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Optimal control strategies of eradicating invisible glioblastoma cells after conventional surgery.

ABSTRACT: Glioblastoma, the most aggressive type of brain cancer, has median survival time of 1 year after diagnosis. It is characterized by alternating modes of rapid proliferation and aggressive invasion in response to metabolic stress in the microenvironment. A particular microRNA, miR-451, and its downstream signalling molecules, AMPK complex, are known to be key determinants in switching cell fate. These components form a core control system determining a balance between cell growth and migration which is regulated by fluctuating glucose levels in the microenvironment. An important factor from the treatment point of view is that low levels of glucose affect metabolism and activate cell migration through the miR-451-AMPK control system, creating 'invisible' migratory cells and making them inaccessible by conventional surgery. In this work, we apply optimal control theory to deal with the problem of maintaining upregulated miR-451 levels that prevent cell infiltration to surrounding brain tissue and thus induce localization of these cancer cells at the surgical site. The model also considers the effect of a drug that blocks inhibitive pathways of miR-451 from AMPK complex. Glucose infusion control and drug infusion control are chosen to represent dose rates of glucose and drug intravenous administrations, respectively. The characteristics of optimal control lead us to investigate the structure of optimal intravenous infusion regimen under various circumstances and predict best clinical outcomes with minimum expense possible.

SUBMITTER: de Los Reyes V AA

PROVIDER: S-EPMC4424672 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Optimal control strategies of eradicating invisible glioblastoma cells after conventional surgery.

de Los Reyes V Aurelio A AA Jung Eunok E Kim Yangjin Y

Journal of the Royal Society, Interface 20150501 106

Glioblastoma, the most aggressive type of brain cancer, has median survival time of 1 year after diagnosis. It is characterized by alternating modes of rapid proliferation and aggressive invasion in response to metabolic stress in the microenvironment. A particular microRNA, miR-451, and its downstream signalling molecules, AMPK complex, are known to be key determinants in switching cell fate. These components form a core control system determining a balance between cell growth and migration whi ...[more]

PMID: 25833239

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Project description:Frequency tagging has been demonstrated to be a useful tool for identifying representational-specific neuronal activity in the auditory and visual domains. However, the slow flicker (<30 Hz) applied in conventional frequency tagging studies is highly visible and might entrain endogenous neuronal oscillations. Hence, stimulation at faster frequencies that is much less visible and does not interfere with endogenous brain oscillatory activity is a promising new tool. In this study, we set out to examine the optimal stimulation parameters of rapid frequency tagging (RFT/RIFT) with magnetoencephalography (MEG) by quantifying the effects of stimulation frequency, size and position of the flickering patch. Rapid frequency tagging using flickers above 50 Hz results in almost invisible stimulation which does not interfere with slower endogenous oscillations; however, the signal is weaker as compared to tagging at slower frequencies so certainty over the optimal parameters of stimulation delivery are crucial. The here presented results examining the frequency range between 60 Hz and 96 Hz suggest that RFT induces brain responses with decreasing strength up to about 84 Hz. In addition, even at the smallest flicker patch (2°) focally presented RFT induces a significant and measurable oscillatory brain signal (steady state visual evoked potential/field, SSVEP/F) at the stimulation frequency (66 Hz); however, the elicited response increases with patch size. While focal RFT presentation elicits the strongest response, off-centre presentations do generally mainly elicit a measureable response if presented below the horizontal midline. Importantly, the results also revealed considerable individual differences in the neuronal responses to RFT stimulation. Finally, we discuss the comparison of oscillatory measures (coherence and power) and sensor types (planar gradiometers and magnetometers) in order to achieve optimal outcomes. Based on our extensive findings we set forward concrete recommendations for using rapid frequency tagging in human cognitive neuroscience investigations.

Dataset Information

Optimal control strategies of eradicating invisible glioblastoma cells after conventional surgery.

Publications

Optimal control strategies of eradicating invisible glioblastoma cells after conventional surgery.

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