Synthetic Lethality of Chk1 Inhibition Combined with p53 and/or p21 Loss During a DNA Damage Response in Normal and Tumor Cells

Cell cycle checkpoints ensure genome integrity and are frequently compromised in human cancers. A therapeutic strategy being explored takes advantage of checkpoint defects in p53-deficient tumors in order to sensitize them to DNA-damaging agents by eliminating Chk1-mediated checkpoint responses. Using mouse models, we demonstrated that p21 is a key determinant of how cells respond to the combination of DNA damage and Chk1 inhibition (combination therapy) in normal cells as well as in tumors. Loss of p21 sensitized normal cells to the combination therapy much more than did p53 loss and the enhanced lethality was partially blocked by CDK inhibition. In addition, basal pools of p21 (p53 independent) provided p53 null cells with protection from the combination therapy. Our results uncover a novel p53-independent function for p21 in protecting cells from the lethal effects of DNA damage followed by Chk1 inhibition. As p21 levels are low in a significant fraction of colorectal tumors, they are predicted to be particularly sensitive to the combination therapy. Results reported in this study support this prediction

Benefits to speech perception in noise from the binaural integration of electric and acoustic signals in simulated unilateral deafness

Objectives: This study used vocoder simulations with normal-hearing (NH) listeners to (a) measure their ability to integrate speech information from a NH ear and a simulated cochlear implant (CI); and (b) investigate whether binaural integration is disrupted by a mismatch in the delivery of spectral information between the ears arising from a misalignment in the mapping of frequency to place. Design: Eight NH volunteers participated in the study and listened to sentences embedded in background noise via headphones. Stimuli presented to the left ear were unprocessed. Stimuli presented to the right ear (referred to as the CI-simulation ear) were processed using an 8-channel noise vocoder with one of three processing strategies. An Ideal strategy simulated a frequency-to-place map across all channels that matched the delivery of spectral information between the ears. A Realistic strategy created a misalignment in the mapping of frequency to place in the CI-simulation ear where the size of the mismatch between the ears varied across channels. Finally, a Shifted strategy imposed a similar degree of misalignment in all channels resulting in consistent mismatch between the ears across frequency. The ability to report key words in sentences was assessed under monaural and binaural listening conditions and at signal-to-noise ratios (SNRs) established by estimating speech-reception thresholds in each ear alone. The SNRs ensured that the monaural performance of the left ear never exceeded that of the CI-simulation ear. Binaural integration advantages were calculated by comparing binaural performance with monaural performance using the CI-simulation ear alone. Thus, these advantages reflected the additional use of the experimentally-constrained left ear and were not attributable to better-ear listening. Results: Binaural performance was as accurate as, or more accurate than, monaural performance with the CI-simulation ear alone. When both ears supported a similar level of monaural performance (50%), binaural integration advantages were found regardless of whether a mismatch was simulated or not. When the CI-simulation ear supported a superior level of monaural performance (71%), evidence of binaural integration was absent when a mismatch was simulated using both the Realistic and Ideal processing strategies. This absence of integration could not be accounted for by ceiling effects or by changes in SNR. Conclusions: If generalizable to unilaterally-deaf CI users, the results of the current simulation study would suggest that benefits to speech perception in noise can be obtained by integrating information from an implanted ear and a normal-hearing ear. A mismatch in the delivery of spectral information between the ears due to a misalignment in the mapping of frequency to place may disrupt binaural integration in situations where both ears cannot support a similar level of monaural speech understanding. Previous studies which have measured the speech perception of unilaterally-deaf individuals after cochlear implantation but with non-individualized frequency-to-electrode allocations may therefore have underestimated the potential benefits of providing binaural hearing. However, it remains unclear whether the size and nature of the potential incremental benefits from individualized allocations are sufficient to justify the time and resources required to derive them based on cochlear imaging or pitch-matching tasks

Evaluation of the Relationship between the NRT-Ratio, Cochlear Anatomy, and Insertions Depth of Perimodiolar Cochlear Implant Electrodes

The position of the cochlear implant electrode array within the scala tympani is essential for an optimal postoperative hearing benefit. If the electrode array changes in between the scalae intracochlearly (i.e., from scala tympani to scala vestibuli), a reduced auditory performance can be assumed. We established a neural response telemetry-ratio (NRT-ratio) which corresponds with the scalar position of the electrodes but shows within its limits a variability. The aim of this study was to determine if insertion depth angle or cochlea size influences the NRT-ratio. The intraoperative electrophysiological NRT data of 26 patients were evaluated. Using a flat panel tomography system, the position of the electrode array was evaluated radiologically. The insertion depth angle of the electrode, the cochlea size, and the NRT-ratio were calculated postoperatively. The radiological results were compared with the intraoperatively obtained electrophysiological data (NRT-ratio) and statistically evaluated. In all patients the NRT-ratio, the insertion depth angle, and the cochlea size could be determined. A significant correlation between insertional depth, cochlear size, and the NRT-ratio was not found. The NRT-ratio is a reliable electrophysiological tool to determine the scalar position of a perimodiolar electrode array. The NRT-ratio can be applied independent from insertion depth and cochlear size.</jats:p

Face and content validity analysis of the Speech, Spatial and Qualities of Hearing Scale for Parents (SSQ-P) when used in a clinical service without interviews or week-long observation periods

Objectives: To assess the face and content validity of the Speech, Spatial and Qualities of Hearing Scale for Parents (SSQ-P) when used in a clinical setting without the recommended interviews and observation periods. Methods: SSQ-P responses completed by 145 parents of children with bilateral cochlear implants (aged between 5 and 16 years old) were analysed. To assess face validity, the proportion of missing/ambiguous and alternative responses was recorded for each of the 23 items. Where additional written comments were included in responses, a thematic-based analysis was used to identify reasons for the missing/ambiguous or alternative responses. Content validity was assessed using item response theory (IRT), with items having information score less than 0.5 and discrimination score less than 2.0 identified as poorly performing items. Results: All items of the SSQ-P exhibited some proportion of missing/ambiguous or alternative responses, with six items having >10% missing/ambiguous or alternative responses. IRT identified thirteen items that performed poorly in terms of information and discrimination. These included four of the six items with the most missing/ambiguous or alternative responses. Conclusions: SSQ-P items that performed worse tended to describe scenarios that parents perceived as too specific, too vague or hazardous. Without the recommended administration via interviews following three week-long observation periods, parents found these items difficult to complete. The SSQ-P is therefore not recommended for use without the recommended administration method. However, several items performed well in terms of face and content validity, despite independent parent completion without formal observation periods. Thematic analysis suggested that minor re-wording might improve the face validity of items with high content validity but a high proportion of missing/ambiguous or alternative responses. Therefore, the results of the analyses form the basis on which a shortened version of the SSQ-P, more suitable for use in a clinical setting, could be developed in future studies