EGFRvIII upregulates DNA mismatch repair resulting in increased temozolomide sensitivity of MGMT promoter methylated glioblastoma

The oncogene epidermal growth factor receptor variant III (EGFRvIII) is frequently expressed in glioblastomas (GBM) but its impact on therapy response is still under controversial debate. Here we wanted to test if EGFRvIII influences the sensitivity towards the alkylating agent temozolomide (TMZ). Therefore, we retrospectively analyzed the survival of 336 GBM patients, demonstrating that under standard treatment, which includes TMZ, EGFRvIII expression is associated with prolonged survival, but only in patients with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated tumors. Using isogenic GBM cell lines with endogenous EGFRvIII expression we could demonstrate that EGFRvIII increases TMZ sensitivity and results in enhanced numbers of DNA double-strand breaks and a pronounced S/G2-phase arrest after TMZ treatment. We observed a higher expression of DNA mismatch repair (MMR) proteins in EGFRvIII+ cells and patient tumor samples, which was most pronounced for MSH2 and MSH6. EGFRvIII-specific knockdown reduced MMR protein expression thereby increasing TMZ resistance. Subsequent functional kinome profiling revealed an increased activation of p38- and ERK1/2-dependent signaling in EGFRvIII expressing cells, which regulates MMR protein expression downstream of EGFRvIII. In summary, our results demonstrate that the oncoprotein EGFRvIII sensitizes a fraction of GBM to current standard of care treatment through the upregulation of DNA MMR

An In-depth Appraisal of Career Termination Experiences in Professional Cricket

This qualitative study explored the career termination experiences of 9 male, retired professional cricketers, between the ages of 28 to 40 (M = 34, SD = 4.65). The participants took part in retrospective, semi-structured interviews. Data from the interviews were inductively content analysed within three transition phases of the retirement process: reasons for retirement, factors affecting adaptation, and reactions to retirement. The reasons for retirement were multicausal with the majority of the participants highlighting contractual pressures and a lack of communication as important precursors to retirement. Three main themes accounted for the factors affecting adaptation: a limited pursuit of other interests, developmental experiences and coping strategies. In terms of reactions to retirement, all of the participants reflected negatively on the termination of their career, with a sense of loss and resentment characterising the post-retirement period. The findings illustrated the sport-specific nature of career termination in professional cricket, and added further support to the emerging consensus that the distinction between voluntary and involuntary retirement is, at best, unclear

Development of a high-resolution, 2D detector system for iodine-131-scintigraphy

During a I-131 therapy of benign and malignant thyroid diseases, precise information about tracer distribution is helpful for patient management. However, the use of established Anger technique for I-131 scintigraphy is difficult because of septal penetration inside the collimator. The aim of this study is to develop a two-dimensional I-131 detector with high spatial resolution and patient-friendly acquisition time.The main components of our system are a position sensitive photomultiplier, EGO scintillation crystals inserted into a lead matrix, a parallel hole collimator and a translation unit to realize well defined displacements. Thus, the septa thickness can be chosen to reduce the septa penetration significantly. Thick septa cause "dead areas" on the photomultiplier. These gaps are filled sequentially by well defined displacements in the projection plane. The individual scintigramms at the different measured positions are composed to a final image.Using the described detector geometry, all details and structures of the measured phantom were visible in a measurement time of 16 minutes. Therefore the developed system is especially suited for I-131 thyroid scintigraphy

Interferometric broadband Fourier spectroscopy with a partially coherent gas-discharge extreme ultraviolet light source

Extreme ultraviolet (EUV) spectroscopy is a powerful tool for studying fundamental processes in plasmas as well as for spectral characterization of EUV light sources and EUV optics. However, a simultaneous measurement covering a broadband spectral range is difficult to realize. Here, we propose a method for interferometric broadband Fourier spectroscopy connecting soft x ray and visible spectral ranges with moderate spectral resolution. We present an analytical model to recover the spectrum from a double-slit interferogram. We apply our model for spectral characterization of a partially coherent gas-discharge EUV light source operated with different gases in the spectral range between 10 and 110 nm wavelengths. Our approach allows a simple and fast broadband spectroscopy with fully or partially spatially coherent light sources, for instance, to characterize out-of-band radiation in EUV lithography applications