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Supercritical fractionation of lignocellulosic biomass enhances the production of lignin-derived hydrocarbons and boosts the digestibility of the cellulose-rich pulp.

This paper shows that debt undermines relational incentives and harms worker morale. We build a dynamic model of a manager who uses limited financial resources to simultaneously repay a creditor and motivate a worker. If the manager can divert or misuse revenue, then debt makes the manager less willing to follow through on promised rewards, leading to low worker effort. In profit-maximizing equilibria, the firm prioritizes repaying its debts, leading to gradual increases in effort and wages. These dynamics can persist even after debts have been fully repaid. Consistent with this analysis, we document that a firm’s financial leverage is negatively related to measures of employee morale, wages, and productivity. This paper was accepted by Joshua Gans, business strategy.

Genotype-phenotype correlations add value to the management of families with hereditary hearing loss (HL), where age-related typical audiograms (ARTAs) are generated from cross-sectional regression equations and used to predict the audiogram phenotype across the lifespan. A seven-generation kindred with autosomal dominant sensorineural HL (ADSNHL) was recruited and a novel pathogenic variant in POU4F3 (c.37del) was identified by combining linkage analysis with whole exome sequencing (WES). POU4F3 is noted for large intrafamilial variation including the age of onset of HL, audiogram configuration and presence of vestibular impairment. Sequential audiograms and longitudinal analyses reveal highly variable audiogram features among POU4F3 (c.37del) carriers, limiting the utility of ARTAs for clinical prognosis and management of HL. Furthermore, a comparison of ARTAs against three previously published families (1 Israeli Jewish, 2 Dutch) reveals significant interfamilial differences, with earlier onset and slower deterioration. This is the first published report of a North American family with ADSNHL due to POU4F3, the first report of the pathogenic c.37del variant, and the first study to conduct longitudinal analysis, extending the phenotypic spectrum of DFNA15.

Supplementary Methods and Tables

Background: Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers, and cancer-related traits.Methods: The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers, and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background.Results: The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis.Conclusions: Results from these analyses will enable researchers to identify new susceptibility loci, perform fine-mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental, and lifestyle-related exposures.Impact: Ongoing analyses will shed light on etiology and risk assessment for many types of cancer. Cancer Epidemiol Biomarkers Prev; 26(1); 126–35. ©2016 AACR.

Sequencing exomes/genomes have been successful for identifying recessive genes; however, discovery of dominant genes including deafness genes (DFNA) remains challenging. We report a new DFNA gene, ATP11A, in a Newfoundland family with a variable form of bilateral sensorineural hearing loss (SNHL). Genome-wide SNP genotyping linked SNHL to DFNA33 (LOD = 4.77), a locus on 13q34 previously mapped in a German family with variable SNHL. Whole-genome sequencing identified 51 unremarkable positional variants on 13q34. Continuous clinical ascertainment identified several key recombination events and reduced the disease interval to 769 kb, excluding all but one variant. ATP11A (NC_000013.11: chr13:113534963G>A) is a novel variant predicted to be a cryptic donor splice site. RNA studies verified in silico predictions, revealing the retention of 153 bp of intron in the 3′ UTR of several ATP11A isoforms. Two unresolved families from Israel were subsequently identified with a similar, variable form of SNHL and a novel duplication (NM_032189.3:c.3322_3327+2dupGTCCAGGT) in exon 28 of ATP11A extended exon 28 by 8 bp, leading to a frameshift and premature stop codon (p.Asn1110Valfs43Ter). ATP11A is a type of P4-ATPase that transports (flip) phospholipids from the outer to inner leaflet of cell membranes to maintain asymmetry. Haploinsufficiency of ATP11A, the phospholipid flippase that specially transports phosphatidylserine (PS) and phosphatidylethanolamine (PE), could leave cells with PS/PE at the extracellular side vulnerable to phagocytic degradation. Given that surface PS can be pharmaceutically targeted, hearing loss due to ATP11A could potentially be treated. It is also likely that ATP11A is the gene underlying DFNA33.

