Epigenetic Inactivation of TRAIL Decoy Receptors at 8p12-21.3 Commonly Deleted Region Confers Sensitivity to Apo2L/TRAIL-Cisplatin Combination Therapy in Cervical Cancer

Multiple chromosomal regions are affected by deletions in cervical cancer (CC) genomes, but their consequence and target gene involvement remains unknown. Our single nucleotide polymorphism (SNP) array identified 8p copy number losses localized to an 8.4 Mb minimal deleted region (MDR) in 36% of CC. The 8p MDR was associated with tumor size, treat- ment outcome, and with multiple HPV infections. Genetic, epigenetic, and expression analyses of candidate genes at MDR identified promoter hypermethylation and/or inactivation of decoy receptors TNFRSF10C and TNFRSF10D in the majority of CC patients. TNFRSF10C methylation was also detected in precancerous lesions suggesting that this change is an early event in cervical tumorigenesis. We further demonstrate here that CC cell lines exhibiting downregulated expression of TNFRSF10C and/or TNFRSF10D effectively respond to TRAIL-induced apoptosis and this affect was synergistic in combi- nation with DNA damaging chemotherapeutic drugs. We show that the CC cell lines harboring epigenetic inactivation of TRAIL decoy receptors effectively activate downstream caspases suggesting a critical role of inactivation of these genes in efficient execution of extrinsic apoptotic pathway and therapy response. Therefore, these findings shed new light on the role of genetic/epigenetic defects in TRAIL decoy receptor genes in the pathogenesis of CC and provide an opportunity to explore strategies to test decoy receptor gene inactivation as a biomarker of response to Apo2L/TRAIL-combination therapy

The Proportional Navigation Dilemma-Pure or True?

Two generic classes of proportional navigation (PN) laws are compared in detail. One class consists of pursuer-velocity-referenced systems, which include pure proportional navigation (PPN) and its variants; the second category consists of line-of-sight- (LOS-) referenced systems such as true proportional navigation (TPN), generalized true proportional navigation (GTPN), and generalized guidance laws. The existing closed-form solutions are discussed in detail, and the classical linear and quasilinear analytical solutions are summarized. A critical comparison is then made with regard to the definition, implementation, and analytical aspects of the guidance laws, including the method, the nature of solution, and an appraisal of the behavior of the pursuer motion resulting from the laws. It is established that, in spite of some restricted advantages in the solvability of the equations of motion, the LOS-referenced PN schemes suffer from serious limitations in terms of implementation and trajectory behavior. Among the major drawbacks are forward velocity variation requirement, relatively large control effort requirement, restrictions on initial engagement conditions to ensure intercept, lack of robustness, and possibility of unbounded acceleration. It is concluded that PPN is a better guidance law in a practical sense than TPN and its generalizations. Thus, although most of the analytical effort hitherto appears to have been concentrated on TPN and its generalizations, more serious effort needs to be made to understand, model, and solve the PPN guidance scheme

Accurate Solution of Proportional Navigation for Maneuvering Targets

An accurate solution is presented of the nonlinear differential equations describing motion under proportional navigation when the target is laterally maneuvering. A quasilinearization (QL) approach is used, followed by a perturbation technique to obtain closed-form solutions for trajectory parameters. An explicit expression for the pursuer lateral acceleration is derived and shown to contain contributions due to initial heading error and target maneuver, with a coupling between the two effects. The solution is shown to be a substantial and consistent generalization or an earlier accurate solution for nonmaneuvering targets and also of classical linear (CL) solutions for maneuvering targets. The generalized QL solution presented provides very accurate estimates of pursuer lateral acceleration over a much broader range of engagement geometries and target maneuvers than presently available closed-form solutions

Generalized Linear Solution of Proportional Navigation

Proportional navigation (PN) equations are not solvable in closed form. Linearized solutions have been widely used for PN system analysis and design, but these are based on overly restrictive assumptions regarding the initial geometry, and are valid only for near-tail-chase pursuits. A generalization of the linearized approach is presented which yields more-accurate estimates of pursuer lateral acceleration than the classical linear solutions as verified by comparison with `exact' numerical solutions. Further, the solution is applicable over a much wider range of engagement geometries. The treatment is based on a closed-form quasilinearized solution of the PN equations followed by the small-angle approximation only to line-of-sight (LOS) angle rate

Optimization of Biased Proportional Navigation

An analytical treatment of the biased proportional navigation (BPN) is carried out with the aim of optimizing the bias parameter. It is shown that optimum biasing can lead to significantly more control-effort-efficient PN guidance in a wide variety of engagement situations, especially those involving higher target maneuvers. The performance of the BPN is compared with the standard (unbiased) PN system for the general case of a maneuvering target, and performance of the BPN is maximised to obtain the optimum bias value. The optimum bias is expressed through a simple algebraic equation, which can be readily solved. For the special (and very useful) case of the effective navigation constant being equal to three, the equation reduces to a quadratic, leading to an explicit expression for the optimum bias. Specific examples are provided to show the benefits of the BPN law. The higher control efficiency of the law is especially useful in extra-atmospheric interception, where the savings in control effort directly translates to a saving of propellent which forms part of the payload