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Objective: To ascertain how anti-tumour necrosis factor (TNF) drug and anti-drug antibody levels testing is used in a 'real-world' setting to optimise inflammatory bowel disease (IBD) treatment., Design: Retrospective cohort study of prospectively collected patient data., Setting: Tertiary IBD centre in London, UK., Patients: All patients at Guy's and St Thomas' Hospitals on anti-TNF who had levels measured between the start of testing in 2012 and October 2014., Interventions: Anti-TNF drug and anti-drug antibody levels as part of routine monitoring., Main Outcome Measures: Indication for measuring levels and changes in management made as a result of the levels., Results: 330 infliximab levels were carried out in 199 patients and 143 adalimumab levels were carried out in 103 patients. Levels were primarily done in those with evidence of loss of response; 37% of infliximab levels and 52% of adalimumab levels. Levels resulted in a change in management in 26% of patients in infliximab group and 25% of patients in adalimumab group; however, this was greater in those with loss of response, 62% and 61% respectively. Anti-drug antibodies were detected in 7% of patients., Conclusions: Our early experience has demonstrated that measuring anti-TNF drug and anti-drug antibody levels can be useful in the optimisation of IBD management. In an increasing number of patients, particularly those with evidence of loss of response, it allows early decisions to be made regarding changing therapy. It also offers the potential for significant cost-saving by preventing pointless dose escalation in the context of therapeutic levels or when high-level anti-drug antibodies are present., Competing Interests: Competing interests: None declared.

Infrastructure associated with coastal communities is likely to not only directly displace natural systems, but also leave environmental footprints' that stretch over multiple scales. Some coastal infrastructure will, there- fore, generate a hidden layer of habitat heterogeneity in sediment systems that is not immediately observable in classical impact assessment frameworks. We examine the hidden heterogeneity associated with one of the most ubiquitous coastal modifications; dense swing moorings fields. Using a model based geo-statistical framework we highlight the variation in sedimentology throughout mooring fields and reference locations. Moorings were correlated with patches of sediment with larger particle sizes, and associated metal(loid) concentrations in these patches were depressed. Our work highlights two important ideas i) mooring fields create a mosaic of habitat in which contamination decreases and grain sizes increase close to moorings, and ii) model- based frameworks provide an information rich, easy-to-interpret way to communicate complex analyses to stakeholders., (Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.)

Historically, marine ecologists have lacked efficient tools that are capable of capturing detailed species distribution data over large areas. Emerging technologies such as high-resolution imaging and associated machine-learning image-scoring software are providing new tools to map species over large areas in the ocean. Here, we combine a novel diver propulsion vehicle (DPV) imaging system with free-to-use machine-learning software to semi-automatically generate dense and widespread abundance records of a habitat-forming algae over ~5,000 m 2 of temperate reef. We employ replicable spatial techniques to test the effectiveness of traditional diver-based sampling, and better understand the distribution and spatial arrangement of one key algal species. We found that the effectiveness of a traditional survey depended on the level of spatial structuring, and generally 10-20 transects (50 × 1 m) were required to obtain reliable results. This represents 2-20 times greater replication than have been collected in previous studies. Furthermore, we demonstrate the usefulness of fine-resolution distribution modeling for understanding patterns in canopy algae cover at multiple spatial scales, and discuss applications to other marine habitats. Our analyses demonstrate that semi-automated methods of data gathering and processing provide more accurate results than traditional methods for describing habitat structure at seascape scales, and therefore represent vastly improved techniques for understanding and managing marine seascapes.

Urbanisation in terrestrial systems has driven architects, planners, ecologists and engineers to collaborate on the design and creation of more sustainable structures. Examples include the development of 'green infrastructure' and the introduction of wildlife corridors that mitigate urban stressors and provide positive ecological outcomes. In contrast, efforts to minimise the impacts of urban developments in marine environments have been far more restricted in their extent and scope, and have often overlooked the ecological role of the built environment as potential habitat. Urban foreshore developments, i.e. those built on the interface of intertidal and/or subtidal zones, have the potential to incorporate clear multi-functional outcomes, by supporting novel ecosystems. We present a step-by-step eco-engineering framework for 'building blue' that will allow coastal managers to facilitate planning and construction of sustainable foreshore developments. Adopting such an approach will incorporate ecological principles, thereby mitigating some of the environmental impacts, creating more resilient urban infrastructure and environments, and maximising benefits to the multiple stakeholders and users of marine urban waterfronts., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Urban land and seascapes are increasingly exposed to artificial lighting at night (ALAN), which is a significant source of light pollution. A broad range of ecological effects are associated with ALAN, but the changes to ecological processes remain largely unstudied. Predation is a key ecological process that structures assemblages and responds to natural cycles of light and dark. We investigated the effect of ALAN on fish predatory behaviour, and sessile invertebrate prey assemblages. Over 21days fish and sessile assemblages were exposed to 3 light treatments (Day, Night and ALAN). An array of LED spotlights was installed under a wharf to create the ALAN treatments. We used GoPro cameras to film during the day and ALAN treatments, and a Dual frequency IDentification SONar (DIDSON) to film during the night treatments. Fish were most abundant during unlit nights, but were also relatively sedentary. Predatory behaviour was greatest during the day and under ALAN than at night, suggesting that fish are using structures for non-feeding purposes (e.g. shelter) at night, but artificial light dramatically increases their predatory behaviour. Altered predator behaviour corresponded with structural changes to sessile prey assemblages among the experimental lighting treatments. We demonstrate the direct effects of artificial lighting on fish behaviour and the concomitant indirect effects on sessile assemblage structure. Current and future projected use of artificial lights has the potential to significantly affect predator-prey interactions in marine systems by altering habitat use for both predators and prey. However, developments in lighting technology are a promising avenue for mitigation. This is among the first empirical evidence from the marine system on how ALAN can directly alter predation, a fundamental ecosystem process, and have indirect trophic consequences., (Copyright © 2016 Elsevier B.V. All rights reserved.)

On polar coasts, seasonal sea-ice duration strongly influences shallow marine environments by affecting environmental conditions, such as light, sedimentation, and physical disturbance. Sea-ice dynamics are changing in response to climate, but there is limited understanding of how this might affect shallow marine environments and benthos. Here we present a unique set of physical and biological data from a single region of Antarctic coast, and use it to gain insights into factors shaping polar benthic communities. At sites encompassing a gradient of sea-ice duration, we measured temporal and spatial variation in light and sedimentation and hard-substrate communities at different depths and substrate orientations. Biological trends were highly correlated with sea-ice duration, and appear to be driven by opposing gradients in light and sedimentation. As sea-ice duration decreased, there was increased light and reduced sedimentation, and concurrent shifts in community structure from invertebrate to algal dominance. Trends were strongest on shallower, horizontal surfaces, which are most exposed to light and sedimentation. Depth and substrate orientation appear to mediate exposure of benthos to these factors, thereby tempering effects of sea-ice and increasing biological heterogeneity. However, while light and sedimentation both varied spatially with sea-ice, their dynamics differed temporally. Light was sensitive to the site-specific date of sea-ice breakout, whereas sedimentation fluctuated at a regional scale coincident with the summer phytoplankton bloom. Sea-ice duration is clearly the overarching force structuring these shallow Antarctic benthic communities, but direct effects are imposed via light and sedimentation, and mediated by habitat characteristics., Competing Interests: The authors have declared that no competing interests exist.

