Siamak Ravanbakhsh

Determination of the optimal tubulin isotype target as a method for the development of individualized cancer chemotherapy

BackgroundAs microtubules are essential for cell growth and division, its constituent protein β-tubulin has been a popular target for various treatments, including cancer chemotherapy. There are several isotypes of human β-tubulin and each type of cell expresses its characteristic distribution of these isotypes. Moreover, each tubulin-binding drug has its own distribution of binding affinities over the various isotypes, which further complicates identifying the optimal drug selection. An ideal drug would preferentially bind only the tubulin isotypes expressed abundantly by the cancer cells, but not those in the healthy cells. Unfortunately, as the distributions of the tubulin isotypes in cancer cells overlap with those of healthy cells, this ideal scenario is clearly not possible. We can, however, seek a drug that interferes significantly with the isotype distribution of the cancer cell, but has only minor interactions with those of the healthy cells.MethodsWe describe a quantitative methodology for identifying this optimal tubulin isotype profile for an ideal cancer drug, given the isotype distribution of a specific cancer type, as well as the isotype distributions in various healthy tissues, and the physiological importance of each such tissue.ResultsWe report the optimal isotype profiles for different types of cancer with various routes of delivery.ConclusionsOur algorithm, which defines the best profile for each type of cancer (given the drug delivery route and some specified patient characteristics), will help to personalize the design of pharmaceuticals for individual patients. This paper is an attempt to explicitly consider the effects of the tubulin isotype distributions in both cancer and normal cell types, for rational chemotherapy design aimed at optimizing the drug’s efficacy with minimal side effects.

Correction: Accurate, Fully-Automated NMR Spectral Profiling for Metabolomics.

The third author’s name is spelled incorrectly. The correct name is: Trent C. Bjorndahl. The correct citation is: Ravanbakhsh S, Liu P, Bjorndahl TC, Mandal R, Grant JR, Wilson M, et al. (2015) Accurate, Fully-Automated NMR Spectral Profiling for Metabolomics. PLoS ONE 10(5): e0124219. doi:10.1371/journal.pone.0124219

Message Passing and Combinatorial Optimization

Graphical models use the intuitive and well-studied methods of graph theory to implicitly represent dependencies between variables in large systems. They can model the global behaviour of a complex system by specifying only local factors. This thesis studies inference in discrete graphical models from an algebraic perspective and the ways inference can be used to express and approximate NP-hard combinatorial problems. We investigate the complexity and reducibility of various inference problems, in part by organizing them in an inference hierarchy. We then investigate tractable approximations for a subset of these problems using distributive law in the form of message passing. The quality of the resulting message passing procedure, called Belief Propagation (BP), depends on the influence of loops in the graphical model. We contribute to three classes of approximations that improve BP for loopy graphs A) loop correction techniques; B) survey propagation, another message passing technique that surpasses BP in some settings; and C) hybrid methods that interpolate between deterministic message passing and Markov Chain Monte Carlo inference. We then review the existing message passing solutions and provide novel graphical models and inference techniques for combinatorial problems under three broad classes: A) constraint satisfaction problems such as satisfiability, coloring, packing, set / clique-cover and dominating / independent set and their optimization counterparts; B) clustering problems such as hierarchical clustering, K-median, K-clustering, K-center and modularity optimization; C) problems over permutations including assignment, graph morphisms and alignment, finding symmetries and traveling salesman problem. In many cases we show that message passing is able to find solutions that are either near optimal or favourably compare with todays state-of-the-art approaches.