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| 2. |
- Bausch, Birke, et al.
(author)
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Germline NF1 mutational spectra and loss-of-heterozygosity analyses in patients with pheochromocytoma and neurofibromatosis type 1.
- 2007
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In: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 92:7, s. 2784-92
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Journal article (peer-reviewed)abstract
- BACKGROUND: Neurofibromatosis type 1 (NF1) is a pheochromocytoma-associated syndrome. Because of the low prevalence of pheochromocytoma in NF1, we ascertained subjects by pheochromocytoma that also had NF1 in the hope of describing the germline NF1 mutational spectra of NF1-related pheochromocytoma.MATERIALS AND METHODS: An international registry for NF1-pheochromocytomas was established. Mutation scanning was performed using denaturing HPLC for intragenic variation and quantitative PCR for large deletions. Loss-of-heterozygosity analysis using markers in and around NF1 was performed.RESULTS: There were 37 eligible subjects (ages 14-70 yr). Of 21 patients with corresponding tumor available, 67% showed somatic loss of the nonmutated allele at the NF1 locus vs. 0 of 12 sporadic tumors (P = 0.0002). Overall, 86% of the 37 patients had exonic or splice site mutations, 14% large deletions or duplications; 79% of the mutations are novel. The cysteine-serine rich domain (CSR) was affected in 35% but the RAS GTPase activating protein domain (RGD) in only 13%. There did not appear to be an association between any clinical features, particularly pheochromocytoma presentation and severity, and NF1 mutation genotype.CONCLUSIONS: The germline NF1 mutational spectra comprise intragenic mutations and deletions in individuals with pheochromocytoma and NF1. NF1 mutations tended to cluster in the CSR over the RAS-GAP domain, suggesting that CSR plays a more prominent role in individuals with NF1-pheochromocytoma than in NF1 individuals without this tumor. Loss-of-heterozygosity of NF1 markers in NF1-related pheochromocytoma was significantly more frequent than in sporadic pheochromocytoma, providing further molecular evidence that pheochromocytoma is a true component of NF1.
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| 3. |
- Christakoudi, Sofia, et al.
(author)
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Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy
- 2020
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In: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 58
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Journal article (peer-reviewed)abstract
- Background: Kidney transplant recipients (KTRs) with "operational tolerance" (OT) maintain a functioning graft without immunosuppressive (IS) drugs, thus avoiding treatment complications. Nevertheless, IS drugs can influence gene-expression signatures aiming to identify OT among treated KTRs. Methods: We compared five published signatures of OT in peripheral blood samples from 18 tolerant, 183 stable, and 34 chronic rejector KTRs, using gene-expression levels with and without adjustment for IS drugs and regularised logistic regression. Findings: IS drugs explained up to 50% of the variability in gene-expression and 20-30% of the variability in the probability of OT predicted by signatures without drug adjustment. We present a parsimonious consensus gene-set to identify OT, derived from joint analysis of IS-drug-adjusted expression of five published signature gene-sets. This signature, including CD40, CTLA4, HSD11B1, IGKV4-1, MZB1, NR3C2, and RAB40C genes, showed an area under the curve 0.92 (95% confidence interval 0.88-0.94) in cross-validation and 0.97 (0.93-1.00) in six months follow-up samples. Interpretation: We advocate including adjustment for IS drug therapy in the development stage of gene-expression signatures of OT to reduce the risk of capturing features of treatment, which could be lost following IS drug minimisation or withdrawal. Our signature, however, would require further validation in an independent dataset and a biomarker-led trial. (c) 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license. (http://creativecommons.org/licenses/by/4.0/)
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| 4. |
- Christakoudi, Sofia, et al.
(author)
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Steroid regulation : An overlooked aspect of tolerance and chronic rejection in kidney transplantation
- 2018
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In: Molecular and Cellular Endocrinology. - : ELSEVIER IRELAND LTD. - 0303-7207 .- 1872-8057. ; 473, s. 205-216
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Journal article (peer-reviewed)abstract
- Steroid conversion (HSD11B1, HSD11B2, H6PD) and receptor genes (NR3C1, NR3C2) were examined in kidney-transplant recipients with "operational tolerance" and chronic rejection (CR), independently and within the context of 88 tolerance-associated genes. Associations with cellular types were explored. Peripheral whole-blood gene-expression levels (RT-qPCR-based) and cell counts were adjusted for immunosuppressant drug intake. Tolerant (n = 17), stable (n = 190) and CR patients (n = 37) were compared. Healthy controls (n= 14) were used as reference. The anti-inflammatory glucocorticoid receptor (NR3C1) and the cortisol-activating HSD11B1 and H6PD genes were up-regulated in CR and were lowest in tolerant patients. The pro-inflammatory mineralocorticoid gene (NR3C2) was downregulated in stable and CR patients. NR3C1 was associated with neutrophils and NR3C2 with T-cells. Steroid conversion and receptor genes, alone, enabled classification of tolerant patients and were major contributors to gene-expression signatures of both, tolerance and CR, alongside known tolerance-associated genes, revealing a key role of steroid regulation and response in kidney transplantation.
