The contribution of OCTN1/2 variants within the IBD5 locus to disease susceptibility and severity in Crohn's disease

Background and Aims: Recent data suggest that polymorphisms in the organic cation transporter (OCTN) genes OCTN1 (SLC22A4) and OCTN2 (SLC22A5) represent disease-causing mutations within the IBD5 locus (chromosome 5q31). We investigated associations with disease susceptibility, phenotype, and evidence for epistasis with CARD15 in 679 patients with Crohn’s disease (CD) or ulcerative colitis (UC). Methods: A total of 374 patients with CD, 305 patients with UC, and 294 healthy controls (HCs) were studied. Genotyping for single nucleotide polymorphisms IGR2096, IGR2198, and IGR2230, OCTN1 variant (SLC22A4 1672C→T), and OCTN2 variant (SLC22A5 −207G→C) was performed using the TaqMan system. Results: The IBD5 OCTN1 and OCTN2 polymorphisms were in strong linkage disequilibrium (D′, >0.959). IGR2198 variant allele frequency (49.1% vs 40.8%; P = .0046) and homozygosity (21% vs 14.8%; P = .044) were associated with CD versus HCs. Variant allelic frequency of OCTN1 (53.6% vs 43%; P = .0008) and OCTN2 (56.1% vs 48.4%; P = .0092) polymorphisms and homozygosity for the OCTN1/2-TC haplotype (28.4% vs 16%; P = .0042) were associated with CD versus HCs. IGR2198 homozygosity and TC homozygosity were associated with stricturing/penetrating disease at follow-up (P = .011 and P = .011, respectively) and disease progression (P = .038 and P = .049, respectively) on univariate analysis and with need for surgery on multivariate analysis (P = .016 and P = .004, respectively). In the absence of the IBD5 risk haplotype, no association of OCTN1/2 variants with CD was detected. No associations were seen with UC. Conclusions: The IBD5 locus influences susceptibility, progression, and need for surgery in CD. However, the contribution of OCTN1/2 variants is not independent of the IBD5 haplotype; a causative role for these genes remains plausible but is not yet proven. Further genetic, functional, and expression data are now required. </p

Refining pathological evaluation of neoadjuvant therapy for adenocarcinoma of the esophagus

AIM: To assess tumour regression grade (TRG) and lymph node downstaging to help define patients who benefit from neoadjuvant chemotherapy.METHODS: Two hundred and eighteen consecutive patients with adenocarcinoma of the esophagus or gastro-esophageal junction treated with surgery alone or neoadjuvant chemotherapy and surgery between 2005 and 2011 at a single institution were reviewed. Triplet neoadjuvant chemotherapy consisting of platinum, fluoropyrimidine and anthracycline was considered for operable patients (World Health Organization performance status ? 2) with clinical stage T2-4 N0-1. Response to neoadjuvant chemotherapy (NAC) was assessed using TRG, as described by Mandard et al. In addition lymph node downstaging was also assessed. Lymph node downstaging was defined by cN1 at diagnosis: assessed radiologically (computed tomography, positron emission tomography, endoscopic ultrasonography), then pathologically recorded as N0 after surgery; ypN0 if NAC given prior to surgery, or pN0 if surgery alone. Patients were followed up for 5 years post surgery. Recurrence was defined radiologically, with or without pathological confirmation. An association was examined between t TRG and lymph node downstaging with disease free survival (DFS) and a comprehensive range of clinicopathological characteristics.RESULTS: Two hundred and eighteen patients underwent esophageal resection during the study interval with a mean follow up of 3 years (median follow up: 2.552, 95%CI: 2.022-3.081). There was a 1.8% (n = 4) inpatient mortality rate. One hundred and thirty-six (62.4%) patients received NAC, with 74.3% (n = 101) of patients demonstrating some signs of pathological tumour regression (TRG 1-4) and 5.9% (n = 8) having a complete pathological response. Forty four point one percent (n = 60) had downstaging of their nodal disease (cN1 to ypN0), compared to only 15.9% (n = 13) that underwent surgery alone (pre-operatively overstaged: cN1 to pN0), (P &lt; 0.0001). Response to NAC was associated with significantly increased DFS (mean DFS; TRG 1-2: 5.1 years, 95%CI: 4.6-5.6 vs TRG 3-5: 2.8 years, 95%CI: 2.2-3.3, P &lt; 0.0001). Nodal down-staging conferred a significant DFS advantage for those patients with a poor primary tumour response to NAC (median DFS; TRG 3-5 and nodal down-staging: 5.533 years, 95%CI: 3.558-7.531 vs TRG 3-5 and no nodal down-staging: 1.114 years, 95%CI: 0.961-1.267, P &lt; 0.0001).CONCLUSION: Response to NAC in the primary tumour and in the lymph nodes are both independently associated with improved DFS