Background: Due to the COVID-19 pandemic, many community palliative healthcare providers shifted from providing care in a patient’s home to providing almost exclusively virtual palliative care, or a combination of in-person and virtual care. Research on virtual palliative care is thus needed to provide evidence-based recommendations aiming to enhance the delivery of palliative care during and beyond the pandemic. Aim: To explore the experiences and perceptions of community palliative care providers, patients and caregivers who delivered or received virtual palliative care as a component of home-based palliative care during the COVID-19 pandemic. Design: Qualitative study using phone and video-based semi-structured interviews. Data were analyzed using thematic analysis. Setting/participants: A total of 37 participants, including community palliative care patients/caregivers ( n = 19) and healthcare providers ( n = 18) recruited from sites in Ottawa and Toronto, Ontario, Canada. Results: Overall, participants preferred in-person palliative care compared to virtual care, but suggested virtual care could be a useful supplement to in-person care. The findings are presented in three main themes: (1) Impact of COVID-19 pandemic on community palliative care services; (2) Factors influencing transition from exclusively virtual model of care back to a blended model of care; and (3) Recommended uses and implementation of virtual palliative care Conclusions: Incorporating virtual palliative care into healthcare provider practice models (blended care models) may be the ideal model of care and standard practice moving forward beyond the COVID-19 pandemic, which has important implications toward organization and delivery of community palliative care services and funding of healthcare providers.

Solvolysis of industrial corn stover lignin was carried out in methanol and ethanol to deconstruct lignin into monomers and small oligomers using various reactor configurations. We demonstrate that it is possible to overcome the limitations inherent to batch reactors by carrying out the solvolytic deconstruction in flow-through reactor systems as they allow for the continuous removal and rapid cooling of the products. Monomers and solvent-soluble product yields achieved in flow-through reactors were higher under all tested reaction conditions. We also investigated the effects of various reaction parameters and phase of solvent (sub- and supercritical) on the distribution and yield of lignin-derived products using complementary characterization techniques. p-Coumaric acid and ferulic acid were obtained as primary monomers with very high selectivity and a maximum monomer yield of 14.45 wt% was achieved at 250 °C and 85 bar in ethanol. Subsequent upgrading of the deconstructed fractions through fast pyrolysis was also studied. In addition to the increased yield of phenolic monomers (23.86 wt% vs. 10.29 wt%), char formation during pyrolysis was substantially decreased (26.36 wt% vs. 40.95 wt%) under optimized conditions. The beneficial impact of the solvolytic pretreatment was also reflected in an enhanced aromatic hydrocarbon yield during catalytic fast pyrolysis.

Consider an agent who can costlessly add mean‐preserving noise to his output. To deter such risk‐taking, the principal optimally offers a contract that makes the agent's utility concave in output. If the agent is risk‐neutral and protected by limited liability, this concavity constraint binds and so linear contracts maximize profit. If the agent is risk averse, the concavity constraint might bind for some outputs but not others. We characterize the unique profit‐maximizing contract and show how deterring risk‐taking affects the insurance‐incentive trade‐off. Our logic extends to costly risk‐taking and to dynamic settings where the agent can shift output over time.

Whole genome approaches are superior for identifying recessive genes, however discovery of dominant genes including deafness genes (DFNA) remains challenging. Herein we report a new DFNA gene, ATP11A, in a Newfoundland family with a variable form of bilateral sensorineural hearing loss (SNHL). Targeted screening of DFNA genes based on audioprofiles was unsuccessful. Genome-wide SNP genotyping linked SNHL to DFNA33 (Lod = 4.77), a locus on 13q34 previously mapped in a German family with variable SNHL in 2009. WGS identified 51 unremarkable positional variants on 13q34. Continuous clinical ascertainment identified several key recombination events and reduced the disease interval to 769 Kb, excluding all but one variant. ATP11A (NC_000013.11: g.190616G > A) is a novel point mutation predicted to be a cryptic donor splice site. RNA studies in patient-derived tissues verified in silico predictions, revealing the retention of 153bp of intron in the 3’ UTR of several ATP11A isoforms. A second, unresolved family from Israel with a similar, variable form of SNHL and a novel duplication in exon 28 of ATP11A that occurs within the splice donor sequence (intron 28). ATP11A is a type of P4-ATPase that transports (flip) phospholipids from the outer to inner leaflet of cell membranes to maintain asymmetry. Haploinsufficiency of ATP11A, the phospholipid flippase that specially transports phosphatidylserine (PS) and phosphatidylethanolamine (PE), could leave cells with PS/PE at the extracellular side vulnerable to phagocytic degradation. Given that surface PS can be pharmaceutically targeted, hearing loss due to ATP11A could potentially be treated. It is also likely that ATP11A is the gene underlying DFNA33.

