Multi-scale agent-based brain cancer modeling and prediction of TKI treatment response: Incorporating EGFR signaling pathway and angiogenesis

ABSTRACT: BACKGROUND: The epidermal growth factor receptor (EGFR) signaling pathway and angiogenesis in brain cancer act as an engine for tumor initiation, expansion and response to therapy. Since the existing literature does not have any models that investigate the impact of both angiogenesis and molecular signaling pathways on treatment, we propose a novel multi-scale, agent-based computational model that includes both angiogenesis and EGFR modules to study the response of brain cancer under tyrosine kinase inhibitors (TKIs) treatment. RESULTS: The novel angiogenesis module integrated into the agent-based tumor model is based on a set of reaction--diffusion equations that describe the spatio-temporal evolution of the distributions of micro-environmental factors such as glucose, oxygen, TGFalpha, VEGF and fibronectin. These molecular species regulate tumor growth during angiogenesis. Each tumor cell is equipped with an EGFR signaling pathway linked to a cell-cycle pathway to determine its phenotype. EGFR TKIs are delivered through the blood vessels of tumor microvasculature and the response to treatment is studied. CONCLUSIONS: Our simulations demonstrated that entire tumor growth profile is a collective behaviour of cells regulated by the EGFR signaling pathway and the cell cycle. We also found that angiogenesis has a dual effect under TKI treatment: on one hand, through neo-vasculature TKIs are delivered to decrease tumor invasion; on the other hand, the neo-vasculature can transport glucose and oxygen to tumor cells to maintain their metabolism, which results in an increase of cell survival rate in the late simulation stages.     

An integrated computational and experimental study for overproducing fatty acids in Escherichia coli

Increasing demands for petroleum have stimulated sustainable ways to produce chemicals and biofuels. Specifically, fatty acids of varying chain lengths (C₆–C₁₆) naturally synthesized in many organisms are promising starting points for the catalytic production of industrial chemicals and diesel-like biofuels. However, bio-production of fatty acids from plants and other microbial production hosts relies heavily on manipulating tightly regulated fatty acid biosynthetic pathways. In addition, precursors for fatty acids are used along other central metabolic pathways for the production of amino acids and biomass, which further complicates the engineering of microbial hosts for higher yields. Here, we demonstrate an iterative metabolic engineering effort that integrates computationally driven predictions and metabolic flux analysis techniques to meet this challenge. The OptForce procedure was used for suggesting and prioritizing genetic manipulations that overproduce fatty acids of different chain lengths from C₆ to C₁₆ starting with wild-type E. coli. We identified some common but mostly chain-specific genetic interventions alluding to the possibility of fine-tuning overproduction for specific fatty acid chain lengths. In accordance with the OptForce prioritization of interventions, fabZ and acyl-ACP thioesterase were upregulated and fadD was deleted to arrive at a strain that produces 1.70 g/L and 0.14 g fatty acid/g glucose (～39% maximum theoretical yield) of C_14–16 fatty acids in minimal M9 medium. These results highlight the benefit of using computational strain design and flux analysis tools in the design of recombinant strains of E. coli to produce free fatty acids.     

Leaf surface characteristics and wetting in Ceratonia siliqua L.

Compound leaves of Ceratonia siliqua L. (carob tree) exhibit a long life span and are exposed to environmental stimuli for approximately twenty months. The micromorphology of the adaxial and the abaxial leaflet surfaces was studied, in comparison with treated waxless epidermises (after the removal of cuticle and epicuticular waxes) and corresponding replicas, respectively. The microstructural surface features are evaluated as possible consistent parameters related to the wetness of leaves. The abaxial leaflet surface is more hydrophobic than the adaxial leaflet surface in C. siliqua, which may be particularly important for the ecophysiological status of its hypostomatic leaves.     

Neuronal caspase 2 activity and function requires RAIDD, but not PIDD

Caspase 2 was initially identified as a neuronally expressed developmentally down-regulated gene (HUGO gene nomenclature CASP2) and has been shown to be required for neuronal death induced by several stimuli, including NGF (nerve growth factor) deprivation and Aβ (β-amyloid). In non-neuronal cells the PIDDosome, composed of caspase 2 and two death adaptor proteins, PIDD (p53-inducible protein with a death domain) and RAIDD {RIP (receptor-interacting protein)-associated ICH-1 [ICE (interleukin-1β-converting enzyme)/CED-3 (cell-death determining 3) homologue 1] protein with a death domain}, has been proposed as the caspase 2 activation complex, although the absolute requirement for the PIDDosome is not clear. To investigate the requirement for the PIDDosome in caspase-2-dependent neuronal death, we have examined the necessity for each component in induction of active caspase 2 and in execution of caspase-2-dependent neuronal death. We find that both NGF deprivation and Aβ treatment of neurons induce active caspase 2 and that induction of this activity depends on expression of RAIDD, but is independent of PIDD expression. We show that treatment of wild-type or PIDD-null neurons with Aβ or NGF deprivation induces formation of a complex of caspase 2 and RAIDD. We also show that caspase-2-dependent execution of neurons requires RAIDD, not PIDD. Caspase 2 activity can be induced in neurons from PIDD-null mice, and NGF deprivation or Aβ use caspase 2 and RAIDD to execute death of these neurons.     

