Enhanced sensitivity to Wnts is an emerging hallmark of a subset of cancers, defined in part by mutations regulating the abundance of their receptors. Whether these mutations identify a clinical opportunity is an important question. Inhibition of Wnt secretion by blocking an essential post-translational modification, palmitoleation, provides a useful therapeutic intervention. We developed a novel potent, orally available PORCN inhibitor, ETC-1922159 (henceforth called ETC-159) that blocks the secretion and activity of all Wnts. ETC-159 is remarkably effective in treating RSPO-translocation bearing colorectal cancer (CRC) patient derived xenografts. This is the first example of effective targeted therapy for this subset of CRC. Consistent with a central role of Wnt signaling in regulation of gene expression, inhibition of PORCN in RSPO3-translocated cancers causes a marked remodeling of the transcriptome, with loss of cell cycle, stem cell, and proliferation genes and an increase in differentiation markers. Inhibition of Wnt signaling by PORCN inhibition holds promise as differentiation therapy in genetically defined human cancers.

Porcupine (PORCN) is a membrane bound O-acyltransferase that is required for Wnt palmitoylation, secretion, and biologic activity. All evaluable human Wnts require PORCN for their activity, suggesting that inhibition of PORCN could be an effective treatment for cancers dependent on excess Wnt activity. In this study, we evaluated the PORCN inhibitor Wnt-C59 (C59), to determine its activity and toxicity in cultured cells and mice. C59 inhibits PORCN activity in vitro at nanomolar concentrations, as assessed by inhibition of Wnt palmitoylation, Wnt interaction with the carrier protein Wntless/WLS, Wnt secretion, and Wnt activation of b-catenin reporter activity. In mice, C59 displayed good bioavailability, as once daily oral administration was sufficient to maintain blood concentrations well above the IC 50 . C59 blocked progression of mammary tumors in MMTV-WNT1 transgenic mice while downregulating Wnt/b-catenin target genes. Surprisingly, mice exhibit no apparent toxicity, such that at a therapeutically effective dose there were no pathologic changes in the gut or other tissues. These results offer preclinical proof-of-concept that inhibiting mammalian Wnts can be achieved by targeting PORCN with small-molecule inhibitors such as C59, and that this is a safe and feasible strategy in vivo. Cancer Res; 73(2); 502-7. Ó2012 AACR.

The Pearl River is one of the large rivers in the world and it discharges to the northern part of the South China Sea. There has been a concern about the deterioration of dissolved oxygen conditions in the Pearl River estuary and adjacent coastal waters. In this study, historical data on dissolved oxygen (DO) from 1980, recent data from a summer cruise in 1999, and a 10-year time series in DO for 1990-2000 were used to examine spatial and temporal distribution of DO in the Pearl River estuary and adjacent coastal waters near Hong Kong. In the adjacent coastal waters, low oxygen waters <4 mg l -1 occurred in large areas during the summer of 1981, but DO rarely dropped to <3 mg l -1 . In the Pearl River estuary, DO was 3.5-4 mg l -1 in the eastern part, but was >4 mg l -1 in the western part in August 1984. In July 1999, DO was < 4 mg l -1 in a near bottom 2 m layer in a large area of the estuary and was Furthermore, the spatial distribution of DO in the bottom layer was parallel to the topography of the bottom, indicating the importance of benthic consumption of DO in the sediment and the subsequent flux of low DO waters from the sediment-water interface resuspended by physical mixing. Relative to the high loading of nitrogen from the Pearl River, the present PO 4 concentration is still low. It is possible that the lack of large areas of hypoxia in the region may be linked to phosphorus limitation as shown in the previous study. Phosphorus may also be a limiting factor for bacterial decomposition which has a strong control on total oxygen consumption in the water column and sediments.

Anti-angiogenesis represents a promising therapeutic strategy for the treatment of various malignancies. Isthmin (ISM) is a gene highly expressed in the isthmus of the midbrain–hindbrain organizer in Xenopus with no known functions. It encodes a secreted 60 kD protein containing a thrombospondin type 1 repeat domain in the central region and an adhesion-associated domain in MUC4 and other proteins (AMOP) domain at the C-terminal. In this work, we demonstrate that ISM is a novel angiogenesis inhibitor. Recombinant mouse ISM inhibited endothelial cell (EC) capillary network formation on Matrigel through its C-terminal AMOP domain. It also suppressed vascular endothelial growth factor (VEGF)-basic fibroblast growth factor (bFGF) induced in vivo angiogenesis in mouse. It mitigated VEGF-stimulated EC proliferation without affecting EC migration. Furthermore, ISM induced EC apoptosis in the presence of VEGF through a caspase-dependent pathway. ISM binds to αvβ5 integrin on EC surface and supports EC adhesion. Overexpression of ISM significantly suppressed mouse B16 melanoma tumour growth through inhibition of tumour angiogenesis without affecting tumour cell proliferation. Knockdown of isthmin in zebrafish embryos using morpholino antisense oligonucleotides led to disorganized intersegmen-tal vessels in the trunk. Our results demonstrate that ISM is a novel endogenous angiogenesis inhibitor with functions likely in physiological as well as pathological angiogenesis.

