Mechanisms of synthetic lethality between BRCA1/2 and 53BP1 deficiencies and DNA polymerase theta targeting.

A synthetic lethal relationship exists between disruption of polymerase theta (Polθ), and loss of either 53BP1 or homologous recombination (HR) proteins, including BRCA1; however, the mechanistic basis of these observations are unclear. Here we reveal two distinct mechanisms of Polθ synthetic lethality, identifying dual influences of 1) whether Polθ is lost or inhibited, and 2) the underlying susceptible genotype. Firstly, we find that the sensitivity of BRCA1/2- and 53BP1-deficient cells to Polθ loss, and 53BP1-deficient cells to Polθ inhibition (ART558) requires RAD52, and appropriate reduction of RAD52 can ameliorate these phenotypes. We show that in the absence of Polθ, RAD52 accumulations suppress ssDNA gap-filling in G2/M and encourage MRE11 nuclease accumulation. In contrast, the survival of BRCA1-deficient cells treated with Polθ inhibitor are not restored by RAD52 suppression, and ssDNA gap-filling is prevented by the chemically inhibited polymerase itself. These data define an additional role for Polθ, reveal the mechanism underlying synthetic lethality between 53BP1, BRCA1/2 and Polθ loss, and indicate genotype-dependent Polθ inhibitor mechanisms.

Hospital Episode Statistics and trends in ophthalmic surgery 1998-2004.

BACKGROUND: Hospital episode statistics (HES) is a UK national database for the National Health Service (NHS), now available online. The purpose of this study was to observe trends in ophthalmic operations performed during the period from 1998 to 2004, using this data. METHODS: From the 'Main Operation' codes within the 'Free data' section of the HES website we analysed data in regard to 28 specific ophthalmic operations. These represented each sub speciality within ophthalmology. RESULTS: The figures show a change in the total number and proportions of operations performed for many of the procedures. For example, there was an increase in numbers of orbital decompressions, but a decrease in numbers of glaucoma filtering operations. Changing trends could be seen in different surgical areas such as the change in operations used for corneal grafting and in retinal surgery. CONCLUSION: The HES database represents an important, potentially useful source of information. There are imitations in interpretation of and validity of such data related to coding inconsistencies. We suggest the benefit of the data comes from observing trends rather than exact numbers. As other studies using this data have suggested, it is important that clinicians are involved in improving the quality of this data.