Complete replication of the genome is an essential prerequisite for normal cell division, but a variety of factors can block the replisome, triggering replication stress and potentially causing mutation or cell death. The cellular response to replication stress involves recruitment of proteins to stabilize the replication fork and transmit a stress signal to pause the cell cycle and allow fork restart. We find that the ubiquitously expressed DNA damage response factor 53BP1 is required for the normal response to replication stress. Using primary, B cells, we showed that a population of 53BP1 cells in early S phase is hypersensitive to short-term exposure to three different agents that induce replication stress. 53BP1 localizes to a subset of replication forks following induced replication stress, and an absence of 53BP1 leads to defective ATR-Chk1-p53 signaling and caspase 3-mediated cell death. Nascent replicated DNA additionally undergoes degradation in 53BP1 cells. These results show that 53BP1 plays an important role in protecting replication forks during the cellular response to replication stress, in addition to the previously characterized role of 53BP1 in DNA double-strand break repair.

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Objective To characterize otologic clinical trials and examine otologic clinical trial trends from 2008 to 2018 using the clinicaltrials.gov database. Methods Data was collected from clinicaltrials.gov and included all clinical trials that focused on otology from 2008 to 2018. Outcome measures include status of trials, funding sources, details regarding otologic conditions studied, and trends in clinical trials. Results There were 992 otology clinical trials from 2008 to 2018.457 (46.1%) were completed and 94 (9.5%) were discontinued. Industry remained the highest (76.5%) contributor to otology clinical trials. The otologic conditions studied, from most common to least common, include hearing loss (40.6%), vestibulopathy (18.8%), tinnitus (18.8%), and otitis media (15.1%). The number of otology clinical trials increased by an average of 12.0 trials per year from 2008 to 2018 (p < 0.001). The number of otology clinical trials focusing on hearing loss and vestibulopathy significantly increased over the studied period (p < 0.001), while those focusing on tinnitus and otitis media did not (p = 0.09 and p = 0.20, respectively). The majority of clinical trials on each of these four conditions focused on treatment options. Conclusion Our study describes trends in otology clinical trials registered on clinicaltrials.gov from 2008 through 2018. The total number of clinical trials over this time period increased significantly, driven by trials investigating hearing loss and vestibulopathy. Furthermore, most clinical trials were industry-sponsored and focused on treatment modalities. Our study provides an outline of otology clinical trials registered in a US web-based database, which may be of use for the development of future clinical trials.