| 1. |
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| 2. |
- Joffrin, E., et al.
(författare)
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Overview of the JET preparation for deuterium-tritium operation with the ITER like-wall
- 2019
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 59:11
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Forskningsöversikt (refereegranskat)abstract
- For the past several years, the JET scientific programme (Pamela et al 2007 Fusion Eng. Des. 82 590) has been engaged in a multi-campaign effort, including experiments in D, H and T, leading up to 2020 and the first experiments with 50%/50% D-T mixtures since 1997 and the first ever D-T plasmas with the ITER mix of plasma-facing component materials. For this purpose, a concerted physics and technology programme was launched with a view to prepare the D-T campaign (DTE2). This paper addresses the key elements developed by the JET programme directly contributing to the D-T preparation. This intense preparation includes the review of the physics basis for the D-T operational scenarios, including the fusion power predictions through first principle and integrated modelling, and the impact of isotopes in the operation and physics of D-T plasmas (thermal and particle transport, high confinement mode (H-mode) access, Be and W erosion, fuel recovery, etc). This effort also requires improving several aspects of plasma operation for DTE2, such as real time control schemes, heat load control, disruption avoidance and a mitigation system (including the installation of a new shattered pellet injector), novel ion cyclotron resonance heating schemes (such as the three-ions scheme), new diagnostics (neutron camera and spectrometer, active Alfven eigenmode antennas, neutral gauges, radiation hard imaging systems...) and the calibration of the JET neutron diagnostics at 14 MeV for accurate fusion power measurement. The active preparation of JET for the 2020 D-T campaign provides an incomparable source of information and a basis for the future D-T operation of ITER, and it is also foreseen that a large number of key physics issues will be addressed in support of burning plasmas.
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| 3. |
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| 5. |
- Korenblik, R., et al.
(författare)
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Dragon 1 Protocol Manuscript : Training, Accreditation, Implementation and Safety Evaluation of Portal and Hepatic Vein Embolization (PVE/HVE) to Accelerate Future Liver Remnant (FLR) Hypertrophy
- 2022
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Ingår i: Cardiovascular and Interventional Radiology. - : Springer. - 0174-1551 .- 1432-086X. ; 45, s. 1391-1398
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Tidskriftsartikel (refereegranskat)abstract
- Study Purpose The DRAGON 1 trial aims to assess training, implementation, safety and feasibility of combined portal- and hepatic-vein embolization (PVE/HVE) to accelerate future liver remnant (FLR) hypertrophy in patients with borderline resectable colorectal cancer liver metastases. Methods The DRAGON 1 trial is a worldwide multicenter prospective single arm trial. The primary endpoint is a composite of the safety of PVE/HVE, 90-day mortality, and one year accrual monitoring of each participating center. Secondary endpoints include: feasibility of resection, the used PVE and HVE techniques, FLR-hypertrophy, liver function (subset of centers), overall survival, and disease-free survival. All complications after the PVE/HVE procedure are documented. Liver volumes will be measured at week 1 and if applicable at week 3 and 6 after PVE/HVE and follow-up visits will be held at 1, 3, 6, and 12 months after the resection. Results Not applicable. Conclusion DRAGON 1 is a prospective trial to assess the safety and feasibility of PVE/HVE. Participating study centers will be trained, and procedures standardized using Work Instructions (WI) to prepare for the DRAGON 2 randomized controlled trial. Outcomes should reveal the accrual potential of centers, safety profile of combined PVE/HVE and the effect of FLR-hypertrophy induction by PVE/HVE in patients with CRLM and a small FLR.
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| 6. |
- Trainer, P J, et al.
(författare)
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Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant.
- 2000
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Ingår i: The New England journal of medicine. - 0028-4793. ; 342:16, s. 1171-7
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Tidskriftsartikel (refereegranskat)abstract
- Patients with acromegaly are currently treated with surgery, radiation therapy, and drugs to reduce hypersecretion of growth hormone, but the treatments may be ineffective and have adverse effects. Pegvisomant is a genetically engineered growth hormone-receptor antagonist that blocks the action of growth hormone.We conducted a 12-week, randomized, double-blind study of three daily doses of pegvisomant (10 mg, 15 mg, and 20 mg) and placebo, given subcutaneously, in 112 patients with acromegaly.The mean (+/-SD) serum concentration of insulin-like growth factor I (IGF-I) decreased from base line by 4.0+/-16.8 percent in the placebo group, 26.7+/-27.9 percent in the group that received 10 mg of pegvisomant per day, 50.1+/-26.7 percent in the group that received 15 mg of pegvisomant per day, and 62.5+/-21.3 percent in the group that received 20 mg of pegvisomant per day (P<0.001 for the comparison of each pegvisomant group with placebo), and the concentrations became normal in 10 percent, 54 percent, 81 percent, and 89 percent of patients, respectively (P<0.001 for each comparison with placebo). Among patients treated with 15 mg or 20 mg of pegvisomant per day, there were significant decreases in ring size, soft-tissue swelling, the degree of excessive perspiration, and fatigue. The score fortotal symptoms and signs of acromegaly decreased significantly in all groups receiving pegvisomant (P< or =0.05). The incidence of adverse effects was similar in all groups.On the basis of these preliminary results, treatment of patients who have acromegaly with a growth hormone-receptor antagonist results in a reduction in serum IGF-I concentrations and in clinical improvement.
