Nodular fasciitis: a comprehensive, time-correlated investigation of 17 cases

The self-limited nature of nodular fasciitis (NF) is well-known but its precise mechanism has not yet been clarified. We observed that "young" NF (preoperative duration 3 months) (similar to 20%). Thus, we hypothesized that our original observation may reflect a connection with the self-limited nature of NF. Seventeen cases with reliable data concerning the onset were selected, thus approximating the lifetime of each tumor. Besides the USP6 interphase FISH examination, we also checked the most common MYH9-USP6 fusion using RT-PCR. Because of the known pathways of the tumorigenesis of NF, the mRNA level of USP6, TRAIL, IFN-beta, JAK1, STAT1, STAT3, JUN, and CDKN2A was measured using qRT-PCR. Regarding proteins, USP6, p16, p27, TRAIL, and IFN-beta were examined using immunohistochemistry. Targeted gene panel next-generation sequencing (NGS) of three cases was additionally performed. We found a strong negative correlation (p = 0.000) between the lifetime and percentage of USP6 break-apart signals and a strong positive relationship (p = 0.000) between USP6 break-apart signals and mitotic counts. Results of immunostainings, along with qRT-PCR results, favored the previously-suggested USP6-induced negative feedback mechanism through activation of TRAIL and IFN-beta, likely resulting in apoptosis and senescence of tumor cells harboring USP6 fusions. Targeted-NGS resulted in the detection of several variants, but no additional recurrent changes in the pathogenesis of these tumors. We revealed on a cellular level the USP6-induced negative feedback mechanism. In conclusion, we emphasize that in "old" NF, the percentage of USP6 break-apart FISH signals can be as low as 14-27% which can be very important from a differential diagnostic point of view. We emphasize that a careful examination and interpretation of the NGS data is needed before clinical decision-making on treatment.Cancer Signaling networks and Molecular Therapeutic

Scaling Properties of Random Walks on Small-World Networks

Using both numerical simulations and scaling arguments, we study the behavior of a random walker on a one-dimensional small-world network. For the properties we study, we find that the random walk obeys a characteristic scaling form. These properties include the average number of distinct sites visited by the random walker, the mean-square displacement of the walker, and the distribution of first-return times. The scaling form has three characteristic time regimes. At short times, the walker does not see the small-world shortcuts and effectively probes an ordinary Euclidean network in $d$-dimensions. At intermediate times, the properties of the walker shows scaling behavior characteristic of an infinite small-world network. Finally, at long times, the finite size of the network becomes important, and many of the properties of the walker saturate. We propose general analytical forms for the scaling properties in all three regimes, and show that these analytical forms are consistent with our numerical simulations.Comment: 7 pages, 8 figures, two-column format. Submitted to PR

Cross-over behaviour in a communication network

We address the problem of message transfer in a communication network. The network consists of nodes and links, with the nodes lying on a two dimensional lattice. Each node has connections with its nearest neighbours, whereas some special nodes, which are designated as hubs, have connections to all the sites within a certain area of influence. The degree distribution for this network is bimodal in nature and has finite variance. The distribution of travel times between two sites situated at a fixed distance on this lattice shows fat fractal behaviour as a function of hub-density. If extra assortative connections are now introduced between the hubs so that each hub is connected to two or three other hubs, the distribution crosses over to power-law behaviour. Cross-over behaviour is also seen if end-to-end short cuts are introduced between hubs whose areas of influence overlap, but this is much milder in nature. In yet another information transmission process, namely, the spread of infection on the network with assortative connections, we again observed cross-over behaviour of another type, viz. from one power-law to another for the threshold values of disease transmission probability. Our results are relevant for the understanding of the role of network topology in information spread processes.Comment: 12 figure

Generation-by-Generation Dissection of the Response Function in Long Memory Epidemic Processes