By the beginning of the twenty-first century in the West, the notion of government-appointed bodies mandated for censoring cinematic content had fallen considerably out of fashion as institutional censorship was largely curtailed. Barring widely shared concerns regarding the exposure of underage children to material deemed inappropriate, newly rebranded “classification” boards have acted to limit the extent to which they themselves can prohibit images from entering the public market, shifting their emphasis away from censorship and toward consumer edification and greater consideration of artistic merit and authorial intent. Such reform brought the policies of censorship boards in Britain, Canada, and Australia into closer alignment with the goals and processes of the Motion Picture Association of America’s ratings system. Can we then assume that cinematic censorship is effectively a thing of the past? Does the impetus to regulate and police film content continue silently to exist? Analysis of controversies surrounding particular films throughout and in the wake of this shift suggests that, while no longer practiced explicitly by governmental institutions, film censorship continues to operate through less immediately recognizable forms of cultural marginalization and restraint. Classification status drastically affects the number of platforms through which a film can be accessed and thus works, as censorship does, to restrict films from audiences. When market demands place external restraints upon film content, familiar processes of cinematic censorship can be reframed as operating within (as opposed to upon) the institutional structures and practices of cultural production. This two-part study will examine, first, the process by which certain postmillennial cinematic artworks, such as Catherine Breillat’s Fat Girl (2001) and Gaspar Noé’s Irreversible (2002), spurred reform in the policies of classification boards by highlighting the rigidity of classification criteria and, secondly, cases in which, following the shift from moral to covert censorship, artistically serious films such as Vincent Gallo’s The Brown Bunny (2003) and Abel Ferrara’s Welcome to New York (2014) have been suppressed or constrained for their challenging subject matter, most notably for their aggressive presentation of sexuality. The main objective will be determining: 1) how the shift from censorship to classification corresponded to the aesthetic strategies of a handful of boundary-pushing films; and 2) how cinematic censorship, in the absence of traditional institutional enforcement, continues to operate in the interactions between alternative networks of disciplinary power and discursive practice.

Correction for ‘One-pot production of oxygenated monomers and selectively oxidized lignin from biomass based on plasma electrolysis’ by Lusi A et al., Green Chem., 2021, 23, 9109–9125, DOI: 10.1039/D1GC03315H.

I prove an efficiency result for repeated games with imperfect public monitoring in which one player's utility is privately known and evolves according to a Markov process. Under certain assumptions, patient players can attain approximately efficient payoffs in equilibrium. The public signal must satisfy a “pairwise full rank” condition that is somewhat stronger than the monitoring condition required in the Folk Theorem proved by Fudenberg, Levine, and Maskin (1994). Under stronger assumptions, the efficiency result partially extends to settings in which one player has private information that determines every player's payoff. The proof is partially constructive and uses an intuitive technique to mitigate the impact of private information on continuation payoffs.

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P −6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

BACKGROUND: Epidemiological studies consistently indicate that alcohol consumption is an independent risk factor for female breast cancer (BC). Although the aldehyde dehydrogenase 2 (ALDH2) polymorphism (rs671: Glu>Lys) has a strong effect on acetaldehyde metabolism, the association of rs671 with BC risk and its interaction with alcohol intake have not been fully elucidated. We conducted a pooled analysis of 14 case-control studies, with individual data on Asian ancestry women participating in the Breast Cancer Association Consortium.METHODS: We included 12,595 invasive BC cases and 12,884 controls for the analysis of rs671 and BC risk, and 2,849 invasive BC cases and 3,680 controls for the analysis of the gene-environment interaction between rs671 and alcohol intake for BC risk. The pooled odds ratios (OR) with 95% confidence intervals (CI) associated with rs671 and its interaction with alcohol intake for BC risk were estimated using logistic regression models.RESULTS: The Lys/Lys genotype of rs671 was associated with increased BC risk (OR = 1.16, 95% CI 1.03-1.30, p = 0.014). According to tumor characteristics, the Lys/Lys genotype was associated with estrogen receptor (ER)-positive BC (OR = 1.19, 95% CI 1.05-1.36, p = 0.008), progesterone receptor (PR)-positive BC (OR = 1.19, 95% CI 1.03-1.36, p = 0.015), and human epidermal growth factor receptor 2 (HER2)-negative BC (OR = 1.25, 95% CI 1.05-1.48, p = 0.012). No evidence of a gene-environment interaction was observed between rs671 and alcohol intake (p = 0.537).CONCLUSION: This study suggests that the Lys/Lys genotype confers susceptibility to BC risk among women of Asian ancestry, particularly for ER-positive, PR-positive, and HER2-negative tumor types.

