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Background: Dormant coronary collaterals are highly prevalent and clinically beneficial in cases of coronary occlusion. However, the magnitude of myocardial perfusion provided by immediate coronary collateral recruitment during acute occlusion is unknown. We aimed to quantify collateral myocardial perfusion during balloon occlusion in patients with coronary artery disease (CAD)., Methods: Patients without angiographically visible collaterals undergoing elective percutaneous transluminal coronary angioplasty (PTCA) to a single epicardial vessel underwent two scans with 99mTc-sestamibi myocardial perfusion single-photon emission computed tomography (SPECT). All subjects underwent at least three minutes of angiographically verified complete balloon occlusion, at which time an intravenous injection of the radiotracer was administered, followed by SPECT imaging. A second radiotracer injection followed by SPECT imaging was performed 24 h after PTCA., Results: The study included 22 patients (median [interquartile range] age 68 [54-72] years. The perfusion defect extent was 19 [11-38] % of the LV, and the collateral perfusion at rest was 64 [58-67]% of normal., Conclusion: This is the first study to describe the magnitude of short-term changes in coronary microvascular collateral perfusion in patients with CAD. On average, despite coronary occlusion and an absence of angiographically visible collateral vessels, collaterals provided more than half of the normal perfusion., (© 2023. The Author(s).)

Oncogene amplification on extrachromosomal DNA (ecDNA) drives the evolution of tumours and their resistance to treatment, and is associated with poor outcomes for patients with cancer 1-6 . At present, it is unclear whether ecDNA is a later manifestation of genomic instability, or whether it can be an early event in the transition from dysplasia to cancer. Here, to better understand the development of ecDNA, we analysed whole-genome sequencing (WGS) data from patients with oesophageal adenocarcinoma (EAC) or Barrett's oesophagus. These data included 206 biopsies in Barrett's oesophagus surveillance and EAC cohorts from Cambridge University. We also analysed WGS and histology data from biopsies that were collected across multiple regions at 2 time points from 80 patients in a case-control study at the Fred Hutchinson Cancer Center. In the Cambridge cohorts, the frequency of ecDNA increased between Barrett's-oesophagus-associated early-stage (24%) and late-stage (43%) EAC, suggesting that ecDNA is formed during cancer progression. In the cohort from the Fred Hutchinson Cancer Center, 33% of patients who developed EAC had at least one oesophageal biopsy with ecDNA before or at the diagnosis of EAC. In biopsies that were collected before cancer diagnosis, higher levels of ecDNA were present in samples from patients who later developed EAC than in samples from those who did not. We found that ecDNAs contained diverse collections of oncogenes and immunomodulatory genes. Furthermore, ecDNAs showed increases in copy number and structural complexity at more advanced stages of disease. Our findings show that ecDNA can develop early in the transition from high-grade dysplasia to cancer, and that ecDNAs progressively form and evolve under positive selection., (© 2023. The Author(s).)

Soil organic carbon can be increased through sympathetic land management and/or directly by incorporating carbon rich amendments. Herein, a field experiment amended paper crumble (PC) to soil at a normal deployment rate of 50 t ha -1 , and at higher rates up to 200 t ha -1 . The nominal 50 t ha -1 PC amendment resulted a mean increase in soil carbon of 12.5 g kg -1 . Using a modified Roth-C carbon fate model, the long-term (50 years) carbon storage potential of a 50 t ha -1 PC amendment was determined to be 0.36 t O C ha -1 . Modelling a rotational (4 yearly) 50 t ha -1 PC amendment indicated 6.65 t O C ha -1 uplift would accrue after 50 years. Contextualised for the average farm in the East of England (~120 ha, with 79 % as arable), PC derived increases in SOC would be equivalent to 2310 t CO 2 e. These results support the use of PC to deliver significant levels of soil recarbonisation. Beyond carbon, PC was observed to influence other soil properties. Benefits observed included, decreased bulk density, increased water holding capacity, and increased cation exchange capacity. While PC amendment did not significantly increase wheat (Triticum aestivum) crop yield, manifold benefits in terms of increased SOC, long-term carbon storage potential, and improved soil quality sustain PC as a beneficial soil conditioner., Competing Interests: Declaration of competing interest Brian Reid reports financial support was provided by Research England., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

While the genomes of normal tissues undergo dynamic changes over time, little is understood about the temporal-spatial dynamics of genomes in premalignant tissues that progress to cancer compared to those that remain cancer-free. Here we use whole genome sequencing to contrast genomic alterations in 427 longitudinal samples from 40 patients with stable Barrett's esophagus compared to 40 Barrett's patients who progressed to esophageal adenocarcinoma (ESAD). We show the same somatic mutational processes are active in Barrett's tissue regardless of outcome, with high levels of mutation, ESAD gene and focal chromosomal alterations, and similar mutational signatures. The critical distinction between stable Barrett's versus those who progress to cancer is acquisition and expansion of TP53-/- cell populations having complex structural variants and high-level amplifications, which are detectable up to six years prior to a cancer diagnosis. These findings reveal the timing of common somatic genome dynamics in stable Barrett's esophagus and define key genomic features specific to progression to esophageal adenocarcinoma, both of which are critical for cancer prevention and early detection strategies., (© 2022. The Author(s).)

Arsenic (As) pollution remains a major threat to the quality of global soils and drinking water. The health effects of As pollution are often severe and have been largely reported across Asia and South America. This study investigated the possibility of using unmodified biochar derived from rice husk (RB) and aspen wood (WB) at 400 °C and 700 °C to enhance the precipitation of calcium/arsenic compounds for the removal of As(III) from solution. The approach was based on utilizing calcium to precipitate arsenic in solution and adding unmodified biochar to enhance the process. Using this approach, As(III) concentration in aqueous solution decreased by 58.1% when biochar was added, compared to 25.4% in the absence of biochar. Varying the pH from acidic to alkaline enabled an investigation into the pH dependent dynamics of the approach. Results indicated that significant precipitation was only possible at near neutral pH (i.e. pH = 6.5) where calcium arsenites (i.e. Ca(AsO 2 ) 2 , and CaAsO 2 OH•½H 2 O) and arsenates (i.e. Ca 5 (AsO 4 ) 3 OH) were precipitated and deposited as aggregates in the pores of biochars. Arsenite was only slightly precipitated under acidic conditions (pH = 4.5) while no arsenite was precipitated under alkaline conditions (pH = 9.5). Arsenite desorption from wood biochar was lowest at pH 6.5 indicating that wood biochar was able to retain a large quantity of the precipitates formed at pH 6.5 compared to pH 4.5 and pH 9.5. Given that the removal of As(III) from solution is often challenging and that biochar modification invites additional cost, the study demonstrated that low cost unmodified biochar can be effective in enhancing the removal of As(III) from the environment through Ca-As precipitation., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Metaldehyde, a widely used molluscicide, is one of the most commonly detected pesticides in aquatic environments in the UK. In this study, metaldehyde concentrations and fluxes in stream water over a ten-year period (2008-2018) are reported for the River Colne catchment (Essex, southeast England), and the influence of hydrological conditions and application regimes are assessed. In general, peaks in metaldehyde concentration in river water occasionally exceeded 0.25 μg L -1 , and concentrations did not typically exceed the European Union Drinking Water Directive (EU DWD) regulatory limit of 0.1 μg L -1 . Metaldehyde concentration peaks displayed a seasonal pattern. Metaldehyde concentrations during periods when the molluscicide was not applied to agricultural land (January, July) and during the spring-summer application period (February to June) were generally low (0.01-0.03 μg L -1 ). Peaks in metaldehyde concentration mainly occurred during the autumn-winter application season (August to December), and were typically associated with high intensity hydrological regimes (daily rainfall ≥10 mm; stream flow up to 18 m 3 s -1 ). Where metaldehyde concentrations exceeded the EU DWD regulatory limit, this was short-lived. The annual flux at the top of the Colne catchment (0.2-0.6 kg a -1 ) tended to be lower than in the middle of the catchment (0.3-1.4 kg a -1 ), with maximum flux values observed at the bottom of the catchment (0.5-25.8 kg a -1 ). Metaldehyde losses from point of application to surface water varied between 0.01 and 0.25%, with a maximum of 1.18% (2012). Annual flux was primarily controlled by the annual precipitation and stream flow (R 2 = 0.9) rather than annual metaldehyde use (kg active applied). Precipitation explained 37% and 81% of variability in metaldehyde concentration and flux, respectively. Annual ranges in metaldehyde concentration were greater in the years 2012 and 2014 with an overall reduction in the range of metaldehyde concentrations evident over the period 2015-2018. It is the expectation that metaldehyde concentrations in stream water will continue to decrease following the withdrawal of metaldehyde for outdoor use in the UK from March 2022., Competing Interests: Declaration of competing interest The authors whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Crown Copyright © 2021. Published by Elsevier B.V. All rights reserved.)