In a number of natural and social systems, the response to an exogenous shock relaxes back to the average level according to a long-memory kernel $\sim 1/t^{1+\theta}$ with $0 \leq \theta <1$. In the presence of an epidemic-like process of triggered shocks developing in a cascade of generations at or close to criticality, this "bare" kernel is renormalized into an even slower decaying response function $\sim 1/t^{1-\theta}$. Surprisingly, this means that the shorter the memory of the bare kernel (the larger $1+\theta$), the longer the memory of the response function (the smaller $1-\theta$). Here, we present a detailed investigation of this paradoxical behavior based on a generation-by-generation decomposition of the total response function, the use of Laplace transforms and of "anomalous" scaling arguments. The paradox is explained by the fact that the number of triggered generations grows anomalously with time at $\sim t^\theta$ so that the contributions of active generations up to time $t$ more than compensate the shorter memory associated with a larger exponent $\theta$. This anomalous scaling results fundamentally from the property that the expected waiting time is infinite for $0 \leq \theta \leq 1$. The techniques developed here are also applied to the case $\theta >1$ and we find in this case that the total renormalized response is a {\bf constant} for $t < 1/(1-n)$ followed by a cross-over to $\sim 1/t^{1+\theta}$ for $t \gg 1/(1-n)$.Comment: 27 pages, 4 figure

Functional analysis of multiple genomic signatures demonstrates that classification algorithms choose phenotype-related genes

Gene expression signatures of toxicity and clinical response benefit both safety assessment and clinical practice; however, difficulties in connecting signature genes with the predicted end points have limited their application. The Microarray Quality Control Consortium II (MAQCII) project generated 262 signatures for ten clinical and three toxicological end points from six gene expression data sets, an unprecedented collection of diverse signatures that has permitted a wide-ranging analysis on the nature of such predictive models. A comprehensive analysis of the genes of these signatures and their nonredundant unions using ontology enrichment, biological network building and interactome connectivity analyses demonstrated the link between gene signatures and the biological basis of their predictive power. Different signatures for a given end point were more similar at the level of biological properties and transcriptional control than at the gene level. Signatures tended to be enriched in function and pathway in an end point and model-specific manner, and showed a topological bias for incoming interactions. Importantly, the level of biological similarity between different signatures for a given end point correlated positively with the accuracy of the signature predictions. These findings will aid the understanding, and application of predictive genomic signatures, and support their broader application in predictive medicine

Efficient and accurate greedy search methods for mining functional modules in protein interaction networks

<p>Abstract</p> <p>Background</p> <p>Most computational algorithms mainly focus on detecting highly connected subgraphs in PPI networks as protein complexes but ignore their inherent organization. Furthermore, many of these algorithms are computationally expensive. However, recent analysis indicates that experimentally detected protein complexes generally contain Core/attachment structures.</p> <p>Methods</p> <p>In this paper, a Greedy Search Method based on Core-Attachment structure (GSM-CA) is proposed. The GSM-CA method detects densely connected regions in large protein-protein interaction networks based on the edge weight and two criteria for determining core nodes and attachment nodes. The GSM-CA method improves the prediction accuracy compared to other similar module detection approaches, however it is computationally expensive. Many module detection approaches are based on the traditional hierarchical methods, which is also computationally inefficient because the hierarchical tree structure produced by these approaches cannot provide adequate information to identify whether a network belongs to a module structure or not. In order to speed up the computational process, the Greedy Search Method based on Fast Clustering (GSM-FC) is proposed in this work. The edge weight based GSM-FC method uses a greedy procedure to traverse all edges just once to separate the network into the suitable set of modules.</p> <p>Results</p> <p>The proposed methods are applied to the protein interaction network of S. cerevisiae. Experimental results indicate that many significant functional modules are detected, most of which match the known complexes. Results also demonstrate that the GSM-FC algorithm is faster and more accurate as compared to other competing algorithms.</p> <p>Conclusions</p> <p>Based on the new edge weight definition, the proposed algorithm takes advantages of the greedy search procedure to separate the network into the suitable set of modules. Experimental analysis shows that the identified modules are statistically significant. The algorithm can reduce the computational time significantly while keeping high prediction accuracy.</p

Efficiency of complex production in changing environment

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