OBJECTIVE: To explore health care providers’ perceptions of the provision of palliative care in the Qikiqtaaluk (formerly known as Baffin) region of Nunavut. DESIGN: An exploratory, qualitative, cross-sectional design using in-depth, semistructured interviews. SETTING: Qikiqtaaluk region of Nunavut. PARTICIPANTS: Seven physicians and 6 registered nurses who worked in Iqaluit or other northern Inuit communities in the Qikiqtaaluk region of Nunavut. METHODS: Thirteen health care providers participated in in-person or telephone semistructured interviews, which were audiorecorded and transcribed verbatim. MAIN FINDINGS: Interviews with the participating health care providers in the Qikiqtaaluk region of Nunavut revealed 5 complex and interwoven themes that influence the provision of comprehensive, culturally competent palliative care services to Indigenous patients: respecting Inuit culture, end-of-life care planning, and the role of family; recognizing the importance of the northern community (sense of home); being aware of the limited health care resources; recognizing the critical role of medical interpreters; and improving the quality of palliative care programs and resources, as well as health care provider training in palliative care and Inuit end-of-life care. CONCLUSION: Health care providers in the Qikiqtaaluk region of Nunavut have identified several important themes that influence the provision of culturally sensitive and comprehensive palliative care, most notably the need to develop palliative care resources and programs. It is hoped that the results of this study can be used to help guide palliative care strategies including program development and educational initiatives for health care providers. These initiatives can help build community capacity within a currently underserviced population and improve end-of-life care services available to Nunavut patients and their families. Further studies are required to determine the perspectives of medical interpreters, as well as palliative care patients and their families.

We consider how a firm dynamically allocates business among several suppliers to motivate them in a relational contract. The firm chooses one supplier who exerts private effort. Output is non-contractible, and each supplier observes only his own relationship with the principal. In this setting, allocation decisions constrain the transfers that can be promised to suppliers in equilibrium. Consequently, optimal allocation decisions condition on payoff-irrelevant past performance to make strong incentives credible. We construct a dynamic allocation rule that attains first-best whenever any allocation rule does. This allocation rule performs strictly better than any rule that depends only on payoff-relevant information. (JEL D21, D82, L14, L24)

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the ‘iCOGS’ genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84−0.87; P=1.7 × 10−43) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology., Previous studies identified an association between the 2q35 locus and breast cancer. Here, the authors show that a SNP at 2q35, rs4442975, is associated with oestrogen receptor positive disease and suggest that this effect is mediated through the downregulation of a known breast cancer gene, IGFBP5.

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1. ispartof: Nature Genetics vol:47 issue:4 pages:373-80 ispartof: location:United States status: published

Clinical data: Presentation and diagnosis. Clinical presentation and diagnosis of cases containing tumor embolism secondary to soft tissue and bone sarcoma. (DOCX 32 kb)

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P

Clinical data: Venous extension and management. Presence of local venous tumor extension and clinical management of cases containing tumor embolism secondary to soft tissue and bone sarcoma. (DOCX 25 kb)