Current carbon pricing and trading mechanisms, despite their efficacy in reducing GHG emissions from industry, will not be sufficient to achieve Net Zero targets. Current mechanisms that redress emissions are largely economic disincentives , in effect financial penalties for emitters. In order to attain Net Zero futures, financial incentives for activities that sequester carbon from the atmosphere are needed. Herein, we present the environmental and economic co-benefits of soil re-carbonization and justify support for soil carbon remuneration. With increasing momentum to develop green economies, and projected increases in carbon price, growth in the global carbon market is inevitable. The establishment of a soil-based carbon economy, within this emerging financial space, has the potential to deliver a paradigm shift that will accelerate climate change mitigation, and concurrently realize net gains for soil health and the delivery of soil ecosystem services. Pivotal to the emergence of a global soil carbon economy will be a consensus on certification instruments used for long-term soil carbon storage, and the development of robust institutional agreements and processes to facilitate soil carbon trading., (© 2021 The Authors.)

Soil ecosystem service (SES) approaches evidence the importance of soil for human well-being, contribute to improving dialogue between science and decision-making and encourage the translation of scientific results into public policies. Herein, through systematic review, we assess the state of the art of SES approaches in tropical regions. Through this review, 41 publications were identified; while most of these studies considered SES, a lack of a consistent framework to define SES was apparent. Most studies measured soil natural capital and processes, while only three studies undertook monetary valuation. Although the number of publications increased (from 1 to 41), between 2001 and 2019, the total number of publications for tropical regions is still small. Countries with the largest number of publications were Brazil ( n = 8), Colombia ( n = 6) and Mexico ( n = 4). This observation emphasizes an important knowledge gap pertaining to SES approaches and their link to tropical regions. With global momentum behind SES approaches, there is an opportunity to integrate SES approaches into policy and practice in tropical regions. The use of SES evaluation tools in tropical regions could transform how land use decisions are informed, mitigating soil degradation and protecting the ecosystems that soil underpins., (© 2021 The Authors.)

Background & Aims: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored., Methods: Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population-based controls. We performed sex-specific GWAS of BE/EA in 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits., Results: We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, P BONF  = .039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, P BONF  = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals., Conclusions: The identified novel sex-specific variants associated with BE/EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance., (Copyright © 2020 AGA Institute. All rights reserved.)

Background & Aims: Esophageal adenocarcinoma (EAC) occurs most frequently in men. We performed a Mendelian randomization analysis to investigate whether genetic factors that regulate levels of sex hormones are associated with risk of EAC or Barrett's esophagus (BE)., Methods: We conducted a Mendelian randomization analysis using data from patients with EAC (n = 2488) or BE (n = 3247) and control participants (n = 2127), included in international consortia of genome-wide association studies in Australia, Europe, and North America. Genetic risk scores or single-nucleotide variants were used as instrumental variables for 9 specific sex hormones. Logistic regression provided odds ratios (ORs) with 95% CIs., Results: Higher genetically predicted levels of follicle-stimulating hormones were associated with increased risks of EAC and/or BE in men (OR, 1.14 per allele increase; 95% CI, 1.01-1.27) and in women (OR, 1.28; 95% CI, 1.03-1.59). Higher predicted levels of luteinizing hormone were associated with a decreased risk of EAC in men (OR, 0.92 per SD increase; 95% CI, 0.87-0.99) and in women (OR, 0.93; 95% CI, 0.79-1.09), and decreased risks of BE (OR, 0.88; 95% CI, 0.77-0.99) and EAC and/or BE (OR, 0.89; 95% CI, 0.79-1.00) in women. We found no clear associations for other hormones studied, including sex hormone-binding globulin, dehydroepiandrosterone sulfate, testosterone, dihydrotestosterone, estradiol, progesterone, or free androgen index., Conclusions: In a Mendelian randomization analysis of data from patients with EAC or BE, we found an association between genetically predicted levels of follicle-stimulating and luteinizing hormones and risk of BE and EAC., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Cancer genomes often harbor hundreds of somatic DNA rearrangement junctions, many of which cannot be easily classified into simple (e.g., deletion) or complex (e.g., chromothripsis) structural variant classes. Applying a novel genome graph computational paradigm to analyze the topology of junction copy number (JCN) across 2,778 tumor whole-genome sequences, we uncovered three novel complex rearrangement phenomena: pyrgo, rigma, and tyfonas. Pyrgo are "towers" of low-JCN duplications associated with early-replicating regions, superenhancers, and breast or ovarian cancers. Rigma comprise "chasms" of low-JCN deletions enriched in late-replicating fragile sites and gastrointestinal carcinomas. Tyfonas are "typhoons" of high-JCN junctions and fold-back inversions associated with expressed protein-coding fusions, breakend hypermutation, and acral, but not cutaneous, melanomas. Clustering of tumors according to genome graph-derived features identified subgroups associated with DNA repair defects and poor prognosis., Competing Interests: Declaration of Interests J.S.R.-F. reports receiving personal/consultancy fees from VolitionRx, Paige.AI, Goldman Sachs, REPARE Therapeutics, GRAIL, Ventana Medical Systems, Roche, Genentech, and InviCRO outside of the scope of the submitted work., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Barrett's Esophagus is a neoplastic condition which progresses to esophageal adenocarcinoma in 5% of cases. Key events affecting the outcome likely occur before diagnosis of Barrett's and cannot be directly observed; we use phylogenetic analysis to infer such past events. We performed whole-genome sequencing on 4-6 samples from 40 cancer outcome and 40 noncancer outcome patients with Barrett's Esophagus, and inferred within-patient phylogenies of deconvoluted clonal lineages. Spatially proximate lineages clustered in the phylogenies, but temporally proximate ones did not. Lineages with inferred loss-of-function mutations in both copies of TP53 and CDKN2A showed enhanced spatial spread, whereas lineages with loss-of-function mutations in other frequently mutated loci did not. We propose a two-phase model with expansions of TP53 and CKDN2A mutant lineages during initial growth of the segment, followed by relative stasis. Subsequent to initial expansion, mutations in these loci as well as ARID1A and SMARCA4 may show a local selective advantage but do not expand far: The spatial structure of the Barrett's segment remains stable during surveillance even in patients who go on to cancer. We conclude that the cancer/noncancer outcome is strongly affected by early steps in formation of the Barrett's segment., Competing Interests: None declared., (© 2020 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.)

