds.</p> <p>Objective</p> <p>Blood markers of LXR agonist exposure/activity were sought to support clinical development of novel synthetic LXR modulators.</p> <p>Methods</p> <p>Transcript levels of LXR target genes ABCA1 and ABCG1 were measured using quantitative reverse transcriptase/polymerase chain reaction assays (qRT-PCR) in peripheral blood from mice and rats (following a single oral dose) and monkeys (following 7 daily oral doses) of synthetic LXR agonists. LXRα, LXRβ, ABCA1, and ABCG1 mRNA were measured by qRT-PCR in human peripheral blood mononuclear cells (PBMC), monocytes, T- and B-cells treated <it>ex vivo </it>with WAY-252623 (LXR-623), and protein levels in human PBMC were measured by Western blotting. ABCA1/G1 transcript levels in whole-blood RNA were measured using analytically validated assays in human subjects participating in a Phase 1 SAD (Single Ascending Dose) clinical study of LXR-623.</p> <p>Results</p> <p>A single oral dose of LXR agonists induced ABCA1 and ABCG1 transcription in rodent peripheral blood in a dose- and time-dependent manner. Induction of gene expression in rat peripheral blood correlated with spleen expression, suggesting LXR gene regulation in blood has the potential to function as a marker of tissue gene regulation. Transcriptional response to LXR agonist was confirmed in primates, where peripheral blood ABCA1 and ABCG1 levels increased in a dose-dependent manner following oral treatment with LXR-623. Human PBMC, monocytes, T- and B cells all expressed both LXRα and LXRβ, and all cell types significantly increased ABCA1 and ABCG1 expression upon <it>ex vivo </it>LXR-623 treatment. Peripheral blood from a representative human subject receiving a single oral dose of LXR-623 showed significant time-dependent increases in ABCA1 and ABCG1 transcription.</p> <p>Conclusion</p> <p>Peripheral blood cells express LXRα and LXRβ, and respond to LXR agonist treatment by time- and dose-dependently inducing LXR target genes. Transcript levels of LXR target genes in peripheral blood are relevant and useful biological indicators for clinical development of synthetic LXR modulators.</p

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

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