Sirolimus inhibits key events of restenosis in vitro/ex vivo: evaluation of the clinical relevance of the data by SI/MPL- and SI/DES-ratio's

<p>Abstract</p> <p>Background</p> <p>Sirolimus (SRL, Rapamycin) has been used successfully to inhibit restenosis both in drug eluting stents (DES) and after systemic application. The current study reports on the effects of SRL in various human in vitro/ex vivo models and evaluates the theoretical clinical relevance of the data by SI/MPL- and SI/DES-ratio's.</p> <p>Methods</p> <p>Definition of the SI/MPL-ratio: relation between <b>s</b>ignificant <b>i</b>nhibitory effects in vitro/ex vivo and the <b>m</b>aximal <b>p</b>lasma <b>l</b>evel after systemic administration in vivo (6.4 ng/ml for SRL). Definition of the SI/DES-ratio: relation between <b>s</b>ignificant <b>i</b>nhibitory effects in vitro/ex vivo and the drug concentration in <b>DES </b>(7.5 mg/ml in the ISAR drug-eluting stent platform). Part I of the study investigated in cytoflow studies the effect of SRL (0.01–1000 ng/ml) on TNF-α induced expression of intercellular adhesion molecule 1 (ICAM-1) in human coronary endothelial cells (HCAEC) and human coronary smooth muscle cells (HCMSMC). Part II of the study analysed the effect of SRL (0.01–1000 ng/ml) on cell migration of HCMSMC. In part III, IV, and V of the study ex vivo angioplasty (9 bar) was carried out in a human organ culture model (HOC-model). SRL (50 ng/ml) was added for a period of 21 days, after 21 and 56 days cell proliferation, apoptosis, and neointimal hyperplasia was studied.</p> <p>Results</p> <p>Expression of ICAM-1 was significantly inhibited both in HCAEC (SRL ≥ 0.01 ng/ml) and HCMSMC (SRL ≥ 10 ng/ml). SRL in concentrations ≥ 0.1 ng/ml significantly inhibited migration of HCMSMC. Cell proliferation and neointimal hyperplasia was inhibited at day 21 and day 56, significance (p < 0.01) was achieved for the inhibitory effect on cell proliferation in the media at day 21. The number of apoptotic cells was always below 1%.</p> <p>Conclusion</p> <p>SI/MPL-ratio's ≤ 1 (ICAM-1 expression, cell migration) characterize inhibitory effects of SRL that can be theoretically expected both after systemic and local high dose administration, a SI/MPL-ratio of 7.81 (cell proliferation) represents an effect that was achieved with drug concentrations 7.81-times the MPL. SI/DES-ratio's between 10^-6and 10^-8indicate that the described inhibitory effects of SRL have been detected with micro to nano parts of the SRL concentration in the ISAR drug-eluting stent platform. Drug concentrations in DES will be a central issue in the future.</p

Confirmation of the topology of the Wendelstein 7-X magnetic field to better than 1:100,000

Fusion energy research has in the past 40 years focused primarily on the tokamak concept, but recent advances in plasma theory and computational power have led to renewed interest in stellarators. The largest and most sophisticated stellarator in the world, Wendelstein 7-X (W7-X), has just started operation, with the aim to show that the earlier weaknesses of this concept have been addressed successfully, and that the intrinsic advantages of the concept persist, also at plasma parameters approaching those of a future fusion power plant. Here we show the first physics results, obtained before plasma operation: that the carefully tailored topology of nested magnetic surfaces needed for good confinement is realized, and that the measured deviations are smaller than one part in 100,000. This is a significant step forward in stellarator research, since it shows that the complicated and delicate magnetic topology can be created and verified with the required accuracy

Major results from the first plasma campaign of the Wendelstein 7-X stellarator

After completing the main construction phase of Wendelstein 7-X (W7-X) and successfully commissioning the device, first plasma operation started at the end of 2015. Integral commissioning of plasma start-up and operation using electron cyclotron resonance heating (ECRH) and an extensive set of plasma diagnostics have been completed, allowing initial physics studies during the first operational campaign. Both in helium and hydrogen, plasma breakdown was easily achieved. Gaining experience with plasma vessel conditioning, discharge lengths could be extended gradually. Eventually, discharges lasted up to 6 s, reaching an injected energy of 4 MJ, which is twice the limit originally agreed for the limiter configuration employed during the first operational campaign. At power levels of 4 MW central electron densities reached 3 1019 m-3, central electron temperatures reached values of 7 keV and ion temperatures reached just above 2 keV. Important physics studies during this first operational phase include a first assessment of power balance and energy confinement, ECRH power deposition experiments, 2nd harmonic O-mode ECRH using multi-pass absorption, and current drive experiments using electron cyclotron current drive. As in many plasma discharges the electron temperature exceeds the ion temperature significantly, these plasmas are governed by core electron root confinement showing a strong positive electric field in the plasma centre.Peer reviewe

Major results from the first plasma campaign of the Wendelstein 7-X stellarator

\u3cp\u3eAfter completing the main construction phase of Wendelstein 7-X (W7-X) and successfully commissioning the device, first plasma operation started at the end of 2015. Integral commissioning of plasma start-up and operation using electron cyclotron resonance heating (ECRH) and an extensive set of plasma diagnostics have been completed, allowing initial physics studies during the first operational campaign. Both in helium and hydrogen, plasma breakdown was easily achieved. Gaining experience with plasma vessel conditioning, discharge lengths could be extended gradually. Eventually, discharges lasted up to 6 s, reaching an injected energy of 4 MJ, which is twice the limit originally agreed for the limiter configuration employed during the first operational campaign. At power levels of 4 MW central electron densities reached 3 10\u3csup\u3e19\u3c/sup\u3e m\u3csup\u3e-3\u3c/sup\u3e, central electron temperatures reached values of 7 keV and ion temperatures reached just above 2 keV. Important physics studies during this first operational phase include a first assessment of power balance and energy confinement, ECRH power deposition experiments, 2nd harmonic O-mode ECRH using multi-pass absorption, and current drive experiments using electron cyclotron current drive. As in many plasma discharges the electron temperature exceeds the ion temperature significantly, these plasmas are governed by core electron root confinement showing a strong positive electric field in the plasma centre.\u3c/p\u3