Session B5: Efficiency of a Nature-Like Bypass Channel at Rodley Weir, River Aire

Abstract: Man-made physical barriers (weirs) have disrupted longitudinal connectivity in many river systems around the world for centuries. Impacts of weirs on fish communities centers on the reduced ability of fish to perform upstream migrations. To counter the potential effects these structures are having on fish communities, a number of fish pass designs have been developed to ease passage around potential barriers. To monitor the effectiveness of a recently constructed nature like bypass on the River Aire, Passive Integrated Transponder (PIT) systems were installed to observe movements of brown trout (Salmo trutta). The array consists of four swim through antennas, two at either end of the pass so that swimming direction could be determined. A total of 111 wild brown trout were caught, PIT tagged and released 380 m downstream of the fish pass entrance. In total 57 brown trout (51%) were detected on the most downstream loop, and of these 49 successfully entered the pass (86%). Thirtyeight of these successfully exited the pass in an upstream direction (78%). Further analysis found that a select number of fish used the pass as an area of refuge during high flows. The possible reasons for these findings are discussed in relation to flow, temperature, time of day, season and fish size. This information is important to improve our understanding of fish pass performance, thus informing future best practice guidance of fish passage designs

Session B4: Fine-Scale 2D Acoustic Tracking of the Behaviour of Salmonids to Investigate Delays and Failures in Fish Passage; Implications for Assessing the Efficiency of Fish Passes

Abstract: Many studies of fish passage are limited to consideration of coarse scale efficiency metrics; however the level of resolution they have for explaining changes in these metrics is often limited. In many cases assessments of fish pass performance are instigated due to (and complicated by) factors such as changes in fish pass design, construction of hydropower schemes and/or associated changes in hydro-morphology. In such cases finer scale descriptions of passage behaviour and fish pass proximity behaviour may be required to identify changes in passage efficiency and elucidate the factors influencing them. This presentation describes a five year acoustic tracking study (3 years pre and 2 years post installation of a co-located hydropower scheme with Larinier fish pass) of the 2D behaviour of 138 sea trout and 18 salmon as they approached the fish pass entrance and hydropower outfall on Ruswarp Weir (River Esk, England). The study determined the fine scale (sub-metre resolution) spatial and temporal utilisation of the fish pass pool and approach behaviours; analysing these in relation to river flows, tidal conditions, operation of the hydropower scheme, a change in design of the fish pass and the associated changes in pool morphology. In particular the analysis considered the delays in fish passage and behaviours of fish that were successful or unsuccessful in using the fish pass, and the different conditions they encountered whilst approaching the fish pass. The results showed that alongside a significant increase in the proportion of failed passages (reduced fish pass efficiency from 100% to 69% for sea trout) there was a significant increase in delay of passages and changes in the behaviour of fish and spatial utilisation of the pool. Some of these changes potentially relate to operation of the hydropower whilst others may relate to changes in the pool morphology and fish pass

Session B8: Changes in Fish Passage Metrics Following the Co-Location of a Low-Head Hydropower Turbine with an Existing Fish Pass; Revealed by an Acoustic Tracking Study of Migratory Salmonids