Enterococcus faecalis y Enterococcus faecium son dos de los principales patógenos nosocomiales a nivel mundial, ocasionando cuadros de endocarditis, infecciones urinarias y septicemias. Esto se debe, entre otras razones, a su elevada resistencia a condiciones adversas del medio y a multitud de antibióticos. Entre los mecanismos que presentan los enterococos para resistir a los antimicrobianos, el de mayor trascendencia clínica es su resistencia intrínseca a las cefalosporinas (un valioso grupo de antibióticos perteneciente a la familia de los beta-lactámicos), lo que limita las opciones terapéuticas disponibles para combatir las infecciones provocadas por estas especies. En la presente Tesis Doctoral, hemos descubierto un fenómeno capaz de anular la resistencia intrínseca de Enterococcus, volviéndole susceptible a la acción de las cefalosporinas. Esto ocurre cuando los enterococos son expuestos a la presencia del ácido sulfhídrico, abreviado como H₂S. Este gas, considerado durante siglos como un metabolito celular de desecho, está reconocido actualmente como un gasotransmisor de gran importancia, regulando diferentes procesos fisiológicos y patológicos en Eucariotas así como en Procariotas. Profundizando en nuestro trabajo, hemos encontrado que la resistencia a las cefalosporinas de Enterococcus no solo se revierte al añadir H₂S al medio, sino que el mismo resultado tiene lugar cuando el H₂S es producido y excretado por otra bacteria, incluso aunque ambas especies se sitúen físicamente separadas entre sí. Por tanto, esta Tesis presenta avances importantes en dos temas. Por un lado, el hecho de que Enterococcus sea susceptible a la combinación de las cefalosporinas con el H₂S abre la puerta al diseño de futuras alternativas terapéuticas frente a patógenos multirresistentes. Por otro lado, hasta donde sabemos es la primera vez que se describe la capacidadde una bacteria para producir, a distancia, un efecto con consecuencias letales sobre otra bacteria, resultado sorprendente, una vez más, la complejidad del mundo bacteriano.

A range of arylgold compounds have been synthesized and investigated as single-component catalysts for the hydrophenoxylation of unactivated internal alkynes. Both carbene and phosphine-ligated compounds were screened as part of this work, and the most efficient catalysts contained either JohnPhos or IPr/SIPr. Phenols bearing either electron-withdrawing or electron-donating groups were efficiently added using these catalysts. No silver salts, acids, or solvents were needed for the catalysis, and either microwave or conventional heating afforded moderate to excellent yields of the vinyl ethers.

In a consortium including 23 637 breast cancer patients and 25 579 controls of East Asian ancestry, we investigated 70 single-nucleotide polymorphisms (SNPs) in 67 independent breast cancer susceptibility loci recently identified by genome-wide association studies (GWASs) conducted primarily in European-ancestry populations. SNPs in 31 loci showed an association with breast cancer risk at P < 0.05 in a direction consistent with that reported previously. Twenty-one of them remained statistically significant after adjusting for multiple comparisons with the Bonferroni-corrected significance level of, published_or_final_version