Thiol-modified rice straw biochar (RS) was prepared by an esterification reaction with β-mercaptoethanol and used for the remediation of Cd and Pb polluted soils. Modified biochar was characterized through elemental analysis, BET analysis, FE-SEM, FT-IR and XPS. These analytical results revealed that thiol groups were successfully grafted onto the surface of the biochar and were involved in metal ion complexation. Batch sorption experiments indicated that Cd 2+ and Pb 2+ sorption onto RS described well by a pseudo second order kinetic model and a Langmuir isotherm. The maximum adsorption capacities for Cd 2+ and Pb 2+ , in the single-metal systems, were 45.1 and 61.4 mg g -1 , respectively. In the binary-metal systems, RS selectively adsorbed Cd 2+ over Pb 2+ . Cd 2+ and Pb 2+ were removed mainly through surface complexation. In the soil incubation experiments (28 days), RS reduced the available Cd by 34.8-39.2 %; while, RS reduced the available Pb by 8.6 %-11.1 %. This research demonstrates RS as a potentially effective amendment for the remediation of heavy metal polluted soils., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Metaldehyde is a molluscicide used to control slugs and snails. Despite its extensive use, very little is known about the capacity of soil microbial communities to degrade this chemical. This research provides a synopsis of the latent capacity of soil microbial communities, present in agricultural (n=14), allotment (n=4) and garden (n=10) soils, to degrade metaldehyde. Extents of 14 C-metaldehyde mineralisation across all soils ranged from 17.7 to 60.0%. Pre-exposure (in situ, in the field) to metaldehyde was not observed to consistently increase extents of metaldehyde mineralisation. Where soils were augmented, (ex situ, in the laboratory) with metaldehyde (28 mg kg -1 ), the mineralisation capacity was increased in some, but not all, soils (uplift ranged from +0.10 to +16.9%). Results indicated that catabolic competence to degrade metaldehyde was evident in both surface (16.7-52.8%) and in sub-surface (30.0-66.4%) soil horizons. Collectively, the results suggest that catabolic competence to degrade metaldehyde was ubiquitous across a diverse range of soil environments; that varied in texture (from sand to silty clay loam), pH (6.15-8.20) and soil organic matter (SOM) content (1.2%-52.1%). Lighter texture soils, in general, were observed to have higher capacity to mineralise metaldehyde. Weak correlations between catabolic competence and soil pH and soil organic matter content were observed; it was noted that above a SOM threshold of 12% metaldehyde mineralisation was always >34%. It was concluded that the common occurrence of metaldehyde in EU waters is unlikely the consequence of low potential for this chemical to be degraded in soil. It is more likely that application regimes (quantities/timings) and meteorological drivers facilitate the transport of metaldehyde from point of application into water resources., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background & Aims: Epidemiology studies of circulating concentrations of 25 hydroxy vitamin D (25(OH)D) and risk of esophageal adenocarcinoma (EAC) have produced conflicting results. We conducted a Mendelian randomization study to determine the associations between circulating concentrations of 25(OH)D and risks of EAC and its precursor, Barrett's esophagus (BE)., Methods: We conducted a Mendelian randomization study using a 2-sample (summary data) approach. Six single-nucleotide polymorphisms (SNPs; rs3755967, rs10741657, rs12785878, rs10745742, rs8018720, and rs17216707) associated with circulating concentrations of 25(OH)D were used as instrumental variables. We collected data from 6167 patients with BE, 4112 patients with EAC, and 17,159 individuals without BE or EAC (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium, as well as studies from Bonn, Germany, and Cambridge and Oxford, United Kingdom. Analyses were performed separately for BE and EAC., Results: Overall, we found no evidence for an association between genetically estimated 25(OH)D concentration and risk of BE or EAC. The odds ratio per 20 nmol/L increase in genetically estimated 25(OH)D concentration for BE risk estimated by combining the individual SNP association using inverse variance weighting was 1.21 (95% CI, 0.77-1.92; P = .41). The odds ratio for EAC risk, estimated by combining the individual SNP association using inverse variance weighting, was 0.68 (95% CI, 0.39-1.19; P = .18)., Conclusions: In a Mendelian randomization study, we found that low genetically estimated 25(OH)D concentrations were not associated with risk of BE or EAC., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

It was highlighted that in the original article [1] the Availability of data and materials section was incorrect.

The "4 per mil" initiative recognizes the pivotal role of soil in carbon resequestration. The need for evidence to substantiate the influence of agricultural practices on chemical nature of soil carbon and microbial biodiversity has become a priority. However, owing to the molecular complexity of soil dissolved organic matter (DOM), specific linkages to microbial biodiversity have eluded researchers. Here, we characterized the chemodiversity of soil DOM, assessed the variation of soil bacterial community composition (BCC), and identified specific linkages between DOM traits and BCC. Sustained organic carbon amendment significantly ( P < 0.05) increased total organic matter reservoirs, resulted in higher chemodiversity of DOM and emergence of recalcitrant moieties (H/C < 1.5). In the meantime, sustained organic carbon amendment shaped the BCC to a more eutrophic state while long-term chemical fertilization directed the BCC toward an oligotrophic state. Meanwhile, higher connectivity and complexity were observed in organic carbon amendment by DOM-BCC network analysis, indicating that soil microbes tended to have more interaction with DOM molecules after organic matter inputs. These results highlight the potential for organic carbon amendments to not only build soil carbon stocks and increase their resilience but also mediate the functional state of soil bacterial communities.

Background & Aims: Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for esophageal adenocarcinoma (EA) and Barrett's esophagus (BE). However, variants in these loci account for a small fraction of cases of EA and BE. Genetic factors might interact with environmental factors to affect risk of EA and BE. We aimed to identify single nucleotide polymorphisms (SNPs) that may modify the associations of body mass index (BMI), smoking, and gastroesophageal reflux disease (GERD), with risks of EA and BE., Methods: We collected data on single BMI measurements, smoking status, and symptoms of GERD from 2284 patients with EA, 3104 patients with BE, and 2182 healthy individuals (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium GWAS, the UK Barrett's Esophagus Gene Study, and the UK Stomach and Oesophageal Cancer Study. We analyzed 993,501 SNPs in DNA samples of all study subjects. We used standard case-control logistic regression to test for gene-environment interactions., Results: For EA, rs13429103 at chromosome 2p25.1, near the RNF144A-LOC339788 gene, showed a borderline significant interaction with smoking status (P = 2.18×10 -7 ). Ever smoking was associated with an almost 12-fold increase in risk of EA among individuals with rs13429103-AA genotype (odds ratio=11.82; 95% CI, 4.03-34.67). Three SNPs (rs12465911, rs2341926, rs13396805) at chromosome 2q23.3, near the RND3-RBM43 gene, interacted with GERD symptoms (P = 1.70×10 -7 , P = 1.83×10 -7 , and P = 3.58×10 -7 , respectively) to affect risk of EA. For BE, rs491603 at chromosome 1p34.3, near the EIF2C3 gene, and rs11631094 at chromosome 15q14, at the SLC12A6 gene, interacted with BMI (P = 4.44×10 -7 ) and pack-years of smoking history (P = 2.82×10 -7 ), respectively., Conclusion: The associations of BMI, smoking, and GERD symptoms with risks of EA and BE appear to vary with SNPs at chromosomes 1, 2, and 15. Validation of these suggestive interactions is warranted., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: We developed comprehensive models to determine risk of Barrett's esophagus (BE) or esophageal adenocarcinoma (EAC) based on genetic and non-genetic factors., Methods: We used pooled data from 3288 patients with BE, 2511 patients with EAC, and 2177 individuals without either (controls) from participants in the international Barrett's and EAC consortium as well as the United Kingdom's BE gene study and stomach and esophageal cancer study. We collected data on 23 genetic variants associated with risk for BE or EAC, and constructed a polygenic risk score (PRS) for cases and controls by summing the risk allele counts for the variants weighted by their natural log-transformed effect estimates (odds ratios) extracted from genome-wide association studies. We also collected data on demographic and lifestyle factors (age, sex, smoking, body mass index, use of nonsteroidal anti-inflammatory drugs) and symptoms of gastroesophageal reflux disease (GERD). Risk models with various combinations of non-genetic factors and the PRS were compared for their accuracy in identifying patients with BE or EAC using the area under the receiver operating characteristic curve (AUC) analysis., Results: Individuals in the highest quartile of risk, based on genetic factors (PRS), had a 2-fold higher risk of BE (odds ratio, 2.22; 95% confidence interval, 1.89-2.60) or EAC (odds ratio, 2.46; 95% confidence interval, 2.07-2.92) than individual in the lowest quartile of risk based on PRS. Risk models developed based on only demographic or lifestyle factors or GERD symptoms identified patients with BE or EAC with AUC values ranging from 0.637 to 0.667. Combining data on demographic or lifestyle factors with data on GERD symptoms identified patients with BE with an AUC of 0.793 and patients with EAC with an AUC of 0.745. Including PRSs with these data only minimally increased the AUC values for BE (to 0.799) and EAC (to 0.754). Including the PRSs in the model developed based on non-genetic factors resulted in a net reclassification improvement for BE of 3.0% and for EAC of 5.6%., Conclusions: We used data from 3 large databases of patients from studies of BE or EAC to develop a risk prediction model based on genetic, clinical, and demographic/lifestyle factors. We identified a PRS that increases discrimination and net reclassification of individuals with vs without BE and EAC. However, the absolute magnitude of improvement is not sufficient to justify its clinical use., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to protect against tetraploidy, aneuploidy, and chromosomal alterations in the metaplastic condition Barrett's esophagus (BE) and to lower the incidence and mortality of esophageal adenocarcinoma (EA). The esophagus is exposed to both intrinsic and extrinsic mutagens resulting from gastric reflux, chronic inflammation, and exposure to environmental carcinogens such as those found in cigarettes. Here we test the hypothesis that NSAID use inhibits accumulation of point mutations/indels during somatic genomic evolution in BE., Methods: Whole exome sequences were generated from 82 purified epithelial biopsies and paired blood samples from a cross-sectional study of 41 NSAID users and 41 non-users matched by sex, age, smoking, and continuous time using or not using NSAIDs., Results: NSAID use reduced overall frequency of point mutations across the spectrum of mutation types, lowered the frequency of mutations even when adjusted for both TP53 mutation and smoking status, and decreased the prevalence of clones with high variant allele frequency. Never smokers who consistently used NSAIDs had fewer point mutations in signature 17, which is commonly found in EA. NSAID users had, on average, a 50% reduction in functional gene mutations in nine cancer-associated pathways and also had less diversity in pathway mutational burden compared to non-users., Conclusions: These results indicate NSAID use functions to limit overall mutations on which selection can act and supports a model in which specific mutant cell populations survive or expand better in the absence of NSAIDs.

