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  • 1
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    Wall shear stress and flow patterns in the ascending aorta in patients with bicuspid aortic valves differ significantly from tricuspid aortic valves: a prospective study (2013)
    Oxford University Press
    Details
    Publication Date: 2013-07-12
    Description: Aims We compared flow and wall shear stress (WSS) patterns in the ascending aorta of individuals with either bicuspid aortic valve (BAV) or tricuspid aortic valve (TAV) using four-dimensional cardiovascular magnetic resonance (4D-CMR). BAV are known to be associated with dilation and dissection of the ascending aorta. However, the cause of vessel disease in patients with BAVs is unknown. Inborn connective tissue disease and also dilation secondary to increased WSS because of altered blood flow patterns in the ascending aorta are discussed as causes for dilation of the aorta. WSS can be estimated non-invasively by 4D-CMR. Methods and results Eighteen, otherwise, healthy individuals with functionally normal BAVs were compared prospectively with an age- and sex-matched control group of healthy individuals with TAV. Blood flow data were obtained by 4D-CMR visualization and WSS was calculated with specific software tools. Eighty-five per cent of the individuals with BAVs showed a high-grade helical flow pattern in the ascending aorta compared with 6% of the individuals with TAV. WSS in the ascending aorta was significantly altered in individuals with BAVs compared with TAV. Conclusion WSS and flow patterns in the ascending aorta in patients with BAVs without concomitant valve or vessel disease are significantly different compared with TAV. The significantly higher shear forces may have an impact on the development of aortic dilation in patients with BAVs.
    Print ISSN: 1525-2167
    Electronic ISSN: 1532-2114
    Topics: Medicine
    Published by Oxford University Press
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  • 2
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    High adenylyl cyclase activity and in vivo cAMP fluctuations in corals suggest central physiological role (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-03-06
    Description: Corals are an ecologically and evolutionarily significant group, providing the framework for coral reef biodiversity while representing one of the most basal of metazoan phyla. However, little is known about fundamental signaling pathways in corals. Here we investigate the dynamics of cAMP, a conserved signaling molecule that can regulate virtually every physiological process. Bioinformatics revealed corals have both transmembrane and soluble adenylyl cyclases (AC). Endogenous cAMP levels in live corals followed a potential diel cycle, as they were higher during the day compared to the middle of the night. Coral homogenates exhibited some of the highest cAMP production rates ever to be recorded in any organism; this activity was inhibited by calcium ions and stimulated by bicarbonate. In contrast, zooxanthellae or mucus had 〉1000-fold lower AC activity. These results suggest that cAMP is an important regulator of coral physiology, especially in response to light, acid/base disturbances and inorganic carbon levels. Scientific Reports 3 doi: 10.1038/srep01379
    Electronic ISSN: 2045-2322
    Topics: Natural Sciences in General
    Published by Nature Publishing Group (NPG)
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  • 3
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    MLL fusion protein-driven AML is selectively inhibited by targeted disruption of the MLL-PAFc interaction (2013)
    American Society of Hematology (ASH)
    In: Blood
    Details
    Publication Date: 2013-09-13
    Description: MLL rearrangements are common in leukemia and considered an adverse risk factor. Through interactions with the polymerase-associated factor complex (PAFc), mixed lineage leukemia (MLL) fusion proteins activate genes critical for blocking differentiation, such as HOXA9 . Here we investigate whether the MLL-PAFc interaction can be exploited therapeutically using both genetic and biochemical approaches. We tested the genetic requirement of the PAFc in acute myeloid leukemia (AML) using a conditional allele of the PAFc subunit, Cdc73 . We show that the PAFc is indiscriminately necessary for the proliferation of AML cells through the epigenetic regulation of proleukemogenic target genes, such as MEIS1 and Bcl2 . To investigate the therapeutic potential of targeting the MLL-PAFc interaction, we engineered a dominant negative fragment of MLL capable of binding to the PAFc. Disruption of the MLL-PAFc interaction selectively inhibits the proliferation of MLL leukemic cells without affecting cells transformed by an unrelated E2A-HLF fusion protein. Using in vivo hematopoietic reconstitution assays, we demonstrate that disruption of the MLL-PAFc does not alter normal hematopoietic stem cell function. Together, our data show a selective growth inhibition of MLL-associated leukemic cells and tolerance of normal hematopoiesis to disruption of the MLL-PAFc interaction establishing the MLL-PAFc interaction as an attractive therapeutic target.
