| 1. |
- De Baetselier, E, et al.
(författare)
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EUPRON: nurses' practice in interprofessional pharmaceutical care in Europe. A cross-sectional survey in 17 countries
- 2020
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 10:6, s. e036269-
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Tidskriftsartikel (refereegranskat)abstract
- Safe pharmaceutical care (PC) requires an interprofessional team approach, involving physicians, nurses and pharmacists. Nurses’ roles however, are not always explicit and clear, complicating interprofessional collaboration. The aim of this study is to describe nurses’ practice and interprofessional collaboration in PC, from the viewpoint of nurses, physicians and pharmacists.DesignA cross-sectional survey.SettingThe study was conducted in 17 European countries, each with their own health systems.ParticipantsPharmacists, physicians and nurses with an active role in PC were surveyed.Main outcome measuresNurses’ involvement in PC, experiences of interprofessional collaboration and communication and views on nurses’ competences.ResultsA total of 4888 nurses, 974 physicians and 857 pharmacists from 17 European countries responded. Providing patient education and information (PEI), monitoring medicines adherence (MMA), monitoring adverse/therapeutic effects (ME) and prescribing medicines were considered integral to nursing practice by 78%, 73%, 69% and 15% of nurses, respectively. Most respondents were convinced that quality of PC would be improved by increasing nurses’ involvement in ME (95%), MMA (95%), PEI (91%) and prescribing (53%). Mean scores for the reported quality of collaboration between nurses and physicians, collaboration between nurses and pharmacists and interprofessional communication were respectively <7/10, ≤4/10, <6/10 for all four aspects of PC.ConclusionsME, MMA, PEI and prescribing are part of nurses’ activities, and most healthcare professionals felt their involvement should be extended. Collaboration between nurses and physicians on PC is limited and between nurses and pharmacists even more.
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| 2. |
- Isfort, I., et al.
(författare)
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Prevalence of the Hippo Effectors YAP1/TAZ in Tumors of Soft Tissue and Bone
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Tumors of soft tissue and bone represent a heterogeneous group of neoplasias characterized by a wide variety of genetic aberrations. Albeit knowledge on tumorigenesis in mesenchymal tumors is continuously increasing, specific insights on altered signaling pathways as a basis for molecularly targeted therapeutic strategies are still sparse. The aim of this study was to determine the involvement ofYAP1/TAZ-mediated signals in tumors of soft tissue and bone. Expression levels of YAP1 and TAZ were analyzed by immunohistochemistry in a large cohort of 486 tumor specimens, comprising angiosarcomas (AS), Ewing sarcomas, leiomyosarcomas, malignant peripheral nerve sheath tumors (MPNST), solitary fibrous tumors, synovial sarcomas (SySa), well-differentiated/dedifferentiated/ pleomorphic and myxoid liposarcomas (MLS). Moderate to strong nuclear staining ofYAP1 and TAZ was detected in 53% and 33%, respectively. YAP1 nuclear expression was most prevalent in MPNST, SySa and MLS, whereas nuclear TAZ was predominately detected in AS, MLS and MPNST. In a set of sarcoma cell lines, immunoblotting confirmed nuclear localization ofYAP1 and TAZ, corresponding to their transcriptionally active pool. Suppression ofYAP1/TAZ-TEAD mediated transcriptional activity significantly impaired sarcoma cell viability in vitro and in vivo. Our findings identify nuclear YAP1 and TAZ positivity as a common feature in subsets of sarcomas of soft tissue and bone and provide evidence ofYAP1/TAZ-TEAD signaling as a specific liability to be considered as a new target for therapeutic intervention. Nuclear YAP1/TAZ expression may represent a biomarker suited to identify patients that could benefit fromYAP1/TAZ-TEAD directed therapeutic approaches within future clinical trials.
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| 3. |
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| 4. |
- Trautmann, M., et al.
(författare)
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FUS-DDIT3 Fusion Protein-Driven IGF-IR Signaling is a Therapeutic Target in Myxoid Liposarcoma
- 2017
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Ingår i: Clinical Cancer Research. - : American Association for Cancer Research (AACR). - 1078-0432 .- 1557-3265. ; 23:20, s. 6227-6238
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Myxoid liposarcoma is an aggressive disease with particular propensity to develop hematogenic metastases. Over 90% of myxoid liposarcoma are characterized by a reciprocal t(12;16)(q13;p11) translocation. The resulting chimeric FUS-DDIT3 fusion protein plays a crucial role in myxoid liposarcoma pathogenesis; however, its specific impact on oncogenic signaling pathways remains to be substantiated. We here investigate the functional role of FUS-DDIT3 in IGF-IR/PI3K/Akt signaling driving myxoid liposarcoma pathogenesis. Experimental Design: Immunohistochemical evaluation of key effectors of the IGF-IR/PI3K/Akt signaling axis was performed in a comprehensive cohort of myxoid liposarcoma specimens. FUS-DDIT3 dependency and biological function of the IGF-IR/PI3K/Akt signaling cascade were analyzed using a HT1080 fibrosarcoma-based myxoid liposarcoma tumor model and multiple tumor-derived myxoid liposarcoma cell lines. An established myxoid liposarcoma avian chorioallantoic membrane model was used for in vivo confirmation of the preclinical in vitro results. Results: A comprehensive subset of myxoid liposarcoma specimens showed elevated expression and phosphorylation levels of various IGF-IR/PI3K/Akt signaling effectors. In HT1080 fibrosarcoma cells, overexpression of FUS-DDIT3 induced aberrant IGF-IR/PI3K/Akt pathway activity, which was dependent on transcriptional induction of the IGF2 gene. Conversely, RNAi-mediated FUS-DDIT3 knockdown in myxoid liposarcoma cells led to an inactivation of IGF-IR/PI3K/Akt signaling associated with diminished IGF2 mRNA expression. Treatment of myxoid liposarcoma cell lines with several IGF-IR inhibitors resulted in significant growth inhibition in vitro and in vivo. Conclusions: Our preclinical study substantiates the fundamental role of the IGF-IR/PI3K/Akt signaling pathway in myxoid liposarcoma pathogenesis and provides a mechanism-based rationale for molecular-targeted approaches in myxoid liposarcoma cancer therapy. (C)2017 AACR.