The low risk of progression of Barrett's esophagus (BE) to esophageal adenocarcinoma can lead to over-diagnosis and over-treatment of BE patients. This may be addressed through a better understanding of the dynamics surrounding BE malignant progression. Although genetic diversity has been characterized as a marker of malignant development, it is still unclear how BE arises and develops. Here we uncover the evolutionary dynamics of BE at crypt and biopsy levels in eight individuals, including four patients that experienced malignant progression. We assay eight individual crypts and the remaining epithelium by SNP array for each of 6-11 biopsies over 2 time points per patient (358 samples in total). Our results indicate that most Barrett's segments are clonal, with similar number and inferred rates of alterations observed for crypts and biopsies. Divergence correlates with geographical location, being higher near the gastro-esophageal junction. Relaxed clock analyses show that genomic instability precedes and is enhanced by genome doubling. These results shed light on the clinically relevant evolutionary dynamics of BE.

Understanding antibiotic biodegradation is important to the appreciation of their fate and removal from the environment. In this research an Isotope Ratio Mass Spectrometry (IRMS) method was developed to evaluate the extent of biodegradation of the antibiotic, sulphanilamide, in contaminated groundwater. Results indicted an enrichment in δ 13 C of 8.44‰ from -26.56 (at the contaminant source) to -18.12‰ (300m downfield of the source). These results confirm reductions in sulphanilamide concentrations (from 650 to 10mg/L) across the contaminant plume to be attributable to biodegradation (56%) vs. other natural attenuation processes, such as dilution or dispersion (42%). To understand the controls on sulphanilamide degradation ex-situ microcosms assessed the influence of sulphanilamide concentration, redox conditions and an alternative carbon source. Results indicated, high levels of anaerobic capacity (~50% mineralisation) to degrade sulphanilamide under high (263mg/L), moderate (10mg/L) and low (0.02mg/L) substrate concentrations. The addition of electron acceptors; nitrate and sulphate, did not significantly enhance the capacity of the groundwater to anaerobically biodegrade sulphanilamide. Interestingly, where alternative carbon sources were present, the addition of nitrate and sulphate inhibited sulphanilamide biodegradation. These results suggest, under in-situ conditions, when a preferential carbon source was available for biodegradation, sulphanilamide could be acting as a nitrogen and/or sulphur source. These findings are important as they highlight sulphanilamide being used as a carbon and a putative nitrogen and sulphur source, under prevailing iron reducing conditions., (Copyright © 2017. Published by Elsevier B.V.)

Excessive transport of fine sediment, and its associated pollutants, can cause detrimental impacts in aquatic environments. It is therefore important to perform accurate sediment source apportionment to identify hot spots of soil erosion. Various tracers have been adopted, often in combination, to identify sediment source type and its spatial origin; these include fallout radionuclides, geochemical tracers, mineral magnetic properties and bulk and compound-specific stable isotopes. In this review, the applicability of these techniques to particular settings and their advantages and limitations are reviewed. By synthesizing existing approaches, that make use of multiple tracers in combination with measured changes of channel geomorphological attributes, an integrated analysis of tracer profiles in deposited sediments in lakes and reservoirs can be made. Through a multi-scale approach for fine sediment tracking, temporal changes in soil erosion and sediment load can be reconstructed and the consequences of changing catchment practices evaluated. We recommend that long-term, as well as short-term, monitoring of riverine fine sediment and corresponding surface and subsurface sources at nested sites within a catchment are essential. Such monitoring will inform the development and validation of models for predicting dynamics of fine sediment transport as a function of hydro-climatic and geomorphological controls. We highlight that the need for monitoring is particularly important for hilly catchments with complex and changing land use. We recommend that research should be prioritized for sloping farmland-dominated catchments.

The inoculation of rice straw biochar with PAH-degrading Mycobacterium gilvum (1.27 × 10 11  ± 1.24 × 10 10  cell g -1 ), and the subsequent amendment of this composite material to PAHs contaminated (677 mg kg -1 ) coke plant soil, was conducted in order to investigate if would enhance PAHs biodegradation in soils. The microbe-biochar composite showed superior degradation capacity for phenanthrene, fluoranthene and pyrene. Phenanthrene loss in the microbe-biochar composite, free cell alone and biochar alone treatments was, respectively, 62.6 ± 3.2%, 47.3 ± 4.1% and non-significant (P > 0.05); whereas for fluoranthene loss it was 52.1 ± 2.3%; non-significant (P > 0.05) and non-significant (P > 0.05); and for pyrene loss it was 62.1 ± 0.9%; 19.7 ± 6.5% and 13.5 ± 2.8%. It was hypothesized that the improved remediation was underpinned by i) biochar enhanced mass transfer of PAHs from the soil to the carbonaceous biochar "sink", and ii) the subsequent degradation of the PAHs by the immobilized M. gilvum. To test this mechanism, a surfactant (Brij 30; 20 mg g -1 soil), was added to impede PAHs mass transfer to biochar and sorption. The surfactant increased solution phase PAH concentrations and significantly (P < 0.05) reduced PAH degradation in the biochar immobilized M. gilvum treatments; indicating the enhanced degradation occurred between the immobilized M. gilvum and biochar sorbed PAHs., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Cancer development is driven by genomic alterations, including copy number aberrations. The detection of copy number aberrations in tumor cells is often complicated by possible contamination of normal stromal cells in tumor samples and intratumor heterogeneity, namely the presence of multiple clones of tumor cells. In order to correctly quantify copy number aberrations, it is critical to successfully de-convolute the complex structure of the genetic information from tumor samples. In this article, we propose a general Bayesian method for estimating copy number aberrations when there are normal cells and potentially more than one tumor clones. Our method provides posterior probabilities for the proportions of tumor clones and normal cells. We incorporate prior information on the distribution of the copy numbers to prioritize biologically more plausible solutions and alleviate possible identifiability issues that have been observed by many researchers. Our model is flexible and can work for both SNP array and next-generation sequencing data. We compare our method to existing ones and illustrate the advantage of our approach in multiple datasets.

