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RATIONALE: Lung clearance index (LCI) has good intravisit repeatability with better sensitivity in detecting lung disease on computed tomography scan compared with forced expiratory volume in 1 second (FEV(1)) in adults with bronchiectasis. Alternative multiple-breath washout parameters have not been systematically studied in bronchiectasis. OBJECTIVES: To determine the validity, repeatability, sensitivity, specificity, and feasibility of standard LCI (LCI(2.5)), shortened LCI (LCI(5.0)), ventilation heterogeneity arising within proximal conducting airways (S(cond)VT), and ventilation heterogeneity arising within the acinar airways (S(acin)VT) in a cross-sectional observational cohort of adults with bronchiectasis. METHODS: Cross-sectional multiple-breath nitrogen washout data (Exhalyzer D; Eco Medics AG) from 132 patients with bronchiectasis across five United Kingdom centers (BronchUK Clinimetrics study) and 88 healthy control subjects were analyzed. RESULTS: Within-test repeatability (mean coefficient of variation) was 2) but in normal FEV(1) (z-score

When escapee farmed Atlantic salmon Salmo salar interbreed with wild fish, the introgression of maladaptive genes can lower wild population productivity and alter key life history traits. To date, only a few European studies have compared wild, farm, and hybrid salmon under common conditions in the wild, isolating the influence of genetics on survival and fitness-related traits. Here, we examined the performance of experimentally derived Atlantic salmon fry from 4 cross types (wild, farm, and reciprocal F1 hybrids) during the first summer of growth at 3 locations in southern Newfoundland. Overall survival was high, with the cross type rank order consistent across sites (mean percent recaptured: wild-mother hybrids 26.2% ≈ wild 26.0% > farm 19.2% > farm-mother hybrids 12.8%). Wild fish were smaller than wild-mother hybrids and farm fish, though differed less in size from farm-mother hybrids. At 2 out of 3 sites, wild-mother hybrids were larger than wild and farm-mother hybrid fish but had only a small size advantage over farm fish. Shape differences were small and mainly related to body depth, with the largest differences between wild and farm fish. Wild-mother hybrids had fewer parr marks than other cross types at a single site, and though differences in the size of marks were minimal, farm fish tended to have the narrowest marks. Overall, these results show that genetic differences exist for fitness-related traits among wild, farm, and hybrid juveniles, even over short temporal scales and under favourable environmental conditions, and may contribute to patterns of reduced farm-mother hybrid and feral farm survival in the wild.

Supplementary Figure S1. Distribution of HER2 expression (measured by HERmark) in all patients (left) and in 3+ IHC cohort patients (right). All patient: n=324; IHC3+: n=232.

Supplementary Table S1. Multivariate Models in the IHC 3+ Subgroup

Purpose: Expression of p95HER2 has been associated with resistance to trastuzumab-based therapy in patients with metastatic breast cancer. Conversely, high levels of HER2 have been linked with increased clinical benefit from anti-HER2 therapy. In this work, we aimed to investigate whether the levels of p95HER2 and HER2 can predict response to anti-HER2 therapy in patients with breast cancer.Experimental Design: We measured p95HER2 and HER2 by VeraTag and HERmark, respectively, in primary tumors of patients enrolled in the neoadjuvant phase III study NeoALTTO and correlated these variables with pathologic complete response (pCR) and progression-free survival (PFS) following lapatinib (L), trastuzumab (T), or the combination of both agents (L+T).Results: A positive correlation between p95HER2 and HER2 levels was found in the 274 cases (60%) in which quantification of both markers was possible. High levels of these markers were predictive for pCR, especially in the hormone receptor (HR)–positive subset of patients. High HER2 expression was associated with increased pCR rate upon L+T irrespective of the HR status. To examine whether the levels of either p95HER2 or HER2 could predict for PFS in patients treated with lapatinib, trastuzumab or L+T, we fit to the PFS data in Cox models containing log2(p95HER2) or log2(HER2). Both variables correlated with longer PFS.Conclusions: Increasing HER2 protein expression correlated with increased benefit of adding lapatinib to trastuzumab. HER2 expression is a stronger predictor of pCR and PFS than p95HER2 for response to lapatinib, trastuzumab and, more significantly, L+T. Clin Cancer Res; 21(3); 569–76. ©2014 AACR.

PURPOSE: Fluid overload is common in critical illness and is associated with mortality. This study investigated the feasibility of a randomised trial comparing conservative fluid administration and deresuscitation (active removal of accumulated fluid using diuretics or ultrafiltration) with usual care in critical illness.METHODS: Open-label, parallel-group, allocation-concealed randomised clinical feasibility trial. Mechanically ventilated adult patients expected to require critical care beyond the next calendar day were enrolled between 24 and 48 h following admission to the intensive care unit (ICU). Patients were randomised to either a 2-stage fluid strategy comprising conservative fluid administration and, if fluid overload was present, active deresuscitation, or usual care. The primary endpoint was fluid balance in the 24 h up to the start of study day 3. Secondary endpoints included cumulative fluid balance, mortality, and duration of mechanical ventilation.RESULTS: One hundred and eighty patients were randomised. After withdrawal of 1 patient, 89 patients assigned to the intervention were compared with 90 patients assigned to the usual care group. The mean plus standard deviation (SD) 24-h fluid balance up to study day 3 was lower in the intervention group (- 840 ± 1746 mL) than the usual care group (+ 130 ± 1401 mL; P CONCLUSIONS: A strategy of conservative fluid administration and active deresuscitation is feasible, reduces fluid balance compared with usual care, and may cause benefit or harm. In view of wide variations in contemporary clinical practice, large, adequately powered trials investigating the clinical effectiveness of conservative fluid strategies in critically ill patients are warranted.

Arctic charr Salvelinus alpinus are a commercially and culturally valued species for northern Indigenous peoples. Climate shifts could have important implications for charr and those that rely on them, but studies that evaluate responses to ecosystem change and the spatial scales at which they occur are rare. We compare marine-phase habitat use, long-term diet patterns, and trends in effective population size of Arctic charr from 2 areas (Nain and Saglek) of Nunatsiavut, Labrador, Canada. Tagged charr in both areas frequently occupied estuaries but some also used other habitats that extended to the headland environments outside of their natal fjords. Despite the relatively small distances separating these study areas (

It has long been clear that interbreeding between domesticated and wild Atlantic salmon can lead to negative fitness consequences for native populations. Few studies, however, have examined these consequences at critical early life stages, particularly in the context of distinct geographical and ancestral relationships among populations as well domestication selection. In Newfoundland (NF), Canada, while the majority of aquaculture sites use the North American (NA) Saint John River strain, site-specific permission has been granted to farm a strain of European origin (EO). We designed a common-garden experiment to compare fitness-related traits (e.g. development time, survival, size and growth) at different early-life stages (eye development, hatch and yolk absorption) among EO and NA farmed, 2 NF wild and F1 hybrid groups. Significant differences (p < 0.001) were observed in development time, survival, growth and energy conversion among farmed, F1 hybrid and wild populations. While pure populations (farmed and wild) differed amongst one another, we found few differences in fitness-related traits between F1 hybrids and their maternal wild/farmed strains. This suggests that the early-life fitness consequences of F1 hybridization will be largely manifested through the action of maternal effects. Additionally, significant associations between the maternal effects of egg size and alevin development time, size, survival, growth, condition and energy conversion efficiency were found. These findings suggest that early-life fitness-related trait differences among farmed, wild and their related F1 hybrids are generated by the geographic and ancestral relationship and maternal effects of egg size and less so by domestication selection.