Artificial reefs provide shelter and can be an important source of food for fish depending on the epibenthic community on the structure. The growth and diversity of this community is influenced by the substratum material and the surface orientation of the reef. Settlement plates of four materials (Perspex, sandstone, wood and steel) were deployed in three orientations (upwards, downwards and vertical) at a depth of 33 m on a designed artificial reef (DAR) off the coast of Sydney, Australia. After three months, the steel surfaces had lower invertebrate species richness, total abundance and diversity compared to other surfaces. Steel was not an ideal material for the initial recruitment and growth of epibenthic invertebrates. A longer duration would be required to develop a mature epibenthic community. Surface orientation had species-specific impacts. Surface material and orientation are important factors for developing epibenthic assemblages, and are thus likely to affect the broader artificial reef assemblage, including fish.

Bone loss is a well-known medical consequence of disuse such as in long-term space flight. Immobilization in many animals mimics the effects of space flight on bone mineral density. Decreases in metabolism are also thought to contribute to a loss of skeletal mass. Hibernating mammals provide a natural model of disuse and metabolic suppression. Hibernating ground squirrels have been shown to maintain bone strength despite long periods of disuse and decreased metabolism during torpor. This study examined if the lack of bone loss during torpor was a result of the decrease in metabolic rate during torpor or an evolutionary change in these animals affording protection against disuse. We delineated changes in bone density during natural disuse (torpor) and forced disuse (sciatic neurectomy) in the hind limbs of the arctic ground squirrel (AGS) over an entire year. We hypothesized that the animals would be resistant to bone loss due to immobilization and disuse during the winter hibernation season when metabolism is depressed but not the summer active season. This hypothesis was not supported. The animals maintained bone density (dual-energy X-ray absorptiometry) and most bone structural and mechanical properties in both seasons. This was observed in both natural and forced disuse, regardless of the known metabolic rate increase during the summer. However, trabecular bone volume fraction (microcomputed tomography) in the distal femur was lower in neurectomized AGS at the study endpoint. These results demonstrate a need to better understand the relationship between skeletal load (use) and bone density that may lead to therapeutics or strategies to maintain bone density in disuse conditions., (© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

Offshore oil and gas activities can result in the discharge of large amounts of drilling muds. While these materials have generally been regarded as non-toxic to marine organisms, recent studies have demonstrated negative impacts to suspension feeding organisms. We exposed the arctic-boreal sponge Geodia barretti to the primary particulate components of two water-based drilling muds; barite and bentonite. Sponges were exposed to barite, bentonite and a natural reference sediment at a range of total suspended solid concentrations (TSS = 0, 10, 50 or 100 mg/L) for 12 h after which we measured a suite of biomarker responses (lysosomal membrane stability, lipid peroxidation and glutathione). In addition, we compared biomarker responses, organic energy content and metal accumulation in sponges, which had been continuously or intermittently exposed to suspended barite and natural sediment for 14 d at relevant concentrations (10 and 30 mg TSS/L). Lysosomal membrane stability was reduced in the sponges exposed to barite at 50 and 100 mg TSS/L after just 12 h and at 30 mg TSS/L for both continuous and intermittent exposures over 14 d. Evidence of compromised cellular viability was accompanied by barite analysis revealing concentrations of Cu and Pb well above reference sediments and Norwegian sediment quality guidelines. Metal bioaccumulation in sponge tissues was low and the total organic energy content (determined by the elemental composition of organic tissue) was not affected. Intermittent exposures to barite resulted in less toxicity than continuous exposure to barite. Short term exposures to bentonite did not alter any biomarker responses. This is the first time that these biomarkers have been used to indicate contaminant exposure in an arctic-boreal sponge. Our results illustrate the potential toxicity of barite and the importance of assessments that reflect the ways in which these contaminants are delivered under environmentally realistic conditions., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Understanding interactive effects of contaminants is critical to predict how human activities change ecosystem structure and function. We examined independent and interactive effects of two contaminants (fertiliser and copper paint) on the recruitment, mortality, and total abundance of developing invertebrate communities in the field, 2, 4, 6, and 8 weeks after substrate submersion. Contaminants affected community structure differently, and produced an intermediate community in combination. Fertiliser increased recruitment and decreased mortality of active filter feeders (ascidians and barnacles), while copper paint decreased recruitment and increased mortality of some taxa. Contaminants applied together affected some taxa (e.g. Didemnid ascidians) antagonistically, as fertiliser mitigated adverse effects of copper paint. Recruitment of active filter feeders appears to be indicative of nutrient enrichment, and their increased abundance may reduce elevated nutrients in modified waterways. This study demonstrates the need to consider both independent and interactive effects of contaminants on marine communities in the field., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Biofilms are integral to many marine processes but their formation and function may be affected by anthropogenic inputs that alter environmental conditions, including fertilisers that increase nutrients. Density composition and connectivity of biofilms developed in situ (under ambient and elevated nutrients) were compared using 454-pyrosequencing of the 16S gene. Elevated nutrients shifted community composition from bacteria involved in higher processes (eg Pseudoalteromonas spp. invertebrate recruitment) towards more nutrient-tolerant bacterial species (eg Terendinibacter sp.). This may enable the persistence of biofilm communities by increasing resistance to nutrient inputs. A core biofilm microbiome was identified (predominantly Alteromonadales and Oceanospirillales) and revealed shifts in abundances of core microbes that could indicate enrichment by fertilisers. Fertiliser decreased density and connectivity within biofilms indicating that associations were disrupted perhaps via changes to energetic allocations within the core microbiome. Density composition and connectivity changes suggest nutrients can affect the stability and function of these important marine communities.

Budd-Chiari syndrome is a rare disorder characterised by hepatic venous outflow obstruction. It affects 1.4 per million people, and presentation depends upon the extent and rapidity of hepatic vein occlusion. An underlying myeloproliferative neoplasm is present in 50% of cases with other causes including infection and malignancy. Common symptoms are abdominal pain, hepatomegaly and ascites; however, up to 20% of cases are asymptomatic, indicating a chronic onset of hepatic venous obstruction and the formation of large hepatic vein collaterals. Doppler ultrasonography usually confirms diagnosis with cross-sectional imaging used for complex cases and to allow temporal comparison. Myeloproliferative neoplasms should be tested for even if a clear causative factor has been identified. Management focuses on anticoagulation with low-molecular-weight heparin and warfarin, with the new oral anticoagulants offering an exciting prospect for the future, but their current effectiveness in Budd-Chiari syndrome is unknown. A third of patients require further intervention in addition to anticoagulation, commonly due to deteriorating liver function or patients identified as having a poorer prognosis. Prognostic scoring systems help guide treatment, but management is complex and patients should be referred to a specialist liver centre. Recent studies have shown comparable procedure-related complications and long-term survival in patients who undergo transjugular intrahepatic portosystemic shunting and liver transplantation in Budd-Chiari syndrome compared with other liver disease aetiologies. Also, the optimal timing of these interventions and which patients benefit from liver transplantation instead of portosystemic shunting remains to be answered., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Global seascapes are increasingly modified to support high levels of human activity in the coastal zone. Modifications include the addition of defense structures and boating infrastructure, such as seawalls and marinas that replace natural habitats. Artificial structures support different macrofaunal communities to those found on natural rocky shores; however, little is known about differences in microbial community structure or function in urban seascapes. Understanding how artificial constructions in marine environments influence microbial communities is important as these assemblages contribute to many basic ecological processes. In this study, the bacterial communities of intertidal biofilms were compared between artificial structures (seawalls) and natural habitats (rocky shores) within Sydney Harbour. Plots were cleared on each type of habitat at eight locations. After 3 weeks the newly formed biofilm was sampled and the 16S rRNA gene sequenced using the Illumina Miseq platform. To account for differences in orientation and substrate material between seawalls and rocky shores that might have influenced our survey, we also deployed recruitment blocks next to the habitats at all locations for 3 weeks and then sampled and sequenced their microbial communities. Intertidal bacterial community structure sampled from plots differed between seawalls and rocky shores, but when substrate material, age and orientation were kept constant (with recruitment blocks) then bacterial communities were similar in composition and structure among habitats. This suggests that changes in bacterial communities on seawalls are not related to environmental differences between locations, but may be related to other intrinsic factors that differ between the habitats such as orientation, complexity, or predation. This is one of the first comparisons of intertidal microbial communities on natural and artificial surfaces and illustrates substantial ecological differences with potential consequences for biofilm function and the recruitment of macrofauna.

