PRMT5 Inhibitors Regulate DNA Damage Repair Pathways in Cancer Cells and Improve Response to PARP Inhibition and Chemotherapies.

Expression of protein arginine methyltransferase 5 (PRMT5) is highly positively correlated to DNA damage repair (DDR) and DNA replication pathway genes in many types of cancer cells, including ovarian and breast cancer. In the current study, we investigated whether pharmacologic inhibition of PRMT5 downregulates DDR/DNA replication pathway genes and sensitizes cancer cells to chemotherapy and PARP inhibition. Potent and selective PRMT5 inhibitors significantly downregulate expression of multiple DDR and DNA replication genes in cancer cells. Mechanistically, PRMT5 inhibition reduces the presence of PRMT5 and H4R3me2s on promoter regions of DDR genes such as BRCA1/2, RAD51, and ATM. PRMT5 inhibition also promotes global alternative splicing changes. Our data suggest that PRMT5 inhibition regulates expression of FANCA, PNKP, and ATM by promoting exon skipping and intron retention. Combining C220 or PRT543 with olaparib or chemotherapeutic agents such as cisplatin demonstrates a potent synergistic interaction in breast and ovarian cancer cells in vitro. Moreover, combination of PRT543 with olaparib effectively inhibits the growth of patient-derived breast and ovarian cancer xenografts. Furthermore, PRT543 treatment significantly inhibits growth of olaparib-resistant tumors in vivo. These studies reveal a novel mechanism of PRMT5 inhibition and suggest beneficial combinatorial effects with other therapies, particularly in patients with tumors that are resistant to therapies dependent on DNA damage as their mechanism of action. SIGNIFICANCE: Patients with advanced cancers frequently develop resistance to chemotherapy or PARP inhibitors mainly due to circumvention and/or restoration of the inactivated DDR pathway genes. We demonstrate that inhibition of PRMT5 significantly downregulates a broad range of the DDR and DNA replication pathway genes. PRMT5 inhibitors combined with chemotherapy or PARP inhibitors demonstrate synergistic suppression of cancer cell proliferation and growth in breast and ovarian tumor models, including PARP inhibitor-resistant tumors.

Effect of focused birth preparedness and complication readiness counseling on pregnancy outcome among females attending tertiary care hospital in Barabanki district, Uttar Pradesh, India.

CONTEXT: Measures related to birth preparedness and complication readiness (BPCR) during pregnancy play an important role in producing better pregnancy outcome. If the pregnant females are properly counseled during antenatal visits, it could help in bringing out desirable behavior changes. AIMS: This study aims to study BPCR-related awareness and practices among the pregnant females and the effect of focused and structured birth preparedness counseling on complication readiness among pregnant females. SUBJECT AND METHODS: A facility-based follow-up study was conducted from July to December 2016, and a total of 130 pregnant females were enrolled. All study participants were initially assessed for various domains of BPCR index consisting of seven key indicators. The index reassessment was done again, after 1 month, during follow-up visit. Information regarding any pregnancy-related complication in due course and behavior was also recorded during successive follow-up. STATISTICAL ANALYSIS USED: The difference in pre- and postcounseling mean BPCR index was assessed using paired t-test, and McNemar's test was used for paired categorical data analysis. P < 0.05 was considered to be statistically significant. RESULTS: The postcounseling BPCR index (70.65 ± 19.18) was found to be significantly much higher as compared to pre-counseling baseline BPCR index (41.12 ± 11.34). Knowledge about danger signs of pregnancy, transportation services provided by government, financial assistance provided in Government schemes, identification of skilled birth attendant, mode of transportation, and arrangement of emergency blood donor was found to increase significantly after counseling. Abortion was found to occur significantly higher (about thrice) among those who had postcounseling BPCR index below average, i.e., <50% (P < 0.05). CONCLUSIONS: The results of the present study revealed that focused birth preparedness counseling on complication readiness could play an important role in increasing the baseline knowledge of pregnant females regarding pregnancy-related complications and bring out desirable ideal health-seeking behavior changes during pregnancy.

An array of target-specific screening strains for antibacterial discovery.

As the global threat of drug- and antibiotic-resistant bacteria continues to rise, new strategies are required to advance the drug discovery process. This work describes the construction of an array of Escherichia coli strains for use in whole-cell screens to identify new antimicrobial compounds. We used the recombination systems from bacteriophages lambda and P1 to engineer each strain in the array for low-level expression of a single, essential gene product, thus making each strain hypersusceptible to specific inhibitors of that gene target. Screening of nine strains from the array in parallel against a large chemical library permitted identification of new inhibitors of bacterial growth. As an example of the target specificity of the approach, compounds identified in the whole-cell screen for MurA inhibitors were also found to block the biochemical function of the target when tested in vitro.