Charge structure in volcanic plumes: a comparison of plume properties predicted by an integral plume model to observations of volcanic lightning during the 2010 eruption of Eyjafjallajökull, Iceland

Cancer is a heterogeneous disease with different combinations of genetic alterations driving its development in different individuals. We introduce CoMEt, an algorithm to identify combinations of alterations that exhibit a pattern of mutual exclusivity across individuals, often observed for alterations in the same pathway. CoMEt includes an exact statistical test for mutual exclusivity and techniques to perform simultaneous analysis of multiple sets of mutually exclusive and subtype-specific alterations. We demonstrate that CoMEt outperforms existing approaches on simulated and real data. We apply CoMEt to five different cancer types, identifying both known cancer genes and pathways, and novel putative cancer genes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-015-0700-7) contains supplementary material, which is available to authorized users

A network approach for managing and processing big cancer data in clouds

Translational cancer research requires integrative analysis of multiple levels of big cancer data to identify and treat cancer. In order to address the issues that data is decentralised, growing and continually being updated, and the content living or archiving on different information sources partially overlaps creating redundancies as well as contradictions and inconsistencies, we develop a data network model and technology for constructing and managing big cancer data. To support our data network approach for data process and analysis, we employ a semantic content network approach and adopt the CELAR cloud platform. The prototype implementation shows that the CELAR cloud can satisfy the on-demanding needs of various data resources for management and process of big cancer data

Mathematical modeling of cell population dynamics in the colonic crypt and in colorectal cancer

Colorectal cancer is initiated in colonic crypts. A succession of genetic mutations or epigenetic changes can lead to homeostasis in the crypt being overcome, and subsequent unbounded growth. We consider the dynamics of a single colorectal crypt by using a compartmental approach [Tomlinson IPM, Bodmer WF (1995) Proc Natl Acad Sci USA 92: 11130-11134], which accounts for populations of stem cells, differential cells, and transit cells. That original model made the simplifying assumptions that each cell popuation divides synchronously, but we relax these assumptions by adopting an age-structured approach that models asynchronous cell division, and by using a continuum model. We discuss two mechanims that could regulate the growth of cell numbers and maintain the equilibrium that is normally observed in the crypt. The first will always maintain an equilibrium for all parameter values, whereas the second can allow unbounded proliferation if the net per capita growth rates are large enough. Results show that an increase in cell renewal, which is equivalent to a failure of programmed cell death or of differentiation, can lead to the growth of cancers. The second model can be used to explain the long lag phases in tumor growth, during which news, higher equilibria are reached, before unlimited growth in cell number ensues

Topological analysis of the vasculature of angiopoietin-expressing tumours through scale-space tracing

This work describes the topological analysis of the vasculature of tumours. The analysis is performed with a scale-space technique, which traces the centrelines of vessels as topological ridges of the image intensities and then obtains a series of measurements, which are used to compare the vasculatures. Besides the measurements directly associated with the centrelines, the scales obtained allow the estimation of width andthusareacoveredwithvessels. Tumours of SW1222 human colorectal carcinoma xenografts were observed when growing in dorsal skin-fold window chambers in mice. Three variants of the tumours expressing either endogenous levels of angiopoietins (WT) or over-expressing either angiopoietin-1 (Ang-1) or angiopoietin-2 (Ang-2) were assessed with/without vascular targeted therapy. The scale-space technique was able to discriminate between the vasculatures of the three different tumour types prior to treatment. Results also suggested that over-expression of Ang-2 was associated with susceptibility of the tumour vasculature to the vascular disrupting agent, combretastatin A4 phosphate (CA4P). Substantiation of this finding would point to the potential of tumour Ang-2 expression as a predictive bio-marker for response to CA4P

One-carbon metabolism in cancer

Cells require one-carbon units for nucleotide synthesis, methylation and reductive metabolism, and these pathways support the high proliferative rate of cancer cells. As such, anti-folates, drugs that target one-carbon metabolism, have long been used in the treatment of cancer. Amino acids, such as serine are a major one-carbon source, and cancer cells are particularly susceptible to deprivation of one-carbon units by serine restriction or inhibition of de novo serine synthesis. Recent work has also begun to decipher the specific pathways and sub-cellular compartments that are important for one-carbon metabolism in cancer cells. In this review we summarise the historical understanding of one-carbon metabolism in cancer, describe the recent findings regarding the generation and usage of one-carbon units and explore possible future therapeutics that could exploit the dependency of cancer cells on one-carbon metabolism

P-rex1 cooperates with PDGFRβ to drive cellular migration in 3D microenvironments

Expression of the Rac-guanine nucleotide exchange factor (RacGEF), P-Rex1 is a key determinant of progression to metastasis in a number of human cancers. In accordance with this proposed role in cancer cell invasion and metastasis, we find that ectopic expression of P-Rex1 in an immortalised human fibroblast cell line is sufficient to drive multiple migratory and invasive phenotypes. The invasive phenotype is greatly enhanced by the presence of a gradient of serum or platelet-derived growth factor, and is dependent upon the expression of functional PDGF receptor β. Consistently, the invasiveness of WM852 melanoma cells, which endogenously express P-Rex1 and PDGFRβ, is opposed by siRNA of either of these proteins. Furthermore, the current model of P-Rex1 activation is advanced through demonstration of P-Rex1 and PDGFRβ as components of the same macromolecular complex. These data suggest that P-Rex1 has an influence on physiological migratory processes, such as invasion of cancer cells, both through effects upon classical Rac1-driven motility and a novel association with RTK signalling complexes

