Systems approaches and algorithms for discovery of combinatorial therapies

Effective therapy of complex diseases requires control of highly non-linear complex networks that remain incompletely characterized. In particular, drug intervention can be seen as control of signaling in cellular networks. Identification of control parameters presents an extreme challenge due to the combinatorial explosion of control possibilities in combination therapy and to the incomplete knowledge of the systems biology of cells. In this review paper we describe the main current and proposed approaches to the design of combinatorial therapies, including the empirical methods used now by clinicians and alternative approaches suggested recently by several authors. New approaches for designing combinations arising from systems biology are described. We discuss in special detail the design of algorithms that identify optimal control parameters in cellular networks based on a quantitative characterization of control landscapes, maximizing utilization of incomplete knowledge of the state and structure of intracellular networks. The use of new technology for high-throughput measurements is key to these new approaches to combination therapy and essential for the characterization of control landscapes and implementation of the algorithms. Combinatorial optimization in medical therapy is also compared with the combinatorial optimization of engineering and materials science and similarities and differences are delineated.Comment: 25 page

The multiple faces of self-assembled lipidic systems

Lipids, the building blocks of cells, common to every living organisms, have the propensity to self-assemble into well-defined structures over short and long-range spatial scales. The driving forces have their roots mainly in the hydrophobic effect and electrostatic interactions. Membranes in lamellar phase are ubiquitous in cellular compartments and can phase-separate upon mixing lipids in different liquid-crystalline states. Hexagonal phases and especially cubic phases can be synthesized and observed in vivo as well. Membrane often closes up into a vesicle whose shape is determined by the interplay of curvature, area difference elasticity and line tension energies, and can adopt the form of a sphere, a tube, a prolate, a starfish and many more. Complexes made of lipids and polyelectrolytes or inorganic materials exhibit a rich diversity of structural morphologies due to additional interactions which become increasingly hard to track without the aid of suitable computer models. From the plasma membrane of archaebacteria to gene delivery, self-assembled lipidic systems have left their mark in cell biology and nanobiotechnology; however, the underlying physics is yet to be fully unraveled

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Abstract Introduction Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects

Randomized clinical trials in oncology stopped early for benefit (RCTSEB)

6039 Background: Randomized clinical trials (RCT) that stop earlier than planned because of apparent benefit often receive great attention. However, how often these early results get confirmed by other subsequent meta-analysis/randomized studies, and how often results get included in clinical guidelines is not known. We conducted systematic review of oncologic RCTSEB to further determine if the results from RCTSEB are confirmed by the subsequent studies and/or included in guidelines. Methods: RCT of any intervention reported as having stopped early because of the results favoring the intervention were previously identified (JAMA.2005;294:2203).Trials with interventions in prevention and treatment of solid and hematologic malignancies were included for this review. Citation search was conducted by two reviewers to identify meta-analysis (MA), systematic reviews (SR) and RCTs that used similar trial design as the RCTSEB. National Comprehensive Cancer Guidelines were reviewed to identify the impact of the results on recommendations on clinical practice. Results: 33 trials were identified, and 5 were excluded because they did not fit the inclusion criteria. MA/SR were available for the assessment of interventions reported in 15/28 RCTSEB. Results of subsequent MA confirmed 12/15 findings, while 3 trials were contradicted. Of the remaining 13 trials, for 7 there was at least one subsequent RCT identified. 6/7 were confirmed as beneficial in the subsequent RCTs and 1 was contradicted. For 6/28 RCTSEB we did not find any subsequent MA/SR/RCTS. We also looked at the inclusion of interventions from RCTSEB in the clinical guidelines. 18/28 interventions from RCTSEB were mentioned in the formulation of clinical guidelines.16/18 were recommended as true positive recommendations. The other 2 interventions which were addressed in the guidelines were either not confirmed (n = 1) or incorrectly recommended (n = 1). Conclusions: In this set of oncology of RCTSEBs the findings were subsequently confirmed in 64% (18/28) cases. Guidelines developers used 2/28 (7%) of RCTSEB for which reliable confirmatory data were available. However, caution should be applied in the interpretation of our results because the same RCTSEB was also included in confirmatory MAs which possibly could have introduced bias. No significant financial relationships to disclose. </jats:p