4 research outputs found
Customizing the therapeutic response of signaling networks to promote antitumor responses by drug combinations
No full textThis work was supported by grants from Breakthrough Breast Cancer and Scottish Funding Council (SRDG), and personal support to Alexey Goltsov from Scottish Informatics and Computer Science Alliance (SICSA) and to James Bown from The Northwood Trust.Drug resistance, de novo and acquired, pervades cellular signaling networks (SNs) from one signaling motif to another as a result of cancer progression and/or drug intervention. This resistance is one of the key determinants of efficacy in targeted anti-cancer drug therapy. Although poorly understood, drug resistance is already being addressed in combination therapy by selecting drug targets where SN sensitivity increases due to combination components or as a result of de novo or acquired mutations. Additionally, successive drug combinations have shown low resistance potential. To promote a rational, systematic development of combination therapies, it is necessary to establish the underlying mechanisms that drive the advantages of combination therapies, and design methods to determine drug targets for combination regimens. Based on a joint systems analysis of cellular SN response and its sensitivity to drug action and oncogenic mutations, we describe an in silico method to analyze the targets of drug combinations. Our method explores mechanisms of sensitizing the SN through a combination of two drugs targeting vertical signaling pathways. We propose a paradigm of SN response customization by one drug to both maximize the effect of another drug in combination and promote a robust therapeutic response against oncogenic mutations. The method was applied to customize the response of the ErbB/PI3K/PTEN/AKT pathway by combination of drugs targeting HER2 receptors and proteins in the down-stream pathway. The results of a computational experiment showed that the modification of the SN response from hyperbolic to smooth sigmoid response by manipulation of two drugs in combination leads to greater robustness in therapeutic response against oncogenic mutations determining cancer heterogeneity. The application of this method in drug combination co-development suggests a combined evaluation of inhibition effects together with the capability of drug combinations to suppress resistance mechanisms before they become clinically manifest.Peer reviewe
The Society of Orthodox Parishes of Petrograd and its Province (1920–1922): the Experience of Sobornost under Persecution
No full textThis article is devoted to the history of the Society of Orthodox Parishes of Petrograd and its Province — a public organization registered by the Soviet government in 1920, which during its 18 months of existence united around 70 parishes of the Petrograd diocese. In 1922, it was administratively dissolved, and its board members found themselves at the centre of accusations of resisting the seizure of church valuables. In addition to the general issues that have been considered to a greater or lesser extent in historiography (the circumstances of the Society’s emergence, its purpose, structure, and main activities), in this article the author explores the founders’ ecclesiological views, finding that their key category for conceiving of church life was sobornost. The author also focuses on the peculiarities of the Society’s legal status and its actual position within the contexts of life within the church and under Soviet legislation in the early 1920s. Here, for the first time, the question of the organization’s relationship with the Petrograd Diocesan Council is posed, and analysis leads us to conclude that there was a conflict between the agencies of diocesan administration and the social movement within the church, which was clearly manifest in the late 1910s and early 1920s. The Society’s potential was realized after the liquidation of the Diocesan Council, when as a group free from the reins of the diocesan administration system, it turned out to be the largest and most representative church association in Petrograd, striving to influence a whole range of issues related to parish life. The article also attempts to outline the connection between the Society and preceding and subsequent phenomena within post-revolutionary church life, including the Local Council of 1917–1918 and the Renovationist movement, whose participants were directly related to the Society
In Silico Screening of Nonsteroidal Anti-Inflammatory Drugs and Their Combined Action on Prostaglandin H Synthase-1
No full textThe detailed kinetic model of Prostaglandin H Synthase-1 (PGHS-1) was applied to in silico screening of dose-dependencies for the different types of nonsteroidal anti-inflammatory drugs (NSAIDs), such as: reversible/irreversible, nonselective/selective to PGHS-1/PGHS-2 and time dependent/independent inhibitors (aspirin, ibuprofen, celecoxib, etc.) The computational screening has shown a significant variability in the IC50s of the same drug, depending on different in vitro and in vivo experimental conditions. To study this high heterogeneity in the inhibitory effects of NSAIDs, we have developed an in silico approach to evaluate NSAID action on targets under different PGHS-1 microenvironmental conditions, such as arachidonic acid, reducing cofactor, and peroxide concentrations. The designed technique permits translating the drug IC50, obtained in one experimental setting to another, and predicts in vivo inhibitory effects based on the relevant in vitro data. For the aspirin case, we elucidated the mechanism underlying the enhancement and reduction (aspirin resistance) of its efficacy, depending on PGHS-1 microenvironment in in vitro/in vivo experimental settings. We also present the results of the in silico screening of the combined action of sets of two NSAIDs (aspirin with ibuprofen, aspirin with celecoxib), and study the mechanism of the experimentally observed effect of the suppression of aspirin-mediated PGHS-1 inhibition by selective and nonselective NSAIDs. Furthermore, we discuss the applications of the obtained results to the problems of standardization of NSAID test assay, dependence of the NSAID efficacy on cellular environment of PGHS-1, drug resistance, and NSAID combination therapy
