3,141 research outputs found
Targeting Chromatin Complexes in Myeloid Malignancies and Beyond: From Basic Mechanisms to Clinical Innovation
The aberrant function of chromatin regulatory networks (epigenetics) is a hallmark of cancer promoting oncogenic gene expression. A growing body of evidence suggests that the disruption of specific chromatin-associated protein complexes has therapeutic potential in malignant conditions, particularly those that are driven by aberrant chromatin modifiers. Of note, a number of enzymatic inhibitors that block the catalytic function of histone modifying enzymes have been established and entered clinical trials. Unfortunately, many of these molecules do not have potent single-agent activity. One potential explanation for this phenomenon is the fact that those drugs do not profoundly disrupt the integrity of the aberrant network of multiprotein complexes on chromatin. Recent advances in drug development have led to the establishment of novel inhibitors of protein–protein interactions as well as targeted protein degraders that may provide inroads to longstanding effort to physically disrupt oncogenic multiprotein complexes on chromatin. In this review, we summarize some of the current concepts on the role epigenetic modifiers in malignant chromatin states with a specific focus on myeloid malignancies and recent advances in early-phase clinical trials
LISA Science Results in the Presence of Data Disturbances
Each spacecraft in the Laser Interferometer Space Antenna houses a proof mass
which follows a geodesic through spacetime. Disturbances which change the proof
mass position, momentum, and/or acceleration will appear in the LISA data
stream as additive quadratic functions. These data disturbances inhibit signal
extraction and must be removed. In this paper we discuss the identification and
fitting of monochromatic signals in the data set in the presence of data
disturbances. We also present a preliminary analysis of the extent of science
result limitations with respect to the frequency of data disturbances
eXframe: reusable framework for storage, analysis and visualization of genomics experiments
<p>Abstract</p> <p>Background</p> <p>Genome-wide experiments are routinely conducted to measure gene expression, DNA-protein interactions and epigenetic status. Structured metadata for these experiments is imperative for a complete understanding of experimental conditions, to enable consistent data processing and to allow retrieval, comparison, and integration of experimental results. Even though several repositories have been developed for genomics data, only a few provide annotation of samples and assays using controlled vocabularies. Moreover, many of them are tailored for a single type of technology or measurement and do not support the integration of multiple data types.</p> <p>Results</p> <p>We have developed eXframe - a reusable web-based framework for genomics experiments that provides 1) the ability to publish structured data compliant with accepted standards 2) support for multiple data types including microarrays and next generation sequencing 3) query, analysis and visualization integration tools (enabled by consistent processing of the raw data and annotation of samples) and is available as open-source software. We present two case studies where this software is currently being used to build repositories of genomics experiments - one contains data from hematopoietic stem cells and another from Parkinson's disease patients.</p> <p>Conclusion</p> <p>The web-based framework eXframe offers structured annotation of experiments as well as uniform processing and storage of molecular data from microarray and next generation sequencing platforms. The framework allows users to query and integrate information across species, technologies, measurement types and experimental conditions. Our framework is reusable and freely modifiable - other groups or institutions can deploy their own custom web-based repositories based on this software. It is interoperable with the most important data formats in this domain. We hope that other groups will not only use eXframe, but also contribute their own useful modifications.</p
Singular solutions of fully nonlinear elliptic equations and applications
We study the properties of solutions of fully nonlinear, positively
homogeneous elliptic equations near boundary points of Lipschitz domains at
which the solution may be singular. We show that these equations have two
positive solutions in each cone of , and the solutions are unique
in an appropriate sense. We introduce a new method for analyzing the behavior
of solutions near certain Lipschitz boundary points, which permits us to
classify isolated boundary singularities of solutions which are bounded from
either above or below. We also obtain a sharp Phragm\'en-Lindel\"of result as
well as a principle of positive singularities in certain Lipschitz domains.Comment: 41 pages, 2 figure
A novel mutation in the miR-128b gene reduces miRNA processing and leads to glucocorticoid resistance of MLL-AF4 Acute Lymphocytic Leukemia cells
MLL-AF4 Acute Lymphocytic Leukemia has a poor prognosis, and the mechanisms by which these leukemias develop are not understood despite intensive research based on well-known concepts and methods. MicroRNAs (miRNAs) are a new class of small noncoding RNAs that post-transcriptionally regulate expression of target mRNA transcripts. We recently reported that ectopic expression of miR-128b together with miR-221, two of the miRNAs downregulated in MLL-AF4 ALL, restores glucocorticoid resistance through downregulation of the MLL-AF4 chimeric fusion proteins MLL-AF4 and AF4-MLL that are generated by chromosomal translocation t(4;11). Here we report the identification of new mutations in miR-128b in RS4;11 cells, derived from MLL-AF4 ALL patient. One novel mutation significantly reduces the processing of miR-128b. Finally, this base change occurs in a primary MLL-AF4 ALL sample as an acquired mutation. These results demonstrate that the novel mutation in miR-128b in MLL-AF4 ALL alters the processing of miR-128b and that the resultant downregulation of mature miR-128b contributes to glucocorticoid resistance through the failure to downregulate the fusion oncogenes.National Institutes of Health (U.S.) (NIH Grant R01 DK068348)Netherlands Organization for Scientific ResearchDutch Cancer SocietyJapan Society for the Promotion of Scienc
Pesticide Ground Water Monitoring Project Phase VIII
During Phase VIII monitoring (March 24, 2000 to June 30, 2001 ), 86 samples were collected from 77 new wells and 9 samples were collected from wells with previous detectable herbicide
Epidemiology of Contemporary Seroincident HIV Infection in the Navy and Marine Corps
Human Immunodeficiency Virus (HIV) infection continues at a steady rate among U.S. Sailors and Marines. This study provides the first service-specific description of HIV infection demographics. All Sailors and Marines identified as HIV infected between January 2005 and August 2010 were included. The project compared personnel and epidemiologic data, and tested reposed sera in the Department of Defense Serum Repository. This group comprised 410 Sailors and 86 Marines, predominantly men. HIV infected Marines were more likely to be foreign born than their Navy counterparts, 42% versus 10%, p \u3c 0.001. Approximately half of the patients had deployed including to the wars in Iraq or Afghanistan. Nearly half of each group was infected by the age of 25. Similar to the U.S. epidemic, Black race was over-represented. Unlike national rates, Hispanic Sailors and Marines were not over-represented. Demographics were distinct for those of specific occupational specialties. Certain ship classes carried lower incidences. Clustering of HIV infection risk occurred around deployment. The Navy and Marine Corps have different patterns of HIV infection, which may merit distinct approaches to prevention. The Navy may have unique targets for prevention efforts to include pipeline training and first assignment as well as particular occupational environments
Phase space density and chiral symmetry restoration in relativistic heavy ion collisions
The effect of altered hadron masses is studied for its effect with regard to
final-state hadronic observables. It is shown that the final phase space
densities of pions and kaons, which can be inferred experimentally, are
sensitive to in-medium properties of the excited matter at earlier stages of
the collision, but that the sensitivity is significantly moderated by
interactions that change the effective numbers of pions and kaons during the
latter part of the collision.Comment: 5 pages, 4 fig.
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