Radiosensitization of HNSCC cells by EGFR inhibition depends on the induction of cell cycle arrests

The increase in cellular radiosensitivity by EGF receptor (EGFR) inhibition has been shown to be attributable to the induction of a G1-arrest in p53-proficient cells. Because EGFR targeting in combination with radiotherapy is used to treat head and neck squamous cell carcinomas (HNSCC) which are predominantly p53 mutated, we tested the effects of EGFR targeting on cellular radiosensitivity, proliferation, apoptosis, DNA repair and cell cycle control using a large panel of HNSCC cell lines. In these experiments EGFR targeting inhibited signal transduction, blocked proliferation and induced radiosensitization but only in some cell lines and only under normal (pre-plating) conditions. This sensitization was not associated with impaired DNA repair (53BP1 foci) or induction of apoptosis. However, it was associated with the induction of a lasting G2-arrest. Both, the radiosensitization and the G2-arrest were abrogated if the cells were re-stimulated (delayed plating) with actually no radiosensitization being detectable in any of the 14 tested cell lines. Therefore we conclude that EGFR targeting can induce a reversible G2 arrest in p53 deficient HNSCC cells, which does not consequently result in a robust cellular radiosensitization. Together with recent animal and clinical studies our data indicate that EGFR inhibition is no effective strategy to increase the radiosensitivity of HNSCC cells.</p

Development of a Simulation Tool to Enable Optimisation of the Energy Consumption of the Industrial Timber-Drying Process

Reducing the liquid content of green products is an important step in the manufacture of many products. Process conditions in the drying phase have significant influences on the quality of the end product and on energy consumption and required manufacturing time. Effective optimisation of the drying process requires accurate representation of the drying product and its interaction with its environment. The development of a computer simulation tool to analyse the industrial batch timber drying process is outlined. A detailed finite difference product model describing the heat and mass transfers within a plank during drying is described. It is integrated with a customised CFD code characterising the process conditions within the drying chamber. Simulation output from the integrated model is used to generate a macroscopic representation of the product in its drying environment. This representation is included as a component in a modular industrial installation simulation environment. Analysis with this global model can lead to optimisation of energy consumption of the industrial timber drying process whilst maintaining product quality and acceptable drying duration

Development of a simulation tool to enable optimisation of the energy consumption of the industrial timber-drying process

Reducing the liquid content of green products is an important step in the manufacture of many products. Process conditions in the drying phase have significant influences on the quality of the end product and on energy consumption and required manufacturing time. Effective optimisation of the drying process requires accurate representation of the drying product and its interaction with its environment. The development of a computer simulation tool to analyse the industrial batch timber drying process is outlined. A detailed finite difference product model describing the heat and mass transfers within a plank during drying is described. It is integrated with a customised CFD code characterising the process conditions within the drying chamber. Simulation output from the integrated model is used to generate a macroscopic representation of the product in its drying environment. This representation is included as a component in a modular industrial installation simulation environment. Analysis with this global model can lead to optimisation of energy consumption of the industrial timber drying process whilst maintaining product quality and acceptable drying duration.

Reducing tin droplet ejection from capillary porous structures under hydrogen plasma exposure in Magnum-PSI

Liquid metal based divertors could be a more robust alternative to a solid tungsten design for DEMO. The liquid is confined in a sponge-like tungsten layer, called a capillary porous structure (CPS). It has been found previously that under certain conditions, many tin droplets eject from a CPS when it is brought into contact with a hydrogen plasma. These would present a contamination issue for the plasma core. Stability analysis suggests that droplet ejection can be suppressed by reduction of the pore size. To test this, stainless-steel CPS targets with pore size ranging from 0.5-100um filled with tin were exposed to identical loading conditions. This was done in the linear plasma device Magnum-PSI, capable of reaching divertor relevant plasma conditions. Furthermore, the influence of the CPS manufacturing techniques is considered by comparing the performance of a 3D printed, a mesh felts and a sintered CPS, all made from tungsten. Each target was surrounded by four witness plates, which were analysed post-mortem for Sn content by Rutherford backscattering. During plasma exposure, tin droplets were observed using a fast visible camera and plasma light emission via survey optical emission spectroscopy. The results imply that Sn erosion can be reduced by a factor of 50 when reducing the pore size. Moreover, it highlights the importance of avoiding overfilling of CPS targets with Sn

