BRPF3 knockdown or inhibition moderately reverses olaparib resistance in high grade serous ovarian carcinoma, but depletion of H3K14 acetylation has no effect

Background: PARP inhibitors (PARPi) kill cancer cells by stalling DNA replication and preventing DNA repair, resulting in a critical accumulation of DNA damage. Resistance to PARPi is a growing clinical problem in the treatment of high grade serous ovarian carcinoma (HGSOC). Acetylation of histone H3 lysine 14 (H3K14ac) and associated histone acetyltransferases (HATs) have known functions in DNA repair and replication, but their expression and activities have not been examined in the context of PARPi-resistant HGSOC. Results: Using mass spectrometry profiling of histone modifications, we observed altered H3K14ac enrichment in PARPi-resistant HGSOC cells relative to isogenic PARPi-sensitive lines. By RT-qPCR and RNA-Seq, we also observed altered expression of numerous HATs in PARPi-resistant HGSOC cells and a PARPi-resistant PDX model. Knockdown of HATs only modestly altered PARPi response, although knockdown and inhibition of PCAF significantly increased resistance. Pharmacologic inhibition of HBO1 severely depleted H3K14ac but did not affect PARPi response. However, knockdown and inhibition of BRPF3, which is known to interact in a complex with HBO1, did reduce PARPi resistance. Conclusions: This study demonstrates that severe depletion of H3K14ac does not affect PARPi response in HGSOC. Our data suggest that bromodomain functions of HAT proteins such as PCAF, or accessory proteins such as BRPF3, may play a greater role in PARPi response than acetyltransferase functions.

Performance and Fracture Analysis of Composite Interfaces for Semi-Flexible Pavement

Semi-flexible pavement is widely used in pavement engineering due to its excellent rutting resistance; however, it mainly fails due to cracking. Therefore, it is important to understand the properties of the aggregate–mortar–asphalt interfacial transition zone, to better understand the cracking mechanism of the semi-flexible pavement. In this work, we used pull-off tests and digital image analysis technology to compare and analyze the interfacial tensile strength and granite–bitumen–mortar interactions in three types of asphalt (70# matrix asphalt, PG76-22 modified asphalt and S-HV modified asphalt) at different curing ages. The analysis results showed that, for the three different bitumen materials, with settled mortar, the peak interfacial tensile strength values all occurred at approximately 14 d of curing. In addition, the order of the tensile strength followed the order of asphalt penetration degree; the order of the interfacial water damage resistance from weak to strong was 70# asphalt cementation specimen, PG76-22 modified asphalt cementation specimen, and S-HV modified asphalt cementation specimen. The results of this analysis highlight the original contributions of the optimum curing time for the composite interface of semi-flexible pavement materials prepared with different asphalts to reach optimum crack resistance.