Motivation: Interferon-β induced JAK-STAT signaling pathways contribute to mucosal immune recognition and an anti-viral state. Though the main molecular mechanisms constituting these pathways are known, neither the detailed structure of the regulatory network, nor its dynamics has yet been investigated. The objective of this work is to build a mathematical model for the pathway that would serve two purposes: (1) to reproduce experimental results in simulation of both early and late response to Interferon-β stimulation and (2) to explain experimental phenomena generating new hypotheses about regulatory mechanisms that cannot yet be tested experimentally. Results: Experimentally determined time dependent changes in the major components of this pathway were used to build a mathematical model describing pathway dynamics in the form of ordinary differential equations. The experimental results suggested existence of unknown negative control mechanisms that were tested numerically using the model. Together, experimental and numerical data show that the epithelial JAK-STAT pathway might be subjected to previously unknown dynamic negative control mechanisms: (1) activation of dormant phosphatases and (2) inhibition of nuclear import of IRF1. Availability: The model, written in Matlab, is available online at www.stat.rice.edu/~jsmieja/IFN Contact:jaroslaw.smieja@polsl.pl Supplementary information: Supplementary data are available at Bioinformatics online.

Elevated temperature induces the heat shock (HS) response, which modulates cell proliferation, apoptosis, the immune and inflammatory responses. However, specific mechanisms linking the HS response pathways to major cellular signaling systems are not fully understood. Here we used integrated computational and experimental approaches to quantitatively analyze the crosstalk mechanisms between the HS-response and a master regulator of inflammation, cell proliferation, and apoptosis the Nuclear Factor κB (NF-κB) system. We found that populations of human osteosarcoma cells, exposed to a clinically relevant 43°C HS had an attenuated NF-κB p65 response to Tumor Necrosis Factor α (TNFα) treatment. The degree of inhibition of the NF-κB response depended on the HS exposure time. Mathematical modeling of single cells indicated that individual crosstalk mechanisms differentially encode HS-mediated NF-κB responses while being consistent with the observed population-level responses. In particular “all-or-nothing” encoding mechanisms were involved in the HS-dependent regulation of the IKK activity and IκBα phosphorylation, while others involving transport were “analogue”. In order to discriminate between these mechanisms, we used live-cell imaging of nuclear translocations of the NF-κB p65 subunit. The single cell responses exhibited “all-or-nothing” encoding. While most cells did not respond to TNFα stimulation after a 60 min HS, 27% showed responses similar to those not receiving HS. We further demonstrated experimentally and theoretically that the predicted inhibition of IKK activity was consistent with the observed HS-dependent depletion of the IKKα and IKKβ subunits in whole cell lysates. However, a combination of “all-or-nothing” crosstalk mechanisms was required to completely recapitulate the single cell data. We postulate therefore that the heterogeneity of the single cell responses might be explained by the cell-intrinsic variability of HS-modulated IKK signaling. In summary, we show that high temperature modulates NF-κB responses in single cells in a complex and unintuitive manner, which needs to be considered in hyperthermia-based treatment strategies. Hyperthermia has been considered a promising strategy to sensitize cancer cells to treatment. As such, it might potentially increase treatment efficacy while reducing negative side effects. So far, this potential has not been fully realized. One of the major obstacles is a lack of quantitative understanding of crosstalk mechanisms involved in the heat shock and other cellular stress-factor systems. In this work, we used experimental population-level and live-cell imaging approaches to characterize the NF-κB signaling system response to physiologically high temperature. We then iteratively applied mathematical modeling of single cells to infer the underlying regulatory mechanisms. We showed experimentally that elevated temperature attenuated cytokine-induced NF-κB system responses, resulting in complex and unintuitive single cell behavior. Our analyses suggested that these responses are consistent with stochastic cell-intrinsic heat-shock-mediated regulation of the NF-κB system via the IKK signaling module. Considering the oncogenic associations of the NF-κB pathway, the crosstalk mechanisms described in this work are important for the understanding of chemo- and radio-resistance to treatment. However, more but similar, quantitative studies are required to ultimately change currently used therapy protocols.

This paper presents analysis and biomedical implications of a certain class of bilinear systems that can be applied in modeling of cancer chemotherapy. It combines models that so far have been studied separately, taking into account both the phenomenon of gene amplification and drug specificity in chemotherapy in their different aspects. The methodology of analysis of such models, based on system decomposition, is discussed. The mathematical description is given by an infinite dimensional state equation with a system matrix, the form of which allows decomposing the model into two interacting subsystems. While the first one, of a finite dimension, can have any form, the second one is infinite-dimensional and tridiagonal. Then the optimal control problem is defined in l1 space. To derive necessary conditions for optimal control, the model description is transformed into an integrodifferential one.

Neuroblastoma (NB), a neuroendocrine tumour, is one of the most prevalent cancers in children. The link between LMO1 polymorphisms and NB has been investigated by several groups, rendering inconclusive results. Here, with this comprehensive systematic review and up‐to‐date meta‐analysis, we aim to distinctively elucidate the possible correlation between LMO1 polymorphisms and NB susceptibility. Eligible studies were systematically researched and identified using PubMed, Web of Science and Scopus databases up to 10 February 2019. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of the associations. Our findings revealed that rs110419 and rs2168101 polymorphisms were significantly associated with a decreased risk of NB in all genetic models. In addition, the rs4758051 variant appeared protective against NB in homozygous, dominant and allele genetic models, whereas the rs10840002 variant markedly decreased the risk of NB in the allele model. In contrast, the rs204938 polymorphism showed a positive association with NB susceptibility in allele genetic models. In summary, our meta‐analysis is the first to provide clear evidence of an association between specific polymorphisms of LMO1 and susceptibility to NB. Of note, additional larger well‐designed studies would be helpful to further evaluate and confirm this association.