Background: Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers and cancer related traits. Methods: The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background. Results: The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis. Conclusions: Results from these analyses will enable researchers to identify new susceptibility loci, perform fine mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental and lifestyle related exposures. Impact: Ongoing analyses will shed light on etiology and risk assessment for many types of cancer. TRICL (Transdisciplinary Research for Cancer of Lung) and International Lung Cancer Consortium (ILCCO): National Institute of Health U19 CA148127-01 (C.I. Amos, J. Byun, Y. Li, X. Xiao, J. L. Forman, A. Risch, H. Bickeböller, M. Waldenberger, I. Brüske, J. Manz, P. Brennan, R. Hung, H. Shen, Y. Shi, A. Kamal, C. I. Amos, J.K. Field), Canadian Cancer Society Research Institute (no. 020214, R. Hung). DRIVE (Discovery, Biology, and Risk of Inherited Variants in Breast Cancer): National Institute of Health U19 CA148065 (D.J. Hazelett, D. F. Easton, S. Lindström, P. Kraft, J. Dennis, A. Dunning, K. Michailidou, L. Fachal, S. Benlloch, J. Cunningham, K. Butterbach, K. Offit, R. Schmutzler, L. Ottini, D. Vincent). CORECT (ColoRectal Transdisciplinary Study): National Institute of Health U19 CA148107; R01 CA81488, P30 CA014089 (S. Gruber, U. Peters, G. Casey). ELLIPSE (ELLIPSE, Elucidating Loci in Prostate Cancer Susceptibility): This work was support by U19 CA148537(F. Schumacher, S.A. Gayther, S.L. Schmit, C.K. Edlund, D.J. Hazelett, G.A. Coetzee, C. Haiman, S. Demetriades, D. Van Den Berg). FOCI (Transdisciplinary Cancer Genetic Association and Interacting Studies): National Institutes of Health U19 CA148112- 01 (T.A. Sellers, C. Phelan), R01-CA122443(B. Hicks) ) P50-CA116201, CA192393 (F. Couch), P50-CA136393(J. Cunningham, F. Couch), OCAC - CA-149429 (C. Phelan). , P30-CA15083 (B. Hicks), Cancer Research UK (C490/A8339(A. Antoniou, P. Pharoah, A. Dunning), C490/A16561(P. Pharoah, A. Dunning), C490/A10119 (A. Dunning, P. Pharoah), C490/A10124 (A. Dunning, P. Pharoah)). ASTERISK: a Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC) (F. Bacot). DACHS: German Research Council (Deutsche Downloaded from cebp.aacrjournals.org on October 31, 2016. © 2016 American Association for Cancer Research. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on October 3, 2016; DOI: 10.1158/1055-9965.EPI-16-0106 Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, and CH 117/1-1, C.K. Edlund), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). Prostate Lung Colon Ovarian Screening trial: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. The GC-HBOC (German Consortium of Hereditary Breast and Ovarian Cancer) is supported by the German Cancer Aid (grant no 110837, coordinator: R. Schmutzler, Cologne). The PERSPECTIVE (J. Simard) project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (MOP-86727, L.E. Kelemen), the Ministère de l’Économie, Innovation et Exportation du Québec through Genome Québec, and thee Quebec Breast Cancer Foundation, including additional funding from the Canadian Breast Cancer Foundation and the National Cancer Institute USA through Breast Cancer Family Registry Cohort (#1UM1CA164920-01A1). European Union Framework Programme for Research and Innovation (MSCA-IF-2014-EF-656144)(L. Fachal). The Breast Cancer Research Foundation, P30 CA08748, Andrew Sabin Foundation (K. Offit). CIDR genotyping for the Oncoarray was conducted under contract 268201200008I to K.Doheny and through grant 1X01HG007491- 01 to C.I. Amos. This is the author accepted manuscript. The final version is available from American Association for Cancer Research via http://dx.doi.org/10.1158/1055-9965.EPI-16-0106

Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10(-8)). More than 70 prostate cancer susceptibility loci, explaining ∼30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.

International audience; Investigating 5-methylcytosine (5mC) has led to many hypotheses regarding molecular mechanism underlying human diseases and disorders. Many of these studies, however, utilize bisulfite conversion alone, which cannot distinguish 5mC from its recently discovered oxidative product, 5-hydroxymethylcytosine (5hmC). Furthermore, previous array-based technologies do not have the necessary probes to adequately investigate both modifications simultaneously. In this manuscript, we used technical replicates of DNA from human brain, human blood, and human saliva, in combination with oxidative bisul-fite conversion and Illumina's Infinium MethylationEPIC array, to analyze 5mC and 5hmC at more than 650 000 and 450 000 relevant loci, respectively, in the human genome. We show the presence of loci with detectable 5mC and 5hmC to be equally distributed across chromosomes and genomic features, while also being present in genomic regions with transcriptional regulatory properties. We also describe 2528 5hmC sites common across tissue types that show a strong association with immune-related functions. Lastly, in human brain, we show that 5hmC accounts for one-third of the total signal from bisulfite-converted data. As such, not only do our results confirm the efficacy and sensitivity of pairing oxidative bisulfite conversion and the EPIC array to detect 5mC and 5hmC in all three tissue types, but they also highlight the importance of dissociating 5hmC from 5mC in future studies related to cytosine modifications.

Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90–0.94; P = 8.96 × 10−15)) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10−09, r2 = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10−11, r2 = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus., published version, peerReviewed

We consider a common managerial problem where an agent strives to achieve a prescribed target. We use this problem as a vehicle for comparing and discussing two approaches to decision making: optimising and “satisficing” (where the latter is a neologism due to H. Simon, 1976 Economics Nobel Prize Winner). We compute the optimising and satisfactory strategies for the problem at hand and highlight the differences in their outcomes.