Beach Response to a Total Exclusion Barrage: Cardiff Bay, South Wales, UK

The regeneration of 1100 ha of derelict industrial land to the south of Cardiff included the construction of the 1.1-km-long Cardiff Bay Barrage (completed November 1999), which impounded two major South Wales rivers. A 160 m groyned beach, composed of four groynes and three bays, adjacent to and seaward of the barrage breakwater was monitored between September 1997 and September 2002 to assess pre- and postconstruction beach evolution. Overall, mean beach levels increased throughout the five-year period, resulting in a net gain of beach covering equivalent to 818.8 m3 (1800 tonnes). After barrage completion, both longshore and cross-shore gradients became less volatile and increased beach levels in the bay nearest the breakwater, prevented tidal action and erosion at the cliff toe. This was a significant change from initial conditions that was verified by parametric and nonparametric tests at the 99% confidence level. Regression analysis determined that there were significant temporal relationships. Spatial analysis identified two highly significant longshore trends with respect to distance from the breakwater and showed that this influence decreased with distance. More than 72 m from the breakwater, the regression equation (R2 = 96%) modelled a trend of falling beach levels caused by net sediment transport. Conversely, from 72 m to the breakwater, beach levels increased at a rate greater than twice the fall in the previous section (R2 = 92%). These trends were further supported by significantly greater level differences across the second groyne. Impacts of temporal and spatial trends, especially subsequent to barrage completion, were evidenced by the change in beach morphology and similar contour orientation in all three bays. Models were developed and proposed as management tools to identify potential changes in coastal processes, as well as the rate of change of the barrage's upstream influence with respect to net sediment flow. Groyne removal was suggested to provide recreational beach space

The receptor tyrosine kinase AXL promotes migration and invasion in colorectal cancer

<div><p>The receptor tyrosine kinases (RTKs) <i>TYRO3</i>, <i>AXL</i> and <i>MERTK</i> (TAM) have well-described oncogenic functions in a number of cancers. Notwithstanding, TAM RTKs are also potent and indispensable inhibitors of inflammation. The combined deletion of <i>Axl</i> and <i>Mertk</i> in mice enhances chronic inflammation and autoimmunity, including increased inflammation in the gut and colitis-associated cancer. On the other hand, deletion of <i>Tyro3</i> increases the risk of allergic responses. Therefore, the indiscriminate inhibition of these TAM RTKs could result in undesirable immunological diseases. Here we show that <i>AXL</i>, but not <i>MERTK</i> or <i>TYRO3</i> expression is enhanced in late stage colorectal cancer (CRC) and <i>AXL</i> expression associates with a cell migration gene signature. Silencing <i>AXL</i> or the inhibition of AXL kinase activity significantly inhibits tumor cell migration and invasion. These results indicate that the selective inhibition of AXL alone might confer sufficient therapeutic benefit in CRC, while preserving at least some of the beneficial, anti-inflammatory effects of MERTK and TYRO3 RTKs.</p></div

Increased expression of <i>AXL</i>, but not <i>MERTK</i> or <i>TYRO3</i>, in late state colorectal cancer.

<p><i>(A)</i> Colorectal cancers stratified based on total expression of TAM RTKs from TCGA Illumina Hi-Seq RNA-seq data. Abundance of <i>TYRO3</i>, <i>AXL</i> and <i>MERTK</i> in each tumor (an individual bar) is represented by red, green and blue segments as indicated. <i>(B)</i> Abundance of <i>AXL</i>, <i>MERTK</i> and <i>TYRO3</i> in colon and rectal adenocarcinomas at the indicated stages based on RNA-seq data from TCGA data sets. Cohen’s <i>d</i> for change in <i>AXL</i> expression between Stage I versus Stage III colorectal cancer is 0.52 (moderate effect size) and between Stage I and Stage IV is 0.54 (moderate effect size). <i>(C)</i> Expression of <i>AXL</i>, <i>MERTK</i> and <i>TYRO3</i> in colorectal adenocarcinomas at the indicated stages, as detected by RT-qPCR. Data are presented as individual samples, mean ± SEM per tumor stage. * <i>p</i><0.05; n.s., non significant.</p

Silencing AXL in human colon cancer cells does not decrease proliferation.

<p><i>(A)</i> Percentage of EdU incorporation normalized to scrambled siRNA control, in the indicated cell types transfected with scrambled or <i>AXL</i> siRNAs. <i>(B)</i> Representative FACS cell cycle analysis and <i>(C)</i> proportion of control siRNA or <i>AXL</i> siRNA-treated RKO-AS45-1 cells in G1, S and G2/M. <i>(D)</i> Representative FACS cell cycle analysis and <i>(E)</i> percentage of HCT116 cells at the indicated stages of the cell cycle after scrambled or <i>AXL</i> siRNAs transfection. <i>(F)</i> Percentage of viable RKO-AS45-1 and HCT116 after scrambled or <i>AXL</i> siRNAs transfection, as measured by Alamar Blue cell viability assay. <i>(G)</i> Representative FACS plots and <i>(H)</i> fold change in Annexin V⁺/Propidium Iodide (PI)^- and Annexin V⁺/(PI)⁺ RKO-AS45-1 cells after scrambled or <i>AXL</i> siRNAs transfection. <i>(I)</i> Representative FACS plots and <i>(J)</i> fold change in Annexin V⁺/Propidium Iodide (PI)^- and Annexin V⁺/(PI)⁺ HCT116 cells after scrambled or <i>AXL</i> siRNAs transfection. Data is presented as representative samples or as mean ± SEM of 3 independent experiments, * <i>p</i><0.05; n.s., non significant.</p

Expression of <i>AXL</i> correlates with the expression of cell migration-associated genes.

<p>Correlation between the expression of selected cell migration-associated genes, Integrins alpha 1, 5, 7 and 11, Integrins beta 1, 2 and 3, E-selectin, VCAM1, ICAM1, neuropilin 1 and 2 and ZEB1 and 2, and <i>AXL</i>, <i>MERTK</i> and <i>TYRO3</i> in TCGA. Strong Pearson correlation values > 0.7 are indicated in bold, while moderate Pearson correlation values (>0.5—<0.69) are underlined and in italics.</p

Silencing or inhibition of AXL kinase activity inhibits migration and invasion of human colon cancer cells.

<p><i>(A)</i> Representative images and <i>(B)</i> relative cell migration in a Boyden chamber assay of RKO-AS45-1 and HCT116 cells transfected with scrambled or <i>AXL</i> siRNAs. <i>(C)</i> Representative images and <i>(D)</i> relative cell invasion in a Matrigel-coated Boyden chamber assay of RKO-AS45-1 and HCT116 cells transfected with scrambled or <i>AXL</i> siRNAs. <i>(E)</i> Representative images and <i>(F)</i> relative cell migration in a scratch wound healing assay of RKO-AS45-1 treated with the indicated concentrations of the small molecule AXL inhibitor, R428 after 24 or 48h. <i>(G)</i> Representative images and <i>(H)</i> relative cell migration in a scratch wound healing assay of HCT116 cultured in the presence of the indicated concentrations of the small molecule AXL inhibitor, R428 after 24 or 48h. Data is presented as representative samples or as mean ± SEM of 3 independent experiments, * <i>p</i><0.05; ** <i>p</i><0.01; *** <i>p</i><0.001; n.s., non significant.</p