Characterizing the nature of genetic differentiation among individuals and populations and its distribution across the genome is increasingly important to inform both conservation and management of exploited species. Atlantic Halibut (Hippoglossus hippoglossus) is an ecologically and commercially important fish species, yet knowledge of population structure and genomic diversity in this species remains lacking. Here, we use restriction-site associated DNA sequencing and a chromosome-level genome assembly to identify over 86 000 single nucleotide polymorphisms mapped to 24 chromosome-sized scaffolds, genotyped in 734 individuals across the Northwest Atlantic. We describe subtle but significant genome-wide regional structuring between the Gulf of St. Lawrence and adjacent Atlantic continental shelf. However, the majority of genetic divergence is associated with a large putative chromosomal rearrangement (5.74 megabases) displaying high differentiation and linkage disequilibrium, but no evidence of geographic variation. Demographic reconstructions suggest periods of expansion coinciding with glacial retreat, and more recent declines in Ne. This work highlights the utility of genomic data to identify multiple sources of genetic structure and genomic diversity in commercially exploited marine species.

Atlantic salmon (Salmo salar) populations throughout the North Atlantic have declined in recent decades largely due to reduced marine survival, yet our understanding of marine distribution patterns and migratory routes remains limited. Here, we assigned archived individual samples (n = 3891) collected over a half century (1968–2018) throughout the North Atlantic to region of origin using range-wide genetic assignment. In the Northwest Atlantic, the distribution of assignments reinforced the importance of the Labrador Sea as an aggregation area, with 73% of all reporting groups detected. Moreover, individuals from six European reporting groups were identified in the Northwest Atlantic, and detections decreased with decreasing latitude spanning an area from Greenland to southern Newfoundland. In the Northeast Atlantic, six North American reporting groups were detected in samples from around the Faroe Islands. Based on the distribution of samples, estimates of trans-Atlantic migration distance averaged 3861 and 2889 km for North American and European salmon respectively. Our analysis highlights the widespread importance of the Labrador Sea and Faroe Islands to the species marine distribution patterns, and the prevalence of long-distance trans-Atlantic migration. Ultimately, the results suggest that environmental conditions experienced by many Atlantic salmon populations span much of the North Atlantic Ocean.

Endocrine therapy (ET) is recommended as first-line therapy for the majority of patients with hormone receptor-positive (HR+), human epidermal growth factor 2-negative advanced breast cancer (ABC); however, the efficacy of ET in patients with visceral metastases (VM) versus patients whose disease is limited to non-visceral metastases (non-VM) is debated. Meta-analyses including available data from randomised controlled trials of first- and second-line endocrine monotherapies for patients with HR+ ABC were performed to address this question. In one and two-stage meta-analyses, progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR) and duration of clinical benefit (DoCB) outcomes were analysed. In the first-line meta-analysis (seven trials; n = 1988) tamoxifen and fulvestrant significantly improved PFS, OS and CBR for patients with non-VM versus those whose disease included VM. The most substantial hazard ratios were observed for fulvestrant 500 mg; 0.56 (95% confidence interval [CI] 0.45−0.70) and 0.55 (95% CI 0.42−0.72) for PFS and OS, respectively. In the second-line meta-analysis (seven trials; n = 2324), all ET combined was more effective (in terms of PFS, OS and DoCB) for non-VM versus VM. In both meta-analyses, patients with non-liver VM had better clinical outcomes than patients with liver VM for all types of ET. Patients whose disease included non-VM sites had better clinical outcomes with endocrine monotherapy compared with patients whose disease included VM. These findings may facilitate better informed treatment decision-making.

Despite widespread biodiversity losses, an understanding of how most taxa will respond to future climate change is lacking. Here we integrate genomics and environmental modelling to assess climate change responses in an ecologically and economically important Arctic species. Environmentally associated genomic diversity and machine learning are used to identify highly vulnerable populations of anadromous (migratory) Arctic charr, and we reconstruct estimates of effective population size spanning the twentieth century to identify past climate-associated declines. We uncover past region-wide declines in effective population size that correspond to decreases in temperature and community biomass in the Northwest Atlantic. We find vulnerable populations near the southern range limit, indicating northward shifts and a possible loss of commercially important life-history variation in response to climate change. The genomic approach used here to investigate climate change response identifies past and future declines that impact species persistence, ecosystem stability and food security in the Arctic. Genomics and environmental modelling are integrated to assess past and future changes in Arctic charr populations in response to changing climate. Southern population vulnerability suggests climate change may lead to northward shifts and the loss of important life-history variation.

Cultured Atlantic salmon Salmo salar are of international socioeconomic value, and the process of domestication has resulted in significant behavioural, morphological, and allelic differences from wild populations. Substantial evidence indicates that direct genetic interactions or interbreeding between wild and escaped farmed Atlantic salmon occurs, genetically altering wild salmon and reducing population viability. However, genetic interactions may also occur through ecological mechanisms (e.g. disease, parasites, predation, competition), both in conjunction with and in the absence of interbreeding. Here we examine existing evidence for ecological and non-reproductive genetic interactions between domestic Atlantic salmon and wild populations and the potential use of genetic and genomic tools to resolve these impacts. Our review identified examples of genetic changes resulting from ecological processes, predominately through pathogen or parasite transmission. In addition, many examples were identified where aquaculture activities have either altered the selective landscape experienced by wild populations or resulted in reductions in population abundance, both of which are consistent with the widespread occurrence of indirect genetic changes. We further identify opportunities for genetic or genomic methods to quantify these impacts, though careful experimental design and pre-impact comparisons are often needed to accurately attribute genetic change to aquaculture activities. Our review indicates that ecological and non-reproductive genetic interactions are important, and further study is urgently needed to support an integrated understanding of aquaculture-ecosystem interactions, their implications for ecosystem stability, and the development of potential mitigation and management strategies.

