| 1. |
- Steinmann, S., et al.
(author)
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Hsp90 inhibition by AUY922 as an effective treatment strategy against myxoid liposarcoma
- 2015
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In: Cancer Letters. - : Elsevier BV. - 0304-3835. ; 367:2, s. 147-156
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Journal article (peer-reviewed)abstract
- Liposarcoma is one of the most common soft tissue sarcomas in adults. Recognized histological subtypes include well differentiated/dedifferentiated liposarcoma (WD/DDLS), myxoid liposarcoma (MLS) and pleomorphic liposarcoma. Currently, there are no proper subtype-specific treatments due to the genetic, histological and clinical heterogeneity of the liposarcoma subentities. In the past decade, the rising understanding of the various genetic and molecular aberrations in liposarcoma led to the development of novel alternative therapeutic strategies. One such therapy is the inhibition of the heat shock protein 90 (Hsp90) which is overexpressed in liposarcomas. In this study, we dissect the functional role of a novel potent Hsp90 inhibitor NVP-AUY922 (AUY922) in different cell lines of myxoid (ML5402, MLS1765) and undifferentiated (SW872) liposarcomas. We show that compared with 17-AAG treatment, lower concentrations of AUY922 achieve markedly cytotoxic effects on tumor cell viability. Combination treatment of AUY922 (20 nM) with Doxorubicin (300 nM) yielded a further reduction in cell viability in comparison to Doxorubicin alone. In vivo, we document an inhibition of tumor growth after AUY922 treatment. Further analyses revealed that Hsp90-inhibition induces apoptotic cell death and cell cycle arrest. In addition, we report striking perturbations of subtype-specific pattern in Raf/MEK/ERK and PI3K signaling after AUY922 application. In conclusion, our results provide evidence that Hsp90-inhibition by AUY922 may be a promising alternative therapeutic strategy for myxoid liposarcoma patients. (C) 2015 Published by Elsevier Ireland Ltd.
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| 3. |
- Dahl, Niklas, et al.
(author)
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Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological dysfunction
- 1997
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 6:7, s. 1147-1152
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Journal article (peer-reviewed)abstract
- Severe glutathione synthetase (GS) deficiency is a rare genetic disorder with neonatal onset. The enzymatic block of the gamma-glutamyl cycle leads to a generalized glutathione deficiency. Clinically affected patients present with severe metabolic acidosis, 5-oxoprolinuria, increased rate of hemolysis and defective function of the central nervous system. The disorder is inherited in an autosomal recessive mode and, until recently, the molecular basis has remained unknown. We have sequenced 18 GS alleles associated with enzyme deficiency and we detected missense mutations by direct sequencing of cDNAs and genomic DNA. In total, 13 different mutations were identified. Four patients were found to be compound heterozygotes and two individuals were apparently homozygous. Reduced enzymatic activities were demonstrated in recombinant protein expressed from cDNAs in four cases with different missense mutations. The results from biochemical analysis of patient specimens, supported by the properties of the expressed mutant proteins, indicate that a residual activity is present in affected individuals. Our results suggest that complete loss of function of both GS alleles is probably lethal. It is postulated that missense mutations will account for the phenotype in the majority of patients with severe GS deficiency.
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| 4. |
- Haykal, A., et al.
(author)
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Decoherence of V-B(-) spin defects in monoisotopic hexagonal boron nitride
- 2022
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In: Nature Communications. - : Nature Portfolio. - 2041-1723. ; 13:1
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Journal article (peer-reviewed)abstract
- Spin defects in hexagonal boron nitride (hBN) are promising quantum systems for the design of flexible two-dimensional quantum sensing platforms. Here we rely on hBN crystals isotopically enriched with either B-10 or B-11 to investigate the isotope-dependent properties of a spin defect featuring a broadband photoluminescence signal in the near infrared. By analyzing the hyperfine structure of the spin defect while changing the boron isotope, we first confirm that it corresponds to the negatively charged boron-vacancy center (V-B(-)). We then show that its spin coherence properties are slightly improved in B-10-enriched samples. This is supported by numerical simulations employing cluster correlation expansion methods, which reveal the importance of the hyperfine Fermi contact term for calculating the coherence time of point defects in hBN. Using cross-relaxation spectroscopy, we finally identify dark electron spin impurities as an additional source of decoherence. This work provides new insights into the properties of V-B(-) spin defects, which are valuable for the future development of hBN-based quantum sensing foils.
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| 5. |
- Ivády, Viktor, et al.
(author)
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Pressure and temperature dependence of the zero-field splitting in the ground state of NV centers in diamond: A first-principles study
- 2014
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In: Physical Review B. Condensed Matter and Materials Physics. - : American Physical Society. - 1098-0121 .- 1550-235X. ; 90:23, s. 235205-
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Journal article (peer-reviewed)abstract
- Nitrogen-vacancy centers in diamond (NV) attract great attention because they serve as a tool in many important applications. The NV center has a polarizable spin S = 1 ground state and its spin state can be addressed by optically detected magnetic resonance (ODMR) techniques. The m(S) = 0 and m(S) = +/- 1 spin levels of the ground state are separated by about 2.88 GHz in the absence of an external magnetic field or any other perturbations. This zero-field splitting (ZFS) can be probed by ODMR. As this splitting changes as a function of pressure and temperature, the NV center might be employed as a sensor operating at the nanoscale. Therefore, it is of high importance to understand the intricate details of the pressure and temperature dependence of this splitting. Here we present an ab initio theory of the ZFS of the NV center as a function of external pressure and temperature including detailed analysis on the contributions of macroscopic and microscopic effects. We found that the pressure dependence is governed by the change in the distance between spins as a consequence of the global compression and the additional local structural relaxation. The local structural relaxation contributes to the change of ZFS with the same magnitude as the global compression. In the case of temperature dependence of ZFS, we investigated the effect of macroscopic thermal expansion as well as the consequent change of the microscopic equilibrium positions. We could conclude that theses effects are responsible for about 15% of the observed decrease of ZFS.
