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- 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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| 2. |
- 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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| 3. |
- 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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| 5. |
- 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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