    Keywords: Myeloid Neoplasia
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology (ASH)
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  • 4
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    Radiosensitive Non-Small Cell Lung Cancer Genotypes (2013)
    The American Association for Cancer Research (AACR)
    Details
    Publication Date: 2013-10-03
    Description: Purpose: Non–small cell lung cancer (NSCLC) includes a spectrum of radiosensitive and radioresistant tumors. However, little is known about the molecular determinants of cellular radiation responses. We examined clinical outcomes after gamma knife radiotherapy for NSCLC intracranial metastases to evaluate the use of this model for determining radiosensitive tumor genotypes. Experimental Design: Between 2005 and 2012, 239 patients with NSCLC were enrolled in a prospective gamma knife data repository. Molecular pathology regarding EGF receptor (EGFR), ALK, and KRAS mutation status was available for 81 patients. Local and distant brain control was determined for 79 patients with 469 brain metastases. Modified Cox proportional hazards models were established to evaluate local control for treated lesions after serial gamma knife treatments. Results: In total, 11% of patients developed in-field recurrence. No patients with metastases from tumors with EGFR mutations (0/164 lesions) or EML4-ALK translocations (0/61 lesions) recurred in-field. In contrast, 19% of patients without these mutations and 18% of patients with KRAS mutations recurred in-field (10/139 and 3/105 lesions, respectively). Rates of distant brain recurrence did not significantly differ across tumor genotypes. The predicted median in-field local control was significantly longer for EGFR-mutant and ALK-translocated tumors compared with other patients with NSCLC ( P 〈 0.001), whereas distant brain recurrence time was equivalent ( P = 0.97). On multivariate analysis, EGFR mutation, ALK translocation, and metastasis size were independent predictors for superior local control after gamma knife treatment. Conclusions: This study suggests that EGFR kinase domain mutations and EML4-ALK translocations are radiosensitive NSCLC genotypes, and proposes a novel model to identify radiosensitive subtypes of NSCLC. Clin Cancer Res; 19(19); 5523–32. ©2013 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
    Published by The American Association for Cancer Research (AACR)
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  • 5
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    Transposable Element Dynamics among Asymbiotic and Ectomycorrhizal Amanita Fungi (2014)
    Oxford University Press
    Details
    Publication Date: 2014-07-04
    Description: Transposable elements (TEs) are ubiquitous inhabitants of eukaryotic genomes and their proliferation and dispersal shape genome architectures and diversity. Nevertheless, TE dynamics are often explored for one species at a time and are rarely considered in ecological contexts. Recent work with plant pathogens suggests a link between symbiosis and TE abundance. The genomes of pathogenic fungi appear to house an increased abundance of TEs, and TEs are frequently associated with the genes involved in symbiosis. To investigate whether this pattern is general, and relevant to mutualistic plant-fungal symbioses, we sequenced the genomes of related asymbiotic (AS) and ectomycorrhizal (ECM) Amanita fungi. Using methods developed to interrogate both assembled and unassembled sequences, we characterized and quantified TEs across three AS and three ECM species, including the AS outgroup Volvariella volvacea . The ECM genomes are characterized by abundant numbers of TEs, an especially prominent feature of unassembled sequencing libraries. Increased TE activity in ECM species is also supported by phylogenetic analysis of the three most abundant TE superfamilies; phylogenies revealed many radiations within contemporary ECM species. However, the AS species Amanita thiersii also houses extensive amplifications of elements, highlighting the influence of additional evolutionary parameters on TE abundance. Our analyses provide further evidence for a link between symbiotic associations among plants and fungi, and increased TE activity, while highlighting the importance individual species’ natural histories may have in shaping genome architecture.
