2 research outputs found
The PARP inhibitor olaparib enhances the sensitivity of Ewing sarcoma to trabectedin
ProducciĂłn CientĂficaRecent preclinical evidence has suggested that Ewing Sarcoma (ES) bearing
EWSR1-ETS fusions could be particularly sensitive to PARP inhibitors (PARPinh) in
combination with DNA damage repair (DDR) agents. Trabectedin is an antitumoral
agent that modulates EWSR1-FLI1 transcriptional functions, causing DNA damage.
Interestingly, PARP1 is also a transcriptional regulator of EWSR1-FLI1, and PARPinh
disrupts the DDR machinery. Thus, given the impact and apparent specificity of both
agents with regard to the DNA damage/DDR system and EWSR1-FLI1 activity in
ES, we decided to explore the activity of combining PARPinh and Trabectedin in in
vitro and in vivo experiments. The combination of Olaparib and Trabectedin was
found to be highly synergistic, inhibiting cell proliferation, inducing apoptosis, and
the accumulation of G2/M. The drug combination also enhanced ÎłH2AX intranuclear
accumulation as a result of DNA damage induction, DNA fragmentation and global DDR
deregulation, while EWSR1-FLI1 target expression remained unaffected. The effect of
the drug combination was corroborated in a mouse xenograft model of ES and, more
importantly, in two ES patient-derived xenograft (PDX) models in which the tumors
showed complete regression. In conclusion, the combination of the two agents leads
to a biologically significant deregulation of the DDR machinery that elicits relevant
antitumor activity in preclinical models and might represent a promising therapeutic
tool that should be further explored for translation to the clinical setting.Ministerio de EconomĂa y Competitividad (PI081828)Ministerio de EconomĂa y Competitividad (RD06/0020/0059 )Ministerio de EconomĂa y Competitividad (RD12/0036/0017)Ministerio de EconomĂa y Competitividad (PT13/0010/0056
The Fitness Cost of Antibiotic Resistance in Streptococcus pneumoniae: Insight from the Field
Laboratory studies have suggested that antibiotic resistance may result in decreased fitness in the bacteria that harbor it. Observational studies have supported this, but due to ethical and practical considerations, it is rare to have experimental control over antibiotic prescription rates.We analyze data from a 54-month longitudinal trial that monitored pneumococcal drug resistance during and after biannual mass distribution of azithromycin for the elimination of the blinding eye disease, trachoma. Prescription of azithromycin and antibiotics that can create cross-resistance to it is rare in this part of the world. As a result, we were able to follow trends in resistance with minimal influence from unmeasured antibiotic use. Using these data, we fit a probabilistic disease transmission model that included two resistant strains, corresponding to the two dominant modes of resistance to macrolide antibiotics. We estimated the relative fitness of these two strains to be 0.86 (95% CI 0.80 to 0.90), and 0.88 (95% CI 0.82 to 0.93), relative to antibiotic-sensitive strains. We then used these estimates to predict that, within 5 years of the last antibiotic treatment, there would be a 95% chance of elimination of macrolide resistance by intra-species competition alone.Although it is quite possible that the fitness cost of macrolide resistance is sufficient to ensure its eventual elimination in the absence of antibiotic selection, this process takes time, and prevention is likely the best policy in the fight against resistance