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| 7. |
- Charalambous, C. D., et al.
(författare)
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Directed Information Subject to a Fidelity. Applications to Conditionally Gaussian Processes
- 2018
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Ingår i: 2018 European Control Conference, ECC 2018. - : Institute of Electrical and Electronics Engineers (IEEE). - 9783952426982 ; , s. 3071-3076
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Konferensbidrag (refereegranskat)abstract
- This paper is concerned with the minimization of directed information over conditional distributions that satisfy a fidelity of reconstructing a conditionally Gaussian random process by another process, causally. This information theoretic extremum problem is directly linked, via bounds to the optimal performance theoretically attainable by non-causal, causal and zero-delay codes of data compression. The application example includes the characterization of causal rate distortion function for conditionally Gaussian random processes subject to a meansquare error fidelity.
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| 8. |
- Georgiou, E., et al.
(författare)
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AAV9-mediated SH3TC2 gene replacement therapy targeted to Schwann cells for the treatment of CMT4C
- 2023
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Ingår i: Molecular Therapy. - 1525-0016. ; 31:11, s. 3290-3307
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Tidskriftsartikel (refereegranskat)abstract
- Type 4C Charcot-Marie-Tooth (CMT4C) demyelinating neuropathy is caused by autosomal recessive SH3TC2 gene mutations. SH3TC2 is highly expressed in myelinating Schwann cells. CMT4C is a childhood-onset progressive disease without effective treatment. Here, we generated a gene therapy for CMT4C mediated by an adeno-associated viral 9 vector (AAV9) to deliver the human SH3TC2 gene in the Sh3tc2-/mouse model of CMT4C. We used a minimal fragment of the myelin protein zero (Mpz) promoter (miniMpz), which was cloned and validated to achieve Schwann cell-targeted expression of SH3TC2. Following the demonstration of AAV9miniMpz.SH3TC2myc vector efficacy to re-establish SH3TC2 expression in the peripheral nervous system, we performed an early as well as a delayed treatment trial in Sh3tc2-/mice. We demonstrate both after early as well as following late treatment improvements in multiple motor performance tests and nerve conduction velocities. Moreover, treatment led to normalization of the organization of the nodes of Ranvier, which is typically deficient in CMT4C patients and bers, increased myelin thickness and reduced g-ratios at both time points of intervention. Taken together, our results provide a proof of concept for an effective and potentially translatable gene replacement therapy for CMT4C treatment.
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| 9. |
- Heestermans, M, et al.
(författare)
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Identification of the factor XII contact activation site enables sensitive coagulation diagnostics
- 2021
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 5596-
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Tidskriftsartikel (refereegranskat)abstract
- Contact activation refers to the process of surface-induced activation of factor XII (FXII), which initiates blood coagulation and is captured by the activated partial thromboplastin time (aPTT) assay. Here, we show the mechanism and diagnostic implications of FXII contact activation. Screening of recombinant FXII mutants identified a continuous stretch of residues Gln317–Ser339 that was essential for FXII surface binding and activation, thrombin generation and coagulation. Peptides spanning these 23 residues competed with surface-induced FXII activation. Although FXII mutants lacking residues Gln317–Ser339 were susceptible to activation by plasmin and plasma kallikrein, they were ineffective in supporting arterial and venous thrombus formation in mice. Antibodies raised against the Gln317–Ser339 region induced FXII activation and triggered controllable contact activation in solution leading to thrombin generation by the intrinsic pathway of coagulation. The antibody-activated aPTT allows for standardization of particulate aPTT reagents and for sensitive monitoring of coagulation factors VIII, IX, XI.
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| 11. |
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| 12. |
- Stavrou, M., et al.
