This experiment is currently in progress. Results will be available at the conclusion of the study.
Aim 1: We anticipate that the induction of lung cancer will have a significant LET component and specifically that as LET increases (probably to a maximum of ~100-200 keV/µm) that the incidence of lung cancer will also increase. It is currently unknown whether a significant difference in lung cancer incidence or aggressiveness will be found in males vs. female cohorts, but the studies are designed with enough statistical power to discern any difference with statistical confidence.
Aim 2A: There are several possibilities for the data outcome in regard to sex: 1. Sex is such a significant factor for carcinogenesis that it changed the whole transcriptome profile and we anticipate seeing the effect in unsupervised analysis. 2. There is a weak difference and more statistical power is need for future study. 3. Having observed a sex-related phenotype such as tumor incidence or aggressiveness, we anticipate discovering the associated gene/miRNA signatures by supervised approaches. Besides investigating sex differences, we also expect to find signatures that associated with radiation-type just like we have shown in mouse HCC model
Aim 2B:We anticipate that the number of candidate miRNA markers will be modest due to the stringent selection process. There is the possibility that we will need to adjust the selection criteria so that it will not be too stringent. Our expectation is to find highly sensitive and biologically active circulating miRNA markers as early indicators of lung carcinogenesis. The marker will also be used to monitor radiation protection of GC4419 in Aim 3. We may have to pool some of the mouse plasma samples for cfDNA extraction because of the minimal 200µl requirement. The sequencing library kit is highly sensitive and we anticipate that we will obtain DNA-seq data with no problems.
Aim 2C: We anticipate high sensitivity for this assay as previous studies have shown a more than 100-fold increase in PS concentration in cancer patients .
Aim 3: We anticipate that GC4419 will both reduce the incidence of lung cancer in animals exposed to ?-rays, 1972 SPE simulated protons, 600 MeV/n 28Si, and 533 MeV/n 40Ca ions at doses of 2, 1, 0.3, and 0.3 Gy respectively. The possibility exists that GC4419 will reduce the background incidence of lung (or other cancers that Balb/c mice are prone to including mammary carcinoma). Further, we anticipate that the anti-carcinogenic effects observed in a 24 clinical setting and in pre-clinical animal models will translate into a reduced aggressiveness in tumors that do arise as evident both in long term survival and cancer progression.
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