The genetic underpinnings of incipient speciation, including the genomic mechanisms which contribute to morphological and ecological differentiation and reproductive isolation, remain poorly understood. The repeated evolution of consistently, phenotypically distinct morphs of Arctic Charr (Salvelinus alpinus) within the Quaternary period offer an ideal model to study the repeatability of evolution at the genomic level. Sympatric morphs of Arctic Charr are found across this species' circumpolar distribution. However, the specific genetic mechanisms driving this morph differentiation are largely unknown despite the cultural and economic importance of the anadromous morph. We used a newly designed 87k SNP chip to investigate the character and consistency of the genomic differences among sympatric morphs within three recently deglaciated and geographically proximate lakes in Labrador, Canada. We found genetically distinct small and large morph Arctic Charr in all three lakes consistent with resident and anadromous morphs, respectively. A degree of reproductive isolation among sympatric morphs is likely given genome-wide distributions of outlier SNPs and high genome-wide FST s. Across all lakes, outlier SNPs were largely nonoverlapping suggesting a lack of genetic parallelism driving morph differentiation. Alternatively, several genes and paralogous copies of the same gene consistently differentiated morphs across multiple lakes suggesting their importance to the manifestation of morphs. Our results confirm the utility of Arctic Charr as a model for investigating the predictability of evolution and support the importance of both genetic parallelism and nonparallelism to the incipient speciation of Arctic Charr morphs.

The resiliency of populations and species to environmental change is dependent on the maintenance of genetic diversity, and as such, quantifying diversity is central to combating ongoing widespread reductions in biodiversity. With the advent of next‐generation sequencing, several methods now exist for resolving fine‐scale population structure, but the comparative performance of these methods for genetic assignment has rarely been tested. Here, we evaluate the performance of sequenced microsatellites and a single nucleotide polymorphism (SNP) array to resolve fine‐scale population structure in a critically important salmonid in north eastern Canada, Arctic Charr (Salvelinus alpinus). We also assess the utility of sequenced microsatellites for fisheries applications by quantifying the spatial scales of movement and exploitation through genetic assignment of fishery samples to rivers of origin and comparing these results with a 29‐year tagging dataset. Self‐assignment and simulation‐based analyses of 111 genome‐wide microsatellite loci and 500 informative SNPs from 28 populations of Arctic Charr in north‐eastern Canada identified largely river‐specific genetic structure. Despite large differences (~4X) in the number of loci surveyed between panels, mean self‐assignment accuracy was similar with the microsatellite loci and the SNP panel (>90%). Subsequent analysis of 996 fishery‐collected samples using the microsatellite panel revealed that larger rivers contribute greater numbers of individuals to the fishery and that coastal fisheries largely exploit individuals originating from nearby rivers, corroborating results from traditional tagging experiments. Our results demonstrate the efficacy of sequence‐based microsatellite genotyping to advance understanding of fine‐scale population structure and harvest composition in northern and understudied species.

Many populations of freshwater fishes are threatened with losses, and increasingly, the release of hatchery individuals is one strategy being implemented to support wild populations. However, stocking of hatchery individuals may pose long‐term threats to wild populations, particularly if genetic interactions occur between wild and hatchery individuals. One highly prized sport fish that has been heavily stocked throughout its range is the brook trout (Salvelinus fontinalis). In Nova Scotia, Canada, hatchery brook trout have been stocked since the early 1900s, and despite continued stocking efforts, populations have suffered declines in recent decades. Before this study, the genetic structure of brook trout populations in the province was unknown; however, given the potential negative consequences associated with hatchery stocking, it is possible that hatchery programs have adversely affected the genetic integrity of wild populations. To assess the influence of hatchery supplementation on wild populations, we genotyped wild brook trout from 12 river systems and hatchery brook trout from two major hatcheries using 100 microsatellite loci. Genetic analyses of wild trout revealed extensive population genetic structure among and within river systems and significant isolation‐by‐distance. Hatchery stocks were genetically distinct from wild populations, and most populations showed limited to no evidence of hatchery introgression (

Genetic interactions (i.e. hybridization) between wild and escaped Atlantic salmon Salmo salar from aquaculture operations have been widely documented, yet the ability to incorporate predictions of risk into aquaculture siting advice has been limited. Here we demonstrate a model-based approach to assessing these potential genetic interactions using a salmon aquaculture expansion scenario in southern Newfoundland as an example. We use an eco-genetic individual-based Atlantic salmon model (IBSEM) parameterized for southern Newfoundland populations, with regional environmental data and field-based estimates of survival, to explore how the proportion of escapees relative to the size of wild populations could potentially influence genetic and demographic changes in wild populations. Our simulations suggest that both demographic decline and genetic change are predicted when the percentage of escapees in a river relative to wild population size is equal to or exceeds 10% annually. The occurrence of escapees in southern Newfoundland rivers under a proposed expansion scenario was predicted using river and site locations and models of dispersal for early and late escapees. Model predictions of escapee dispersal suggest that under the proposed expansion scenario, the number of escapees is expected to increase by 49% and the highest escapee concentrations will shift westward, consistent with the location of proposed expansion (20 rivers total >10% escapees, max 24%). Our results identify susceptible rivers and potential impacts predicted under the proposed aquaculture expansion scenario and illustrate how model-based predictions of both escapee dispersal and genetic impacts can be used to inform both aquaculture management decisions and wild salmon conservation.

Supergenes are sets of genes that are inherited as a single marker and encode complex phenotypes through their joint action. They are identified in an increasing number of organisms, yet their origins and evolution remain enigmatic. In Atlantic cod, four megabase-scale supergenes have been identified and linked to migratory lifestyle and environmental adaptations. Here we investigate the origin and maintenance of these four supergenes through analysis of whole-genome-sequencing data, including a new long-read-based genome assembly for a non-migratory Atlantic cod individual. We corroborate the finding that chromosomal inversions underlie all four supergenes, and we show that they originated at different times between 0.40 and 1.66 million years ago. We reveal gene flux between supergene haplotypes where migratory and stationary Atlantic cod co-occur and conclude that this gene flux is driven by gene conversion, on the basis of an increase in GC content in exchanged sites. Additionally, we find evidence for double crossover between supergene haplotypes, leading to the exchange of an ~275 kilobase fragment with genes potentially involved in adaptation to low salinity in the Baltic Sea. Our results suggest that supergenes can be maintained over long timescales in the same way as hybridizing species, through the selective purging of introduced genetic variation.