(författare)
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A translatable RNAi-driven gene therapy silences PMP22/Pmp22 genes and improves neuropathy in CMT1A mice
- 2022
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Ingår i: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738 .- 1558-8238. ; 132:13
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Tidskriftsartikel (refereegranskat)abstract
- Charcot-Marie-Tooth disease type 1A (CMT1A), the most common inherited demyelinating peripheral neuropathy, is caused by PMP22 gene duplication. Overexpression of WT PMP22 in Schwann cells destabilizes the myelin sheath, leading to demyelination and ultimately to secondary axonal loss and disability. No treatments currently exist that modify the disease course. The most direct route to CMT1A therapy will involve reducing PMP22 to normal levels. To accomplish this, we developed a gene therapy strategy to reduce PMP22 using artificial miRNAs targeting human PMP22 and mouse Pmp22 mRNAs. Our lead therapeutic miRNA, miR871, was packaged into an adeno-associated virus 9 (AAV9) vector and delivered by lumbar intrathecal injection into C61-het mice, a model of CMT1A. AAV9-miR871 efficiently transduced Schwann cells in C61-het peripheral nerves and reduced human and mouse PMP22 mRNA and protein levels. Treatment at early and late stages of the disease significantly improved multiple functional outcome measures and nerve conduction velocities. Furthermore, myelin pathology in lumbar roots and femoral motor nerves was ameliorated. The treated mice also showed reductions in circulating biomarkers of CMT1A. Taken together, our data demonstrate that AAV9-miR871-driven silencing of PMP22 rescues a CMT1A model and provides proof of principle for treating CMT1A using a translatable gene therapy approach.
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| 13. |
- Englert, Hanna, et al.
(författare)
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Targeting NETs using dual-active DNase1 variants
- 2023
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundNeutrophil Extracellular Traps (NETs) are key mediators of immunothrombotic mechanisms and defective clearance of NETs from the circulation underlies an array of thrombotic, inflammatory, infectious, and autoimmune diseases. Efficient NET degradation depends on the combined activity of two distinct DNases, DNase1 and DNase1-like 3 (DNase1L3) that preferentially digest double-stranded DNA (dsDNA) and chromatin, respectively.MethodsHere, we engineered a dual-active DNase with combined DNase1 and DNase1L3 activities and characterized the enzyme for its NET degrading potential in vitro. Furthermore, we produced a mouse model with transgenic expression of the dual-active DNase and analyzed body fluids of these animals for DNase1 and DNase 1L3 activities. We systematically substituted 20 amino acid stretches in DNase1 that were not conserved among DNase1 and DNase1L3 with homologous DNase1L3 sequences.ResultsWe found that the ability of DNase1L3 to degrade chromatin is embedded into three discrete areas of the enzyme's core body, not the C-terminal domain as suggested by the state-of-the-art. Further, combined transfer of the aforementioned areas of DNase1L3 to DNase1 generated a dual-active DNase1 enzyme with additional chromatin degrading activity. The dual-active DNase1 mutant was superior to native DNase1 and DNase1L3 in degrading dsDNA and chromatin, respectively. Transgenic expression of the dual-active DNase1 mutant in hepatocytes of mice lacking endogenous DNases revealed that the engineered enzyme was stable in the circulation, released into serum and filtered to the bile but not into the urine.ConclusionTherefore, the dual-active DNase1 mutant is a promising tool for neutralization of DNA and NETs with potential therapeutic applications for interference with thromboinflammatory disease states.
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| 14. |
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| 15. |
- Labberton, L, et al.
(författare)
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Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection
- 2016
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7, s. 12616-
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Tidskriftsartikel (refereegranskat)abstract
- Polyphosphate is an inorganic procoagulant polymer. Here we develop specific inhibitors of polyphosphate and show that this strategy confers thromboprotection in a factor XII-dependent manner. Recombinant Escherichia coli exopolyphosphatase (PPX) specifically degrades polyphosphate, while a PPX variant lacking domains 1 and 2 (PPX_Δ12) binds to the polymer without degrading it. Both PPX and PPX_Δ12 interfere with polyphosphate- but not tissue factor- or nucleic acid-driven thrombin formation. Targeting polyphosphate abolishes procoagulant platelet activity in a factor XII-dependent manner, reduces fibrin accumulation and impedes thrombus formation in blood under flow. PPX and PPX_Δ12 infusions in wild-type mice interfere with arterial thrombosis and protect animals from activated platelet-induced venous thromboembolism without increasing bleeding from injury sites. In contrast, targeting polyphosphate does not provide additional protection from thrombosis in factor XII-deficient animals. Our data provide a proof-of-concept approach for combating thrombotic diseases without increased bleeding risk, indicating that polyphosphate drives thrombosis via factor XII.