Globally, rapid urbanization, along with economic development, is dramatically changing the balance of biogeochemical cycles, impacting upon ecosystem services and impinging on United Nation global sustainability goals (inter alia: sustainable cities and communities; responsible consumption and production; good health and well-being; clean water and sanitation, and; to protect and conserve life on land and below water). A key feature of the urban ecosystems is that nutrient stocks, carbon (C), nitrogen (N) and phosphorus (P), are being enriched. Furthermore, urban ecosystems are highly engineered, biogeochemical cycling of nutrients within urban ecosystems is spatially segregated, and nutrients exported (e.g. in food) from rural/peri-urban areas are not being returned to support primary production in these environments. To redress these imbalances we propose the concept of the Peri-URban Ecosystem (PURE). Through the merging of conceptual approaches that relate to Critical Zone science and the dynamics of successional climax PURE serves at the symbiotic interface between rural/natural and urban ecosystems and allow re-coupling of resource flows. PURE provides a framework for tackling the most pressing of societal challenges and supporting global sustainability goals., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Greenhouse experiments were conducted to investigate the influence of rice straw biochar (RSB) on soil cadmium (Cd) availability and accumulation in lettuce. The RSB was applied either in bands or broadcast in the test site of four greenhouses with soil Cd concentrations ranging from 1.70-3.14 μg g -1 . Biochar doses applied in bands were half of those broadcast. The Cd levels in the shoots of lettuce were observed to be reduced by up to 57% with increasing RSB application rate (0, 6, 12, 18 t ha -1 ). Following RSB application, shoot Cd concentrations of lettuce were reduced to below the Chinese threshold value set for food, and hazard quotients for Cd associated with vegetable consumption were reduced from 0.70-1.11 to 0.42-0.65. A decrease in soil bulk density (11%) and increases in water holding capacity (16%), available phosphorus (30%), available potassium (197%), and lettuce yield (15%) were observed after RSB application. Multiple linear regression analysis suggested that the soil extractable Cd level (but not biomass dilution) and soil bulk density, as influenced by RSB addition, were the dominant contributors to the shoot Cd levels in lettuce and lettuce yield, respectively. These results highlight the potential for RSB to mitigate the phytoaccumulation of Cd and thereby to reduce human exposure from vegetable consumption. Application of biochar in band, rather than broadcasting over the entire area, represents an opportunity to halve the biochar cost while retaining a good remediation effect.

Introduction/objectives: Incidence of esophageal adenocarcinoma (EA), an often fatal cancer, has increased sharply over recent decades. Several important risk factors (reflux, obesity, smoking) have been identified for EA and its precursor, Barrett's esophagus (BE), but a key challenge remains identifying individuals at highest risk, since most with reflux do not develop BE, and most with BE do not progress to cancer. Metabolomics represents an emerging approach for identifying novel biomarkers associated with cancer development., Methods: We used targeted liquid chromatography-mass spectrometry (LC-MS) to profile 57 metabolites in 322 serum specimens derived from individuals with gastroesophageal reflux disease (GERD), BE, high-grade dysplasia (HGD), or EA, drawn from two well-annotated epidemiologic parent studies., Results: Multiple metabolites differed significantly (P<0.05) between BE versus GERD (n=9), and between HGD/EA versus BE (n=4). Several top candidates (FDR q≤0.15), including urate, homocysteine, and 3-nitrotyrosine, are linked to inflammatory processes, which may contribute to BE/EA pathogenesis. Multivariate modeling achieved moderate discrimination between HGD/EA and BE (AUC=0.75), with less pronounced separation for BE versus GERD (AUC=0.64)., Conclusion: Serum metabolite differences can be detected between individuals with GERD versus BE, and between those with BE versus HGD/EA, and may help differentiate patients at different stages of progression to EA., Competing Interests: Statement : D.R. holds equity and an executive role in Matrix-Bio, Inc. (IN, USA). The authors have no other potential conflicts of interest to disclose.

In The Cancer Genome Atlas the goals were to define how to treat advanced cancers with targeted therapy. However, the challenges facing cancer interception for early detection and prevention include length bias in which current screening and surveillance approaches frequently miss rapidly progressing cancers that then present at advanced stages in the clinic with symptoms (underdiagnosis). In contrast, many early detection strategies detect benign conditions that may never progress to cancer during a lifetime, and the patient dies of unrelated causes (overdiagnosis). This challenge to cancer interception is believed to be due to the speed at which the neoplasm evolves, called length bias sampling ; rapidly progressing cancers are missed by current early detection strategies. In contrast, slowly or non-progressing cancers or their precursors are selectively detected. This has led to the concept of cancer interception, which can be defined as active interception of a biological process that drives cancer development before the patient presents in the clinic with an advanced, symptomatic cancer. The solutions needed to advance strategies for cancer interception require assessing the rate at which the cancer evolves over time and space. This is an essential challenge that needs to be addressed by robust study designs including normal and non-progressing controls when known to be appropriate.

Understanding of the adsorption behavior of organic pollutants on carbon nanotubes (CNTs) and its governing factors are crucial for the assessment of transport and fate of organic pollutants. This study explored adsorption characteristics of linear alkylbenzene sulfonates (LAS) on carboxyl modified multi-walled carbon nanotubes (CMMWCNTs) and the effect of solution chemistry and temperature on LAS sorption. Results indicted LAS adsorption isotherms to display five distinct regions of sorption at 25°C and 60°C. Regardless of temperature, the adsorption isotherm of LAS on the CMMWCNTs was well described using the Freundlich equation. This result indicated heterogeneous distribution of adsorption sites on the CMMWCNT surface. At low initial LAS concentrations, below the critical micelle concentration, (2, 10 and 50mgL -1 ) LAS adsorption on the CMMWCNTs followed pseudo second-order kinetics. The highest LAS adsorption was observed at ionic strengths of 1.0molL -1 for NaCl; and 0.2molL -1 for both CaCl 2 and MgCl 2 . However, LAS sorption was greatest in the presence of sodium-divalent anion salts and at higher temperatures. These findings are of relevance to the fate and environmental risk of LAS in the presence of CMMWCNTs in high salinity wastewaters or effluents and brackish receiving surface water bodies (e.g., at estuaries)., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Much research has considered the influence of biochars on the availability and phytoaccumulation of potentially toxic elements (PTEs) from soil. However, the vast majority of these studies use, what are arguably, unrealistic and unpractical amounts of biochar (10, 50 and even up to 100 t/ha). To offer a more realistic insight into the influence of biochar on PTE partitioning and phytoaccumulation, a field study, using modest rates of biochar application (1.5, 3.0 t/ha), was undertaken. Specifically, the research investigated the influence of sewage sludge biochar (SSBC) on the accumulation of Cd into rice (Oryza sativa L.) grown in Cd contaminated (0.82 ± 0.07 mg/kg) paddy soil. Results indicated, Cd concentrations in rice grains to significantly (p < 0.05) decrease from 1.35 ± 0.09 mg/kg in the control to 0.82 ± 0.07 mg/kg and 0.80 ± 0.21 mg/kg in the 1.5 t/ha and 3.0 t/ha treatments, respectively. Accordingly, the hazardous quotient (HQ) indices for Cd, associated with rice grain consumption, were also reduced by ∼40%. SSBC amendment significantly (p < 0.05) increased grain yields from 1.90 ± 0.08 g/plant in the control to 2.17 ± 0.30 g/plant and 3.40 ± 0.27 g/plant in the 1.5 t/ha and 3.0 t/ha treatments, respectively. Thus, the amendment of SSBC to contaminated paddy soils, even at low application rates, could be an effective approach to mitigate Cd accumulation into rice plants, to improve rice grain yields, and to thereby improve food security and protect public health., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Many cancers offer an extended window of opportunity for early detection and therapeutic intervention that could lead to a reduction in cause-specific mortality. The pursuit of early detection in screening settings has resulted in decreased incidence and mortality for some cancers (e.g., colon and cervical cancers), and increased incidence with only modest or no effect on cause-specific mortality in others (e.g., breast and prostate). Whereas highly sensitive screening technologies are better at detecting a number of suspected "cancers" that are indolent and likely to remain clinically unimportant in the lifetime of a patient, defined as overdiagnosis, they often miss cancers that are aggressive and tend to present clinically between screenings, known as interval cancers. Unrecognized overdiagnosis leads to overtreatment with its attendant (often long-lasting) side effects, anxiety, and substantial financial harm. Existing methods often cannot differentiate indolent lesions from aggressive ones or understand the dynamics of neoplastic progression. To correctly identify the population that would benefit the most from screening and identify the lesions that would benefit most from treatment, the evolving genomic and molecular profiles of individual cancers during the clinical course of progression or indolence must be investigated, while taking into account an individual's genetic susceptibility, clinical and environmental risk factors, and the tumor microenvironment. Practical challenges lie not only in the lack of access to tissue specimens that are appropriate for the study of natural history, but also in the absence of targeted research strategies. This commentary summarizes the recommendations from a diverse group of scientists with expertise in basic biology, translational research, clinical research, statistics, and epidemiology and public health professionals convened to discuss research directions. J. Cell. Physiol. 231: 1870-1875, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

