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

Radiological evaluation of a new straight electrode array compared to its precursors

Objective!#!The aim of this study is to examine electrode array coverage, scalar position and dislocation rate in straight electrode arrays with special focus on a new electrode array with 26 mm in lengths.!##!Study design!#!Retrospective study.!##!Setting!#!Tertiary academic center.!##!Patients!#!201 ears implanted between 2013 and 2019.!##!Main outcome measures!#!We conducted a comparative analysis of patients implanted with lateral wall electrode arrays of different lengths (F24 = MED-EL Flex!##!Results!#!Study groups show no significant differences regarding cochlear size which excludes influences by cochlear morphology. As expected, the F24 showed significant shorter insertion angles compared to the longer electrode arrays. The F26 electrode array showed no signs of dislocation or SV insertion. The electrode array with the highest rate of ST dislocations was the F31.5 (26.3%). The electrode array with the highest rates of SV insertions was the F28 (5.75%). Most of the included electrode arrays dislocate between 320° and 360° (mean: 346.4°; range from 166° to 502°).!##!Conclusion!#!The shorter F24 and the new straight electrode array F26 show less or no signs of scalar dislocation, neither for round window nor for cochleostomy insertion than the longer F28 and the F31.5 array. As expected, the cochlear coverage is increasing with length of the electrode array itself but with growing risk for scalar dislocation and with the highest rates of dislocation for the longest electrode array F31.5. Position of intracochlear dislocation is in the apical cochlear part in the included lateral wall electrode arrays

Safety and effectiveness of the Bonebridge transcutaneous active direct-drive bone-conduction hearing implant at 1-year device use

International audienceThe objective of this study is to evaluate the safety and efficacy of a new transcutaneous bone-conduction implant (BCI BB) in patients with conductive and mixed hearing loss or with single-sided deafness (SSD), 1 year after surgical implantation. The study design is multicentric prospective, intra-subject measurements. Each subject is his/her own control. The setting is nine university hospitals: 7 French and 2 Belgian. Sixteen subjects with conductive or mixed hearing loss with bone-conduction hearing thresholds under the upper limit of 45 dB HL for each frequency from 500 to 4000 Hz, and 12 subjects with SSD (contralateral hearing within normal range) were enrolled in the study. All subjects were older than 18 years. The intervention is rehabilitative. The main outcome measure is the evaluation of skin safety, audiological measurements, benefit, and satisfaction questionnaires with a 1-year follow up. Skin safety was rated as good or very good. For the mixed or conductive hearing loss groups, the average functional gain (at 500 Hz, 1, 2, 4 kHz) was 26.1 dB HL (SD 13.7), and mean percentage of speech recognition in quiet at 65 dB was 95 % (vs 74 % unaided). In 5/6 SSD subjects, values of SRT in noise were lower with BB. Questionnaires revealed patient benefit and satisfaction. The transcutaneous BCI is very well tolerated at 1-year follow up, improves audiometric thresholds and intelligibility for speech in quiet and noise, and gives satisfaction to both patients with mixed and conductive hearing loss and patients with SSD