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

Survey of CT radiation doses and iodinated contrast medium administration: an international multicentric study

ObjectiveTo assess the relationship between intravenous iodinated contrast media (ICM) administration usage and radiation doses for contrast-enhanced (CE) CT of head, chest, and abdomen-pelvis (AP) in international, multicenter settings. MethodsOur international (n = 16 countries), multicenter (n = 43 sites), and cross-sectional (ConRad) study had two parts. Part 1: Redcap survey with questions on information related to CT and ICM manufacturer/brand and respective protocols. Part 2: Information on 3,258 patients (18-96 years; M:F 1654:1604) who underwent CECT for a routine head (n = 456), chest (n = 528), AP (n = 599), head CT angiography (n = 539), pulmonary embolism (n = 599), and liver CT examinations (n = 537) at 43 sites across five continents. The following information was recorded: hospital name, patient age, gender, body mass index [BMI], clinical indications, scan parameters (number of scan phases, kV), IV-contrast information (concentration, volume, flow rate, and delay), and dose indices (CTDIvol and DLP). ResultsMost routine chest (58.4%) and AP (68.7%) CECT exams were performed with 2-4 scan phases with fixed scan delay (chest 71.4%; AP 79.8%, liver CECT 50.7%) following ICM administration. Most sites did not change kV across different patients and scan phases; most CECT protocols were performed at 120-140 kV (83%, 1979/2685). There were no significant differences between radiation doses for non-contrast (CTDIvol 24 [16-30] mGy; DLP 633 [414-702] mGycm) and post-contrast phases (22 [19-27] mGy; 648 [392-694] mGycm) (p = 0.142). Sites that used bolus tracking for chest and AP CECT had lower CTDIvol than sites with fixed scan delays (p < 0.001). There was no correlation between BMI and CTDIvol (r2 <= - 0.1 to 0.1, p = 0.931). ConclusionOur study demonstrates up to ten-fold variability in ICM injection protocols and radiation doses across different CT protocols. The study emphasizes the need for optimizing CT scanning and contrast protocols to reduce unnecessary contrast and radiation exposure to patients. Clinical relevance statementThe wide variability and lack of standardization of ICM media and radiation doses in CT protocols suggest the need for education and optimization of contrast usage and scan factors for optimizing image quality in CECT

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

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.Peer reviewe

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

Exploring smartphone-related digital divide among South Korean older adults

Purpose: One of the crucial steps towards fully grasping the benefits of smartphone use for all is to explore the existence of a digital divide and its relationship to different outcomes of smartphone use. In so doing, this study explored the smartphone-related digital divide among South Korean older adults in terms of access, use and outcomes. Design/methodology/approach: In-person interviews using questionnaires were conducted to collect the data from a total number of 372 older adults aged 60 and above in eleven community centers in the Seoul Metropolitan area in Korea, 223 of whom owned a smartphone. Results: This study found that most participants use smartphones to communicate with personal relationships and support system. There were, however, differences among groups related to gender, age, and ICT training in terms of the extent of smartphone usage and participation in virtual communities. In three age groups of 60+, 70+ and 80+, a younger cohort and those with ICT training had higher smartphone literacy, harnessing the potential of smartphones. Those who used smartphones to stay connected to their social group and for entertainment showed a lower level of loneliness. Conclusion: This study shows that older adults (i.e., 60+) are not a homogenous group when it comes to using smartphones. There are distinct differences in older smartphone users, especially in the age groups 60+, 70+ and 80+. Older adults should be encouraged to use smartphones for better connectivity with their social groups and entertainment, potentially decreasing their feeling of loneliness