The article by Banerjee and colleagues published in this issue of the journal involving a randomized control prevention trial of ursodeoxycholic acid (UDCA) in Barrett esophagus reported a null outcome despite being well designed and executed. Possible reasons for this null outcome are discussed focusing on use of surrogate endpoints in the trial. The trial is especially topical because it comes at a time when there are calls for a Pre-Cancer Genome Atlas (PCGA) for "understanding the earliest molecular and cellular events associated with cancer initiation…" This commentary discusses current concepts in prevention research including branched evolution that leads to therapeutic resistance. Length bias sampling postulates underdiagnosis is due to rapidly progressing disease that is difficult to detect by screening because it progresses to cancer too rapidly and that overdiagnosis is the result of very slowly or nonprogressing disease that is easy to detect by screening because it persists for a lifetime and the patient dies of unrelated causes. Finally, it also explores study designs, including surrogate endpoints in Barrett esophagus trials, and opportunities and pitfalls for a PCGA in the context of high levels of over and underdiagnosis of Barrett esophagus as well as many other cancers and their precursors. Cancer Prev Res; 9(7); 512-7. ©2016 AACRSee related article by Banerjee, et al., p. 528., (©2016 American Association for Cancer Research.)

Mutations detected in cancers are often divided into "drivers" and "passengers." We suggest that this classification is potentially misleading for purposes of early detection and prevention. Specifically, some mutations are frequent in tumors and thus appear to be drivers, but are poor predictors of cancer; other mutations are individually rare and thus appear to be passengers, but may collectively explain a large proportion of risk. The assumptions bundled into the terms "driver" and "passenger" can lead to misunderstandings of neoplastic progression, with unintended consequences including overdiagnosis, overtreatment, and failure to identify the true sources of risk. We argue that samples from healthy, benign, or neoplastic tissues are critical for evaluating the risk of future cancer posed by mutations in a given gene. Cancer Prev Res; 9(5); 335-8. ©2016 AACR., (©2016 American Association for Cancer Research.)

A hydrologically contained field study, to assess biochar (produced from mixed crop straws) influence upon soil hydraulic properties and dissolved organic carbon (DOC) leaching, was conducted on a loamy soil (entisol). The soil, noted for its low plant-available water and low soil organic matter, is the most important arable soil type in the upper reaches of the Yangtze River catchment, China. Pore size distribution characterization (by N2 adsorption, mercury intrusion, and water retention) showed that the biochar had a tri-modal pore size distribution. This included pores with diameters in the range of 0.1-10 μm that can retain plant-available water. Comparison of soil water retention curves between the control (0) and the biochar plots (16 t ha(-1) on dry weight basis) demonstrated biochar amendment to increase soil water holding capacity. However, significant increases in DOC concentration of soil pore water in both the plough layer and the undisturbed subsoil layer were observed in the biochar-amended plots. An increased loss of DOC relative to the control was observed upon rainfall events. Measurements of excitation-emission matrix (EEM) fluorescence indicated the DOC increment originated primarily from the organic carbon pool in the soil that became more soluble following biochar incorporation.

In the early 1970s, studies in Leland Hartwell's laboratory at the University of Washington launched the genetic analysis of the eukaryotic cell cycle and set the path that has led to our modern understanding of this centrally important process. This 45th-anniversary Retrospective reviews the steps by which the project took shape, the atmosphere in which this happened, and the possible morals for modern times. It also provides an up-to-date look at the 35 original CDC genes and their human homologues., (© 2015 Reid et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).)

Here we report the widespread natural occurrence of a known antibiotic and antineoplastic compound, hydroxyurea in animals from many taxonomic groups. Hydroxyurea occurs in all the organisms we have examined including invertebrates (molluscs and crustaceans), fishes from several major groups, amphibians and mammals. The species with highest concentrations was an elasmobranch (sharks, skates and rays), the little skate Leucoraja erinacea with levels up to 250 μM, high enough to have antiviral, antimicrobial and antineoplastic effects based on in vitro studies. Embryos of L. erinacea showed increasing levels of hydroxyurea with development, indicating the capacity for hydroxyurea synthesis. Certain tissues of other organisms (e.g. skin of the frog (64 μM), intestine of lobster (138 μM) gills of the surf clam (100 μM)) had levels high enough to have antiviral effects based on in vitro studies. Hydroxyurea is widely used clinically in the treatment of certain human cancers, sickle cell anemia, psoriasis, myeloproliferative diseases, and has been investigated as a potential treatment of HIV infection and its presence at high levels in tissues of elasmobranchs and other organisms suggests a novel mechanism for fighting disease that may explain the disease resistance of some groups. In light of the known production of nitric oxide from exogenously applied hydroxyurea, endogenous hydoxyurea may play a hitherto unknown role in nitric oxide dynamics.

Background: Important risk factors for esophageal adenocarcinoma and its precursor, Barrett's esophagus, include gastroesophageal reflux disease, obesity, and cigarette smoking. Recently, genome-wide association studies have identified seven germline single-nucleotide polymorphisms (SNP) that are associated with risk of Barrett's esophagus and esophageal adenocarcinoma. Whether these genetic susceptibility loci modify previously identified exposure-disease associations is unclear., Methods: We analyzed exposure and genotype data from the BEACON Consortium discovery phase GWAS, which included 1,516 esophageal adenocarcinoma case patients, 2,416 Barrett's esophagus case patients, and 2,187 control participants. We examined the seven newly identified susceptibility SNPs for interactions with body mass index, smoking status, and report of weekly heartburn or reflux. Logistic regression models were used to estimate ORs for these risk factors stratified by SNP genotype, separately for Barrett's esophagus and esophageal adenocarcinoma., Results: The odds ratio for Barrett's esophagus associated with at least weekly heartburn or reflux varied significantly with the presence of at least one minor allele of rs2687201 (nominal P = 0.0005, FDR = 0.042). ORs (95% CIs) for weekly heartburn or reflux among participants with 0, 1, or 2 minor alleles of rs2687201 were 6.17 (4.91-7.56), 3.56 (2.85-4.44), and 3.97 (2.47-6.37), respectively. No statistically significant interactions were observed for smoking status and body mass index., Conclusion: Reflux symptoms are more strongly associated with Barrett's esophagus risk among persons homozygous for the major allele of rs2687201, which lies approximately 75 kb downstream of the transcription factor gene FOXP1., Impact: The novel gene-exposure interaction discovered in this study provides new insights into the etiology of esophageal adenocarcinoma., (©2015 American Association for Cancer Research.)