Strategies for managing biological invasions are often based on the premise that characteristics of invading species and the invaded environment are key predictors of the invader's distribution. Yet, for either biological traits or environmental characteristics to explain distribution, adequate time must have elapsed for species to spread to all potential habitats. We compiled and analyzed a database of natural history and ecological traits of 138 coastal marine invertebrate species, the environmental conditions at sites to which they have been introduced, and their date of first introduction. We found that time since introduction explained the largest fraction (20%) of the variability in non-native range size, while traits of the species and environmental variables had significant, but minimal, influence on non-native range size. The positive relationship between time since introduction and range size indicates that non-native marine invertebrate species are not at equilibrium and are still spreading, posing a major challenge for management of coastal ecosystems.

A 75-year-old woman was incidentally found to have deranged liver function tests (LFTs). She was well, apart from 2 years of dyspnoea. Investigations had revealed atrial fibrillation and a right pleural effusion, without identified aetiology. On examination, the only finding was a palpable liver edge. Initial blood and ultrasound screening suggested no cause. The patient underwent liver biopsy. Microscopy showed κ-immunoglobulin light chains deposited exclusively in portal tracts, within blood vessel and bile duct walls. This pattern, although unusual, raised the possibility of κ-light chain disease. Serum electrophoresis was normal, as were serum immunoglobulin values. Serum concentrations of κ-light chains were elevated and microscopy of aspirated bone marrow found light-chain deposits with 10% plasmacytosis. Serum amyloid P (SAP) scintigraphy demonstrated splenic uptake. Myeloma, κ-light chain, with light-chain amyloidosis was diagnosed. The patient has responded well to cyclophosphamide, bortazomib and dexamethasone chemotherapy, and her LFTs are now nearly normal., (2015 BMJ Publishing Group Ltd.)

Multi-use marine parks achieve conservation through spatial management of activities. Zoning of marine parks in New South Wales, Australia, includes high conservation areas and special purpose zones (SPZ) where maritime activities are concentrated. Although such measures geographically constrain anthropogenic impacts, we have limited understanding of potential ecological effects. We assessed sediment communities and contaminants adjacent to boating infrastructure (boat ramps, jetties and a marina) in a SPZ from the Clyde Estuary in Batemans Marine Park. Metal concentrations and fines content were elevated at boating structures compared to reference sites. Species richness was higher at sites with boating structures, where capitellid polychaetes and nematodes dominated the communities. Changes associated with boating structures were localised and did not extend beyond breakwalls or to reference sites outside the SPZ. The study highlights the benefits of appropriate zoning in a multi-use marine park and the potential to minimise stress on pristine areas through the application of spatial management.

Resuspended contaminated sediments represent an important route of contaminant exposure for aquatic organisms. During resuspension events, filter-feeding organisms are exposed to contaminants, in both the dissolved form (at the gills) and the particulate form (in the digestive system). In addition, these organisms must manage the physical stress associated with an increase in total suspended solids (TSS). To date, few studies have experimentally compared the contributions to biological stress of contaminated and clean suspended solids. The authors mixed field-collected sediments (<63 μm) from clean and contaminated field sites to create 4 treatments of increasing metal concentrations. Sydney rock oysters were then exposed to sediment treatments at different TSS concentrations for 4 d, and cellular biomarkers (lysosomal membrane stability, lipid peroxidation, and glutathione) were measured to evaluate sublethal toxicity. Lysosomal membrane stability was the most sensitive biomarker for distinguishing effects from resuspended contaminated sediments, as increasing amounts of contaminated TSS increased lysosomal membrane destabilization. The authors' results illustrate the importance of considering contaminant exposures from resuspended sediments when assessing the toxicity of contaminants to aquatic organisms., (© 2015 SETAC.)

Ecosystems modified by human activities are generally predicted to be biologically impoverished. However, much pollution impact theory stems from laboratory or small-scale field studies, and few studies replicate at the level of estuary. Furthermore, assessments are often based on sediment contamination and infauna, and impacts to epibiota (sessile invertebrates and algae) are seldom considered. We surveyed epibiota in six estuaries in south-east Australia. Half the estuaries were relatively pristine, and half were subject to internationally high levels of contamination, urbanisation, and industrialisation. Contrary to predictions, epibiota in modified estuaries had greater coverage and were similarly diverse as those in unmodified estuaries. Change in epibiota community structure was linearly correlated with sediment-bound copper, and the tubeworm Hydroides elegans showed a strong positive correlation with sediment metals. Stressors such as metal contamination can reduce biodiversity and productivity, but others such as nutrient enrichment and resource provision may obscure signals of impact., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Sydney rock oysters (Saccostrea glomerata) were exposed to environmental stressors at contaminated field sites or in a controlled laboratory setting. RNA seq transcriptome data were generated for the gill and digestive gland using Roche's 454 pyrosequencing technology. 28,685 contigs were de novo assembled which encoded 11,671 different protein products. The data will act as a reference for future studies in ecology, immunology and environmental toxicology., (Crown Copyright © 2014. Published by Elsevier B.V. All rights reserved.)

Background: Hemorrhagic shock (HS) following trauma is a leading cause of death among persons under the age of 40. During HS the body undergoes systemic warm ischemia followed by reperfusion during medical intervention. Ischemia/reperfusion (I/R) results in a disruption of cellular metabolic processes that ultimately lead to tissue and organ dysfunction or failure. Resistance to I/R injury is a characteristic of hibernating mammals. The present study sought to identify circulating metabolites in the rat as biomarkers for metabolic alterations associated with poor outcome after HS. Arctic ground squirrels (AGS), a hibernating species that resists I/R injury independent of decreased body temperature (warm I/R), was used as a negative control., Methodology/principal Findings: Male Sprague-Dawley rats and AGS were subject to HS by withdrawing blood to a mean arterial pressure (MAP) of 35 mmHg and maintaining the low MAP for 20 min before reperfusing with Ringers. The animals' temperature was maintained at 37 ± 0.5 °C for the duration of the experiment. Plasma samples were taken immediately before hemorrhage and three hours after reperfusion. Hydrophilic and lipid metabolites from plasma were then analyzed via 1H-NMR from unprocessed plasma and lipid extracts, respectively. Rats, susceptible to I/R injury, had a qualitative shift in their hydrophilic metabolic fingerprint including differential activation of glucose and anaerobic metabolism and had alterations in several metabolites during I/R indicative of metabolic adjustments and organ damage. In contrast, I/R injury resistant AGS, regardless of season or body temperature, maintained a stable metabolic homeostasis revealed by a qualitative 1H-NMR metabolic profile with few changes in quantified metabolites during HS-induced global I/R., Conclusions/significance: An increase in circulating metabolites indicative of anaerobic metabolism and activation of glycolytic pathways is associated with poor prognosis after HS in rats. These same biomarkers are absent in AGS after HS with warm I/R.