Hybridization between wild and escaped cultured Atlantic salmon (Salmo salar) can threaten the stability and persistence of locally adapted wild populations. Here we describe the development and validation of a genomic-based approach to quantify recent hybridization between escapee and wild salmon in the western Atlantic. Based on genome-wide single nucleotide polymorphism (SNP) scans of wild and cultured salmon, collectively diagnostic panels were created for Newfoundland and the Canadian Maritimes. These panels were capable of both discriminating hybrids from nonhybrids and of correctly assigning individuals to hybrid class (i.e., pure wild, pure farm, F1, F2, and backcrosses) with a high degree of accuracy (Newfoundland 96 SNPs > 90%, Maritimes 720 SNPs > 80%). These genomic panels permit the assessment of the impacts of past and future farmed salmon escape events on wild populations and can inform the protection and conservation of wild Atlantic salmon genetic integrity in the western Atlantic.

To develop more reliable marine species distribution models (SDMs), we examine how genetic, climatic, and biotic interaction gradients give rise to prediction error in marine SDM. Genetic lineages with distinct ecological requirements spanning genetic gradients have yet to be treated separately in marine SDM, which are often constrained to modeling the potential distribution of one biological unit (e.g. lineage or species) at a time. By comparing SDM performance for the whole species or where observation and predictions were partitioned among geographically discontinuous genetic lineages, we first identified the appropriate biological unit for modeling sea scallop. Prediction errors, in particular contiguous omissions at the northern range margins were effectively halved in genetic lineage SDM (Total error=15%) verses whole species SDM. Remaining SDM prediction error was strongly associated with: i) Sharp climatic gradients (abrupt and persistent spatial shifts in limiting temperatures) found within continental shelf breaks and bottom channels. ii) A biotic gradient in the predation of sea scallop juveniles by the sand star within the Hudson Shelf USA. Our findings highlight how the accuracy of marine SDM is dependent on capturing the appropriate biological unit for modeling (e.g. lineages rather than species) and adequately resolving limiting abiotic and biotic interaction gradients.

Pleistocene glaciations drove repeated range contractions and expansions shaping contemporary intraspecific diversity. Atlantic salmon (Salmo salar) in the western and eastern Atlantic diverged >600,000 years before present, with the two lineages isolated in different southern refugia during glacial maxima, driving trans-Atlantic genomic and karyotypic divergence. Here, we investigate the genomic consequences of glacial isolation and trans-Atlantic secondary contact using 108,870 single nucleotide polymorphisms genotyped in 80 North American and European populations. Throughout North America, we identified extensive interindividual variation and discrete linkage blocks within and between chromosomes with known trans-Atlantic differences in rearrangements: Ssa01/Ssa23 translocation and Ssa08/Ssa29 fusion. Spatial genetic analyses suggest independence of rearrangements, with Ssa01/Ssa23 showing high European introgression (>50%) in northern populations indicative of post-glacial trans-Atlantic secondary contact, contrasting with low European ancestry genome-wide (3%). Ssa08/Ssa29 showed greater intrapopulation diversity, suggesting a derived chromosome fusion polymorphism that evolved within North America. Evidence of potential selection on both genomic regions suggests that the adaptive role of rearrangements warrants further investigation in Atlantic salmon. Our study highlights how Pleistocene glaciations can influence large-scale intraspecific variation in genomic architecture of northern species.

There is a prevailing belief that ET for HR+ advanced BC is not as effective in patients with visceral metastases (VM) compared to non-visceral metastases (nVM), particularly with later lines of ET. Recently fulvestrant 500mg (Ful 500), has been reported to have greater efficacy in nVM compared to i) VM treated by Ful 500 but also compared to ii) nVM treated by Ful 250 (2nd line) and iii) nVM treated by aromatase inhibitor (AI), anastrozole (1st Line) – implying both site and agent related efficacy. Absence of significant overall survival (OS) difference in PALOMA 3 (2nd line) has increased the debate regarding when to add CDK 4/6is to ET, especially given the OS advantage for Ful 500 monotherapy in the 1st & 2nd line settings. Patients & Methods: Anonymised, individual patient level data was obtained from randomised controlled trials (RCTs) involving AI & SERD used as mono-theraphy in 2nd or 3rd Line setting in known HR+ BC. All the trials were Phase 3 double-blind, placebo RCTs. All were rigorously assessed for clinical benefit (CB), progression free survival (PFS), duration of CB (DoCB) and OS. Details of the studies, types of ET and patient numbers are shown in the Table. Results: Outcome data is presented for each study and then summarised under AI, SERD (Ful 250 or 500) and 'all Ets combined'. Odds ratios (Ors) & hazard ratios (HRs) for VM versus nVM by endocrine agents are shown in the Table. AgentStudyTotal Pats.HR+ Pats.CBRPFSOSDoCBAI(n)(n)OR (95%Cis)HR (95%Cis)HR (95%Cis)HR (95%Cis)Exe00202301831.181.441.271.50Exe00211931681.151.951.832.12AnaEFECT3403360.941.521.201.10AnaSOFEA2492491.291.181.051.41subtotal7636871.11 (0.84-1.48)1.47*** (1.22-1.79)1.21* (1.01-1.45)1.43** (1.10-1.86)SERDFul 25000202191601.791.701.401.23Ful 25000212041771.281.811.322.06Ful 250EFECT3513450.791.401.311.03Ful 250SOFEA2312310.701.171.242.22Ful 250CONFIRM1521521.131.071.510.84Subtotal9268341.05 (0.75-1.45)1.39*** (1.16-1.67)1.34*** (1.14-1.57)1.36 (0.93-1.98)SERDFul 500CONFIRM1441442.24 (1.12-4.48)1.30 (0.90-1.87)1.33 (1.14-1.57)0.97 (0.55-1.66)All ETsTotal183316651.13 (0.92-1.39)1.42*** (1.26-1.59)1.28*** (1.14-1.44)1.35** (1.09-1.66) [Pats=Patients; (n)=number; CBR-Clinical Benefit Rate; p-values p Median PFS (months) for nVM for AI, SERD250, SERD500 & ‘all Ets combined’ were 5.4, 5.5, 11.0 & 5.5 respectively: for VM they were 2.9, 3.5, 5.5 & 3.2 respectively. Median OS (months) for nVM for AI, SERD250, SERD500 & ‘all Ets combined’ was 24.2, 26.0, 35.4 & 25.4 respectively: for VM the figures were 22.8, 20.8, 26.4 & 22.0 respectively.Conclusions:1) In the 2nd line HR+ setting AI & Ful 250 both significantly increased PFS & OS in nVM versus VM. Longer PFS appears due to longer duration of control (DoCB) than increasing the number of patients responding (CBR). 2) Median OS for nVM ranged from 24 – 35 months versus 20.8-26.4 months for VM: for the majority of patients the 2nd line ET setting is not ‘immediately life threating’ and ET is therefore an option to consider. 3) These data on site of disease (nVM vs VM) contribute to the selection of which patients should receive endocrine mono- and which endocrine combination therapy (ie plus mTORi or CDK4/6i) in the second line setting. Citation Format: Robertson JFR, Di Leo A, Johnston S, Chia S, Bliss J, Bradbury I, Campbell C. Meta-analyses of visceral versus non-visceral metastases treated by AI & SERD agents as 2nd line endocrine therapy (ET) for HR+ breast cancer (BC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-13.

