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

Ptychographic imaging with a tin plasma based EUV light source

We present results of lens-less imaging experiments performed using a laser assisted discharge plasma source. The experiments have been performed using tin emission spectrum of extreme ultraviolet (EUV) radiation near 13.5 nm wavelength. Through a scanning diffraction imaging technique, namely ptychography, the reconstruction of a test object has been demonstrated with the resolution down to 100 nm

Coherent Diffractive Imaging with a Laboratory-Scale, Gas-Discharge Plasma Extreme Ultraviolet Light Source

Coherent diffractive imaging (CDI) and related techniques enable a new type of diffraction-limited high resolution microscopy and have been widely used in the extreme ultraviolet (EUV) and X-ray communities. In this experiment, we demonstrate CDI using a compact gas-discharge EUV light source with a wavelength of 17.3 nm (oxygen VI emission). Our image reconstruction method accounts for the partial spatial coherence of the radiation using a deconvolution technique. Our results are promising for future laboratory-scale CDI applications, including mask inspection for EUV lithography and EUV metrolog