Inhibition of MAP kinase pathways by selective BRAF inhibitors, such as vemurafenib and dabrafenib, have evolved as key therapies of BRAF-mutated melanoma. However, tumor relapse and therapy resistance have remained as major problems, which may be addressed by combination with other pathway inhibitors. Here we identified the potassium channel inhibitor TRAM-34 as highly effective in combination with vemurafenib. Thus apoptosis was significantly enhanced and cell viability was decreased. The combination vemurafenib/TRAM-34 was also effective in vemurafenib-resistant cells, suggesting that acquired resistance may be overcome. Vemurafenib decreased ERK phosphorylation, suppressed antiapoptotic Mcl-1 and enhanced proapoptotic Puma and Bim. The combination resulted in enhancement of proapoptotic pathways as caspase-3 and loss of mitochondrial membrane potential. Indicating a special mechanism of vemurafenib-induced apoptosis, we found strong enhancement of intracellular ROS levels already at 1 h of treatment. The critical role of ROS was demonstrated by the antioxidant vitamin E (alpha-tocopherol), which decreased intracellular ROS as well as apoptosis. Also caspase activation and loss of mitochondrial membrane potential were suppressed, proving ROS as an upstream effect. Thus ROS represents an initial and independent apoptosis pathway in melanoma cells that is of particular importance for vemurafenib and its combination with TRAM-34.
Das prolongierte Weaning von Patienten mit neurologischen oder neurochirurgischen Erkrankungen weist Besonderheiten auf, denen die Deutsche Gesellschaft für Neurorehabilitation e. V. in einer eigenen Leitlinie Rechnung trägt.
Im Hinblick auf Definitionen (z. B. Weaningerfolg und -versagen), Weaningkategorien, Pathophysiologie des Weaningversagens und allgemeine Weaningstrategien wird ausdrücklich auf die aktuelle S2k-Leitlinie der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin e. V. verwiesen.
In der neurologisch-neurochirurgischen Frührehabilitation werden Patienten mit zentralen Störungen der Atmungsregulation (z. B. Hirnstammläsionen), des Schluckaktes (neurogene Dysphagien), mit neuromuskulären Problemen (z. B. Critical-illness-Polyneuropathie, Guillain-Barre-Syndrom, Querschnittlähmungen, Myasthenia gravis) und/oder kognitiven Störungen (z. B. Bewusstseins- und Vigilanzstörungen, schwere Kommunikationsstörungen) versorgt, deren Betreuung bei der Entwöhnung von der Beatmung neben intensivmedizinischer Kompetenz auch neurologische bzw. neurochirurgische und neurorehabilitative Expertise erfordert. In Deutschland wird diese Kompetenz in Zentren der neurologisch-neurochirurgischen Frührehabilitation vorgehalten, und zwar als Krankenhausbehandlung.
Der Leitlinie liegt eine systematische Recherche von Leitliniendatenbanken und Medline zugrunde. Unter Moderation durch die Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) erfolgte die Konsensfindung mittels nominalen Gruppenprozesses und Delphi-Verfahren.
In der vorliegenden Leitlinie der DGNR wird auf die strukturellen und inhaltlichen Besonderheiten der neurologisch-neurochirurgischen Frührehabilitation sowie vorhandene Studien zum Weaning in Frührehabilitationseinrichtungen eingegangen.
Adressaten der Leitlinie sind Neurologen, Neurochirurgen, Anästhesisten, Palliativmediziner, Logopäden, Intensivpflegekräfte, Ergotherapeuten, Physiotherapeuten und Neuropsychologen. Ferner richtet sich diese Leitlinie zur Information an Fachärzte für Physikalische Medizin und Rehabilitation (PMR), Pneumologen, Internisten, Atmungstherapeuten, den Medizinischen Dienst der Krankenkassen (MDK) und des Spitzenverbands Bund der Krankenkassen e. V. (MDS). Das wesentliche Ziel dieser Leitlinie ist es, den aktuellen Wissensstand zum Thema „Prolongiertes Weaning in der neurologisch-neurochirurgischen Frührehabilitation“ zu vermitteln.
Silk protein-based materials show promise for application as biomaterials for tissue engineering. The simple and rapid photochemical modification of silk protein-based materials composed of either Bombyx mori silkworm silk or engineered spider silk proteins (eADF4(C16)) is reported. Radicals formed on the silk-based materials initiate the polymerization of monomers (acrylic acid, methacrylic acid, or allylamine) which functionalize the surface of the silk materials with poly(acrylic acid) (PAA), poly(methacrylic acid) (PMAA), or poly(allylamine) (PAAm). To demonstrate potential applications of this type of modification, the polymer-modified silks are mineralized. The PAA- and PMAA-functionalized silks are mineralized with calcium carbonate, whereas the PAAm-functionalized silks are mineralized with silica, both of which provide a coating on the materials that may be useful for bone tissue engineering, which will be the subject of future investigations.
Ground-based gamma-ray astronomy has had a major breakthrough with the impressive results obtained using systems of imaging atmospheric Cherenkov telescopes. Ground-based gamma-ray astronomy has a huge potential in astrophysics, particle physics and cosmology. CTA is an international initiative to build the next generation instrument, with a factor of 5-10 improvement in sensitivity in the 100 GeV-10 TeV range and the extension to energies well below 100 GeV and above 100 TeV. CTA will consist of two arrays (one in the north, one in the south) for full sky coverage and will be operated as open observatory. The design of CTA is based on currently available technology. This document reports on the status and presents the major design concepts of CTA.
Introducing the CTA concept
(2013)
The Cherenkov Telescope Array (CTA) is a new observatory for very high-energy (VHE) gamma rays. CTA has ambitions science goals, for which it is necessary to achieve full-sky coverage, to improve the sensitivity by about an order of magnitude, to span about four decades of energy, from a few tens of GeV to above 100 TeV with enhanced angular and energy resolutions over existing VHE gamma-ray observatories. An international collaboration has formed with more than 1000 members from 27 countries in Europe, Asia, Africa and North and South America. In 2010 the CTA Consortium completed a Design Study and started a three-year Preparatory Phase which leads to production readiness of CTA in 2014. In this paper we introduce the science goals and the concept of CTA, and provide an overview of the project.
Cost degression in photovoltaics, wind-power and battery storage has been faster than previously anticipated. In the future, climate policy to limit global warming to 1.5–2 °C will make carbon-based fuels increasingly scarce and expensive. Here we show that further progress in solar- and wind-power technology along with carbon pricing to reach the Paris Climate targets could make electricity cheaper than carbon-based fuels. In combination with demand-side innovation, for instance in e-mobility and heat pumps, this is likely to induce a fundamental transformation of energy systems towards a dominance of electricity-based end uses. In a 1.5 °C scenario with limited availability of bioenergy and carbon dioxide removal, electricity could account for 66% of final energy by mid-century, three times the current levels and substantially higher than in previous climate policy scenarios assessed by the Intergovernmental Panel on Climate Change. The lower production of bioenergy in our high-electrification scenarios markedly reduces energy-related land and water requirements.