Predicting how species will respond to future climate change is of central importance in the midst of the global biodiversity crisis, and recent work has demonstrated the utility of population genomics for improving these predictions. Here, we suggest a broadening of the approach to include other types of genomic variants that play an important role in adaptation, like structural (e.g. copy number variants) and epigenetic variants (e.g. DNA methylation). These data could provide additional power for forecasting response, especially in weakly structured or panmictic species. Incorporating structural and epigenetic variation into estimates of climate change vulnerability, or maladaptation, may not only improve prediction power but also provide insight into the molecular mechanisms underpinning species' response to climate change.

The post-glacial colonization of Gander Lake in Newfoundland, Canada, by Arctic Charr (Salvelinus alpinus) provides the opportunity to study the genomic basis of adaptation to extreme deep-water environments. Colonization of deep-water (>50 m) habitats often requires extensive adaptation to cope with novel environmental challenges from high hydrostatic pressure, low temperature, and low light, but the genomic mechanisms underlying evolution in these environments are rarely known. Here, we compare genomic divergence between a deep-water morph adapted to depths of up to 288 m and a larger, piscivorous pelagic morph occupying shallower depths. Using both a SNP array and resequencing of whole nuclear and mitochondrial genomes, we find clear genetic divergence (FST = 0.11-0.15) between deep and shallow water morphs, despite an absence of morph divergence across the mitochondrial genome. Outlier analyses identified many diverged genomic regions containing genes enriched for processes such as gene expression and DNA repair, cardiac function, and membrane transport. Detection of putative copy number variants (CNVs) uncovered 385 genes with CNVs distinct to piscivorous morphs, and 275 genes with CNVs distinct to deep-water morphs, enriched for processes associated with synapse assembly. Demographic analyses identified evidence for recent and local morph divergence, and ongoing reductions in diversity consistent with postglacial colonization. Together, these results show that Arctic Charr morph divergence has occurred through genome-wide differentiation and elevated divergence of genes underlying multiple cellular and physiological processes, providing insight into the genomic basis of adaptation in a deep-water habitat following postglacial recolonization.

Supergenes are sets of genes that are inherited as a single marker and encode complex phenotypes through their joint action. They are identified in an increasing number of organisms, yet their origins and evolution remain enigmatic. In Atlantic cod, four large supergenes have been identified and linked to migratory lifestyle and environmental adaptations. Here, we investigate the origin and fate of these four supergenes through analysis of whole-genome-sequencing data, including a new long-read-based genome assembly for a non-migratory Atlantic cod individual. We corroborate that chromosomal inversions underlie all four supergenes, and show that they originated separately, between 0.40 and 1.66 million years ago. While introgression was not involved in the origin of the four supergenes, we reveal gene flow between inverted and noninverted supergene haplotypes, occurring both through gene conversion and double crossover. Moreover, the presence of genes linked to salinity adaptations in a sequence transferred through double crossover indicates that these sequences exchanged between the haplotypes are subject to selection. Our results suggest that the fate of supergenes is comparable to that of hybridizing species, by depending on the degree to which separation is maintained through purging of introduced genetic variation.

Chromosomal rearrangements (e.g., inversions, fusions, and translocations) have long been associated with environmental variation in wild populations. New genomic tools provide the opportunity to examine the role of these structural variants in shaping adaptive differences within and among wild populations of non-model organisms. In Atlantic Salmon (Salmo salar), variations in chromosomal rearrangements exist across the species natural range, yet the role and importance of these structural variants in maintaining adaptive differences among wild populations remains poorly understood. We genotyped Atlantic Salmon (n = 1429) from 26 populations within a highly genetically structured region of southern Newfoundland, Canada with a 220K SNP array. Multivariate analysis, across two independent years, consistently identified variation in a structural variant (translocation between chromosomes Ssa01 and Ssa23), previously associated with evidence of trans-Atlantic secondary contact, as the dominant factor influencing population structure in the region. Redundancy analysis suggested that variation in the Ssa01/Ssa23 chromosomal translocation is strongly correlated with temperature. Our analyses suggest environmentally mediated selection acting on standing genetic variation in genomic architecture introduced through secondary contact may underpin fine-scale local adaptation in Placentia Bay, Newfoundland, Canada, a large and deep embayment, highlighting the importance of chromosomal structural variation as a driver of contemporary adaptive divergence.

Significance Both theory and experiments suggest that fishing can drive the evolution of an earlier maturation age. However, determining whether changes in the wild are the result of fisheries-induced evolution has been difficult. Temporal, genome-wide datasets can directly reveal responses to selection. Here, we investigate the genomes of two wild Atlantic cod populations from samples that pre- and postdate periods of intensive fishing. Although phenotypic changes suggest fisheries-induced evolution, we do not find evidence for any strong genomic change or loss of genetic diversity. While evolution could have occurred through undetectable frequency changes at many loci, the irreversible loss of late-maturing genotypes appears unlikely. Instead, we suggest that recovery of former phenotypes is possible with reduced fishing pressure., The mode and extent of rapid evolution and genomic change in response to human harvesting are key conservation issues. Although experiments and models have shown a high potential for both genetic and phenotypic change in response to fishing, empirical examples of genetic responses in wild populations are rare. Here, we compare whole-genome sequence data of Atlantic cod (Gadus morhua) that were collected before (early 20th century) and after (early 21st century) periods of intensive exploitation and rapid decline in the age of maturation from two geographically distinct populations in Newfoundland, Canada, and the northeast Arctic, Norway. Our temporal, genome-wide analyses of 346,290 loci show no substantial loss of genetic diversity and high effective population sizes. Moreover, we do not find distinct signals of strong selective sweeps anywhere in the genome, although we cannot rule out the possibility of highly polygenic evolution. Our observations suggest that phenotypic change in these populations is not constrained by irreversible loss of genomic variation and thus imply that former traits could be reestablished with demographic recovery.

