Oncogene-evoked replication stress (RS) fuels genomic instability in diverse cancer types. Here we report that BRCA1, traditionally regarded a tumour suppressor, plays an unexpected tumour-promoting role in glioblastoma (GBM), safeguarding a protective response to supraphysiological RS levels. Higher BRCA1 positivity is associated with shorter survival of glioma patients and the abrogation of BRCA1 function in GBM enhances RS, DNA damage (DD) accumulation and impairs tumour growth. Mechanistically, we identify a novel role of BRCA1 as a transcriptional co-activator of RRM2 (catalytic subunit of ribonucleotide reductase), whereby BRCA1-mediated RRM2 expression protects GBM cells from endogenous RS, DD and apoptosis. Notably, we show that treatment with a RRM2 inhibitor triapine reproduces the BRCA1-depletion GBM-repressive phenotypes and sensitizes GBM cells to PARP inhibition. We propose that GBM cells are addicted to the RS-protective role of the BRCA1-RRM2 axis, targeting of which may represent a novel paradigm for therapeutic intervention in GBM.
BackgroundExposure to particulate air pollution increases respiratory and cardiovascular morbidity and mortality, especially in elderly, possibly through inflammation and vascular dysfunction.MethodsWe examined potential beneficial effects of indoor air filtration in the homes of elderly, including people taking vasoactive drugs.Forty-eight nonsmoking subjects (51 to 81 years) in 27 homes were included in this randomized, double-blind, crossover intervention study with consecutive two-week periods with or without the inclusion of a high-efficiency particle air filter in re-circulating custom built units in their living room and bedroom. We measured blood pressure, microvascular and lung function and collected blood samples for hematological, inflammation, monocyte surface and lung cell damage markers before and at day 2, 7 and 14 during each exposure scenario.ResultsThe particle filters reduced the median concentration of PM2.5 from approximately 8 to 4 μg/m3 and the particle number concentration from 7669 to 5352 particles/cm3. No statistically significant effects of filtration as category were observed on microvascular and lung function or the biomarkers of systemic inflammation among all subjects, or in the subgroups taking (n = 11) or not taking vasoactive drugs (n = 37). However, the filtration efficacy was variable and microvascular function was within 2 days significantly increased with the actual PM2.5 decrease in the bedroom, especially among 25 subjects not taking any drugs.ConclusionSubstantial exposure contrasts in the bedroom and no confounding by drugs appear required for improved microvascular function by air filtration, whereas no other beneficial effect was found in this elderly population.
Selection of sampling device, sampling location and period are important first steps in the measurement of exposure to bioaerosols in indoor air. The steps following the sampling include treatment of samples and laboratory analysis. In this study, settling bacteria, endotoxin, fungi and serine protease have been measured in Danish homes using Electrostatic Dust Fall Collectors (EDCs). The effects of the presence of occupants, sampling on open surfaces versus in bookcases and treatment of samples have been studied. Concentrations of bacteria and endotoxin were significantly higher when occupants were at home than when they were absent. Across homes, higher concentrations of fungi were found in spring than in winter, as was the total inflammatory potential, while higher concentrations of protease were found in winter than in spring. The placement of the EDCs in bookcases versus on an open surface significantly affected the measured concentrations of bacteria and endotoxin. Direct extraction of EDC cloths caused a higher measured concentration of bacteria, fungi and serine protease than if EDC cloths were extracted post-storage at -20 °C. Extraction of EDC cloths caused an average of 51% and 58% extraction of bacteria and fungi respectively. In conclusion, EDCs should be placed on open surfaces during the sampling, how much occupants are present in their home during sampling and sampling season should be considered, EDC cloths should not be stored in a freezer before extraction of microorganisms, but extraction suspensions can be stored at -80 °C without affecting the number of microorganisms significantly.
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