A reaction-diffusion model for the growth of avascular tumor

A nutrient-limited model for avascular cancer growth including cell proliferation, motility and death is presented. The model qualitatively reproduces commonly observed morphologies for primary tumors, and the simulated patterns are characterized by its gyration radius, total number of cancer cells, and number of cells on tumor periphery. These very distinct morphological patterns follow Gompertz growth curves, but exhibit different scaling laws for their surfaces. Also, the simulated tumors incorporate a spatial structure composed of a central necrotic core, an inner rim of quiescent cells and a narrow outer shell of proliferating cells in agreement with biological data. Finally, our results indicate that the competition for nutrients among normal and cancer cells may be a determinant factor in generating papillary tumor morphology.Comment: 9 pages, 6 figures, to appear in PR

Tumour invasiveness, the local and systemic environment and the basis of staging systems in colorectal cancer

background: The present study aimed to examine the relationship between tumour invasiveness (T stage), the local and systemic environment and cancer-specific survival (CSS) of patients with primary operable colorectal cancer. methods: The tumour microenvironment was examined using measures of the inflammatory infiltrate (Klintrup-Makinen (KM) grade and Immunoscore), tumour stroma percentage (TSP) and tumour budding. The systemic inflammatory environment was examined using modified Glasgow Prognostic Score (mGPS) and neutrophil:lymphocyte ratio (NLR). A 5-year CSS was examined. results: A total of 331 patients were included. Increasing T stage was associated with colonic primary, N stage, poor differentiation, margin involvement and venous invasion (P<0.05). T stage was significantly associated with KM grade (P=0.001), Immunoscore (P=0.016), TSP (P=0.006), tumour budding (P<0.001), and elevated mGPS and NLR (both P<0.05). In patients with T3 cancer, N stage stratified survival from 88 to 64%, whereas Immunoscore and budding stratified survival from 100 to 70% and from 91 to 56%, respectively. The Glasgow Microenvironment Score, a score based on KM grade and TSP, stratified survival from 93 to 58%. conclusions: Although associated with increasing T stage, local and systemic tumour environment characteristics, and in particular Immunoscore, budding, TSP and mGPS, are stage-independent determinants of survival and may be utilised in the staging of patients with primary operable colorectal cancer

An expression signature of the angiogenic response in gastrointestinal neuroendocrine tumours: correlation with tumour phenotype and survival outcomes.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are heterogeneous with respect to biological behaviour and prognosis. As angiogenesis is a renowned pathogenic hallmark as well as a therapeutic target, we aimed to investigate the prognostic and clinico-pathological role of tissue markers of hypoxia and angiogenesis in GEP-NETs. METHODS: Tissue microarray (TMA) blocks were constructed with 86 tumours diagnosed from 1988 to 2010. Tissue microarray sections were immunostained for hypoxia inducible factor 1α (Hif-1α), vascular endothelial growth factor-A (VEGF-A), carbonic anhydrase IX (Ca-IX) and somatostatin receptors (SSTR) 1–5, Ki-67 and CD31. Biomarker expression was correlated with clinico-pathological variables and tested for survival prediction using Kaplan–Meier and Cox regression methods. RESULTS: Eighty-six consecutive cases were included: 51% male, median age 51 (range 16–82), 68% presenting with a pancreatic primary, 95% well differentiated, 51% metastatic. Higher grading (P=0.03), advanced stage (P<0.001), high Hif-1α and low SSTR-2 expression (P=0.03) predicted for shorter overall survival (OS) on univariate analyses. Stage, SSTR-2 and Hif-1α expression were confirmed as multivariate predictors of OS. Median OS for patients with SSTR-2+/Hif-1α-tumours was not reached after median follow up of 8.8 years, whereas SSTR-2-/Hif-1α+ GEP-NETs had a median survival of only 4.2 years (P=0.006). CONCLUSION: We have identified a coherent expression signature by immunohistochemistry that can be used for patient stratification and to optimise treatment decisions in GEP-NETs independently from stage and grading. Tumours with preserved SSTR-2 and low Hif-1α expression have an indolent phenotype and may be offered less aggressive management and less stringent follow up

The TASCC of Secretion

Author Manuscript 2012 July 05The oncogene-induced activation of signaling pathways involving the tumor suppressor proteins p53 and retinoblastoma is likely an important mechanism for preventing the proliferation of potential cancer cells (1, 2). This activation causes cells to exit the cell division cycle and enter a senescent state, which is characterized by major changes in chromatin structure that are thought to render senescence irreversible. Despite the absence of proliferation, senescent cells are not as quiescent as first thought, as they signal to their surrounding environment by activating a protein secretion program (3, 4). On page 966 of this issue, Narita et al. (5) show that to enable this secretory state, a senescent cell profoundly reorganizes its endomembrane system