Checkpoint kinase 1 protein expression indicates sensitization to therapy by checkpoint kinase 1 inhibition in non–small cell lung cancer

Background

When presenting with advanced stage disease, lung cancer patients have <5% 5-y survival. The overexpression of checkpoint kinase 1 (CHK1) is associated with poorer outcomes and may contribute to therapy resistance. Targeting CHK1 with small-molecule inhibitors in p53 mutant tumors might improve the effectiveness of chemotherapy and radiotherapy in non–small cell lung cancer (NSCLC).

Methods

We evaluated CHK1 messenger RNA and protein levels in multiple NSCLC cell lines. We assessed cell line sensitization to gemcitabine, pemetrexed, and radiotherapy by CHK1 inhibition with the small molecule AZD7762 using proliferation and clonogenic cell survival assays. We analyzed CHK1 signaling by Western blotting to confirm that AZD7762 inhibits CHK1.

Results

We selected two p53 mutant NSCLC cell lines with either high (H1299) or low (H1993) CHK1 levels for further analysis. We found that AZD7762 sensitized both cell lines to gemcitabine, pemetrexed, and radiotherapy. Chemosensitization levels were greater, however, for the higher CHK1 protein expressing cell line, H1299, when compared with H1993. Furthermore, analysis of the CHK1 signaling pathway showed that H1299 cells have an increased dependence on the CHK1 pathway in response to chemotherapy. There was no increased sensitization to radiation in H1299 versus H1993.

Conclusions

CHK1 inhibition by AZD7762 preferentially sensitizes high CHK1 expressing cells, H1299, to anti-metabolite chemotherapy as compared with low CHK1 expressing H1993 cells. Thus, CHK1 inhibitors may improve the efficacy of standard lung cancer therapies, especially for those subgroups of tumors harboring higher expression levels of CHK1 protein.     

Systematic review of the prevalence and characteristics of battle casualties from NATO coalition forces in Iraq and Afghanistan

Background

The North Atlantic Treaty Organization (NATO) coalition forces remain heavily committed on combat operations overseas. Understanding the prevalence and characteristics of battlefield injury of coalition partners is vital to combat casualty care performance improvement. The aim of this systematic review was to evaluate the prevalence and characteristics of battle casualties from NATO coalition partners in Iraq and Afghanistan. The primary outcome was mechanism of injury and the secondary outcome anatomical distribution of wounds.

Methods

This systematic review was performed based on all cohort studies concerning prevalence and characteristics of battlefield injury of coalition forces from Iraq and Afghanistan up to December 20th 2013. Studies were rated on the level of evidence provided according to criteria by the Centre for Evidence Based Medicine in Oxford. The methodological quality of observational comparative studies was assessed by the modified Newcastle-Ottawa Scale.

Results

Eight published articles, encompassing a total of n = 19,750 battle casualties, were systematically analyzed to achieve a summated outcome. There was heterogeneity among the included studies and there were major differences in inclusion and exclusion criteria regarding the target population among the included trials, introducing bias. The overall distribution in mechanism of injury was 18% gunshot wounds, 72% explosions and other 10%. The overall anatomical distribution of wounds was head and neck 31%, truncal 27%, extremity 39% and other 3%.

Conclusions

The mechanism of injury and anatomical distribution of wounds observed in the published articles by NATO coalition partners regarding Iraq and Afghanistan differ from previous campaigns. There was a significant increase in the use of explosive mechanisms and a significant increase in the head and neck region compared with previous wars.