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| 6. |
- Nagy, Roland, et al.
(author)
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High-fidelity spin and optical control of single silicon-vacancy centres in silicon carbide
- 2019
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In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 10
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Journal article (peer-reviewed)abstract
- Scalable quantum networking requires quantum systems with quantum processing capabilities. Solid state spin systems with reliable spin-optical interfaces are a leading hardware in this regard. However, available systems suffer from large electron-phonon interaction or fast spin dephasing. Here, we demonstrate that the negatively charged silicon-vacancy centre in silicon carbide is immune to both drawbacks. Thanks to its (4)A(2) symmetry in ground and excited states, optical resonances are stable with near-Fourier-transform-limited linewidths, allowing exploitation of the spin selectivity of the optical transitions. In combination with millisecond-long spin coherence times originating from the high-purity crystal, we demonstrate high-fidelity optical initialization and coherent spin control, which we exploit to show coherent coupling to single nuclear spins with similar to 1 kHz resolution. The summary of our findings makes this defect a prime candidate for realising memory-assisted quantum network applications using semiconductor-based spin-to-photon interfaces and coherently coupled nuclear spins.
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| 7. |
- Shan, Yuexin, et al.
(author)
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ATF3 Protects Pulmonary Resident Cells from Acute and Ventilator-Induced Lung Injury by Preventing Nrf2 Degradation
- 2015
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In: Antioxidants & Redox Signaling. - : Mary Ann Liebert Inc. - 1557-7716 .- 1523-0864. ; 22:8, s. 651-668
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Journal article (peer-reviewed)abstract
- Aims: Ventilator-induced lung injury (VILI) contributes to mortality in patients with acute respiratory distress syndrome, the most severe form of acute lung injury (ALI). Absence of activating transcription factor 3 (ATF3) confers susceptibility to ALI/VILI. To identify cell-specific ATF3-dependent mechanisms of susceptibility to ALI/VILI, we generated ATF3 chimera by adoptive bone marrow (BM) transfer and randomized to inhaled saline or lipopolysacharide (LPS) in the presence of mechanical ventilation (MV). Adenovirus vectors to silence or overexpress ATF3 were used in primary human bronchial epithelial cells and murine BM-derived macrophages from wild-type or ATF3-deficient mice. Results: Absence of ATF3 in myeloid-derived cells caused increased pulmonary cellular infiltration. In contrast, absence of ATF3 in parenchymal cells resulted in loss of alveolar-capillary membrane integrity and increased exudative edema. ATF3-deficient macrophages were unable to limit the expression of pro-inflammatory mediators. Knockdown of ATF3 in resident cells resulted in decreased junctional protein expression and increased paracellular leak. ATF3 overexpression abrogated LPS induced membrane permeability. Despite release of ATF3-dependent Nrf2 transcriptional inhibition, mice that lacked ATF3 expression in resident cells had increased Nrf2 protein degradation. Innovation: In our model, in the absence of ATF3 in parenchymal cells increased Nrf2 degradation is the result of increased Keap-1 expression and loss of DJ-1 (Parkinson disease [autosomal recessive, early onset] 7), previously not known to play a role in lung injury. Conclusion: Results suggest that ATF3 confers protection to lung injury by preventing inflammatory cell recruitment and barrier disruption in a cell-specific manner, opening novel opportunities for cell specific therapy for ALI/VILI. Antioxid. Redox Signal. 22, 651-668.
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| 9. |
- Willson, Melina L., et al.
(author)
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Questionnaires used to assess barriers of clinical guideline use among physicians are not comprehensive, reliable, or valid: a scoping review
- 2017
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In: Journal of Clinical Epidemiology. - : Elsevier BV. - 0895-4356 .- 1878-5921. ; 86, s. 25-38
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Research review (peer-reviewed)abstract
- Objective This study described the number and characteristics of questionnaires used to assess barriers of guideline use among physicians. Study Design and Setting A scoping review was conducted. MEDLINE and EMBASE were searched from 2005 to June 2016. English-language studies that administered a questionnaire to assess barriers of guideline use among practicing physicians were eligible. Summary statistics were used to report study and questionnaire characteristics. Questionnaire content was assessed with a checklist of 57 known barriers. Results Each of the 178 included studies administered a unique questionnaire. The number of questionnaires increased yearly from 2005 to 2015. Few were pilot-tested (50, 28.1%) or tested for psychometric properties (3, 1.7%). Two were based on theory. None probed for the full range of known barriers. Ten included a free-text option. The majority assessed professional barriers (177, 99.4%) but few of the 14 factors within this domain. Questionnaire characteristics did not change over time. Conclusion Organizations administered questionnaires that were not reliable or valid and did not comprehensively assess barriers and may have selected interventions unlikely to promote guideline use. Research is needed to construct a questionnaire that is practical, adaptable, and robust and leads to the selection of interventions that support guideline use.
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