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Abstract Background Pancreatic cancer retains a poor prognosis among the gastrointestinal cancers. It affects 230,000 individuals worldwide, has a very high mortality rate, and remains one of the most challenging malignancies to treat successfully. Treatment with gemcitabine, the most widely used chemotherapeutic against pancreatic cancer, is not curative and resistance may occur. Combinations of gemcitabine with other chemotherapeutic drugs or biological agents have resulted in limited improvement. Methods In order to improve gemcitabine response in pancreatic cancer cells, we utilized a synthetic lethal RNAi screen targeting 572 known kinases to identify genes that when silenced would sensitize pancreatic cancer cells to gemcitabine. Results Results from the RNAi screens identified several genes that, when silenced, potentiated the growth inhibitory effects of gemcitabine in pancreatic cancer cells. The greatest potentiation was shown by siRNA targeting checkpoint kinase 1 (CHK1). Validation of the screening results was performed in MIA PaCa-2 and BxPC3 pancreatic cancer cells by examining the dose response of gemcitabine treatment in the presence of either CHK1 or CHK2 siRNA. These results showed a three to ten-fold decrease in the EC50 for CHK1 siRNA-treated cells versus control siRNA-treated cells while treatment with CHK2 siRNA resulted in no change compared to controls. CHK1 was further targeted with specific small molecule inhibitors SB 218078 and PD 407824 in combination with gemcitabine. Results showed that treatment of MIA PaCa-2 cells with either of the CHK1 inhibitors SB 218078 or PD 407824 led to sensitization of the pancreatic cancer cells to gemcitabine. Conclusion These findings demonstrate the effectiveness of synthetic lethal RNAi screening as a tool for identifying sensitizing targets to chemotherapeutic agents. These results also indicate that CHK1 could serve as a putative therapeutic target for sensitizing pancreatic cancer cells to gemcitabine.

We introduce an efficient numerical method for studying the detectability of absorptive inclusions in a multiple-scattering optical medium. Use of the method is demonstrated by the forward calculation of integrated and time-gated photon intensities. Schemes for positioning the light source above an inclusion and otherwise determining the location of a hidden object, involving either reflected or transmitted reemissions, are discussed as examples. They are investigated for several illustrative models, and images are calculated as a function of the size and shape of the inclusion.

The gas phase of cigarette smoke, separated into its components by gas chromatography, was passed across a ciliated specimen. The acetaldehyde, acrolein, and hydrogen cyanide produced strong inhibition of the ciliary beat. A filter which removed most of the acetaldehyde and acrolein from smoke did not reduce the inhibitory effect of the gas phase of that smoke, whereas a filter that removed most of the hydrogen cyanide did reduce inhibition.