Habitat complexity strongly affects the structure and dynamics of ecological communities, with increased complexity often leading to greater species diversity and abundance. However, habitat complexity changes as communities develop, and some species alter their environment to themselves provide habitat for other species. Most experimental studies manipulate basal substrate complexity, and while the importance of complexity likely changes during community development, few studies have examined the temporal dynamics of this variable. We used two experiments to quantify the importance of basal substrate complexity to sessile marine invertebrate community development through space and time. First, we compared effects of substrate complexity at 70 sites across ten estuaries. Sites differed in recruitment and community development rates, and after three months provided spatial variation in community development stage. Second, we tested for effects of substrate complexity at multiple times at a single site. In both experiments, complexity affected marine sessile invertebrate community composition in the early stages of community development when resource availability was high. Effects of complexity diminished through time as the amount of available space (the primary limiting resource) declined. Our work suggests the presence of a bare-space threshold, at which structural complexity of the basal substrate is overwhelmed by secondary biotic complexity. This threshold will be met at different times depending on local recruitment and growth rates and is likely to vary with productivity gradients.

Purpose: To define the safety, efficacy, and pharmacogenetic and pharmacodynamic effects of sorafenib with gemcitabine-based chemoradiotherapy (CRT) in locally advanced pancreatic cancer., Methods and Materials: Patients received gemcitabine 1000 mg/m(2) intravenously weekly × 3 every 4 weeks per cycle for 1 cycle before CRT and continued for up to 4 cycles after CRT. Weekly gemcitabine 600 mg/m(2) intravenously was given during concurrent intensity modulated radiation therapy of 50 Gy to gross tumor volume in 25 fractions. Sorafenib was dosed orally 400 mg twice daily until progression, except during CRT when it was escalated from 200 mg to 400 mg daily, and 400 mg twice daily. The maximum tolerated dose cohort was expanded to 15 patients. Correlative studies included dynamic contrast-enhanced MRI and angiogenesis genes polymorphisms (VEGF-A and VEGF-R2 single nucleotide polymorphisms)., Results: Twenty-seven patients were enrolled. No dose-limiting toxicity occurred during induction gemcitabine/sorafenib followed by concurrent CRT. The most common grade 3/4 toxicities were fatigue, hematologic, and gastrointestinal. The maximum tolerated dose was sorafenib 400 mg twice daily. The median progression-free survival and overall survival for 25 evaluable patients were 10.6 and 12.6 months, respectively. The median overall survival for patients with VEGF-A -2578 AA, -1498 CC, and -1154 AA versus alternate genotypes was 21.6 versus 14.7 months. Dynamic contrast-enhanced MRI demonstrated higher baseline K(trans) in responding patients., Conclusions: Concurrent sorafenib with CRT had modest clinical activity with increased gastrointestinal toxicity in localized unresectable pancreatic cancer. Select VEGF-A/VEGF-R2 genotypes were associated with favorable survival., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Cost-effective and sensitive measures of anthropogenic stress are necessary tools in any environmental monitoring program. When implementing new monitoring tools in a region, rigorous laboratory and field studies are essential for characterizing the sensitivity and efficacy of the approach. We exposed the oyster Saccostrea glomerata to various individual contaminants through multiple exposure pathways (water- and food-borne) in the laboratory and measured two biomarker responses, lysosomal membrane stability (LMS) and lipid peroxidation (LPO). LMS was sensitive to both contaminant exposure pathways. We subsequently measured this biomarker in oysters which had been experimentally deployed at multiple sites in each of ten estuaries with varying levels of contamination associated with re-suspended sediments. There was a strong association between LMS and metal exposure, despite substantial natural variation in water quality parameters. Our results illustrate the potential use of LMS as a pragmatic indicator of biotic injury in environmental monitoring programs for re-suspended contaminated sediments., (Copyright © 2014. Published by Elsevier Ltd.)

Survival of incipient non-indigenous populations is dramatically altered by early predation on new colonisers. These effects can be influenced by morphological traits, such as coloniser size and density. The Australian non-native Pacific Oyster Crassostrea gigas is generally more fecund and faster growing compared to the native Saccostrea glomerata found in the same habitat. It is therefore important to quantify how the two species differ in survival across coloniser density and predation gradients. This information could become pertinent to the management of wild and aquaculture populations of the non-native C. gigas. Using a field-based factorial experiment we model the survival of incipient populations of both the native S. glomerata and the non-indigenous C. gigas as a function of coloniser density, predator reduction and individual size. Unexpectedly, survival of the non-indigenous C. gigas increased compared to S. glomerata when individuals were larger. The proportional survival of newly colonised oyster populations also increased with larger initial populations, regardless of species identity. Further, predator reduction resulted in increased survival of both oyster species, irrespective of coloniser size or initial density. Here we quantitatively demonstrate the effects of recruit density and size on enhancing the survivability of incipient oyster populations.

Several risk factors have been identified as potential contributors to pancreatic cancer development, including environmental and lifestyle factors, such as smoking, drinking and diet, and medical conditions such as diabetes and pancreatitis, all of which generate oxidative stress and DNA damage. Oxidative stress status can be modified by environmental factors and also by an individual's unique genetic makeup. Here we examined the contribution of environment and genetics to an individual's level of oxidative stress, DNA damage and susceptibility to pancreatic cancer in a pilot study using three groups of subjects: a newly diagnosed pancreatic cancer group, a healthy genetically-unrelated control group living with the case subject, and a healthy genetically-related control group which does not reside with the subject. Oxidative stress and DNA damage was evaluated by measuring total antioxidant capacity, direct and oxidative DNA damage by Comet assay, and malondialdehyde levels. Direct DNA damage was significantly elevated in pancreatic cancer patients (age and sex adjusted mean ± standard error: 1.00 ± 0.05) versus both healthy unrelated and related controls (0.70 ± 0.06, p<0.001 and 0.82 ± 0.07, p = 0.046, respectively). Analysis of 22 selected SNPs in oxidative stress and DNA damage genes revealed that CYP2A6 L160H was associated with pancreatic cancer. In addition, DNA damage was found to be associated with TNFA -308G>A and ERCC4 R415Q polymorphisms. These results suggest that measurement of DNA damage, as well as select SNPs, may provide an important screening tool to identify individuals at risk for development of pancreatic cancer.