Beginning in the 1980s, an alarming rise in the incidence of esophageal adenocarcinoma (EA) led to screening of patients with reflux to detect Barrett's esophagus (BE) and surveillance of BE to detect early EA. This strategy, based on linear progression disease models, resulted in selective detection of BE that does not progress to EA over a lifetime (overdiagnosis) and missed BE that rapidly progresses to EA (underdiagnosis). Here we review the historical thought processes that resulted in this undesired outcome and the transformation in our understanding of genetic and evolutionary principles governing neoplastic progression that has come from application of modern genomic technologies to cancers and their precursors. This new synthesis provides improved strategies for prevention and early detection of EA by addressing the environmental and mutational processes that can determine "windows of opportunity" in time to detect rapidly progressing BE and distinguish it from slowly or nonprogressing BE., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: The strong male predominance in oesophageal adenocarcinoma (OAC) and Barrett's oesophagus (BO) continues to puzzle. Hormonal influence, e.g. oestrogen or oxytocin, might contribute., Methods: This genetic-epidemiological study pooled 14 studies from three continents, Australia, Europe, and North America. Polymorphisms in 3 key genes coding for the oestrogen pathway (receptor alpha (ESR1), receptor beta (ESR2), and aromatase (CYP19A1)), and 3 key genes of the oxytocin pathway (the oxytocin receptor (OXTR), oxytocin protein (OXT), and cyclic ADP ribose hydrolase glycoprotein (CD38)), were analysed using a gene-based approach, versatile gene-based test association study (VEGAS)., Results: Among 1508 OAC patients, 2383 BO patients, and 2170 controls, genetic variants within ESR1 were associated with BO in males (p = 0.0058) and an increased risk of OAC and BO combined in males (p = 0.0023). Genetic variants within OXTR were associated with an increased risk of BO in both sexes combined (p = 0.0035) and in males (p = 0.0012). We followed up these suggestive findings in a further smaller data set, but found no replication. There were no significant associations between the other 4 genes studied and risk of OAC, BO, separately on in combination, in males and females combined or in males only., Conclusion: Genetic variants in the oestrogen receptor alpha and the oxytocin receptor may be associated with an increased risk of BO or OAC, but replication in other large samples are needed.

Background: Telomere shortening is associated with increasing age, male gender and lifestyle factors such as obesity and smoking. Inflammation has also been implicated in cellular senescence and may promote telomere shortening in chronic conditions such as obesity and diabetes. However, little is known about the relationship between markers of obesity and inflammation, and leukocyte telomere length (LTL)., Methods: LTL was measured using quantitative polymerase chain reaction in peripheral leukocytes from 295 individuals diagnosed with Barrett's esophagus (BE) between 1995 and 2009. Data on lifestyle variables including obesity and smoking were collected at in-person interviews. Biomarkers of obesity (leptin, adiponectin), diabetes (glucose, insulin), inflammation (C-reactive protein, Interleukin-6, surface tumor necrosis factor receptor (sTNFR) I & II) and oxidative stress (F2-isoprostanes) were measured in stored blood samples. We examined associations between these covariates and LTL in a cross-sectional analysis using linear and logistic regression models, adjusting for possible confounders., Results: LTL was significantly associated with age (r = -0.30, p < 0.001), gender (r = 0.14 for females, p = 0.01) and inversely associated with cigarette pack-years (r = -0.11, p = 0.04). Odds of having short LTL were significantly higher for participants in the highest tertile for sTNF-RI (Odds ratio adjusted for age, gender, smoking, and obesity = 2.19; 95 % CI 1.00-4.85, p-trend = 0.02). LTL was not significantly associated with any other lifestyle factors, including smoking or obesity, or other inflammation-, obesity-/diabetes-related biomarkers measured., Conclusions: Increasing age, male gender, smoking history, and sTNF-RI levels were associated with short LTL among persons with BE but no correlations were observed between LTL and other inflammatory markers or measures of obesity. Larger longitudinal studies are necessary in order to further establish the potential relationships between obesity, inflammation markers and LTL.

Cancers detected at a late stage are often refractory to treatments and ultimately lethal. Early detection can significantly increase survival probability, but attempts to reduce mortality by early detection have frequently increased overdiagnosis of indolent conditions that do not progress over a lifetime. Study designs that incorporate biomarker trajectories in time and space are needed to distinguish patients who progress to an early cancer from those who follow an indolent course. Esophageal adenocarcinoma is characterized by evolution of punctuated and catastrophic somatic chromosomal alterations and high levels of overall mutations but few recurrently mutated genes aside from TP53. Endoscopic surveillance of Barrett's esophagus for early cancer detection provides an opportunity for assessment of alterations for cancer risk in patients who progress to esophageal adenocarcinoma compared with nonprogressors. We investigated 1,272 longitudinally collected esophageal biopsies in a 248 Barrett's patient case-cohort study with 20,425 person-months of follow-up, including 79 who progressed to early-stage esophageal adenocarcinoma. Cancer progression risk was assessed for total chromosomal alterations, diversity, and chromosomal region-specific alterations measured with single-nucleotide polymorphism arrays in biopsies obtained over esophageal space and time. A model using 29 chromosomal features was developed for cancer risk prediction (area under receiver operator curve, 0.94). The model prediction performance was robust in two independent esophageal adenocarcinoma sets and outperformed TP53 mutation, flow cytometric DNA content, and histopathologic diagnosis of dysplasia. This study offers a strategy to reduce overdiagnosis in Barrett's esophagus and improve early detection of esophageal adenocarcinoma and potentially other cancers characterized by punctuated and catastrophic chromosomal evolution., (©2015 American Association for Cancer Research.)

The effects of sewage sludge (SS) and its derived biochar (SSBC) on the availability and uptake of polycyclic aromatic hydrocarbons (PAHs) and potential toxic elements (PTEs) by Solanum lycopersicum (tomato) fruits grown in contaminated urban soil were investigated. Increasing application rates of SS and SSBC (2, 5, and 10%) decreased PAH availability and, correspondingly, PAH accumulation (22-39 and 48-62%, respectively) into tomato. SSBC was more effective in this regard. The available concentrations of PAHs (Σ16PAH) in the SSBC treatments were significantly reduced (from 30.0-47.3%) as compared to the control treatment. The availability of high-molecular-weight PAHs (containing four to six benzene rings) was greatly affected, while low-molecular-weight PAHs (containing two to three benzene rings) was less affected by SSBC amendments. The addition of SSBC showed the least effect on bioaccumulation of naphthalene (two-ring PAH; 24.5-32.6%), while the highest effect was observed for benzo(b)fluoranthene (five-ring PAH; 3.1-86.8%) and benzo(g,h,i)perylene (six-ring PAH; 51.8-84.2%). In contrast, increasing application rates of SS successively increased PTE (As, Cd, Cu, Pb, and Zn) availability and accumulation (15-139%) into tomato while SSBC successively decreased PTE availability and accumulation (17-91%). Changes in accumulation varied with PTE and the extent to which PTE concentrations in soil was elevated.