Background: It remains clinically important to identify ER positive breast cancers likely to respond to tamoxifen (TAM) and so we aimed to select a group of biomarkers able to predict response. We also assessed whether data from different sample types [tumor microarrays (TMAs) and core biopsies] or tumor sites could be combined for biomarker studies. Methods: A total of 123 endocrine treatment naïve patients with known ER and HER2 status treated with TAM had paraffin-embedded tumor tissue available either as TMAs (n=102) or core biopsies (n=21). TMA cores were collected from three different tumor sites, two central and one peripheral. Ten biomarkers were evaluated by immunohistochemistry, for % positivity and/or H-Score, comprising: ER, HER2, Ki67, phosphorylated forms of ER (Ser118), IGF1R, PRAS40, Akt & MAPK (ERK1/2), and PTEN & androgen receptor expression (AR). Each tumor was analysed for Akt1 E17K somatic mutation using BEAMing technology. Patient outcome was assessed by clinical benefit (CB) rate & survival analyses [time to progression (TTP) and time to death (TTD)]. Results: There was no significant difference in % positivity or H-Score between central & peripheral tumor sites for all biomarkers examined. After False Discovery Rate (FDR) correction differences (P

Changes in the genetic mechanisms that control sexual determination have occurred independently across the tree of life, and with exceptional frequency in teleost fishes. To investigate the genomic changes underlying the evolution of sexual determination, we sequenced a chromosome-level genome, multi-tissue transcriptomes, and reduced representation population data for the Atlantic halibut (Hippoglossus hippoglossus), which has an XY/XX sex determination mechanism and has recently diverged (0.9-3.8 MYA) from the Pacific halibut (Hippoglossus stenolepis), which has a ZZ/ZW system. We used frequency and coverage-based population approaches to identify a putative sex-determining factor, GSDF. We characterized regions with elevated heterozygosity and linkage disequilibrium indicating suppression of recombination across a nascent sex chromosome. We detected testis-specific expression of GSDF, the sequence of which is highly conserved across flatfishes. Based on evidence from genome-wide association, coverage, linkage disequilibrium, testis and brain transcriptomes, and sequence conservation with other flatfishes, we propose a mechanism for the recent evolution of an XY sex-determination mechanism in Atlantic halibut. Changes to the ancestral sex-determining gene DMRT1 in regulating the downstream gene GSDF likely coincided with GSDF, or a proximal regulatory element of it, becoming the primary sex-determining factor. Our results suggest changes to a small number of elements can have drastic repercussions for the genomic substrate available to sex-specific evolutionary forces, providing insight into how certain elements repeatedly evolve to control sex across taxa. Our chromosome-level assembly, multi-tissue transcriptomes, and population genomic data provide a valuable resource and understanding of the evolution of sexual systems in fishes.

Background Four randomised controlled trials (RCTs) in postmenopausal women with advanced breast cancer (ABC) comparing aromatase inhibitors (AIs) versus the selective estrogen receptor modulator tamoxifen, each individually reported significantly longer progression free survival (PFS) but none showed a significant difference in overall survival (OS). In these trials between 6.8%–55% of tumours were hormone receptor (HR) status unknown or negative. This meta-analysis restricted the comparison to HR-positive (HR+) tumours. MethodsAnonymised individual patient data were obtained from three RCTs, EORTC (exemestane versus tamoxifen), Study 0027 and Study 0030 (both anastrozole versus tamoxifen). For the remaining RCT (Femara Study PO25; letrozole versus tamoxifen), odds ratio (OR) or hazard ratio (HzR), with confidence intervals were obtained from the clinical study report, for patients with HR+ tumours, in addition to published data. In total, data were obtained from 2296 patients; 1560 (68%) had HR+ ABC. FindingsThe OR for clinical benefit rate was 1·56, in favour of AIs (p[less than] 0·001). The duration of clinical benefit was not significantly increased by AIs (hazard ratio [HzR] 0·88; p=0·08). For PFS the HzR (0·82) was in favour of AIs (p=0·007). However, for OS the HzR (1·05) was not significantly different between AIs and tamoxifen (p=0·42).InterpretationAlthough third generation AIs put significantly more patients into ‘clinical benefit’, their tumours were not controlled for significantly longer. Overall, while this resulted in a significantly greater PFS in favour of the AIs, this did not translate into improvement in OS.

Throughout their native range, wild Atlantic salmon populations are threatened by hybridization and introgression with escapees from net‐pen salmon aquaculture. Although domestic–wild hybrid offspring have shown reduced fitness in laboratory and field experiments, consequential impacts on population abundance and genetic integrity remain difficult to predict in the field, in part because the strength of selection against domestic offspring is often unknown and context‐dependent. Here, we follow a single large escape event of farmed Atlantic salmon in southern Newfoundland and monitor changes in the in‐river proportions of hybrids and feral individuals over time using genetically based hybrid identification. Over a three‐year period following the escape, the overall proportion of wild parr increased consistently (total wild proportion of 71.6%, 75.1% and 87.5% each year, respectively), with subsequent declines in feral (genetically pure farmed individuals originating from escaped, farmed adults) and hybrid parr. We quantify the strength of selection against parr of aquaculture ancestry and explore the genetic and demographic consequences for populations in the region. Within‐cohort changes in the relative proportions of feral and F1 parr suggest reduced relative survival compared to wild individuals over the first (0.15 and 0.81 for feral and F1, respectively) and second years of life (0.26, 0.83). These relative survivorship estimates were used to inform an individual‐based salmon eco‐genetic model to project changes in adult abundance and overall allele frequency across three invasion scenarios ranging from short‐term to long‐term invasion and three relative survival scenarios. Modelling results indicate that total population abundance and time to recovery were greatly affected by relative survivorship and predict significant declines in wild population abundance under continued large escape events and calculated survivorship. Overall, this work demonstrates the importance of estimating the strength of selection against domestic offspring in the wild to predict the long‐term impact of farmed salmon escape events on wild populations.

Restriction site-associated DNA sequencing (RADseq) is a powerful tool for genotyping of individuals, but the identification of loci and assignment of sequence reads is a crucial and often challenging step. The optimal parameter settings for a given de novo RADseq assembly vary between data sets and can be difficult and computationally expensive to determine. Here, we introduce RADProc, a software package that uses a graph data structure to represent all sequence reads and their similarity relationships. Storing sequence-comparison results in a graph eliminates unnecessary and redundant sequence similarity calculations. De novo locus formation for a given parameter set can be performed on the precomputed graph, making parameter sweeps far more efficient. RADProc also uses a clustering approach for faster nucleotide-distance calculation. The performance of RADProc compares favourably with that of the widely used Stacks software. The run-time comparisons between RADProc and Stacks for 32 different parameter settings using 20 green-crab (Carcinus maenas) samples showed that RADProc took as little as 2 hr 40 min compared to 78 hr by Stacks, while 16 brown trout (Salmo trutta L.) samples were processed by RADProc and Stacks in 23 and 263 hr, respectively. Comparisons of the de novo loci formed, and catalog built using both the methods demonstrate that the improvement in processing speeds achieved by RADProc does not affect much the actual loci formed and the results of downstream analyses based on those loci.