We are now beginning to understand the role of intraspecific diversity on fundamental ecological phenomena. There exists a paucity of knowledge, however, regarding how intraspecific, or genetic diversity, may covary with other important factors such as propagule pressure. A combination of theoretical modelling and experimentation was used to explore the way propagule pressure and genetic richness may interact. We compare colonization rates of the Australian bivalve Saccostrea glomerata (Gould 1885). We cross propagule size and genetic richness in a factorial design in order to examine the generalities of our theoretical model. Modelling showed that diversity and propagule pressure should generally interact synergistically when positive feedbacks occur (e.g. aggregation). The strength of genotype effects depended on propagule size, or the numerical abundance of arriving individuals. When propagule size was very small (<4 individuals), however, greater genetic richness unexpectedly reduced colonization. The probability of S. glomerata colonization was 76% in genetically rich, larger propagules, almost 39 percentage points higher than in genetically poor propagules of similar size. This pattern was not observed in less dense, smaller propagules. We predict that density-dependent interactions between larvae in the water column may explain this pattern., (© 2013 The Authors. Journal of Animal Ecology © 2013 British Ecological Society.)

Some ecosystems can undergo abrupt transformation in response to relatively small environmental change. Identifying imminent 'tipping points' is crucial for biodiversity conservation, particularly in the face of climate change. Here, we describe a tipping point mechanism likely to induce widespread regime shifts in polar ecosystems. Seasonal snow and ice-cover periodically block sunlight reaching polar ecosystems, but the effect of this on annual light depends critically on the timing of cover within the annual solar cycle. At high latitudes, sunlight is strongly seasonal, and ice-free days around the summer solstice receive orders of magnitude more light than those in winter. Early melt that brings the date of ice-loss closer to midsummer will cause an exponential increase in the amount of sunlight reaching some ecosystems per year. This is likely to drive ecological tipping points in which primary producers (plants and algae) flourish and out-compete dark-adapted communities. We demonstrate this principle on Antarctic shallow seabed ecosystems, which our data suggest are sensitive to small changes in the timing of sea-ice loss. Algae respond to light thresholds that are easily exceeded by a slight reduction in sea-ice duration. Earlier sea-ice loss is likely to cause extensive regime shifts in which endemic shallow-water invertebrate communities are replaced by algae, reducing coastal biodiversity and fundamentally changing ecosystem functioning. Modeling shows that recent changes in ice and snow cover have already transformed annual light budgets in large areas of the Arctic and Antarctic, and both aquatic and terrestrial ecosystems are likely to experience further significant change in light. The interaction between ice-loss and solar irradiance renders polar ecosystems acutely vulnerable to abrupt ecosystem change, as light-driven tipping points are readily breached by relatively slight shifts in the timing of snow and ice-loss., (© 2013 John Wiley & Sons Ltd.)

Ecological communities are increasingly exposed to multiple chemical and physical stressors, but distinguishing anthropogenic impacts from other environmental drivers remains challenging. Rarely are multiple stressors investigated in replicated studies over large spatial scales (>1000 kms) or supported with manipulations that are necessary to interpret ecological patterns. We measured the composition of sediment infaunal communities in relation to anthropogenic and natural stressors at multiple sites within seven estuaries. We observed increases in the richness and abundance of polychaete worms in heavily modified estuaries with severe metal contamination, but no changes in the diversity or abundance of other taxa. Estuaries in which toxic contaminants were elevated also showed evidence of organic enrichment. We hypothesised that the observed response of polychaetes was not a 'positive' response to toxic contamination or a reduction in biotic competition, but due to high levels of nutrients in heavily modified estuaries driving productivity in the water column and enriching the sediment over large spatial scales. We deployed defaunated field-collected sediments from the surveyed estuaries in a small scale experiment, but observed no effects of sediment characteristics (toxic or enriching). Furthermore, invertebrate recruitment instead reflected the low diversity and abundance observed during field surveys of this relatively 'pristine' estuary. This suggests that differences observed in the survey are not a direct consequence of sediment characteristics (even severe metal contamination) but are related to parameters that covary with estuary modification such as enhanced productivity from nutrient inputs and the diversity of the local species pool. This has implications for the interpretation of diversity measures in large-scale monitoring studies in which the observed patterns may be strongly influenced by many factors that covary with anthropogenic modification.

In this study, 454 pyrosequencing of the 16S rRNA gene was used to investigate sediment bacterial community response to contaminant disturbance across six estuaries with differing levels of 'modification'. We observed a significant influence of metal and polycyclic aromatic hydrocarbon contaminants in shaping bacterial community composition, structure and diversity, with metals being the more influential contaminant. An abundant and pervasive 'core' set of bacteria found in every sample were largely responsible for mediating community response to contamination. These 13 core operational taxonomic units were mostly comprised of Gamma-, Delta-, Alphaproteobacteria and Acidobacteria. Sediment silt and metals together explained the most variation in bacterial community composition (19.7%). Following this strong contaminant signature, salinity and temperature represented important environmental variables predicting 10.9% of community variation. While overall network connectivity measures supported the idea of an inherently diverse soil microbiome with some degree of functional redundancy, lower values observed in contaminated sediments indicate potential structural perturbations in the community from fracturing or loss of bacterial associations. The large number of unclassified sequences obtained in this study contribute to improving our understanding of environmentally relevant strains in relation to anthropogenic contamination, which have been overlooked in laboratory studies., (© 2013 John Wiley & Sons Ltd and Society for Applied Microbiology.)

Despite many estuaries having high levels of metal pollution, species are found to persist in these stressful environments. Populations of estuarine invertebrates exposed to toxic concentrations of such metals may be under selection. However, in species with a wide-dispersal potential, any short-term results of localized selection may be counteracted by external recruitment from populations not under selection. The barnacle Amphibalanus variegatus is found in nearshore coastal environments as well as sheltered embayments and estuaries, including metal-impacted estuaries, from New South Wales, Australia to Western Australia. The fertilised eggs of A. variegatus are brooded internally and released as larvae (nauplii), which remain in the water-column for ~14 days before settling. Hence the species has a considerable dispersal capacity. The purpose of this study was to examine whether populations of A. variegatus from metal-impacted sites, displayed a greater tolerance to a toxicant (copper) than reference populations. Adult barnacles where collected from twenty sites within two metal-impacted and fourteen sites within two reference estuaries. Within 24 h, adults were induced to spawn and the offspring were exposed to copper in a laboratory assay. Larvae collected from the metal-impacted estuaries demonstrated a greater tolerance to copper compared to those from reference sites. To determine if selection/localised in the metal impacted sites was occurring, the genetic structure of populations at three sites was examined using an AFLP methodology. No evidence of unique population identity and or selection (outlier loci) was detected suggesting that: (1) the tolerance displayed in the assay was derived from acclimation during development; and/or (2) that the populations are open preventing the fixation of any unique alleles.

Metal-contaminated sediments pose a recognised threat to sediment-dwelling fauna. Re-mobilisation of contaminated sediments however, may impact more broadly on benthic ecosystems, including on diverse assemblages living on hard substrata patches immediately above sediments. We used manipulative field experiments to simultaneously test for the effects of metal contamination on recruitment to marine sediments and overlying hard substrata. Recruitment to sediments was strongly and negatively affected by metal contamination. However, while assemblage-level effects on hard-substratum fauna and flora were observed, most functional groups were unaffected or slightly enhanced by exposure to contaminated sediments. Diversity of hard-substratum fauna was also enhanced by metal contamination at one site. Metal-contaminated sediments appear to pose less of a hazard to hard-substratum than sediment-dwelling assemblages, perhaps due to a lower direct contaminant exposure or to indirect effects mediated by contaminant impacts on sediment fauna. Our results indicate that current sediment quality guidelines are protective of hard-substrata organisms., (Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.)