Purpose: Goblet cells may represent a potentially successful adaptive response to acid and bile by producing a thick mucous barrier that protects against cancer development in Barrett's esophagus (BE). The aim of this study was to determine the relationship between goblet cells (GC) and risk of progression to adenocarcinoma, and DNA content flow cytometric abnormalities, in BE patients., Experimental Design: Baseline mucosal biopsies (N=2988) from 213 patients, 32 of whom developed cancer during the follow up period, enrolled in a prospective dynamic cohort of BE patients were scored in a blinded fashion, for the total number (#) of GC, mean # of GC/crypt (GC density), # of crypts with ≥ 1 GC, and the proportion of crypts with ≥1 GC, in both dysplastic and non-dysplastic epithelium separately. The relationship between these four GC parameters and DNA content flow cytometric abnormalities and adenocarcinoma outcome was compared, after adjustment for age, gender, and BE segment length., Results: High GC parameters were inversely associated with DNA content flow cytometric abnormalities, such as aneuploidy, ploidy >2.7N, and an elevated 4N fraction > 6%, and with risk of adenocarcinoma. However, a Kaplan-Meier analysis showed that the total # of GC and the total # crypts with ≥1 GC were the only significant GC parameters (p<0.001 and 0.003, respectively)., Conclusions: The results of this study show, for the first time, an inverse relationship between high GC counts and flow cytometric abnormalities and risk of adenocarcinoma in BE. Further studies are needed to determine if GC depleted foci within esophageal columnar mucosa are more prone to neoplastic progression or whether loss of GC occurs secondary to underlying genetic abnormalities.

A field experiment was conducted to investigate the effect of bean stalk (BBC) and rice straw (RBC) biochars on the bioavailability of metal(loid)s in soil and their accumulation into rice plants. Phytoavailability of Cd was most dramatically influenced by biochars addition. Both biochars significantly decreased Cd concentrations in iron plaque (35-81 %), roots (30-75 %), shoots (43-79 %) and rice grain (26-71 %). Following biochars addition, Zinc concentrations in roots and shoots decreased by 25.0-44.1 and 19.9-44.2 %, respectively, although no significant decreases were observed in iron plaque and rice grain. Only RBC significantly reduced Pb concentrations in iron plaque (65.0 %) and roots (40.7 %). However, neither biochar significantly changed Pb concentrations in rice shoots and grain. Arsenic phytoavailability was not significantly altered by biochars addition. Calculation of hazard quotients (HQ) associated with rice consumption revealed RBC to represent a promising candidate to mitigate hazards associated with metal(loid) bioaccumulation. RBC reduced Cd HQ from a 5.5 to 1.6. A dynamic factor's way was also used to evaluate the changes in metal(loid) plant uptake process after the soil amendment with two types of biochar. In conclusion, these results highlight the potential for biochar to mitigate the phytoaccumulation of metal(loid)s and to thereby reduce metal(loid) exposure associated with rice consumption.

Background: The incidence of esophageal adenocarcinoma (EAC) has increased nearly five-fold over the last four decades in the United States. Barrett's esophagus, the replacement of the normal squamous epithelial lining with a mucus-secreting columnar epithelium, is the only known precursor to EAC. Like other parts of the gastrointestinal (GI) tract, the esophagus hosts a variety of bacteria and comparisons among published studies suggest bacterial communities in the stomach and esophagus differ. Chronic infection with Helicobacter pylori in the stomach has been inversely associated with development of EAC, but the mechanisms underlying this association remain unclear., Methodology: The bacterial composition in the upper GI tract was characterized in a subset of participants (n=12) of the Seattle Barrett's Esophagus Research cohort using broad-range 16S PCR and pyrosequencing of biopsy and brush samples collected from squamous esophagus, Barrett's esophagus, stomach corpus and stomach antrum. Three of the individuals were sampled at two separate time points. Prevalence of H. pylori infection and subsequent development of aneuploidy (n=339) and EAC (n=433) was examined in a larger subset of this cohort., Results/significance: Within individuals, bacterial communities of the stomach and esophagus showed overlapping community membership. Despite closer proximity, the stomach antrum and corpus communities were less similar than the antrum and esophageal samples. Re-sampling of study participants revealed similar upper GI community membership in two of three cases. In this Barrett's esophagus cohort, Streptococcus and Prevotella species dominate the upper GI and the ratio of these two species is associated with waist-to-hip ratio and hiatal hernia length, two known EAC risk factors in Barrett's esophagus. H. pylori-positive individuals had a significantly decreased incidence of aneuploidy and a non-significant trend toward lower incidence of EAC.

Incidence of esophageal adenocarcinoma (EA) has increased substantially in recent decades. Multiple risk factors have been identified for EA and its precursor, Barrett's esophagus (BE), such as reflux, European ancestry, male sex, obesity, and tobacco smoking, and several germline genetic variants were recently associated with disease risk. Using data from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) genome-wide association study (GWAS) of 2,515 EA cases, 3,295 BE cases, and 3,207 controls, we examined single nucleotide polymorphisms (SNPs) that potentially affect the biogenesis or biological activity of microRNAs (miRNAs), small non-coding RNAs implicated in post-transcriptional gene regulation, and deregulated in many cancers, including EA. Polymorphisms in three classes of genes were examined for association with risk of EA or BE: miRNA biogenesis genes (157 SNPs, 21 genes); miRNA gene loci (234 SNPs, 210 genes); and miRNA-targeted mRNAs (177 SNPs, 158 genes). Nominal associations (P<0.05) of 29 SNPs with EA risk, and 25 SNPs with BE risk, were observed. None remained significant after correction for multiple comparisons (FDR q>0.50), and we did not find evidence for interactions between variants analyzed and two risk factors for EA/BE (smoking and obesity). This analysis provides the most extensive assessment to date of miRNA-related SNPs in relation to risk of EA and BE. While common genetic variants within components of the miRNA biogenesis core pathway appear unlikely to modulate susceptibility to EA or BE, further studies may be warranted to examine potential associations between unassessed variants in miRNA genes and targets with disease risk.

Background & Aims: Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations., Methods: We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls., Results: We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09-1.18; P = 1.8 × 10(-11)) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 × 10(-9)). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87-0.93; P = 3.72 × 10(-9))., Conclusions: We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Incidence of esophageal adenocarcinoma (EA) in Western countries has increased markedly in recent decades. Although several risk factors have been identified for EA and its precursor, Barrett's esophagus (BE), including reflux, Caucasian race, male gender, obesity, and smoking, less is known about the role of inherited genetic variation. Frequent somatic mutations in the tumor suppressor genes CDKN2A and TP53 were recently reported in EA tumors, while somatic alterations at 9p (CDKN2A) and 17p (TP53) have been implicated as predictors of progression from BE to EA. Motivated by these findings, we used data from a genome-wide association study of 2515 EA cases and 3207 controls to analyze 37 germline single nucleotide polymorphisms at the CDKN2A and TP53 loci. Three CDKN2A polymorphisms were nominally associated (P < 0.05) with reduced risk of EA: rs2518720 C>T [intronic, odds ratio 0.90, P = 0.0121, q = 0.3059], rs3088440 G>A (3'UTR, odds ratio 0.84, P = 0.0186, q = 0.3059), and rs4074785 C>T (intronic, odds ratio 0.85, P = 0.0248, q = 0.3059). None of the TP53 single nucleotide polymorphisms reached nominal significance. Two of the CDKN2A variants identified were also associated with reduced risk of progression from BE to EA, when assessed in a prospective cohort of 408 BE patients: rs2518720 (hazard ratio 0.57, P = 0.0095, q = 0.0285) and rs3088440 (hazard ratio 0.34, P = 0.0368, q = 0.0552). In vitro functional studies of rs3088440, a single nucleotide polymorphism located in the seed sequence of a predicted miR-663b binding site, suggested a mechanism whereby the G>A substitution may attenuate miR-663b-mediated repression of the CDKN2A transcript. This study provides the first evidence that germline variation at the CDKN2A locus may influence EA susceptibility., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)