The coexpression of the MLL partial tandem duplication (PTD) and the FLT3 internal tandem duplication (ITD) mutations associate with a poor outcome in cytogenetically normal acute myeloid leukemia ...(AML). In mice, a double knock-in (dKI) of MllPTD/wt and Flt3ITD/wt mutations induces spontaneous AML with an increase in DNA methyltransferases (Dnmt1, 3a, and 3b) and global DNA methylation index, thereby recapitulating its human AML counterpart. We determined that a regulator of Dnmts, miR-29b, is downregulated in bone marrow of dKI AML mice. Bortezomib exerted a dose-dependent increase in miR-29b expression in AML blasts ex vivo, followed by decreased Dnmts, reduced proliferation, and increased apoptosis. In vivo, bortezomib was not active against dKI AML, yet liposomal-encapsulated bortezomib, as a single agent, reversed downregulation of miR-29b in vivo and induced a long-term (90-day) disease-free remission in 80% of dKI AML mice that exhibited high leukemic burden at the start of therapy, yet showed no signs of relapse at autopsy. Taken together, these data support that liposomal bortezomib, as a single agent, eradicates MllPTD/wt:Flt3ITD/wt AML in mouse and may represent a powerful and potentially curative approach to high-risk human disease.
•The MllPTD/wt:Flt3ITD/wt mouse is a relevant AML model in which the miR-29b–mediated epigenetics-kinome crosstalk is targetable by bortezomib.•An original liposomal formulation of bortezomib eradicates AML and yields curative therapy for MllPTD/wt:Flt3ITD/wt AML.
High-sensitivity C-reactive protein (hs-CRP) adds prognostic information beyond that provided by the Framingham risk score. The clinical utility of hs-CRP evaluation per guidelines was investigated ...by determining how it changed the cardiovascular risk stratification of 100 patients deemed at intermediate risk. Screening guidelines defined the cardiovascular risk due to hs-CRP as low (<1.0 mg/L), intermediate (1.0 to 3.0 mg/L), or high (>3.0 mg/L). After hs-CRP evaluation, risk was adjusted in 66% of the patients. Because hs-CRP evaluation significantly altered the cardiovascular risk strata of most intermediate-risk patients, it may therefore be a useful test during primary cardiovascular disease prevention.
Overexpression of the E2F-1 cDNA in mammalian cells disrupts normal control of the cell cycle and drives cells into S phase. Whereas eliminating E2F activity would test its inferred involvement in ...the G1-S transition, elimination is complicated by the existence of gene families encoding mammalian E2F. Here we identify mutations in a single essential Drosophila gene, dE2F, that encodes a homolog of the mammalian E2F gene family. Embryos homozygous for null mutations of dE2F complete early cell cycles, presumably using maternal contributions of gene products, but DNA synthesis falls to virtually undetectable levels in cycle 17. Mutant embryos also lack the pulses of coordinate transcription of genes encoding replication functions that usually accompany each transition from quiescence to S phase. We conclude that in most cells dE2F is essential for a G1-S transcriptional program and for G1-S progression.
Both the heterodimeric transcription factor, E2F, and the G1 cyclin, cyclin E, are required for the G1-S transition at the start of the metazoan cell cycle. It has been established that cyclin E can ...act as an upstream activator of E2F. In addition to this action, we show here that cyclin E has an essential role in DNA replication distinct from activating E2F. We have created transgenic Drosophila capable of inducible, ectopic production of E2F activity. Simultaneous overexpression of both Drosophila E2F subunits, dE2F and dDP, in embryos stimulated the expression of multiple E2F-target genes including cyclin E, and also caused the initiation of S phase. Mutation of cyclin E prevented the initiation of S phase after overexpression of dE2F/dDP without affecting induction of target gene expression. Thus, E2F-directed transcription cannot bypass loss of cyclin E in Drosophila embryos.
This volume explores the conceptual "topography" of landscape: It examines the character of landscape as itself a mode of place as well as the modes of place that appear in relation to ...landscape.Leading scholars from a range of disciplines explore the concept of landscape, including its supposed relation to the spectatorial, its character as time-space, its relation to indigenous notions of "country," and its liminality. They examine landscape as it appears within a variety of contexts, from geography through photography and garden history to theology; and more specific studies look at the forms of landscape in medieval landscape painting, film and television, and in relation to national identity. The essays demonstrate that the study of landscape cannot be restricted to any one genre, cannot be taken as the exclusive province of any one discipline, and cannot be exhausted by any single form of analysis. What the place of landscape now evokes is itself a wide-ranging terrain encompassing issues concerning the nature of place, of human being in place, and of the structures that shape such being and are shaped by it.
Objectives: The report describes the strategic design, steps to full implementation and outcomes achieved by the Western Australian Data Linkage System (WADLS), instigated in 1995 to link up to 40 ...years of data from over 30 collections for an historical population of 3.7 million. Staged development has seen its expansion, initially from a linkage key to local health data sets, to encompass links to national and local health and welfare data sets, genealogical links and spatial references for mapping applications. Applications: The WADLS has supported over 400 studies with over 250 journal publications and 35 graduate research degrees. Applications have occurred in health services utilisation and outcomes, aetiologic research, disease surveillance and needs analysis, and in methodologic research. Benefits: Longitudinal studies have become cheaper and more complete; deletion of duplicate records and correction of data artifacts have enhanced the quality of information assets; data linkage has conserved patient privacy; community machinery necessary for organised responses to health and social problems has been exercised; and the commercial return on research infrastructure investment has exceeded 1000%. Most importantly, there have been unbiased contributions to medical knowledge and identifiable advances in population health arising from the research.
Methylmercury in dried shark fins and shark fin soup from American restaurants Nalluri, Deepthi; Zofia BaumannauthorDepartment of Marine Sciences, University of Connecticut, Avery Point, Groton, CT 06340, United States; Debra L. AbercrombieauthorSchool of Marine and Atmospheric Sciences, Stony Brook University, Stony Brook, NY 11794-5000, United States ...
2015
Journal Article
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