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 6
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    C/EBP{alpha} is required for Hoxa9/Meis1 leukemogenesis [Medical Sciences] (2014)
    National Academy of Sciences
    Details
    Publication Date: 2014-07-09
    Description: Homeobox A9 (HOXA9) is a homeodomain-containing transcription factor that plays a key role in hematopoietic stem cell expansion and is commonly deregulated in human acute leukemias. A variety of upstream genetic alterations in acute myeloid leukemia (AML) lead to overexpression of HOXA9, almost always in association with overexpression of its...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 7
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    Targeting DOT1L Recruitment [Molecular Bases of Disease] (2013)
    The American Society for Biochemistry and Molecular Biology (ASBMB)
    Details
    Publication Date: 2013-10-19
    Description: The MLL fusion proteins, AF9 and ENL, activate target genes in part via recruitment of the histone methyltransferase DOT1L (disruptor of telomeric silencing 1-like). Here we report biochemical, biophysical, and functional characterization of the interaction between DOT1L and MLL fusion proteins, AF9/ENL. The AF9/ENL-binding site in human DOT1L was mapped, and the interaction site was identified to a 10-amino acid region (DOT1L865–874). This region is highly conserved in DOT1L from a variety of species. Alanine scanning mutagenesis analysis shows that four conserved hydrophobic residues from the identified binding motif are essential for the interactions with AF9/ENL. Binding studies demonstrate that the entire intact C-terminal domain of AF9/ENL is required for optimal interaction with DOT1L. Functional studies show that the mapped AF9/ENL interacting site is essential for immortalization by MLL-AF9, indicating that DOT1L interaction with MLL-AF9 and its recruitment are required for transformation by MLL-AF9. These results strongly suggest that disruption of interaction between DOT1L and AF9/ENL is a promising therapeutic strategy with potentially fewer adverse effects than enzymatic inhibition of DOT1L for MLL fusion protein-associated leukemia.
    Print ISSN: 0021-9258
    Electronic ISSN: 1083-351X
    Topics: Biology , Chemistry and Pharmacology
    Published by The American Society for Biochemistry and Molecular Biology (ASBMB)
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  • 8
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    Gain of chromosome band 7q11 in papillary thyroid carcinomas of young patients is associated with exposure to low-dose irradiation [Medical Sciences] (2011)
    National Academy of Sciences
    Details
    Publication Date: 2011-06-08
    Description: The main consequence of the Chernobyl accident has been an increase in papillary thyroid carcinomas (PTCs) in those exposed to radioactive fallout as young children. Our aim was to identify genomic alterations that are associated with exposure to radiation. We used array comparative genomic hybridization to analyze a main (n = 52) and a validation cohort (n = 28) of PTC from patients aged
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 9
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    Expression of podoplanin in human astrocytic brain tumors is controlled by the PI3K-AKT-AP-1 signaling pathway and promoter methylation (2012)
    Oxford University Press
    Details
    Publication Date: 2012-04-16
    Description: Recently, we found strong overexpression of the mucin-type glycoprotein podoplanin (PDPN) in human astrocytic brain tumors, specifically in primary glioblastoma multiforme (GB). In the current study, we show an inverse correlation between PDPN expression and PTEN levels in primary human GB and glioma cell lines, and we report elevated PDPN protein levels in the subventricular zone of brain tissue sections of PTEN-deficient mice. In human glioma cells lacking functional PTEN, reintroduction of wild-type PTEN, inhibition of the PTEN downstream target protein kinase B/AKT, or interference with transcription factor AP-1 function resulted in efficient downregulation of PDPN expression. In addition, we observed hypoxia-dependent PDPN transcriptional control and demonstrated that PDPN expression is subject to negative transcriptional regulation by promoter methylation in human GB and in glioma cell lines. Treatment of PTEN-negative glioma cells with demethylating agents induced expression of PDPN. Together, our findings show that increased PDPN expression in human GB is caused by loss of PTEN function and activation of the PI3K-AKT-AP-1 signaling pathway, accompanied by epigenetic regulation of PDPN promoter activity. Silencing of PDPN expression leads to reduced proliferation and migration of glioma cells, suggesting a functional role of PDPN in glioma progression and malignancy. Thus, specific targeting of PDPN expression and/or function could be a promising strategy for the treatment of patients with primary GB.
    Print ISSN: 1522-8517
    Electronic ISSN: 1523-5866
    Topics: Medicine
    Published by Oxford University Press on behalf of The Society for Neuro-Oncology (SNO).
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  • 10
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    Active nanoplasmonic metamaterials (2012)
    Springer Nature
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    Publication Date: 2012-07-09
    Description: Active nanoplasmonic metamaterials Nature Materials 11, 573 (2012). doi:10.1038/nmat3356 Authors: O. Hess, J. B. Pendry, S. A. Maier, R. F. Oulton, J. M. Hamm & K. L. Tsakmakidis
    Print ISSN: 1476-1122
    Electronic ISSN: 1476-4660
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Natural Sciences in General , Physics
    Published by Springer Nature
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