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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.

Objective: To report complications in dogs with naturally occurring cranial cruciate ligament rupture following single-stage bilateral tibial tuberosity advancement (SS-BTTA) procedures, and to compare these complications to a population of dogs undergoing unilateral tibial tuberosity advancement (UTTA)., Methods: Medical records and radiographs of client-owned dogs treated with tibial tuberosity advancement between August 2008 and December 2011 were reviewed. Forty-four client-owned dogs with bilateral cranial cruciate ligament rupture that underwent SS-BTTA procedures and 82 client-owned dogs that underwent UTTA procedures were randomly selected from our hospital population. Complications were recorded and analysed. Major complications were defined as fractures or any complication requiring a second surgery. Minor complications were any problem identified that did not require surgical management., Results: Incidence for major and minor complications in the UTTA group was 2.3% and 24.4%, respectively. Incidence for major and minor complications in the SS-BTTA group was 12.5% and 26.1%, respectively. Single-stage bilateral tibial tuberosity advancement procedures had a four- to five-fold increase in odds of a major complication (p <0.050) compared to UTTA., Clinical Significance: The findings of our study indicate that SS-BTTA procedures are associated with an increased risk of major complications compared to UTTA procedures.

Multiple, independent sites or domains behave, on chemical change, in a manner predicted by Langmuir. Distortions of this behavior have been attributed to interactions between the domains, which vary with the progress of the changes occurring at the sites or domains. The two main models for nearest neighbor interactions perturbing the Langmuir prediction for independent domains are those of Ising and Pauling. If we designate the initial site as (-) and the changed site as (+), then the Langmuir requirement for independence of sites yields a set of nearest neighbor interactions such that the (- -), (- +), (+ -), and (+ +) interactions are all identical. This identity is usually characterized as "no interactions." Ising, in dealing with electron pairs, invoked nearest neighbor interactions such that the interactions of the (- -) paris equaled those of the (+ +) pairs, but with the (- +) and (+ -) pairs differing from the reference (- -) pair. Pauling, on the other hand, postulated that only the (- -) and (+ -) pairs interacted differently. A dichotomy has arisen in the application of these two models, with some investigators ignoring or overlooking one of the models. We explore these models, alone and combined, with exact partition functions generated in reasonable computer times for hundreds of sites employing our combinatorial algorithm.

The most commonly used measure of resolution for chromatographic and electrophoretic separations does not take into account the possibility of there being different amounts of each of the molecular species. A modification of a measure of resolution recently suggested by Aldroubi and Garner (BioTechniques 1992, 13, 620-624) can incorporate this effect explicitly. Their criterion for resolution is based on the time to observe a valley of specified magnitude separating two peaks. We examine how this measure depends on different physically relevant parameters that characterize the system.

Analysis of the cooperative binding of ligands may provide insight into the underlying mechanisms of biological control. Binding of L-tryptophan at each juncture in the ring of 11 subunits of the trp RNA-binding attenuation protein exhibits cooperativity. To analyze binding of this kind we have developed both the matrix and combinatorial procedures for binding to large numbers of sites. A new, exact, and fast combinatorial procedure is presented. In this procedure the sites may be single or overlapping in a linear lattice or in the form of a ring. The dimensions of the ring of 11 binding sites for L-tryptophan on the trp RNA-binding attenuation protein are such as to prevent direct interactions between the L-tryptophan molecules. Reasonable and explicit assumptions on analyzing the binding data lead to the conclusion that binding of L-tryptophan raises the energy level of (destabilizes) the 11 membered structure.

A recent analysis of the optimization of magnetization transfer experiments to estimate first-order rate constants is extended to the design of experiments for measuring these constants and T1 when both parameters are initially unknown. When the number of measurement times is fixed, an optimal design will consist of a set of measurement times which ensures that the precision of the estimates of the combination of k and T1 is as small as possible in a worst-case scenario. Simple expressions are given for the parameters that characterize the optimal design.

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.