Contrasting patterns in the diversity-invasibility relationship have intrigued ecologists for many years, and are now known as the "invasion paradox." Experiments usually detect negative relationships, while field surveys find them to be positive. It is widely believed that the paradox is driven by differences in spatial scale, but this is challenged by field surveys that find positive relationships at all spatial scales. If factors that determine invasion dynamics change during the invasion process, the paradox may be partially driven by differences in temporal scale. Here we used simulation (cellular automata) models to explore the generality of temporal change in the diversity-invasibility relationship. The probability of invaders colonizing an area was inversely related to the density of natives, creating a negative native-exotic correlation when invaders first arrived. Over time, native and exotic populations were both shaped by the same post-introduction processes (disturbance, dispersal, and recolonization), shifting their correlation to positive. The rate of temporal change in the diversity-invasibility relationship was mainly dependent upon the fecundity of invaders. Greater fecundity meant that invaders spread through the landscape faster and were subject to post-introduction processes sooner. We propose a unified conceptual model where the diversity-invasiblity relationship is a function of both spatial and temporal scales.

Anthropogenic modifications to waterways are common and their ecological consequences must be understood to effectively conserve local biodiversity. The facilitation of recreational boating activities often requires substantial alteration of natural areas, however the environmental and ecological consequences of such alterations are rarely described in the scientific literature. In this study, ecological and physico-chemical conditions were investigated in a recreational boating marina, located inside a marine park on the south-east coast of Australia. Recruitment panels were deployed for 8 weeks both inside and outside the marina, and differences in the composition of the developing fouling communities were observed. The recruitment of taxa, which often have short-lived larvae, was increased inside the marina (bryozoans, spirorbids and sponges) while the recruitment of taxa, which often have longer-lived larvae, was reduced or absent (barnacles, solitary ascidians and non-spirorbid polychaetes). Differences were also observed in environmental conditions inside the marina cf. directly outside. The marina environment had higher turbidity, temperature and pH along with higher concentrations of lead and copper in suspended sediments, while flow rates and trapped sediment loads were reduced inside the marina. The differences observed in the study suggest that there may be marked environmental changes associated with marina developments. The potential ecological consequences of these changes should be a primary consideration during the planning process, particularly for developments in locations of notable ecological value.

We measured a suite of common biomarker responses for the first time in the Sydney rock oyster Saccostrea glomerata to evaluate their utility as biological effects measures for pollution monitoring. To examine the relationship between biomarker responses and population level effects, fertilisation and embryo development assays were also conducted. Adult oysters were deployed in two contaminated estuaries and a reference estuary in Sydney, Australia. The concentrations of various contaminants (metals and polycyclic aromatic hydrocarbon, PAHs) were quantified in oyster's tissue from each site and both metals and total PAHs were significantly elevated in contaminated estuaries relative to the reference estuary. Lysosomal membrane destabilisation, lipid peroxidation levels and glutathione (GSH) concentrations were measured in the digestive gland of oysters. Of all biomarkers measured, lysosomal membrane destabilisation proved to be the most useful indicator of oysters facing anthropogenic stress and we suggest this may be an especially useful biomarker for incorporation into local environmental monitoring programs. Moreover, lysosomal membrane destabilisation showed good correlations with fertilisation, normal embryo development and estuary status. GSH and lipid peroxidation were not as valuable for distinguishing between estuaries exposed to differing levels of anthropogenic stress, but did provide additional valuable information regarding overall health status of the oysters.

The global spread of invasive species may be facilitated by adaptation to the practices that humans use to manage those species. For example, marine invertebrates that adapt to metal-based antifouling biocides on ship hulls may be more likely to be introduced to and establish in metal-polluted environments. We tested this idea by studying clonal variation in tolerance to, and ability to recover from, exposure to copper in a widespread invasive marine bryozoan, Watersipora subtorquata. We cloned colonies of this organism to independently test multiple environments in a genotype by environment design, and then created a genetic variance-covariance matrix. Genotypes were exposed to a gradient of copper concentrations and growth measured during exposure and after a recovery period. There was a significant genotype × environment interaction in growth during exposure and recovery. We found clonal variation in tolerance and ability to recover from exposure to copper, with growth during exposure apparently trading off against growth after exposure. A weak genetic correlation between growth during and after exposure further indicated that they are separate traits. Overall, the genetic variation within this population indicates that there is considerable potential for adaptation to copper, but this comes at a cost to growth in unpolluted environments.

With many environments worldwide experiencing at least some degree of anthropogenic modification, there is great urgency to identify sensitive indicators of ecosystem stress. Estuarine organisms are particularly vulnerable to anthropogenic contaminants. This study presents bacterial communities as sensitive indicators of contaminant stress. Sediments were collected from multiple sites within inner and outer zones of three heavily modified and three relatively unmodified estuaries. Bacterial communities were censused using Automated Ribosomal Intergenic Spacer Analysis and analysed for a suite of metal and PAH contaminants. Shifts in both bacterial community composition and diversity showed strong associations with sediment contaminant concentrations, particularly with metals. Importantly, these changes are discernable from environmental variation inherent to highly complex estuarine environments. Moreover, variation in bacterial communities within sites was limited. This allowed for differences between sites, zones and estuaries to be explained by variables of interest such as contaminants that vary between, but not within individual sites., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Several studies have described strong relationships between body size and the accumulation of trace metals in animal tissues. However, few of these studies have utilized aging techniques to control for age related effects. We utilized relative body size (gy(-1)) of a model flounder species, Pseudorhombus jenynsii, in order to control for age related effects on growth and size measurements. We investigated links between relative body size, concentrations of trace metals in flounder muscle tissue, physico-chemical variables (temperature, salinity, pH, and turbidity), and levels of trace metals in the sediment. Flounder were sampled using an otter trawl net in the inner areas of eight estuaries that were either heavily modified or relatively unmodified by urbanization and industrial activity. Our results indicate that this commonly eaten fish is accumulating significant levels of some trace metals in their muscle tissue, both in relatively unmodified and heavily modified estuaries. Concentrations of Cu, Zn and Fe in muscle tissue, as well as temperature, showed a negative relationship to the relative body size of flounder. In contrast, Se and Hg in muscle showed a positive relationship to relative body size. Observed growth patterns indicate that these effects are not driven by age related differences in metabolic activity. Instead, our results suggest that differences in food supply or toxicological effects may be responsible for the observed relationships between relative body size and concentrations of Cu, Zn, and Se in muscle tissues. The use of otolith aging and growth measurement techniques represents a novel method for assessing the relationships between trace metal accumulation and the relative body size of fish in a field environment., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Ecological assessments over large spatial scales require that anthropogenic impacts be distinguishable above natural variation, and that monitoring tools are implemented to maximise impact detection and minimise cost. For three heavily modified and four relatively 'pristine' estuaries (disturbance category), chemical indicators (metals and PAHs) of anthropogenic stress were measured in benthic sediments, suspended sediments and deployed oysters, together with other environmental variables. These were compared with infaunal and hard-substrate invertebrate communities. Univariate analyses were useful for comparing contaminant loads between different monitoring tools and identified the strongest relationships between benthic and suspended sediments. However, multivariate analyses were necessary to distinguish ecological response to anthropogenic stressors from environmental "noise" over a large spatial scale and to identify sites that were being impacted by contaminants. These analyses provide evidence that suspended sediments are a useful alternative monitoring tool to detect potential anthropogenic impacts on benthic (infaunal and hard-substrate) communities., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Biomonitors are commonly used to assess levels of bioavailable contaminants in the environment, however the relationships between biomonitor tissue concentrations and ecological effects are rarely assessed. The present study investigated metal contamination within a highly industrialised harbour and ecological effects on sessile invertebrates. The native oyster Saccostrea glomerata was deployed as a biomonitor across twenty-six sites to test for correlations between metal levels in their tissues and the recruitment of hard-substrate invertebrates. Concentrations of lead and copper in oyster tissues were negatively correlated with densities of the dominant barnacle, Amphibalanus variegatus, and positively correlated with densities of the dominant polychaete, Hydroides elegans, and the two native encrusting bryozoans Celloporaria nodulosa and Arachnopusia unicornis. Results suggest that highly localised events drive contaminant availability and that these events pose a significant risk to fauna. Biomonitoring studies may be enhanced by running concurrent ecological surveys., (This journal is © The Royal Society of Chemistry 2012)

