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  • 2010-2014  (6)
  • 2012  (6)
  • 1
    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
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  • 2
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    The American Society for Biochemistry and Molecular Biology (ASBMB)
    Publication Date: 2012-12-22
    Description: The mixed lineage leukemia protein MLL1 contains four highly conserved plant homeodomain (PHD) fingers, which are invariably deleted in oncogenic MLL1 fusion proteins in human leukemia. Here we show that the second PHD finger (PHD2) of MLL1 is an E3 ubiquitin ligase in the presence of the E2-conjugating enzyme CDC34. This activity is conserved in the second PHD finger of MLL4, the closest homolog to MLL1 but not in MLL2 or MLL3. Mutation of PHD2 leads to MLL1 stabilization, as well as increased transactivation ability and MLL1 recruitment to the target gene loci, suggesting that PHD2 negatively regulates MLL1 activity.
    Print ISSN: 0021-9258
    Electronic ISSN: 1083-351X
    Topics: Biology , Chemistry and Pharmacology
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  • 3
    Publication Date: 2012-06-08
    Description: Platelet characteristics, such as platelet dose, platelet source (apheresis vs pooled), platelet donor-recipient ABO compatibility, and duration of platelet storage, can affect posttransfusion platelet increments, but it is unclear whether these factors impact platelet transfusion efficacy on clinical bleeding. We performed secondary analyses of platelet transfusions given in the prospective randomized Platelet Dose Study, which included 1272 platelet-transfused hematology-oncology patients who received 6031 prophylactic platelet transfusions. The primary outcome of these analyses was time from first transfusion to first World Health Organization ≥ grade 2 bleeding. Platelet transfusion increments were assessed at 0.25 to 4 hours and 16 to 32 hours after platelet transfusion. There were 778 patients evaluable for analysis of time to bleeding. Adjusted models showed that randomized dose strategy, platelet source, ABO compatibility, and duration of storage did not predict this outcome. Platelet increments were generally higher for transfusions of apheresis platelets, ABO-identical platelets, and platelets stored 3 days versus 4 to 5 days. Thus, although platelet source, ABO compatibility, and duration of storage exert a modest impact on both absolute and corrected posttransfusion platelet increments, they have no measurable impact on prevention of clinical bleeding. This trial was registered at www.clinicaltrials.gov as #NCT00128713.
    Keywords: Transfusion Medicine
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 4
    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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  • 5
    Publication Date: 2012-08-18
    Description: Despite the passage of ∼30 years since the complete primary sequence of the intermediate filament (IF) protein vimentin was reported, the structure remains unknown for both an individual protomer and the assembled filament. In this report, we present data describing the structure of vimentin linker 1 (L1) and rod 1B. Electron paramagnetic resonance spectra collected from samples bearing site-directed spin labels demonstrate that L1 is not a flexible segment between coiled-coils (CCs) but instead forms a rigid, tightly packed structure. An x-ray crystal structure of a construct containing L1 and rod 1B shows that it forms a tetramer comprising two equivalent parallel CC dimers that interact with one another in the form of a symmetrical anti-parallel dimer. Remarkably, the parallel CC dimers are themselves asymmetrical, which enables them to tetramerize rather than undergoing higher order oligomerization. This functionally vital asymmetry in the CC structure, encoded in the primary sequence of rod 1B, provides a striking example of evolutionary exploitation of the structural plasticity of proteins. EPR and crystallographic data consistently suggest that a very short region within L1 represents a minor local distortion in what is likely to be a continuous CC from the end of rod 1A through the entirety of rod 1B. The concordance of this structural model with previously published cross-linking and spectral data supports the conclusion that the crystallographic oligomer represents a native biological structure.
    Print ISSN: 0021-9258
    Electronic ISSN: 1083-351X
    Topics: Biology , Chemistry and Pharmacology
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  • 6
    Publication Date: 2012-10-30
    Description: Aims Data about the long-term outcome after cryoablation for atrioventricular nodal reentrant tachycardia (AVNRT) in the paediatric population indicate that recurrence rates are higher with cryo than with radiofrequency energy (RF). The purpose of this study was to review our institutional long-term outcome after cryoablation for AVNRT and to seek for predictors of recurrence. Methods and results Forty-nine patients (28 female, age 14 ± 2.7 years) undergoing slow-pathway modulation or ablation for AVNRT at our institution from 2004 to 2008 were included in the study.  Acute success was obtained in all patients (100%) with a mean procedure time of 164 ± 50 min and a mean fluoroscopy time of 13 ± 8 min. During a follow-up time of 30 ± 1.9 months, AVNRT recurrence occurred in 11/49 patients (22.4%). Age, sex, number of cryomappings or ablations, catheter tip (4 mm vs. 6 mm), or ablation endpoint (slow-pathway ablation vs. modulation) were not predictive for recurrence. In eight patients, reablation using cryo was performed. All these patients remained free of arrhythmia symptoms during a follow-up of 30 ± 8 months following the second procedure. Conclusion Although cryoablation for the treatment for AVNRT in paediatric and adolescent patients is safe and associated with a high acute success rate, AVNRT recurrence occurs in 22% of patients during long-term follow-up without identifiable predictors for recurrence. A second cryoablation procedure leads to a success rate of 100% during long-term follow-up.
    Print ISSN: 1099-5129
    Electronic ISSN: 1532-2092
    Topics: Medicine
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