Relationships between substance abuse/dependence and psychiatric disorders based on polygenic scores

Genetic susceptibility to substance use disorders (SUDs) is partially shared between substances. Heritability of any substance dependence, estimated as 54%, is partly explained by additive effects of common variants. Comorbidity between SUDs and other psychiatric disorders is frequent. The present study aims to analyze the additive role of common variants in this comorbidity using polygenic scores (PGSs) based on genome‐wide association study discovery samples of schizophrenia (SCZ), bipolar disorder, attention‐deficit/hyperactivity disorder, autism spectrum disorder, major depressive disorder and anxiety disorders, available from large consortia. PGSs were calculated for 534 patients meeting DSM‐IV criteria for dependence of a substance and abuse/dependence of another substance between alcohol, tobacco, cannabis, cocaine, opiates, hypnotics, stimulants, hallucinogens and solvents; and 587 blood donors from the same population, Iberians from Galicia, as controls. Significance of the PGS and percentage of variance explained were calculated by logistic regression. Using discovery samples of similar size, significant associations with SUDs were detected for SCZ PGS. SCZ PGS explained more variance in SUDs than in most psychiatric disorders. Cross‐disorder PGS based on five psychiatric disorders was significant after adjustment for the effect of SCZ PGS. SCZ PGS was significantly higher in women than in men abusing alcohol. Our findings indicate that SUDs share genetic susceptibility with SCZ to a greater extent than with other psychiatric disorders, including externalizing disorders such as attention‐deficit/hyperactivity disorder. Women have lower probability to develop substance abuse/dependence than men at similar PGS probably because of a higher social pressure against excessive drug use in women.     

Chemical composition of the essential oil from leaves of Lippia citriodora H.B.K. (Verbenaceae) at two developmental stages

The chemical composition of the essential oil extracted from fresh leaves of Lippia citriodora (Verbenaceae) was analyzed by GC-FID and GC–MS in May, when growth rates are maximal, and in September, in full bloom. In both samples the main constituents were geranial, neral and limonene constituting 66.3% of the total essential oil yield in May and increasing to 69% in September. Their individual percentage values, however, changed considerably for geranial and neral decreasing from 38.7 to 26.8% and from 24.5 to 21.8%, respectively, and for limonene increasing from 5.8 to 17.7%. All other components remained more or less unchanged both qualitatively and quantitatively. FT-IR spectrometry was also applied for the qualitative determination of the main components.     

Is oviposition and larval damage by the leaf-mining fly Calycomyza eupatorivora (Agromyzidae) on its target weed,Chromolaena odorata (Asteraceae), restricted by leaf-quality preferences?

The leaf-mining fly Calycomyza eupatorivora Spencer (Diptera: Agromyzidae) was released in the eastern coastal regions of South Africa for the biological control of the invasive shrub Chromolaena odorata (L.) King and Robinson. Despite widespread establishment, its ability to inflict sufficient foliar damage has been questioned. This laboratory study was initiated to provide some insight into how increasing fly populations (represented by 1, 5 and 10 mating pairs per plant) are likely to influence leaf-mining intensity and the levels of damage. On average, individual plants exposed to five mating pairs displayed significantly more larval mines (248) than those exposed to single pairs (69), while plants exposed to 10 mating pairs were intermediate (125). Similarly, at densities of five mating pairs per plant, the percentages of available leaves that were exploited peaked at 36%, while the percentages of available leaf area that were removed by larval leaf mining peaked at 22%. The non-linear relationship between leaf mining and fly density and the high percentages of unexploited leaves suggest that leaf mining may be influenced by leaf quality, the nature of which is currently unconfirmed. These results also suggest that the levels of leaf exploitation by C. eupatorivora will be too low to have any meaningful impact in the field. Field evaluations, to be reported in a later contribution, have indeed confirmed that the impact of C. eupatorivora on mature populations of C. odorata is negligible.     

Seasonal activity,habitat preferences and larval mortality of the leaf-mining fly Calycomyza eupatorivora (Agromyzidae), a biological control agent established on Chromolaena odorata (Asteraceae) in South Africa

The leaf-mining fly Calycomyza eupatorivora Spencer (Diptera: Agromyzidae) has become widely established in the eastern regions of South Africa, following its release for the biological control of the invasive shrub Chromolaena odorata (L.) King and Robinson. This study was conducted to gain some insight into the impact of C. eupatorivora populations, by assessing their seasonal activity, habitat preferences, levels of leaf exploitation and extent of larval mortality in the field over a 1-year period. Leaf mining intensity was poorly synchronised with leaf availability, with leaf exploitation peaking at the end of the growing season of C. odorata. Although significantly more mines were recovered on plants growing in shaded situations, the percentage of available leaves that were exploited for mining was not significantly different between plants growing in shaded versus open situations. Overall, the levels of leaf damage were trivial with mines recovered from <5% of available leaves that were sampled during the study. Besides leaf-quality requirements, these low levels of leaf exploitation may have been influenced by high larval mortality which varied between 60 and 83%, depending on whether lower or higher estimates were used. These evaluations have verified the results of earlier laboratory studies which suggested that the impact of C. eupatorivora on mature populations of C. odorata in South Africa will be negligible.