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| 16. |
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| 17. |
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| 18. |
- Simons, L., et al.
(författare)
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Simulating dust in magnum-PSI and JET
- 2018
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Ingår i: 45th EPS Conference on Plasma Physics, EPS 2018. - : European Physical Society (EPS). ; , s. 1720-1723
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Konferensbidrag (refereegranskat)abstract
- Dust injection experiments performed at Magnum-PSI are used to benchmark ion drag and heating models used in the dust tracking code DTOKS using HERMES simulated background plasma. Dust particles follow similar trajectories with a period of free-fall under gravity reaching temperatures in excess of Td > 2500 K followed by deflection in the ion flow and exiting with a constant velocity of v = 7:61:4ms-1. Utilising this benchmark of the DTOKS code, investigative simulations of breakup events observed in JET. Simulations incorporating this effect reproduce the expected lifetimes and qualitative structures of observed trajectories in JET, providing an attractive technique for mitigating transport of large impurities into the core plasma.
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| 19. |
- Stavrou, N. A., et al.
(författare)
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Indices of psychological strain during hypoxic bedrest and confinement
- 2013
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Ingår i: Proceedings of Life in space for life on earth, 18-22 June 2012, Aberdeen. - : European Space Agency. - 9789290922704
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Konferensbidrag (refereegranskat)abstract
- Much attention has been devoted to the physiological changes that occur during bed rest. However, there has been a lack of focus on the psychological aspects per se. We investigated indices of psychological strain during three 10-d interventions, designed to assess the combined effects of inactivity/unloading and normobaric hypoxia on several physiological systems. Eleven male participants underwent three 10-d campaigns in a randomized manner: 1) normobaric hypoxic ambulatory confinement (HAMB), 2) normobaric hypoxic bed rest (HBR) and 3) normoxic bed rest (NBR). The most negative psychological profile appeared on BR10 of HBR and HAmb conditions (hypoxic conditions). Concomitantly a decrease in positive emotions was observed from BR-2 to BR10. Bed rest and exposure to hypoxic environments seems to exert a negative effect on person's psychological mood.
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| 20. |
- Stavrou, N.A.M., et al.
(författare)
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Psychological strain : Examining the effect of hypoxic bedrest and confinement
- 2015
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Ingår i: Physiology and Behavior. - : Elsevier BV. - 0031-9384 .- 1873-507X. ; 139, s. 497-504
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Tidskriftsartikel (refereegranskat)abstract
- The aim was to assess the effect of a 10-day exposure to the environmental stressors anticipated in future lunar habitats on indices of psychological strain. In addition to the reduced gravity of the Moon, future habitats on the Moon will likely maintain a hypobaric hypoxic environment. The hypobaric environment will eliminate the need for long decompression profiles prior to each extra-vehicular activity. We investigated the indices of psychological strain during three 10-day conditions, designed to assess the separate and combined effects of inactivity/unloading and normobaric hypoxia on several physiological systems. Eleven male participants underwent three 10-day campaigns in a randomised manner: 1) normobaric normoxic bed rest (NBR), 2) normobaric hypoxic bed rest (HBR) and 3) normobaric hypoxic ambulatory confinement (HAMB). The most negative psychological profile appeared on day 10 of the HBR and HAMB (hypoxic) conditions. Concomitantly, a decrease in positive emotions was observed from baseline to day 10 of the HBR and NBR conditions. Thus, confinement in a hypoxic environment seems to exert a negative effect on an individual's psychological mood.
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| 21. |
- Stavrou, N., et al.