Artificial structures associated with shipping and boating activities provide habitats for a diverse suite of non-indigenous marine species. Little is known about the proportion of invader success in nearby waters that is attributable to these structures. Areas close to piles, wharves and piers are likely to be exposed to increasing levels of propagule pressure, enhancing the recruitment of non-indigenous species. Recruitment of non-indigenous and native marine biofouling taxa were evaluated at different distances from a large commercial shipping pier. Since artificial structures also represent a desirable habitat for fish, how predation on marine invertebrates influences the establishment of non-indigenous and native species was also evaluated. The colonisation of several non-indigenous marine species declined rapidly with distance from the structure. Little evidence was found to suggest that predators have much influence on the colonisation success of marine sessile invertebrate species, non-indigenous or otherwise. It is suggested that propagule pressure, not predation, more strongly predicts establishment success in these biofouling assemblages.

Background: Patients with advanced hepatocellular (HCC) and biliary tract carcinomas (BTC) have poor prognosis. While the EGFR pathway is overactive in HCC and BTC, single agent anti-EGFR therapies confer modest activity. Preclinical data showed synergistic antiproliferative and proapoptotic effects between anti-EGFR therapies and taxanes. We conducted a phase I study of erlotinib and docetaxel in solid tumors, and noted good tolerability and sustained complete (5 years +) and partial responses in patients with HCC and BTC. This trial evaluated the efficacy of erlotinib with docetaxel in refractory hepatobiliary cancers., Methods: Eligible patients were allowed to have two prior systemic therapies. Docetaxel 30 mg/m2 i.v. was administered on days 1, 8, 15, and erlotinib 150 mg was dosed orally on days 2-7, 9-14, 16-28 of each 28-day cycle. The primary endpoint was 16 weeks progression-free survival (PFS), and secondary endpoints included response, stable disease, and overall survival. Tumor samples were analyzed for KRAS gene mutations and E-cadherin expression by immunohistochemistry (IHC). Patients with BTC and HCC were accrued and assessed in separate strata for the efficacy endpoints, but for the two-stage initial design of the study, combined PFS was considered. A Simon optimal two-stage design tested the hypothesis that the 16-week PFS is ≤ 15% (clinically inactive) versus the alternative of ≥ 30% (warranting further study)., Results: Twenty-five patients, 14 with HCC and 11 with BTC, were enrolled. Common toxicities were rash (76%), diarrhea (56%), and fatigue (52%), mostly grade 1 or 2. No objective responses were seen. Seven BTC (64%) and 6 HCC patients (46%) had stable disease as best response, with a median duration of 16.1 weeks (95% CI 3.7-56.3) for BTC, and 17.6 weeks (95% CI 8.1-49.8) for HCC. The 16-week PFS was 64% for BTC (95% CI 29.7-84.5), and 38% for HCC (95% CI 14.1-62.8). Median overall survival was 5.7 and 6.7 months for BTC and HCC patients, respectively. BTC patients with grade ≥ 2 rash had higher median PFS (6.2 vs 2.2 months) and OS (14.2 vs. 4.2 months). HCC patients with negative/low E-cadherin expression had higher median PFS (6.7 vs. 2.1 months) and OS (14.5 vs. 4 months)., Conclusion: Erlotinib with docetaxel met the 16-week PFS ≥ 30% endpoint, but overall survival was comparable to that seen with single-agent erlotinib. With the limitation of small numbers of patients, grade ≥ 2 rash (in BTC), and negative/low E-cadherin expression (HCC) were associated with higher PFS and OS. Discussion Refractory biliary tract and hepatocellular cancers are difficult to treat, and no chemotherapy or biologically targeted therapies have impacted survival. Based on preclinical synergism and prior phase I data, we conducted a multi-institutional study sequentially combining the EGFR-targeted agent erlotinib with docetaxel. Results from this study show that the primary endpoint, 16-week PFS of ≥ 30%, was met for the combined group of BTC and HCC patients (as originally planned in the study design), as well as in each disease category: 63.6% for BTC and 38.5% for HCC patients. Nevertheless, no patients attained an objective response and the median survival of 5.7 months for BTC, and 6.7 months for HCC patients (while heavily pretreated), is comparable to that seen with single-agent EGFR-targeted therapies. Safety analysis shows that this regimen was generally well tolerated, and most adverse events were grade 1 or 2. Few patients had reversible grade 3 transaminase elevation (8%), and severe anorexia, fatigue, and rash were uncommon. As expected, patients with grade ≥ 2 rash experienced higher PFS and OS, but this was noted only among the BTC group, likely because too few HCC patients had grade ≥ 2 rash. KRAS is an important predictive marker for anti-EGFR therapies for lung and colorectal cancers, but for HCC or the heterogeneous group of BTC (with 10-50% KRAS mutations) no significant correlations have been established. We were not able to identify a correlation between KRAS and benefit from erlotinib-based therapy, as all but one HCC patient had KRAS wild type gene status. Preclinical data in multiple tumor types showed that E-cadherin, a signature marker for an "epithelial" tumor phenotype when overexpressed, predicts EGFR pathway activation and determines sensitivity to EGFR-targeted agents. E-cadherin is often seen as a poor prognostic marker when downregulated, as noted during cancer progression. Not all studies demonstrate beneficial effects from E-cadherin overexpression, possibly due to histological expression variability or tumor type specificity for this biomarker. Six BTC and 8 HCC patients had evaluable tumor samples for E-cadherin analysis. While the numbers were small and conclusions should be viewed with caution, negative/low E-cadherin expression was associated with improved PFS and OS for hepatobiliary cancers (most significant in HCC) in this refractory patient population where we expected lower expression levels. In conclusion, the combination of erlotinib with docetaxel provided a 16-week PFS of ≥ 30% but showed no appreciable differences in overall survival from historical data with single-agent erlotinib. While EGFR represents an important target in this group of malignancies, it is clear that hepatobiliary cancers are heterogeneous, thus a meaningful improvement in survival most likely will require careful treatment selection based on patient tumor's molecular and genetic profiling.