Abstract: Co-location of hydropower turbine outfalls with fish pass entrances has been suggested as current best practice to optimise the attraction flows for the fish pass and to mitigate the perceived negative impacts of small run-of-river hydropower schemes. To test this a five year acoustic tracking study was instigated to monitor the installation of a low-head Archimedes screw turbine alongside an existing pool-traverse fish pass on Ruswarp Weir, at the tidal limit of the River Esk (England). The study tracked the behaviour of salmon and sea trout as they approached the weir and fish pass and determined the overall passage rate (% of tagged fish ascending the weir by any route), the attraction efficiency (% of tagged fish entering the pool below the fish pass) and the fish pass efficiency (% of tagged fish detected in the pool below the fish pass that ascended the weir via the pass). Over the five years (3 years pre and 2 years post) 138 sea trout and 18 salmon were tracked using acoustic tags with arrays of fixed and mobile hydrophones to determine large-scale behaviour in the tideway and in the approach to the fish pass (a pool-traverse pass, replaced by a Larinier pass during construction of the turbine). The study showed that following the co-location of the turbine and the construction of the Larinier pass there was a significant increase in the attraction efficiency (35% to 69%) and the overall passage rate (35% to 53%) but a significant reduction in fish pass efficiency (100% to 69%) for sea trout. These results support the concept of colocating outfalls to increase attraction efficiency whilst at the same time raise concerns that this also reduced the fish pass efficiency; perhaps causing a distraction and delay to migrants, with an associated increased risk of predation

Upstream passage of adult sea trout (Salmo trutta) at a low-head weir with an Archimedean screw hydropower turbine and co-located fish pass

© 2018 CSIRO. The exploitation of riverine systems for renewable energy has resulted in large numbers of small-scale hydropower schemes on low-head weirs. Although considered a clean and 'green' energy source in terms of emissions, hydropower can affect upstream migrating species by diverting flow away from viable routes over the impoundment and attract fish towards the turbine outfall. In an attempt to reduce this negative effect, hydropower outfalls with co-located fish-passage entrances are recommended, utilising turbine flows to attract fish towards the fish pass. The present study used acoustic telemetry to understand the performance of a co-located Larinier fish pass at a low-head hydropower scheme at a weir on the tidal Yorkshire Esk, England. The majority of the sea trout (anadromous Salmo trutta L) individuals that approached the impediment were attracted to the hydropower and the co-located fish pass. Fish ascended through the pass under a wide range of river flows, tide heights, downstream river levels and hydropower flows, and there was no evidence that the hydropower operation affected fish-pass ascent. The information presented is urgently required to inform management decisions on the operation of hydropower schemes during the migratory period of salmonid fish, and help determine best-practice designs and operation at these facilities

Ontogenetic Variation in Movements and Depth Use, and Evidence of Partial Migration in a Benthopelagic Elasmobranch

Tope (Galeorhinus galeus) is a highly mobile elasmobranch in the temperate to subtropical northeast Atlantic. It is highly migratory and has been shown to display complex movement patterns, such as partial migration, in the southern hemisphere. In the northeast Atlantic, previous mark-recapture studies have struggled to identify movement patterns and the species behavior is poorly described, yet identification of migratory behaviors and habitats of importance for the species is of paramount importance for effective management. Here, we combined fisheries independent survey data with mark-recapture (MR) data to investigate the distribution of different age classes of tope across the northeast Atlantic. We further investigated depth use in detail with archival electronic tags and a pop-up satellite archival tag (PSAT). We suggest previous studies struggling to find consistent movement patterns using MR data were confounded by a combination of site fidelity, partial migration by females, and increasing depth and home range of juveniles. Survey and MR data showed immature tope <40 cm were caught exclusively in continental shelf waters <45 m deep, showing a significant relationship between habitat depth and total length. Immature individuals seemed to remain on the continental shelf, while mature tope of both genders were caught in both shelf and offshore waters. This use of deeper water habitats by mature tope was further supported by archival tags, which indicated individuals use both shallow (<200 m depth) and deep-water habitats, diving to depths of 826 m; the deepest record for this species. The PSAT tag tracked the horizontal movements of an adult male, which confirmed utilization of both shallow inshore and deep offshore habitats. Most tope remained within 500 km of their tagging site, although some mature females had a larger, more southerly range, including connectivity with the Mediterranean. This study clearly demonstrates the highly migratory habits of tope, and suggests larger individuals divide their time between shallow and deep-water habitats. It shows the northeast Atlantic tope population should benefit from consistent management throughout its range

