Colorectal Cancer Through Simulation and Experiment

Colorectal cancer has continued to generate a huge amount of research interest over several decades, forming a canonical example of tumourigenesis since its use in Fearon and Vogelstein’s linear model of genetic mutation. Over time, the field has witnessed a transition from solely experimental work to the inclusion of mathematical biology and computer-based modelling. The fusion of these disciplines has the potential to provide valuable insights into oncologic processes, but also presents the challenge of uniting many diverse perspectives. Furthermore, the cancer cell phenotype defined by the ‘Hallmarks of Cancer’ has been extended in recent times and provides an excellent basis for future research. We present a timely summary of the literature relating to colorectal cancer, addressing the traditional experimental findings, summarising the key mathematical and computational approaches, and emphasising the role of the Hallmarks in current and future developments. We conclude with a discussion of interdisciplinary work, outlining areas of experimental interest which would benefit from the insight that mathematical and computational modelling can provide

Radial-Growth Response of Forest-Tundra Trees to Climate in the Western Hudson Bay Lowlands

The effects of climate on radial growth of Larix laricina (Du Roi) K. Koch, Picea glauca (Moench) Voss, and Picea mariana (Mill) BSP were investigated in the Hudson Bay Lowlands of northern Manitoba. The objective was to characterize spatial and temporal variations in growth of trees across the forest-tundra ecotone. Along a 250 km transect, 299 trees were sampled in three zones: northern forest, central tundra, and southern forest. Ring-width indices were compared with climate through correlation- and response-function analyses. Numerous years of suppressed growth at the three locales resulted from cooling that followed major volcanic eruptions at much lower latitudes. Temperatures during July of the current year and autumn of the previous year were most limiting, particularly for L. laricina, which was temperature-sensitive across the region. A weakened growth response to temperature during the 1940–60 period was likely due to atmospheric circulation shifts. Most chronologies were intercorrelated, which suggests common environmental forcing, though environmental influences differed in the southern forest (particularly for P. mariana). The source of this disparity has yet to be determined.Les effets du climat sur la croissance radiale de Larix laricina (Du Roi) K. Koch, de Picea glauca (Moench) Voss et de Picea mariana (Mill) BSP ont fait l’objet d’une étude dans les basses-terres de la baie d’Hudson, au nord du Manitoba. L’objectif de cette étude consistait à caractériser les variations spatiales et temporelles en matière de croissance des arbres à l’échelle de l’écotone de la toundra forestière. Le long d’un transect de 250 km, 299 arbres ont été échantillonnés dans trois zones : la forêt septentrionale, la toundra centrale et la forêt méridionale. Les indices de la largeur des cernes ont été comparés aux données climatiques au moyen d’analyses de corrélation et de fonction de réponse. De nombreuses années de croissance affaiblie aux trois endroits découlaient du refroidissement ayant suivi d’importantes éruptions volcaniques à des latitudes beaucoup moins élevées. Les températures enregistrées en juillet de l’année courante et à l’automne de l’année précédente étaient plus restrictives, particulièrement dans le cas de L. laricina, qui était sensible aux températures dans toute la région. La réponse de croissance affaiblie enregistrée par rapport aux températures au cours de la période allant de 1940 à 1960 était vraisemblablement attribuable aux décalages de circulation atmosphérique. La plupart des chronologies ont fait l’objet d’inter-corrélations, et celles-ci laissent entrevoir un forçage environnemental courant, bien que les influences environnementales différaient dans la forêt méridionale (particulièrement dans le cas de P. mariana). La source de cette disparité n’a toujours pas été déterminée. Mots clés : dendroclimatologie, toundra forestière, Churchill, largeur des cernes, Picea glauca, Picea mariana, Larix laricina, parc national Wapusk, fonction de réponse, basses-terres de la baie d’Hudso

Skin TLR7 triggering promotes accumulation of respiratory dendritic cells and natural killer cells.

The TLR7 agonist imiquimod has been used successfully as adjuvant for skin treatment of virus-associated warts and basal cell carcinoma. The effects of skin TLR7 triggering on respiratory leukocyte populations are unknown. In a placebo-controlled experimental animal study we have used multicolour flow cytometry to systematically analyze the modulation of respiratory leukocyte subsets after skin administration of imiquimod. Compared to placebo, skin administration of imiquimod significantly increased respiratory dendritic cells (DC) and natural killer cells, whereas total respiratory leukocyte, alveolar macrophages, classical CD4+ T helper and CD8+ T killer cell numbers were not or only moderately affected. DC subpopulation analyses revealed that elevation of respiratory DC was caused by an increase of respiratory monocytic DC and CD11b(hi) DC subsets. Lymphocyte subpopulation analyses indicated a marked elevation of respiratory natural killer cells and a significant reduction of B lymphocytes. Analysis of cytokine responses of respiratory leukocytes after stimulation with Klebsiella pneumonia indicated reduced IFN-γ and TNF-α expression and increased IL-10 and IL-12p70 production after 7 day low dose skin TLR7 triggering. Additionally, respiratory NK cytotoxic activity was increased after 7d skin TLR7 triggering. In contrast, lung histology and bronchoalveolar cell counts were not affected suggesting that skin TLR7 stimulation modulated respiratory leukocyte composition without inducing overt pulmonary inflammation. These data suggest the possibility to modulate respiratory leukocyte composition and respiratory cytokine responses against pathogens like Klebsiella pneumonia through skin administration of a clinically approved TLR7 ligand. Skin administration of synthetic TLR7 ligands may represent a novel, noninvasive means to modulate respiratory immunity

Comparison of multi-year and reference year building simulations

Copyright © 2010 by SAGE PublicationsBuildings are generally modelled for compliance using reference weather years. In the UK these are the test reference year (TRY) used for energy analysis and the design summer year (DSY) used for assessing overheating in the summer. These reference years currently exist for 14 locations around the UK and consist of either a composite year compiled of the most average months from 23 years worth of observed weather data (TRY) or a single contiguous year representing a hot but non-extreme summer (DSY). In this paper, we compare simulations run using the reference years and the results obtained from simulations using the base data sets from which these reference years were chosen. We compare the posterior statistic to the reference year for several buildings examining energy use, internal temperatures, overheating and thermal comfort. We find that while the reference years allow rapid thermal modelling of building designs they are not always representative of the average energy use (TRY) exposed by modelling with many weather years. Also they do not always give an accurate indication of the internal conditions within a building and as such can give a misleading representation of the risk of overheating (DSY). Practical applications: An understanding of the limitations of the current reference years is required to allow creation of updated reference years for building simulation of future buildings. By comparing the reference years to the base data sets of historical data from which they were compiled an understanding of the benefit of multiple simulations in determining risk can be obtained