Natural systems are increasingly being modified by the addition of artificial habitats which may facilitate invasion. Where invaders are able to disperse from artificial habitats, their impact may spread to surrounding natural communities and therefore it is important to investigate potential factors that reduce or enhance invasibility. We surveyed the distribution of non-indigenous and native invertebrates and algae between artificial habitats and natural reefs in a marine subtidal system. We also deployed sandstone plates as experimental 'reefs' and manipulated the orientation, starting assemblage and degree of shading. Invertebrates (non-indigenous and native) appeared to be responding to similar environmental factors (e.g. orientation) and occupied most space on artificial structures and to a lesser extent reef walls. Non-indigenous invertebrates are less successful than native invertebrates on horizontal reefs despite functional similarities. Manipulative experiments revealed that even when non-indigenous invertebrates invade vertical "reefs", they are unlikely to gain a foothold and never exceed covers of native invertebrates (regardless of space availability). Community ecology suggests that invertebrates will dominate reef walls and algae horizontal reefs due to functional differences, however our surveys revealed that native algae dominate both vertical and horizontal reefs in shallow estuarine systems. Few non-indigenous algae were sampled in the study, however where invasive algal species are present in a system, they may present a threat to reef communities. Our findings suggest that non-indigenous species are less successful at occupying space on reef compared to artificial structures, and manipulations of biotic and abiotic conditions (primarily orientation and to a lesser extent biotic resistance) on experimental "reefs" explained a large portion of this variation, however they could not fully explain the magnitude of differences.

The global spread of fouling invasive species is continuing despite the use of antifouling biocides. Furthermore, previous evidence suggests that non-indigenous species introduced via hull fouling may be capable of adapting to metal-polluted environments. Using a laboratory based toxicity assay, we investigated tolerance to copper in the non-indigenous bryozoan Watersipora subtorquata from four source populations. Individual colonies were collected from four sites within Port Hacking (Sydney, Australia) and their offspring exposed to a range of copper concentrations. This approach, using a full-sib, split-family design, tests for a genotype by environment (G×E) interaction. Settlement and complete metamorphosis (recruitment) were measured as ecologically relevant endpoints. Larval sizes were also measured for each colony. Successful recruitment was significantly reduced by the highest copper concentration of 80μgL(-1). While there was no difference in pollution tolerance between sites, there was a significant G×E interaction, with large variation in the response of colony offspring within sites. Larval size differed significantly both between sites and between colonies and was positively correlated with tolerance. The high level of variation in copper tolerance between colonies suggests that there is considerable potential within populations to adapt to elevated copper levels, as tolerance is a heritable trait. Also, colonies that produce large larvae are more tolerant to copper, suggesting that tolerance may be a direct consequence of larger size., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Boat harbours are an increasingly common form of artificial habitat. This paper presents a comparative study of contaminants and foulers of a habitat-forming native kelp (Saccharina latissima) in four marinas and four reference locations along the south-west coast of the UK. Fouling of algal laminae was light (<2% cover) in reference locations, while epibiota cover ranged from 25% to 80% of laminae in marinas. Metals associated with antifouling paints were up to six times more concentrated in algal tissues from marinas than from the reference locations. Marinas also carried the greatest cover and diversity of non-indigenous epibiota on the kelp laminae. This indicates not only a potential stress to kelps in these environments, but also the possibility that detached laminae will act as vectors for the dispersal of non-indigenous species. The development of boat harbours creates habitats that are high risk source localities for pollution-tolerant fouling organisms., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Changes to larval fish assemblages may have far reaching ecological impacts. Correlations between habitat modification, contamination and marine larval fish communities have rarely been assessed in situ. We investigated links between the large-scale distribution of stressors and larval fish assemblages in estuarine environments. Larval fish communities were sampled using a benthic sled within the inner and outer zones of three heavily modified and three relatively unmodified estuaries. Larval abundances were significantly greater in modified estuaries, and there were trends towards greater diversity in these systems. Differences in larval community composition were strongly related to sediment metal levels and reduced seagrass cover. The differences observed were driven by two abundant species, Paedogobius kimurai and Ambassis jacksoniensis, which occurred in large numbers almost exclusively in highly contaminated and pristine locations respectively. These findings suggest that contamination and habitat alteration manifest in substantial differences in the composition of estuarine larval fish assemblages., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Manipulative field studies are useful for investigating cause-effect relationships between contamination and benthic community health. However, there are many challenges for creating environmentally relevant exposures and determining what measurements are necessary to correctly interpret the results. This study describes the physical and chemical changes in the properties of metal-spiked marine sediments deployed in four different locations for up to 11 months. The test sediments lost between 20% and 75% of their volume during the deployment period, with the greatest losses occurring at sites affected by strong hydrodynamic activity. More sediment was lost from clean treatments than those spiked with high metal concentrations and corresponded with differential recruitment of infauna to these treatments. In general, a greater proportion of spiked-metals remained at lower energy sites (48-85%) than at higher energy sites (15-48%). The decreased metal concentrations were attributed mostly to the loss of the metal-spiked sediments (through resuspension) and their dilution with sediments depositing from the surrounding environment. A range of recommendations are made for optimising the information gained from field-based studies using metal-spiked sediments. These include the careful documentation of physico-chemical sediment properties pre- and post-deployment, the use of co-located sediment traps and knowledge of site-specific hydrodynamic processes., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Biofouling increases drag on marine vessels resulting in higher fuel consumption and can also facilitate the transport of harmful non-indigenous species (NIS). Antifouling technologies incorporating biocides (e.g., copper and tributyltin) have been developed to prevent settlement of organisms on vessels, but their widespread use has introduced high levels of contamination into the environment and raised concerns about their toxic effects on marine communities. The recent global ban on tributyltin (1 January 2008) and increasing regulation of copper have prompted research and development of non-toxic paints. This review synthesises existing information regarding the ecological impact of biocides in a wide range of organisms and highlights directions for the management of antifouling paints. We focus particularly on representatives of the recent past (copper and tributyltin) and present (copper and 'booster') biocides. We identify knowledge gaps in antifouling research and provide recommendations relating to the regulation and phasing-out of copper., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

While contaminants are predicted to have measurable impacts on fish assemblages, studies have rarely assessed this potential in the context of natural variability in physico-chemical conditions within and between estuaries. We investigated links between the distribution of sediment contamination (metals and PAHs), physico-chemical variables (pH, salinity, temperature, turbidity) and beach fish assemblages in estuarine environments. Fish communities were sampled using a beach seine within the inner and outer zones of six estuaries that were either heavily modified or relatively unmodified by urbanization and industrial activity. All sampling was replicated over two years with two periods sampled each year. Shannon diversity, biomass and abundance were all significantly higher in the inner zone of estuaries while fish were larger on average in the outer zone. Strong differences in community composition were also detected between the inner and outer zones. Few differences were detected between fish assemblages in heavily modified versus relatively unmodified estuaries despite high concentrations of sediment contaminants in the inner zones of modified estuaries that exceeded recognized sediment quality guidelines. Trends in species distributions, community composition, abundance, Shannon diversity, and average fish weight were strongly correlated to physico-chemical variables and showed a weaker relationship to sediment metal contamination. Sediment PAH concentrations were not significantly related to the fish assemblage. These findings suggest that variation in some physico-chemical factors (salinity, temperature, pH) or variables that co-vary with these factors (e.g., wave activity or grain size) have a much greater influence on this fish assemblage than anthropogenic stressors such as contamination.