Reducing tin droplet ejection from capillary porous structures under hydrogen plasma exposure in Magnum-PSI

Liquid metal based divertors could be a more robust alternative to a solid tungsten design for DEMO. The liquid is confined in a sponge-like tungsten layer, called a capillary porous structure (CPS). It has been found previously that under certain conditions, many tin droplets eject from a CPS when it is brought into contact with a hydrogen plasma. These would present a contamination issue for the plasma core. Stability analysis suggests that droplet ejection can be suppressed by reduction of the pore size. To test this, stainless-steel CPS targets with pore size ranging from 0.5–100µm filled with tin were exposed to identical loading conditions. This was done in the linear plasma device Magnum-PSI, capable of reaching divertor relevant plasma conditions. Furthermore, the influence of the CPS manufacturing techniques is considered by comparing the performance of a 3D printed, a mesh felts and a sintered CPS, all made from tungsten. Each target was surrounded by four witness plates, which were analysed post-mortem for Sn content by Rutherford backscattering. During plasma exposure, tin droplets were observed using a fast visible camera and plasma light emission via survey optical emission spectroscopy. The results imply that Sn erosion can be reduced by a factor of 50 when reducing the pore size. Moreover, it highlights the importance of avoiding overfilling of CPS targets with Sn

Reducing tin droplet ejection from capillary porous structures under hydrogen plasma exposure in Magnum-PSI

Liquid metal based divertors could be a more robust alternative to a solid tungsten design for DEMO. The liquid is confined in a sponge-like tungsten layer, called a capillary porous structure (CPS). It has been found previously that under certain conditions, many tin droplets eject from a CPS when it is brought into contact with a hydrogen plasma. These would present a contamination issue for the plasma core. Stability analysis suggests that droplet ejection can be suppressed by reduction of the pore size. To test this, stainless-steel CPS targets with pore size ranging from 0.5-100um filled with tin were exposed to identical loading conditions. This was done in the linear plasma device Magnum-PSI, capable of reaching divertor relevant plasma conditions. Furthermore, the influence of the CPS manufacturing techniques is considered by comparing the performance of a 3D printed, a mesh felts and a sintered CPS, all made from tungsten. Each target was surrounded by four witness plates, which were analysed post-mortem for Sn content by Rutherford backscattering. During plasma exposure, tin droplets were observed using a fast visible camera and plasma light emission via survey optical emission spectroscopy. The results imply that Sn erosion can be reduced by a factor of 50 when reducing the pore size. Moreover, it highlights the importance of avoiding overfilling of CPS targets with Sn

Increased replication stress and R-loop accumulation in EGFRvIII-expressing glioblastoma present new therapeutic opportunities.

Background: The oncogene epidermal growth factor receptor variant III (EGFRvIII) is expressed in approximately one-third of all glioblastomas (GBMs). So far it is not clear if EGFRvIII expression induces replication stress in GBM cells, which might serve as a therapeutical target. Methods: Isogenetic EGFRvIII- and EGFRvIII+ cell lines with endogenous EGFRvIII expression were used. Markers of oncogenic and replication stress such as γH2AX, RPA, 53BP1, ATR, and CHK1 were analyzed using western blot, immunofluorescence, and flow cytometry. The DNA fiber assay was performed to analyze replication, transcription was measured by incorporation of EU, and genomic instability was investigated by micronuclei and CGH-Array analysis. Immunohistochemistry staining was used to detect replication stress markers and R-loops in human GBM samples. Results: EGFRvIII+ cells exhibit an activated replication stress response, increased spontaneous DNA damage, elevated levels of single-stranded DNA, and reduced DNA replication velocity, which are all indicative characteristics of replication stress. Furthermore, we show here that EGFRvIII expression is linked to increased genomic instability. EGFRvIII-expressing cells display elevated RNA synthesis and R-loop formation, which could also be confirmed in EGFRvIII-positive GBM patient samples. Targeting replication stress by irinotecan resulted in increased sensitivity of EGFRvIII+ cells. Conclusion: This study demonstrates that EGFRvIII expression is associated with increased replication stress, R-loop accumulation, and genomic instability. This might contribute to intratumoral heterogeneity but may also be exploited for individualized therapy approaches