Integrated analysis of DNA methylation and gene expression reveals specific signaling pathways associated with platinum resistance in ovarian cancer

<p>Abstract</p> <p>Background</p> <p>Cisplatin and carboplatin are the primary first-line therapies for the treatment of ovarian cancer. However, resistance to these platinum-based drugs occurs in the large majority of initially responsive tumors, resulting in fully chemoresistant, fatal disease. Although the precise mechanism(s) underlying the development of platinum resistance in late-stage ovarian cancer patients currently remains unknown, CpG-island (CGI) methylation, a phenomenon strongly associated with aberrant gene silencing and ovarian tumorigenesis, may contribute to this devastating condition.</p> <p>Methods</p> <p>To model the onset of drug resistance, and investigate DNA methylation and gene expression alterations associated with platinum resistance, we treated clonally derived, drug-sensitive A2780 epithelial ovarian cancer cells with increasing concentrations of cisplatin. After several cycles of drug selection, the isogenic drug-sensitive and -resistant pairs were subjected to global CGI methylation and mRNA expression microarray analyses. To identify chemoresistance-associated, biological pathways likely impacted by DNA methylation, promoter CGI methylation and mRNA expression profiles were integrated and subjected to pathway enrichment analysis.</p> <p>Results</p> <p>Promoter CGI methylation revealed a positive association (Spearman correlation of 0.99) between the total number of hypermethylated CGIs and GI₅₀values (<it>i.e</it>., increased drug resistance) following successive cisplatin treatment cycles. In accord with that result, chemoresistance was reversible by DNA methylation inhibitors. Pathway enrichment analysis revealed hypermethylation-mediated repression of cell adhesion and tight junction pathways and hypomethylation-mediated activation of the cell growth-promoting pathways PI3K/Akt, TGF-beta, and cell cycle progression, which may contribute to the onset of chemoresistance in ovarian cancer cells.</p> <p>Conclusion</p> <p>Selective epigenetic disruption of distinct biological pathways was observed during development of platinum resistance in ovarian cancer. Integrated analysis of DNA methylation and gene expression may allow for the identification of new therapeutic targets and/or biomarkers prognostic of disease response. Finally, our results suggest that epigenetic therapies may facilitate the prevention or reversal of transcriptional repression responsible for chemoresistance and the restoration of sensitivity to platinum-based chemotherapeutics.</p

Toward Adaptation and Reuse of Advanced Robotic Software

Abstract — As robotic software systems become larger and more complex, it is increasingly important to reuse existing software components to control development costs. For relatively simple components, such as perception algorithms and actuation interfaces, this is a reasonably straightforward process, and many excellent frameworks have been developed in recent years that support reuse of such components in novel systems. For more advanced software components, such as for modeling and interacting with the robot’s environment, reuse is, however, a more challenging problem. In particular, these advanced algorithms tend to be highly sensitive to the perception and actuation capabilities of the robots they are deployed on, and they often require nontrivial modification to accommodate the specific capabilities of any one robotic system. This work examines the nature of this sensitivity and proposes a novel design methodology for isolating a stable, reusable “core ” algorithm from any platform-specific enhancements, or “supplemental ” effects. Modern software engineering techniques are used to encapsulate these supplemental effects separately from the core algorithm, allowing platform-specific details to be accommodated by modular substitution instead of direct modification of the “core ” component. This methodology is experimentally evaluated on existing software for autonomous driving behaviors, yielding useful insights into the creation of highly adaptable robotic software components. I

Novel Tire Force Estimation Strategy for Real-Time Implementation on Vehicle Applications

This paper proposes a novel unified structure to estimate tire forces. The proposed structure uses estimation modules to calculate/estimate tire forces by means of nonlinear observers. The novelty in the proposed approach lies in the independence of the estimates from the vehicle tire model, thereby making the structure robust against variations in vehicle mass, tire parameters due to tire wear, and, most importantly, road surface conditions. In the proposed structure, we have a dedicated module to estimate the longitudinal tire forces and another to calculate the vertical tire forces. Subsequently, these forces are fed into a third module that utilizes a nonlinear observer to estimate lateral tire forces. The proposed structure is validated through experimental studies