(författare)
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The effect of moderate exercise on emotional state during hypoxic confinement
- 2014
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Konferensbidrag (refereegranskat)abstract
- Normobaric hypoxic training is routinely used by athletes to improve their altitude and sea level performance. A multitude of schedules are being used, combining inactive and active exposure to hypoxic environments. The live high – train low regimen, in particular, requires athletes to spend a majority of time confined to a normobaric hypoxic environment. Despite the known positive effects of hypoxic training on physical performance, there is a lack of information regarding the influence of hypoxia and physical activity on emotional state. This was the principal aim of the current study. Specifically, we tested the hypothesis that physical activity alleviates the hypoxia-induced increases in negative feelings. Fourteen male subjects were confined to 10-day continuous hypoxia (fraction of inspired O2=0.139±0.003; 4000m simulated altitude). Subjects were assigned to either the Hypoxic Confinement: Exercise group (HCE: N=8, two 1 hour training sessions/day at 50% hypoxic peak power output) or the Hypoxic Confinement: Sedentary group (HCS: N=6, no exercise). Subjects were administered the Profile of Mood States (POMS) and the Positive and Negative Affect Schedule (PANAS) tests two days prior to hypoxic confinement (D-2), on days 3 (D3), 7 (D7) and 10 (D10) of hypoxic confinement and on the first day of recovery following the confinement period (R+1). The ANOVA repeated measure of the PANAS determined that positive affect differed significantly across the five time measures between HCS and HCE. Bonferroni post hoc analysis revealed that the HCS group elicited a reduction of positive emotion from D-2 to D7 and to D10 with a concomitant increase of negative emotion from D-2 to D10. In addition, an increase of tension from D-2 to D7 and to D10 was revealed in HCS, whereas an increase in tension on D10 was indicated in HCE. Based on the POMS, an increase of depression from D-2 to D7 was found in HCS, whereas no differences were revealed in HCE, among the five time measures. Finally, no significant differences revealed between D10 and R+1 in the PANAS or POMS in either HCS or HCE. The results indicate that in sedentary subjects hypoxic confinement increases tension and negative emotions, and decreases vigor and positive emotions. It is concluded that hypoxia negatively affects the emotional state, but that increasing the level of physical activity ameliorates such feelings.
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| 22. |
- Stavrou, P. A., et al.
(författare)
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Filtering with fidelity for time-varying Gauss-Markov processes
- 2016
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Ingår i: Proceedings of the 55th IEEE Conference on Decision and Control (CDC 2016). - 0743-1546. - 9781509018376 ; , s. 5465-5470
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Konferensbidrag (refereegranskat)abstract
- In this paper, we revisit the relation between Nonanticipative Rate Distortion (NRD) theory and real-time realizable filtering theory. Specifically, we give the closed form expression for the optimal nonstationary (time-varying) reproduction distribution of the Finite Time Horizon (FTH) Nonanticipative Rate Distortion Function (NRDF) and we establish its connection to real-time realizable filtering theory via a realization scheme utilizing time-varying fully observable multidimensional Gauss-Markov processes. As an application we provide the optimal filter with respect to a mean square error constraint. Unlike classical filtering theory, our filtering approach based on FTH NRDF is performed with waterfilling. We also derive a universal lower bound to the mean square error of any causal estimator to Gaussian processes based on the closed form expression of FTH NRDF. Our theoretical results are demonstrated via an illustrative example.
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| 23. |
- van der Lely, A J, et al.
(författare)
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Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist.
- 2001
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Ingår i: Lancet (London, England). - 0140-6736. ; 358:9295, s. 1754-9
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Tidskriftsartikel (refereegranskat)abstract
- Pegvisomant is a new growth hormone receptor antagonist that improves symptoms and normalises insulin-like growth factor-1 (IGF-1) in a high proportion of patients with acromegaly treated for up to 12 weeks. We assessed the effects of pegvisomant in 160 patients with acromegaly treated for an average of 425 days.Treatment efficacy was assessed by measuring changes in tumour volume by magnetic resonance imaging, and serum growth hormone and IGF-1 concentrations in 152 patients who received pegvisomant by daily subcutaneous injection for up to 18 months. The safety analysis included 160 patients some of whom received weekly injections and are excluded from the efficacy analysis.Mean serum IGF-1 concentrations fell by at least 50%: 467 mg/L (SE 24), 526 mg/L (29), and 523 mg/L (40) in patients treated for 6, 12 and 18 months, respectively (p<0.001), whereas growth hormone increased by 12.5 mg/L (2.1), 12.5 mg/L (3.0), and 14.2 mg/L (5.7) (p<0.001). Of the patients treated for 12 months or more, 87 of 90 (97%) achieved a normal serum IGF-1 concentration. In patients withdrawn from pegvisomant (n=45), serum growth hormone concentrations were 8.0 mg/L (2.5) at baseline, rose to 15.2 mg/L (2.4) on drug, and fell back within 30 days of withdrawal to 8.3 mg/L (2.7). Antibodies to growth hormone were detected in 27 (16.9%) of patients, but no tachyphylaxis was seen. Serum insulin and glucose concentrations were significantly decreased (p<0.05). Two patients experienced progressive growth of their pituitary tumours, and two other patients had increased alanine and asparate aminotransferase concentrations requiring withdrawal from treatment. Mean pituitary tumour volume in 131 patients followed for a mean of 11.46 months (0.70) decreased by 0.033 cm(3) (0.057; p=0.353).Pegvisomant is an effective medical treatment for acromegaly.
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