Marine protected areas (MPAs) can serve as effective tools for the management and conservation of exploited marine species. The Gilbert Bay MPA in coastal Labrador was created to protect a genetically distinct population of Atlantic cod (Gadus morhua); however, decreases in abundance continue to occur potentially due to exploitation outside the MPA. We developed a single-nucleotide polymorphism (SNP) panel to identify Gilbert Bay cod in areas outside MPA boundaries where mixing with offshore cod occurs. In total, 361 individuals from Gilbert Bay, surrounding areas, and offshore were genotyped for 10 913 SNPs. Using FSTrankings and guided regularized random forest, we selected 23 SNPs that together generate 100% accuracy in individual assignment and accurately estimate the proportion of Gilbert Bay cod in fishery samples from sites outside MPA boundaries: on average, fishery samples included 17.3% Gilbert Bay cod. Estimates of effective population size for the Gilbert Bay population ranged from 655 to 1114. Our findings demonstrate the power of using genomic approaches for management of an exploited marine species and enhancing the design of MPAs.

GPs have a wide range of attitudes to spirituality which contribute to variations in reported spiritual care. Study aims were: to assess concepts of spirituality and their application in a sample of GP trainers; explore statistically the relationship between personal spiritual affiliation, attitudes to, and reported practice of, spiritual care and; to examine whether GP trainers consider training in spiritual care to be adequate. Questionnaire involving 87 GP trainers using Likert scale responses and multinomial trend tests to analyse the relationships between 'concept of spirituality' and attitude to, or practice of, spiritual care. Cluster and latent class analysis to investigate whether groups of GPs are categorically different. Results were GPs largely considered spirituality to be a meaningful, useful, but unclear concept. 8% did not wish involvement in spiritual care, 27.6% had reservations, 46% were pragmatically willing and 12.6% expressed keenness. 35.6% reported they tend not to discuss spiritual matters. Latent class analysis suggests two groups exist: two thirds being pragmatic supporters of spiritual care and one third are tentative sceptics. GPs vary widely in their attitude to, and practice of spiritual care. Only 10.3% reported receiving adequate training in spiritual care.

Hybridization of escaped farmed Atlantic salmon Salmo salar with wild populations occurs throughout their native range and can threaten wild population stability and persistence. The extent of hybridization is often population-specific and can drive changes in phenotype and genotype. Current understanding of the forces that contribute to the spatial distribution of hybridization is insufficient despite its potential to inform conservation and management efforts. Using a panel of 95 single nucleotide polymorphisms previously validated for identifying parr of farmed, wild, or hybrid descent, we present a novel exploration of inter- and intra-river distribution of hybrids from 33 locations across 9 rivers in southern Newfoundland, Canada. The proportion of hybrids varied significantly across (p < 0.001) and within rivers (p < 0.05 in 4 rivers). Binomial mixed models and logistic regression showed increased proportions of hybrid and feral offspring within smaller rivers (p < 0.0001). Within-river distribution of hybrid parr was strongly associated with the migration effort required to reach spawning sites; the hybrid proportion decreased significantly (p < 0.05) with increased elevation, geographic distance and the presence of obstructions. These observations support previous hypotheses that the distribution of escaped farmed Atlantic salmon can be restricted by migratory challenges, which result in the reduction of hybrid individuals in upstream spawning sites relative to downstream locations. Our research demonstrates that levels of hybridization vary spatially and are associated with landscape features. We suggest that consideration of spatial variation in levels of hybridization will be essential for the evaluation of impacts that escaped farmed salmon impose on wild Atlantic salmon populations.

Conservation of exploited species requires an understanding of both genetic diversity and the dominant structuring forces, particularly near range limits, where climatic variation can drive rapid expansions or contractions of geographic range. Here, we examine population structure and landscape associations in Atlantic salmon (Salmo salar) across a heterogeneous landscape near the northern range limit in Labrador, Canada. Analysis of two amplicon-based data sets containing 101 microsatellites and 376 single nucleotide polymorphisms (SNPs) from 35 locations revealed clear differentiation between populations spawning in rivers flowing into a large marine embayment (Lake Melville) compared to coastal populations. The mechanisms influencing the differentiation of embayment populations were investigated using both multivariate and machine-learning landscape genetic approaches. We identified temperature as the strongest correlate with genetic structure, particularly warm temperature extremes and wider annual temperature ranges. The genomic basis of this divergence was further explored using a subset of locations (n = 17) and a 220K SNP array. SNPs associated with spatial structuring and temperature mapped to a diverse set of genes and molecular pathways, including regulation of gene expression, immune response, and cell development and differentiation. The results spanning molecular marker types and both novel and established methods clearly show climate-associated, fine-scale population structure across an environmental gradient in Atlantic salmon near its range limit in North America, highlighting valuable approaches for predicting population responses to climate change and managing species sustainability.

Restriction‐site associated DNA sequencing (RAD‐seq) can identify and score thousands of genetic markers from a group of samples for population‐genetics studies. One challenge of de novo RAD‐seq analysis is to distinguish paralogous sequence variants (PSVs) from true single‐nucleotide polymorphisms (SNPs) associated with orthologous loci. In the absence of a reference genome, it is difficult to differentiate true SNPs from PSVs, and their impact on downstream analysis remains unclear. Here, we introduce a network‐based approach, PMERGE that connects fragments based on their DNA sequence similarity to identify probable PSVs. Applying our method to de novo RAD‐seq data from 150 Atlantic salmon (Salmo salar) samples collected from 15 locations across the Southern Newfoundland coast allowed the identification of 87% of total PSVs identified through alignment to the Atlantic salmon genome. Removal of these paralogs altered the inferred population structure, highlighting the potential impact of filtering in RAD‐seq analysis. PMERGE is also applied to a green crab (Carcinus maenas) data set consisting of 242 samples from 11 different locations and was successfully able to identify and remove the majority of paralogous loci (62%). The PMERGE software can be run as part of the widely used Stacks analysis package.

