Glioblastoma is a very aggressive form of brain tumor with limited therapeutic options. Usually, glioblastoma is treated with ionizing radiation (IR) and chemotherapy after surgical removal. However, ...radiotherapy is frequently unsuccessful, among others owing to resistance mechanisms the tumor cells have developed. Antiapoptotic B-cell leukemia (Bcl)-2 family members can contribute to radioresistance by interfering with apoptosis induction in response to IR. Bcl-2 and the closely related Bcl-xL and Mcl-1 are often overexpressed in glioblastoma cells. In contrast to Bcl-2 and Bcl-xL, Mcl-1 is a short-lived protein whose stability is closely regulated by ubiquitylation-dependent proteasomal degradation. Although ubiquitin ligases facilitate degradation, the deubiquitylating enzyme ubiquitin-specific protease 9x (USP9x) interferes with degradation by removing polyubiquitin chains from Mcl-1, thereby stabilizing this protein. Thus, an inability to downregulate Mcl-1 by enhanced USP9x activity might contribute to radioresistance. Here we analyzed the impact of USP9x on Mcl-1 levels and radiosensitivity in glioblastoma cells. Correlating Mcl-1 and USP9x expressions were significantly higher in human glioblastoma than in astrocytoma. Downregulation of Mcl-1 correlated with apoptosis induction in established glioblastoma cell lines. Although Mcl-1 knockdown by siRNA increased apoptosis induction after irradiation in all glioblastoma cell lines, USP9x knockdown significantly improved radiation-induced apoptosis in one of four cell lines and slightly increased apoptosis in another cell line. In the latter two cell lines, USP9x knockdown also increased radiation-induced clonogenic death. The massive downregulation of Mcl-1 and apoptosis induction in A172 cells transfected with USP9x siRNA shows that the deubiquitinase regulates cell survival by regulating Mcl-1 levels. In contrast, USP9x regulated radiosensitivity in Ln229 cells without affecting Mcl-1 levels. We conclude that USP9x can control survival and radiosensitivity in glioblastoma cells by Mcl-1-dependent and Mcl-1-independent mechanisms.
Summer storage of snow for tourism has seen an increasing interest in the last years. Covering large snow piles with materials such as sawdust enables more than two-thirds of the initial snow volume ...to be conserved. We present detailed mass balance measurements of two sawdust-covered snow piles obtained by terrestrial laser scanning during summer 2015. Results indicate that 74 and 63 % of the snow volume remained over the summer for piles in Davos, Switzerland and Martell, Italy. If snow mass is considered instead of volume, the values increase to 83 and 72 %. The difference is attributed to settling and densification of the snow. Additionally, we adapted the one-dimensional, physically based snow cover model SNOWPACK to perform simulations of the sawdust-covered snow piles. Model results and measurements agreed extremely well at the point scale. Moreover, we analysed the contribution of the different terms of the surface energy balance to snow ablation for a pile covered with a 40 cm thick sawdust layer and a pile without insulation. Short-wave radiation was the dominant source of energy for both scenarios, but the moist sawdust caused strong cooling by long-wave emission and negative sensible and latent heat fluxes. This cooling effect reduces the energy available for melt by up to a factor of 12. As a result only 9 % of the net short-wave energy remained available for melt. Finally, sensitivity studies of the parameters thickness of the sawdust layer, air temperature, precipitation and wind speed were performed. We show that sawdust thickness has a tremendous effect on snow loss. Higher air temperatures and wind speeds increase snow ablation but less significantly. No significant effect of additional precipitation could be found as the sawdust remained wet during the entire summer with the measured quantity of rain. Setting precipitation amounts to zero, however, strongly increased melt. Overall, the 40 cm sawdust provides sufficient protection for mid-elevation (approx. 1500 m a.s.l.) Alpine climates and can be managed with reasonable effort.
Pyoderma gangraenosum and subcorneal pustulosis are neutrophilic diseases. Different neutrophilic dermatoses can very rarely occur together in one patient, even with a latent period. Furthermore, ...there seems to be a direct association between IgA gammopathy and neutrophilic dermatosis. Therefore, a gammopathy must always be clarified in the presence of a neutrophilic dermatosis.
Zusammenfassung
Das Pyoderma gangraenosum und die subkorneale Pustulose sind neutrophile Erkrankungen. Bei einem Patienten können sehr selten unterschiedliche neutrophile Dermatosen gemeinsam ...auftreten, auch mit einer zeitlichen Latenz. Darüber hinaus scheint es einen indirekten Zusammenhang zwischen einer Ig(Immunglobulin)A-Gammopathie und einer neutrophilen Dermatose zugeben. Deshalb muss bei Vorliegen einer neutrophilen Dermatose eine Gammopathie immer abgeklärt werden.
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