| 1. |
- Gehlen, J., et al.
(author)
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First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B
- 2022
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In: Human Genetics and Genomics Advances. - : Elsevier BV. - 2666-2477. ; 3:2
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Journal article (peer-reviewed)abstract
- Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene CTNNA3 (p = 2.11 × 10−8; odds ratio [OR] = 3.94; 95% confidence interval [CI], 3.10–5.00), on chromosome 16q24 next to the FOX gene cluster (p = 2.25 × 10−10; OR = 1.47; 95% CI, 1.38–1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 × 10−16; OR = 1.75; 95% CI, 1.64–1.87). We next carried out an esophageal/tracheal transcriptome profiling in rat embryos at four selected embryonic time points. Based on these data and on already published data, the implicated genes at all three GWAS loci are promising candidates for EA/TEF development. We also analyzed the genetic EA/TEF architecture beyond the single marker level, which revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of around 37% ± 14% standard deviation. In addition, we examined the polygenicity of EA/TEF and found that EA/TEF is less polygenic than other complex genetic diseases. In conclusion, the results of our study contribute to a better understanding on the underlying genetic architecture of ET/TEF with the identification of three risk loci and candidate genes. © 2022 The Authors
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| 2. |
- Kessing, C. F., et al.
(author)
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High Number of Activated CD8(+) T Cells Targeting HIV Antigens Are Present in Cerebrospinal Fluid in Acute HIV Infection
- 2017
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In: Jaids-Journal of Acquired Immune Deficiency Syndromes. - 1525-4135. ; 75:1, s. 108-117
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Journal article (peer-reviewed)abstract
- Background: Central nervous system (CNS) infiltration by CD8(+) T cells is associated with neuroinflammation in many neurodegenerative diseases, including HIV-associated dementia. However, the role of CD8(+) T cells in the CNS during acute HIV infection (AHI) is unknown. Methods: We analyzed the phenotype, gene expression, T cell receptor (TCR) repertoire, and HIV specificity of CD8(+) T cells in cerebrospinal fluid (CSF) of a unique cohort captured during the earliest stages of AHI (n = 26), chronic (n = 23), and uninfected (n = 8). Results: CSF CD8(+) T cells were elevated in AHI compared with uninfected controls. The frequency of activated CSF CD8(+) T cells positively correlated to CSF HIV RNA and to markers of CNS inflammation. In contrast, activated CSF CD8(+) T cells during chronic HIV infection were associated with markers of neurological injury and microglial activation. CSF CD8(+) T cells in AHI exhibited increased functional gene expression profiles associated with CD8(+) T cells effector function, proliferation, and TCR signaling, a unique restricted TCR Vbeta repertoire and contained HIV-specific CD8(+) T cells directed to unique HIV epitopes compared with the periphery. Conclusions: These results suggest that CSF CD8(+) T cells in AHI expanding in the CNS are functional and directed against HIV antigens. These cells could thus play a beneficial role protective of injury seen in chronic HIV infection if combination antiretroviral therapy is initiated early.
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| 3. |
- Trautmann, M., et al.
(author)
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FUS-DDIT3 Fusion Protein-Driven IGF-IR Signaling is a Therapeutic Target in Myxoid Liposarcoma
- 2017
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In: Clinical Cancer Research. - : American Association for Cancer Research (AACR). - 1078-0432 .- 1557-3265. ; 23:20, s. 6227-6238
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Journal article (peer-reviewed)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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| 4. |
- Isfort, I., et al.
(author)
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Prevalence of the Hippo Effectors YAP1/TAZ in Tumors of Soft Tissue and Bone
- 2019
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9
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Journal article (peer-reviewed)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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| 5. |
- Trautmann, M., et al.
(author)
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Phosphatidylinositol-3-kinase (PI3K)/Akt Signaling is Functionally Essential in Myxoid Liposarcoma
- 2019
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In: Molecular Cancer Therapeutics. - 1535-7163. ; 18:4, s. 834-844
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Journal article (peer-reviewed)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. |
- Akay, Alpaslan, 1975, et al.
(author)
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Attitudes toward uncertainty among the poor: An experiment in rural Ethiopia
- 2012
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In: Theory and Decision. - : Springer Science and Business Media LLC. - 0040-5833 .- 1573-7187. ; 73:3, s. 453-464
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Journal article (peer-reviewed)abstract
- We investigate risk and ambiguity attitudes among Ethiopian farmers in one of the poorest regions of the world. Strong risk aversion and ambiguity aversion were found with the Ethiopian farmers. We compared their attitudes to those of a Western university student sample elicited by the same decision task. Ambiguity aversion was similar for farmers and students, but farmers were more risk averse. Our results show that ambiguity aversion is not restricted to Western student populations, and that studies of agricultural decisions may benefit from explicitly considering ambiguity attitudes.
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| 7. |
- Berthold, R., et al.
(author)
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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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In: Oncogenesis. - : Springer Science and Business Media LLC. - 2157-9024. ; 11:1
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Journal article (peer-reviewed)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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| 8. |
- Kocher, Martin G., et al.
(author)
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Ambiguity aversion is not universal
- 2018
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In: European Economic Review. - : Elsevier BV. - 0014-2921 .- 1873-572X. ; 101, s. 268-283
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Journal article (peer-reviewed)abstract
- Assuming universal ambiguity aversion, an extensive theoretical literature studies how ambiguity can account for market anomalies from the perspective of expected utility-based theories. We provide a systematic experimental assessment of ambiguity attitudes in different likelihood ranges, and in the gain domain, the loss domain and with mixed outcomes. We draw on a unified framework to elicit preferences across these domains. We replicate the usual finding of ambiguity aversion for moderate likelihood gains. However, when introducing losses or lower likelihoods, we observe predominantly ambiguity neutrality or seeking, rejecting universal ambiguity aversion. (C) 2017 Elsevier B.V. All rights reserved.
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| 9. |
- Kocher, Martin G., et al.
(author)
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An experimental study of precautionary bidding
- 2015
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In: European Economic Review. - : Elsevier BV. - 0014-2921. ; 78, s. 27-38
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Journal article (peer-reviewed)abstract
- Auctions often involve goods exhibiting a common-knowledge ex-post risk. In such auctions, precautionary bidding predicts that under expected utility, DARA bidders reduce their bids by more than the appropriate risk premium. Because the degree of riskiness of an auctioned good and bidders' levels of risk aversion are difficult to observe in field settings, we conduct experimental auctions that allow us to identify the precautionary premium directly. We find strong evidence for precautionary bidding. The effect is robust to changes in experimental design features. Our experiment provides the first empirical demonstration of precautionary motives in a strategic setting. (C) 2015 Elsevier B.V. All rights reserved.
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| 10. |
- Kocher, Martin G., et al.
(author)
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Tempus Fugit: Time Pressure in Risky Decisions
- 2013
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In: Management Science. - : Institute for Operations Research and the Management Sciences (INFORMS). - 0025-1909 .- 1526-5501. ; 59:10, s. 2380-2391
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Journal article (peer-reviewed)abstract
- We study the effects of time pressure on risky decisions for pure gain prospects, pure loss prospects, and mixed prospects involving both gains and losses. In two experiments we find that time pressure has no effect on risk attitudes for gains, but increases risk aversion for losses. For mixed prospects, subjects become simultaneously more loss averse and more gain seeking under time pressure, depending on the framing of the prospects. The results suggest the importance of aspiration levels, and thus the overall probability to break even, under time pressure. We discuss the implications of our findings for decision-making situations that involve time pressure.
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