BackgroundAnthropogenically-induced climate change can alter the current climatic habitat of non-native species and can have complex effects on potentially invasive species. Predictions of the potential distributions of invasive species under climate change will provide critical information for future conservation and management strategies. Aquatic ecosystems are particularly vulnerable to invasive species and climate change, but the effect of climate change on invasive species distributions has been rather neglected, especially for notorious global invaders.Methodology/Principal FindingsWe used ecological niche models (ENMs) to assess the risks and opportunities that climate change presents for the red swamp crayfish (Procambarus clarkii), which is a worldwide aquatic invasive species. Linking the factors of climate, topography, habitat and human influence, we developed predictive models incorporating both native and non-native distribution data of the crayfish to identify present areas of potential distribution and project the effects of future climate change based on a consensus-forecast approach combining the CCCMA and HADCM3 climate models under two emission scenarios (A2a and B2a) by 2050. The minimum temperature from the coldest month, the human footprint and precipitation of the driest quarter contributed most to the species distribution models. Under both the A2a and B2a scenarios, P. clarkii shifted to higher latitudes in continents of both the northern and southern hemispheres. However, the effect of climate change varied considerately among continents with an expanding potential in Europe and contracting changes in others.Conclusions/SignificanceOur findings are the first to predict the impact of climate change on the future distribution of a globally invasive aquatic species. We confirmed the complexities of the likely effects of climate change on the potential distribution of globally invasive species, and it is extremely important to develop wide-ranging and effective control measures according to predicted geographical shifts and changes.

With accelerating species introductions in an era of globalization, co-occurring alien species have become increasingly common. Understanding the combined ecological impacts of multiple invaders is not only crucial for wildlife managers attempting to ameliorate biodiversity loss, but also provides key insights into invasion success and species coexistence mechanisms in natural ecosystems. Compared with much attentions given to single-invader impacts, little is known about the impacts of multiple co-occurring invaders. The American bullfrog (Lithobates catesbeianus = Rana catesbeiana) and the red swamp crayfish (Procambarus clarkii) are two aquatic invasive species in many different areas of the globe. They coexist with native anurans in a variety of permanent lentic waters, which provide an ideal model system to explore the combined effects of multiple invaders from different trophic levels on native species. Based on a global diet analysis covering 34 native and invasive bullfrog populations, and data from 10-year field surveys across 157 water bodies in the Zhoushan Archipelago, China, we observed a reduced impact of bullfrogs on native anurans at high crayfish densities when the two invaders co-occurred. The global diet analysis showed that crayfish occurrence reduced the number of native anuran prey consumed by bullfrogs in both native and invasive populations. After accounting for pseudoreplication of different observations among water bodies, islands, and survey time, model averaging analyses based on GLMMs showed a negative relationship between bullfrog density and native anuran densities for field observations of invasive bullfrogs alone and co-invaded observations with low crayfish density. However, this negative relationship disappeared when the two invaders co-occurred with high crayfish density. Structural equation modelling (SEM) analyses further validated that the impacts of bullfrogs on native frogs were mitigated by the negative interactions between crayfish and bullfrogs. Our results provide novel evidence of a density-dependent antagonistic effect of two sympatric invaders from different trophic levels on native species. This study highlights the importance of considering complex interactions among co-invaders and native species when prioritizing conservation and management actions and will facilitate the development of a more precise framework to predict invasion impacts.

RONO: 00Founder effects and genetic drift can reduce the genetic diversity and alter the genetic composition of introduced species during the processes of population establishment and spread. Thus, founder effects are of particular concern for introduced commercial populations (usually founded from few individuals) and for the natural populations they interact with. Bullfrogs were initially introduced in China for aquaculture purposes and escapes from farms have established many feral populations. Most of the bullfrog farms currently operative have been founded from a limited number of descendents from the original introductions, providing an excellent framework to elucidate the importance of founder effects and genetic diversity in the establishment and persistence of invasive species introduced for commercial purposes. We sequenced a region of the mitochondrial cytochrome b gene in 510 samples collected from feral and farm individuals across China and compared them to populations in their native range. Only two haplotypes (H43 and H7) were identified, and H43 identified in this study for the first time was present at high frequency in both feral and commercial populations. We show a significant difference in the relative frequency of the two identified haplotypes in commercial and feral populations, and suggest that sequential founding events are responsible for the emerging widely distributed new haplotype and the observed differences in genetic structure between bullfrog populations. Our findings indicate that lack of genetic diversity does not necessarily impair the colonizing ability of invasive species and highlight the potential threat posed by introduced commercial populations, given their unique genetic makeup.Peer reviewe

Abstract. Globally, ceremonial wildlife release events, originated from the traditions of Buddhism and other Asian religions take place in large numbers every year, and have caused conservation concerns. These releases pose a paradox in that Buddhism is generally considered to have great respect for the environment and a desire to cause no harm to any living being, yet Buddhist wildlife releases have resulted in biological invasions. We explored this paradox by evaluating the release of two highly invasive species (American bullfrogs Lithobates catesbeianus and red-eared slider turtles Trachemys scripta elegans) by 123 Buddhist temples surveyed across four provinces in China and validating survey results with intensive field surveys of release sites. We found that ecological knowledge of invasive species reduced the probability of release; conversely, market availability increased this probability. We suggest that this invasion paradox stems largely from a lack of invasive species knowledge and thus targeted public education about invasive species could be an effective strategy for preventing religious release of invasive species on a global scale.