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| 5. |
- Mavrina, E., et al.
(author)
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Multi-Omics Interdisciplinary Research Integration to Accelerate Dementia Biomarker Development (MIRIADE)
- 2022
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In: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 13
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Journal article (peer-reviewed)abstract
- Proteomics studies have shown differential expression of numerous proteins in dementias but have rarely led to novel biomarker tests for clinical use. The Marie Curie MIRIADE project is designed to experimentally evaluate development strategies to accelerate the validation and ultimate implementation of novel biomarkers in clinical practice, using proteomics-based biomarker development for main dementias as experimental case studies. We address several knowledge gaps that have been identified in the field. First, there is the technology-translation gap of different technologies for the discovery (e.g., mass spectrometry) and the large-scale validation (e.g., immunoassays) of biomarkers. In addition, there is a limited understanding of conformational states of biomarker proteins in different matrices, which affect the selection of reagents for assay development. In this review, we aim to understand the decisions taken in the initial steps of biomarker development, which is done via an interim narrative update of the work of each ESR subproject. The results describe the decision process to shortlist biomarkers from a proteomics to develop immunoassays or mass spectrometry assays for Alzheimer's disease, Lewy body dementia, and frontotemporal dementia. In addition, we explain the approach to prepare the market implementation of novel biomarkers and assays. Moreover, we describe the development of computational protein state and interaction prediction models to support biomarker development, such as the prediction of epitopes. Lastly, we reflect upon activities involved in the biomarker development process to deduce a best-practice roadmap for biomarker development.
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| 6. |
- Mohaupt, P., et al.
(author)
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A new concept for test equipment for testing large HV and UHV cables on-site
- 2010
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In: Elektrotechnik und Informationstechnik. - : Springer Science and Business Media LLC. - 0932-383X. ; 127:12, s. 350-353
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Journal article (peer-reviewed)abstract
- The number of projects involving long and extra long HV and UHV AC cables as well as HVDC cable connections can be observed to increase (Cao et al., 2008; Kabouris et al., 2006). At the same time, operating voltage levels are increasing, accentuating the need for more powerful on-site test systems needed to prove the integrity of the insulation before energization. Low cost and ease of operation are other important features of such systems. As a matter of fact, traditional methods and test systems for routine and on-site testing of these cables come to their limit - technically and economically - as the lengths and voltage levels increase (Marelli, 2008). The logistics for the arrangement of tests as well as the testing itself are challenging (Schröder et al., 2006). Development of power electronics has now made it possible to realize high voltage DC interconnections that do not exhibit polarity reversal at reversal of power flow. As a result of this, extruded XLPE cables are now coming to the fore in high voltage DC application, although methods and test equipment for routine and on-site testing show some open issues so far. Space charges in the insulation, initiated by the test voltage during testing, are unacceptable, and this leads to the requirement that testing must be made at an alternating voltage, which can be very low frequency without creating space charge. Available test equipment for power frequency testing is not feasible for testing extruded DC cables, among other reasons, due to the lengths usually associated with DC cables. These open issues can be solved with a newly developed on-site test system that provides the reliability of established test methods and test equipment, but exhibiting lower weight, dimensions and power consumption compared to existing systems. At the same time, the on-site test system as well as the prearrangement of the tests and the testing itself are less cost intensive. Extra long cables (i.e. high capacitance) could be tested with the equipment, which by virtue of its smaller dimension is easier to handle and thus reducing the testing logistics dramatically. For example where one of the systems on the market would require two trailers of equipment for a test on a high voltage cable, only a single trailer would be needed with the new system, or a roll on/roll off test can be carried out without the use of any crane on-site. A reduction in weight by a factor of 3 is expected compared to today's on-site test equipment, a gain which also is reflected in reduced volume. © 2010 Springer-Verlag.
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| 8. |
- Mohaupt, P., et al.
(author)
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Extension and optimization of the load range of DRT test systems for testing extra long HV and UHV cables
- 2012
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In: 44th International Conference on Large High Voltage Electric Systems 2012.