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| 5. |
- Trautmann, M., et al.
(författare)
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Phosphatidylinositol-3-kinase (PI3K)/Akt Signaling is Functionally Essential in Myxoid Liposarcoma
- 2019
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Ingår i: Molecular Cancer Therapeutics. - 1535-7163. ; 18:4, s. 834-844
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Tidskriftsartikel (refereegranskat)abstract
- Myxoid liposarcoma (MLS) is an aggressive soft-tissue tumor characterized by a specific reciprocal t(12;16) translocation resulting in expression of the chimeric FUS-DDIT3 fusion protein, an oncogenic transcription factor. Similar to other translocation-associated sarcomas, MLS is characterized by a low frequency of somatic mutations, albeit a subset of MLS has previously been shown to be associated with activating PIK3CA mutations. This study was performed to assess the prevalence of PI3K/Akt signaling alterations in MIS and the potential of PI3Kdirected therapeutic concepts. In a large cohort of MIS, key components of the PI3K/Akt signaling cascade were evaluated by next generation seqeuncing (NGS), fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC). In threevi IS cell lines, PI3K activitywas inhibited by RNAi and the small-molecule PI3 K inhibitor BKM120 (buparlisib) in vitro. An MLS cell line-based avian chorioallantoic membrane model was applied for in vivo confirmation. In total, 26.8% of MLS cases displayed activating alterations in PI3K/Akt signaling components, with PIK3CA gain-of-function mutations representing the most prevalent finding (14.2%). IHC suggested PI3K/Akt activation in a far larger subgroup of MIS, implying alternative mechanisms of pathway activation. P13K-directed therapeutic interference showed that MIS cell proliferation and viability significantly depended on PI3K-mediated signals in vitro and in viva Our predinical study underlines the elementary role of PI3K/Akt signals in MLS tumorigenesis and provides a molecularly based rationale for a PI3K-targeted therapeutic approach which may be particularly effective in the subgroup of tumors carrying activating genetic alterations in P13K/Akt signaling components.
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| 6. |
- Berthold, R., et al.
(författare)
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Fusion protein-driven IGF-IR/PI3K/AKT signals deregulate Hippo pathway promoting oncogenic cooperation of YAP1 and FUS-DDIT3 in myxoid liposarcoma
- 2022
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Ingår i: Oncogenesis. - : Springer Science and Business Media LLC. - 2157-9024. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Myxoid liposarcoma (MLS) represents a common subtype of liposarcoma molecularly characterized by a recurrent chromosomal translocation that generates a chimeric FUS-DDIT3 fusion gene. The FUS-DDIT3 oncoprotein has been shown to be crucial in MLS pathogenesis. Acting as a transcriptional dysregulator, FUS-DDIT3 stimulates proliferation and interferes with adipogenic differentiation. As the fusion protein represents a therapeutically challenging target, a profound understanding of MLS biology is elementary to uncover FUS-DDIT3-dependent molecular vulnerabilities. Recently, a specific reliance on the Hippo pathway effector and transcriptional co-regulator YAP1 was detected in MLS; however, details on the molecular mechanism of FUS-DDIT3-dependent YAP1 activation, and YAP1 ' s precise mode of action remain unclear. In elaborate in vitro studies, employing RNA interference-based approaches, small-molecule inhibitors, and stimulation experiments with IGF-II, we show that FUS-DDIT3-driven IGF-IR/PI3K/AKT signaling promotes stability and nuclear accumulation of YAP1 via deregulation of the Hippo pathway. Co-immunoprecipitation and proximity ligation assays revealed nuclear co-localization of FUS-DDIT3 and YAP1/TEAD in FUS-DDIT3-expressing mesenchymal stem cells and MLS cell lines. Transcriptome sequencing of MLS cells demonstrated that FUS-DDIT3 and YAP1 co-regulate oncogenic gene signatures related to proliferation, cell cycle progression, apoptosis, and adipogenesis. In adipogenic differentiation assays, we show that YAP1 critically contributes to FUS-DDIT3-mediated adipogenic differentiation arrest. Taken together, our study provides mechanistic insights into a complex FUS-DDIT3-driven network involving IGF-IR/PI3K/AKT signals acting on Hippo/YAP1, and uncovers substantial cooperative effects of YAP1 and FUS-DDIT3 in the pathogenesis of MLS.
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