Identification of inhibitors synergizing gemcitabine sensitivity in the squamous subtype of pancreatic ductal adenocarcinoma (PDAC).

Pancreatic adenocarcinoma (PDAC) is a highly aggressive cancer with a high chance of recurrence, limited treatment options, and poor prognosis. A recent study has classified pancreatic cancers into four molecular subtypes: (1) squamous, (2) immunogenic, (3) pancreatic progenitor and (4) aberrantly differentiated endocrine exocrine. Among all the subtypes, the squamous subtype has the worst prognosis. This study aims to utilize large scale genomic datasets and computational systems biology to identify potential drugs targeting the squamous subtype of PDAC through combination therapy. Using the transcriptomic data available from the International Cancer Genome Consortium, Cancer Cell Line Encyclopedia and Connectivity Map, we identified 26 small molecules that could target the squamous subtype of PDAC. Among them include inhibitors targeting the SRC proto-oncogene (SRC) and the mitogen-activated protein kinase kinase 1/2 (MEK1/2). Further analyses demonstrated that the SRC inhibitors (dasatinib and PP2) and MEK1/2 inhibitor (pimasertib) synergized gemcitabine sensitivity specifically in the squamous subtype of PDAC cells (SW1990 and BxPC3), but not in the PDAC progenitor cells (AsPC1). Further analysis revealed that the synergistic effects are dependent on SRC or MEK1/2 activities, as overexpression of SRC or MEK1/2 completely abrogated the synergistic effects SRC inhibitors (dasatinib and PP2) and MEK1/2 inhibitor (pimasertib). In contrast, no significant toxicity was observed in the MRC5 human lung fibroblast and ARPE-19 human retinal pigment epithelial cells. Together, our findings suggest that combinations of SRC or MEK inhibitors with gemcitabine possess synergistic effects on the squamous subtype of PDAC cells and warrant further investigation.

Preliminary Evaluation of a Smartphone App for Refractive Error Measurement.

Purpose: The purpose of this study was to evaluate the potential feasibility of using a smartphone app in myopia screening. Methods: The app estimates myopic refractive error by measuring the far point distance for reading three 20/20 Tumbling E letters. In total, 113 myopic subjects with astigmatism no greater than -1.75 diopters (D) were enrolled from 5 sites. The mean age was 22 ± 8.5 years. The app measurement was compared with noncycloplegic subjective refraction measurement or autorefractor if subjective refraction was not available. In addition, 22 subjects were tested with the app for repeatability. Results: For 201 eyes included, the range of spherical equivalent refraction error was 0 to -10.2 D. The app measurement and clinical measurement was highly correlated (Pearson R = 0.91, P < 0.001). There was a small bias (0.17 D) in the app measurement overall, and it was significantly different across the 5 sites due to different age of subjects enrolled at those sites (P = 0.001) - young adults in their 20s were underestimated the most by 0.49 D, whereas children were overestimated by 0.29 D. The mean absolute deviation of the app measurement was 0.65 D. The repeatability of multiple testing in terms of 95% limit of agreement was ±0.61 D. Conclusions: Overall, the app measurement is consistent with clinical measurement performed by vision care professionals. The repeatability is comparable with that of some autorefractors. Age-associated human factors may influence the app measurement. Translational Relevance: The app could be potentially used as a mass screening tool for myopia.