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Conference paper (peer-reviewed)abstract
- In the last few years, the demand for testing extra-long cables, such as submarine cables has grown rapidly. The existing testing methods have been complemented by a new testing technology called DRT (Differential Resonance Technology). This testing method enables testing of extra-long cables by comparably small and light-weight equipment using a low frequency for the test voltage, e.g. 0.1Hz up to 5Hz. This leads to a significant decrease of the required power of the test source [1]. In a resonant circuit only the losses of the generator's individual components, specifically the high voltage reactor, have to be covered by the mains. The testing power itself remains fully compensated. Typical ratios between the testing power and the input power of resonant test systems start at 50 and go up to 100, depending on the load. Unfortunately, voltage generation based on inductive generation principles such as resonant circuits cannot economically be used for frequencies below 10Hz due to the massive iron cores needed for such a low frequency. The DRT method for the generation of low frequency high voltage is based on a high frequency voltage whose amplitude is modulated by the desired low frequency. Using a resonator, which is tuned to the high frequency, and a demodulator, the desired low frequency high voltage can be generated [1,2]. The input power required - and in direct relation to this the size and weight of the equipment - is significantly smaller than for other existing methods. In order to optimize the operation performance of the DRT system, this paper describes mathematical methods and algorithms, which have already been implemented and tested in a DRT test set. The basis for these algorithms is a mathematical description of the system based on an envelope model. Using this mathematical description of the nonlinear system behavior, a systematic analysis of the performance and the limits of the system can be given. The theoretical approach was experimentally proven by measuring the output voltage and the input power of a prototype unit ultimately designed to produce 200 kV rms. A first test was performed at SP Technical Research Institute of Sweden, using their reference measurement system for very low frequency (VLF) [3, 4] to measure the high VLF voltage. The reference measurement system provides a traceable uncertainty of down to 0.04 % over a voltage range up to 200 kV rms. The frequency range of the reference system is from 0.1 Hz up to 50 Hz. This system permits acquisition of complete waveforms that can be analysed for harmonic content and/or THD (Total Harmonic Distortion). Further tests are planned, where the connected load will be increased to the specified maximum 1 μF at 200 kV, and the characteristics will be explored both as regards to output voltage quality, input power requirements and distortion on the input current.
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| 9. |
- Mohaupt, P., et al.
(author)
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Extension and optimization of the load range of DRT test systems for testing extra-long HV and UHV cables
- 2013
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In: Elektrotechnik und Informationstechnik. - : Springer Science and Business Media LLC. - 0932-383X.
-
Journal article (peer-reviewed)abstract
- In the last few years, the demand for testing extra-long cables, such as submarine cables has grown rapidly. The existing testing methods have been complemented by a new testing technology called DRT (Differential Resonance Technology). This testing method enables testing of extra-long cables by comparably small and light-weight equipment using a low frequency for the test voltage, e.g. 0.1 Hz up to 5 Hz. This leads to a significant decrease of the required power of the test source (P. Mohaupt and A. Bergman in CIGRE 2010). In a resonant circuit only the losses of the generator's individual components, specifically the high voltage reactor, have to be covered by the mains. The testing power itself remains fully compensated. Typical ratios between the testing power and the input power of resonant test systems start at 50 and go up to 100, depending on the load. Unfortunately, voltage generation based on inductive generation principles such as resonant circuits cannot economically be used for frequencies below 10 Hz due to the massive iron cores needed for such a low frequency. The DRT method for the generation of low frequency high voltage is based on a high frequency voltage whose amplitude is modulated by the desired low frequency. Using a resonator, which is tuned to the high frequency, and a demodulator, the desired low frequency high voltage can be generated (P. Mohaupt and A. Bergman in CIGRE 2010; P. Mohaupt and T. Mehl in Jicable 2011). The input power required-and in direct relation to this the size and weight of the equipment-is significantly smaller than for other existing methods. In order to optimize the operation performance of the DRT system, this paper describes mathematical methods and algorithms, which have already been implemented and tested in a DRT test set. The basis for these algorithms is a mathematical description of the system based on an envelope model. Using this mathematical description of the nonlinear system behavior, a systematic analysis of the performance and the limits of the system can be given. The theoretical approach was experimentally proven by measuring the output voltage and the input power of a prototype unit ultimately designed to produce 200 kV rms. A first test was performed at SP Technical Research Institute of Sweden, using their reference measurement system for very low frequency (VLF) S. Bergman and A. Bergman (Proc. CPEM Conf. Dig., pp. 682-683, 2010; IEEE Trans. Instrum. Meas. 60:2422-2426, 2011) to measure the high VLF voltage. The reference measurement system provides a traceable uncertainty of down to 0.04 % over a voltage range up to 200 kV rms. The frequency range of the reference system is from 0.1 Hz up to 50 Hz. This system permits acquisition of complete wave-forms that can be analysed for harmonic content and/or THD (Total Harmonic Distortion). Further tests are planned, where the connected load will be increased to the specified maximum 1 μF at 200 kV, and the characteristics will be explored both as regards to output voltage quality, input power requirements and distortion on the input current. © 2013 CIGRE -- Reprint from www.cigre.org with kind permission.
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