Two genetically distinct lineages of European green crabs (Carcinus maenas) were independently introduced to eastern North America, the first in the early 19th century and the second in the late 20th century. These lineages first came into secondary contact in southeastern Nova Scotia, Canada (NS), where they hybridized, producing latitudinal genetic clines. Previous studies have documented a persistent southward shift in the clines of different marker types, consistent with existing dispersal and recruitment pathways. We evaluated current clinal structure by quantifying the distribution of lineages and fine‐scale hybridization patterns across the eastern North American range (25 locations, ~39 to 49°N) using informative single nucleotide polymorphisms (SNPs; n = 96). In addition, temporal changes in the genetic clines were evaluated using mitochondrial DNA and microsatellite loci (n = 9–11) over a 15‐year period (2000–2015). Clinal structure was consistent with prior work demonstrating the existence of both northern and southern lineages with a hybrid zone occurring between southern New Brunswick (NB) and southern NS. Extensive later generation hybrids were detected in this region and in southeastern Newfoundland. Temporal genetic analysis confirmed the southward progression of clines over time; however, the rate of this progression was slower than predicted by forecasting models, and current clines for all marker types deviated significantly from these predictions. Our results suggest that neutral and selective processes contribute to cline dynamics, and ultimately, highlight how selection, hybridization, and dispersal can collectively influence invasion success.

In the northwest Atlantic Ocean, sea scallop (Placopecten magellanicus) has been characterized by a latitudinal genetic cline with a breakpoint between northern and southern genetic clusters occurring at ~45°N along eastern Nova Scotia, Canada. Using 96 diagnostic single-nucleotide polymorphisms (SNPs) capable of discriminating between northern and southern clusters, we examined fine-scale genetic structure of scallops among 27 sample locations, spanning the largest geographic range evaluated in this species to date (~37-51°N). Here, we confirmed previous observations of northern and southern groups, but we show that the boundary between northern and southern clusters is not a discrete latitudinal break. Instead, at latitudes near the previously described boundary, we found unexpected patterns of fine-scale genetic structure occurring between inshore and offshore sites. Scallops from offshore sites, including St. Pierre Bank and the eastern Scotian Shelf, clustered with southern stocks, whereas inshore sites at similar latitudes clustered with northern stocks. Our analyses revealed significant genetic divergence across small spatial scales (i.e., 129-221 km distances), and that spatial structure over large and fine scales was strongly associated with temperature during seasonal periods of thermal minima. Clear temperature differences between inshore and offshore locations may explain the fine-scale structuring observed, such as why southern lineages of scallop occur at higher latitudes in deeper, warmer offshore waters. Our study supports growing evidence that fine-scale population structure in marine species is common, often environmentally associated, and that consideration of environmental and genomic data can significantly enhance the identification of marine diversity and management units.

The escape of Atlantic salmon (Salmo salar) from aquaculture facilities can result in both negative genetic and ecological interactions with wild populations, yet the ability to predict the associated risk to wild populations has remained elusive. Here we assess the potential of a spatiotemporal database of aquaculture facility locations, production estimates, and escape events to predict the distribution of escaped farmed salmon and genetic impacts on wild populations in the Northwest Atlantic. Industry production data, reported escape events, and in-river detections of escaped farmed salmon were collected from across the Northwest Atlantic. Genetic estimates of impact were obtained using single nucleotide polymorphisms (95 loci) representing aquaculture and wild salmon throughout the region (30 populations, 3048 individuals). Both the number of escaped farmed salmon detected at counting facilities and the magnitude of genetic impacts were positively correlated with a cumulative spatial measure of aquaculture production. Our results suggest that the risk of escapees and genetic introgression from wild–farmed salmon interactions can be assessed using information on farm production characteristics. This represents a first step in predicting the impact of existing cage-based farms on wild Atlantic salmon.

Genetic-environment associations are increasingly revealed through population genomic data and can occur through a number of processes, including secondary contact, divergent natural selection, or isolation by distance. Here, we investigate the influence of the environment, including seasonal temperature and salinity, on the population structure of the invasive European green crab (Carcinus maenas) in eastern North America. Green crab populations in eastern North America are associated with two independent invasions, previously shown to consist of distinct northern and southern ecotypes, with a contact zone in southern Nova Scotia, Canada. Using a RAD-seq panel of 9,137 genomewide SNPs, we detected 41 SNPs (0.49%) whose allele frequencies were highly correlated with environmental data. A principal components analysis of 25 environmental variables differentiated populations into northern, southern, and admixed sites in concordance with the observed genomic spatial structure. Furthermore, a spatial principal components analysis conducted on genomic and geographic data revealed a high degree of global structure (p < .0001) partitioning a northern and southern ecotype. Redundancy and partial redundancy analyses revealed that among the environmental variables tested, winter sea surface temperature had the strongest association with spatial structuring, suggesting that it is an important factor defining range and expansion limits of each ecotype. Understanding environmental thresholds associated with intraspecific diversity will facilitate the ability to manage current and predict future distributions of this aquatic invasive species.

Background A-to-I RNA editing, a post-transcriptional modification of the RNA catalyzed by the ADAR family of enzymes, is emerging as a widespread phenomenon in breast cancer (BC). A-to-I RNA editing is more frequent in the highly repetitive Alu regions but can affect both coding and non-coding regions. It has been shown to greatly impact cell functionality. In a recent report, we have shown that A-to-I RNA editing is regulated both by ADAR copy number and type I interferon response (Fumagalli et al. Cell Rep 2015). The main aim of the current study was to investigate the extent and profile of A-to-I RNA editing in HER2+ BC patients (pts) treated in the NeoALTTO trial, and to explore its impact on pathologic complete response (pCR) and survival. Methods Aligned RNAseq reads of sufficient quality and quantity were obtained for 252 of the 455 pts enrolled in the study, as described previously (Fumagalli et al. JAMA Oncol 2016). Editing sites from the rediPortal database were assessed. The editing level at a given site was computed by counting the number of Gs and As. Sites with coverage more than 10 were considered for further analyses. Editing in normal tissues was obtained from the GTEx project of the rediPortal database. Tumor infiltrating lymphocytes (TILs) and copy number aberrations were previously reported. Correlations between different parameters were assessed using Spearman correlations (ρ). The Mann-Whitney test was used to relate binary and numerical features. Event-free survival (EFS) analysis was performed using the Cox proportional hazard model. Results There was a median of 71470 edited sites per sample. As expected, mean editing per sample correlated with ADAR expression (ρ=59%, p Conclusions Our study shows for the first time that deregulated RNA editing, as compared to editing in normal tissues, is a widespread phenomenon in HER2+ BC patients treated in the NeoALTTO trial and is associated with poor outcome. These results may provide new perspectives for the treatment of HER2+ disease by developing therapies targeting RNA editing. Citation Format: Venet D, Rothé F, Dupont F, Maetens M, Fumagalli D, Salgado R, Bradbury I, Pusztai L, Harbeck N, Izquierdo M, de la Pena L, Ignatiadis M, de Azambuja E, Huober J, Nuciforo P, Baselga J, Piccart M, Loi S, Sotiriou C. Deregulation of A-to-I RNA editing is associated with poor prognosis in HER2+ breast cancers in the neoALTTO trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-05-04.