Identification of a novel ligand for the ATAD2 bromodomain with selectivity over BRD4 through a fragment growing approach

Structure-guided expansion of a fragment hit for the ATAD2 bromodomain enabled improvement in ATAD2 inhibition and selectivity over BRD4.</p

Tumour infiltrating lymphocytes correlate with improved survival in patients with oesophageal adenocarcinoma

BACKGROUND: Oesophageal adenocarcinoma (OAC) is increasingly common in the west, and survival remains poor at 10-15 % at 5 years. Immune responses are increasingly implicated as a determining factor of tumour progression. The ability of lymphocytes to recognise tumour antigens provides a mechanism for a host immune attack against cancer providing a potential treatment strategy.MATERIALS AND METHODS: Tumour infiltrating lymphocytes (TILs: CD3+, CD4+, CD8+ and FOXp3+) were assessed by immunohistochemistry using tissue microarrays in a contemporary and homogeneous cohort of OAC patients (n = 128) undergoing curative treatment.RESULTS: Multivariate analysis identified three independent prognostic factors for improved cancer-specific survival (CSS): increased CD8+ TILs (p = 0.003), completeness of resection (p &lt; 0.0001) and lower pathological N stage (p &lt; 0.0001). Independent prognostic factors for favourable disease-free survival included surgery-only treatment (p = 0.015), completeness of resection (p = 0.001), increased CD8+ TILs (p &lt; 0.0001) and reduced pathological N stage (p &lt; 0.0001). Higher levels of TILs in the pathological specimen were associated with significant pathological response to neoadjuvant chemotherapy (NAC). On multivariate analysis increased levels of CD4+ (p = 0.017) and CD8+ TILs (p = 0.005) were associated with significant local tumour regression and lymph node downstaging, respectively.DISCUSSION: Our results establish an association of TILs and survival in OAC, as seen in other solid tumours, and identify particular TIL subsets that are present at higher levels in patients who responded to NAC compared to non-responders. These findings highlight potential therapeutic strategies in EAC based on utilising the host immunological response and highlight the immune responses biomarker potential

Developing and enhancing biodiversity monitoring programmes: a collaborative assessment of priorities

1.Biodiversity is changing at unprecedented rates, and it is increasingly important that these changes are quantified through monitoring programmes. Previous recommendations for developing or enhancing these programmes focus either on the end goals, that is the intended use of the data, or on how these goals are achieved, for example through volunteer involvement in citizen science, but not both. These recommendations are rarely prioritized. 2.We used a collaborative approach, involving 52 experts in biodiversity monitoring in the UK, to develop a list of attributes of relevance to any biodiversity monitoring programme and to order these attributes by their priority. We also ranked the attributes according to their importance in monitoring biodiversity in the UK. Experts involved included data users, funders, programme organizers and participants in data collection. They covered expertise in a wide range of taxa. 3.We developed a final list of 25 attributes of biodiversity monitoring schemes, ordered from the most elemental (those essential for monitoring schemes; e.g. articulate the objectives and gain sufficient participants) to the most aspirational (e.g. electronic data capture in the field, reporting change annually). This ordered list is a practical framework which can be used to support the development of monitoring programmes. 4.People's ranking of attributes revealed a difference between those who considered attributes with benefits to end users to be most important (e.g. people from governmental organizations) and those who considered attributes with greatest benefit to participants to be most important (e.g. people involved with volunteer biological recording schemes). This reveals a distinction between focussing on aims and the pragmatism in achieving those aims. 5.Synthesis and applications. The ordered list of attributes developed in this study will assist in prioritizing resources to develop biodiversity monitoring programmes (including citizen science). The potential conflict between end users of data and participants in data collection that we discovered should be addressed by involving the diversity of stakeholders at all stages of programme development. This will maximize the chance of successfully achieving the goals of biodiversity monitoring programmes