Experimental assessment of head losses through elliptical and sharp-edged orifices

Due to the European electricity market liberalization and the appearance of other renewable electricity producers, an increase of installed peak power capacity is relevant to provide larger amount of electricity in a shorter turbine duration. When the discharge increase is not too large, it is frequently efficient to place an orifice at the entrance of the existing surge tank. Actually, the surge tank modifications have to be designed case-by-case. The introduction of head losses helps to manage maximum and minimum water level following the management of downstream discharge control and transient events. It allows to keep the same safety level. The placed orifice should commonly produce asymmetric losses. It is important to note that target head losses are evaluated with a unidimensional numerical model which performs transient simulation for relevant flow directions in the whole water way system and hydropower plant. A previous study performed by the authors focused on the effects of sharp-edged orifice parameters. This research carries out the analysis of corresponding elliptical orifices to tested sharp-edged orifices. The goal is to evaluate the head loss modification in both directions due to the shape change

Comprehensive functional annotation of 77 prostate cancer risk loci.

Genome-wide association studies (GWAS) have revolutionized the field of cancer genetics, but the causal links between increased genetic risk and onset/progression of disease processes remain to be identified. Here we report the first step in such an endeavor for prostate cancer. We provide a comprehensive annotation of the 77 known risk loci, based upon highly correlated variants in biologically relevant chromatin annotations--we identified 727 such potentially functional SNPs. We also provide a detailed account of possible protein disruption, microRNA target sequence disruption and regulatory response element disruption of all correlated SNPs at r(2) ≥ 0.88%. 88% of the 727 SNPs fall within putative enhancers, and many alter critical residues in the response elements of transcription factors known to be involved in prostate biology. We define as risk enhancers those regions with enhancer chromatin biofeatures in prostate-derived cell lines with prostate-cancer correlated SNPs. To aid the identification of these enhancers, we performed genomewide ChIP-seq for H3K27-acetylation, a mark of actively engaged enhancers, as well as the transcription factor TCF7L2. We analyzed in depth three variants in risk enhancers, two of which show significantly altered androgen sensitivity in LNCaP cells. This includes rs4907792, that is in linkage disequilibrium (r(2) = 0.91) with an eQTL for NUDT11 (on the X chromosome) in prostate tissue, and rs10486567, the index SNP in intron 3 of the JAZF1 gene on chromosome 7. Rs4907792 is within a critical residue of a strong consensus androgen response element that is interrupted in the protective allele, resulting in a 56% decrease in its androgen sensitivity, whereas rs10486567 affects both NKX3-1 and FOXA-AR motifs where the risk allele results in a 39% increase in basal activity and a 28% fold-increase in androgen stimulated enhancer activity. Identification of such enhancer variants and their potential target genes represents a preliminary step in connecting risk to disease process

Circulating vitamin D concentration and risk of seven cancers: Mendelian randomisation study

Objective To determine if circulating concentrations of vitamin D are causally associated with risk of cancer.Design Mendelian randomisation study.Setting Large genetic epidemiology networks (the Genetic Associations and Mechanisms in Oncology (GAME-ON), the Genetic and Epidemiology of Colorectal Cancer Consortium (GECCO), and the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortiums, and the MR-Base platform).Participants 70 563 cases of cancer (22 898 prostate cancer, 15 748 breast cancer, 12 537 lung cancer, 11 488 colorectal cancer, 4369 ovarian cancer, 1896 pancreatic cancer, and 1627 neuroblastoma) and 84 418 controls.Exposures Four single nucleotide polymorphisms (rs2282679, rs10741657, rs12785878 and rs6013897) associated with vitamin D were used to define a multi-polymorphism score for circulating 25-hydroxyvitamin D (25(OH)D) concentrations.Main outcomes measures The primary outcomes were the risk of incident colorectal, breast, prostate, ovarian, lung, and pancreatic cancer and neuroblastoma, which was evaluated with an inverse variance weighted average of the associations with specific polymorphisms and a likelihood based approach. Secondary outcomes based on cancer subtypes by sex, anatomic location, stage, and histology were also examined.Results There was little evidence that the multi-polymorphism score of 25(OH)D was associated with risk of any of the seven cancers or their subtypes. Specifically, the odds ratios per 25 nmol/L increase in genetically determined 25(OH)D concentrations were 0.92 (95% confidence interval 0.76 to 1.10) for colorectal cancer, 1.05 (0.89 to 1.24) for breast cancer, 0.89 (0.77 to 1.02) for prostate cancer, and 1.03 (0.87 to 1.23) for lung cancer. The results were consistent with the two different analytical approaches, and the study was powered to detect relative effect sizes of moderate magnitude (for example, 1.20-1.50 per 25 nmol/L decrease in 25(OH)D for most primary cancer outcomes. The Mendelian randomisation assumptions did not seem to be violated.Conclusions There is little evidence for a linear causal association between circulating vitamin D concentration and risk of various types of cancer, though the existence of causal clinically relevant effects of low magnitude cannot be ruled out. These results, in combination with previous literature, provide evidence that population-wide screening for vitamin D deficiency and subsequent widespread vitamin D supplementation should not currently be recommended as a strategy for primary cancer prevention

Quantifying the Genetic Correlation between Multiple Cancer Types.

Background: Many cancers share specific genetic risk factors, including both rare high-penetrance mutations and common SNPs identified through genome-wide association studies (GWAS). However, little is known about the overall shared heritability across cancers. Quantifying the extent to which two distinct cancers share genetic origin will give insights to shared biological mechanisms underlying cancer and inform design for future genetic association studies.Methods: In this study, we estimated the pair-wise genetic correlation between six cancer types (breast, colorectal, lung, ovarian, pancreatic, and prostate) using cancer-specific GWAS summary statistics data based on 66,958 case and 70,665 control subjects of European ancestry. We also estimated genetic correlations between cancers and 14 noncancer diseases and traits.Results: After adjusting for 15 pair-wise genetic correlation tests between cancers, we found significant (P < 0.003) genetic correlations between pancreatic and colorectal cancer (rg = 0.55, P = 0.003), lung and colorectal cancer (rg = 0.31, P = 0.001). We also found suggestive genetic correlations between lung and breast cancer (rg = 0.27, P = 0.009), and colorectal and breast cancer (rg = 0.22, P = 0.01). In contrast, we found no evidence that prostate cancer shared an appreciable proportion of heritability with other cancers. After adjusting for 84 tests studying genetic correlations between cancer types and other traits (Bonferroni-corrected P value: 0.0006), only the genetic correlation between lung cancer and smoking remained significant (rg = 0.41, P = 1.03 × 10-6). We also observed nominally significant genetic correlations between body mass index and all cancers except ovarian cancer.Conclusions: Our results highlight novel genetic correlations and lend support to previous observational studies that have observed links between cancers and risk factors.Impact: This study demonstrates modest genetic correlations between cancers; in particular, breast, colorectal, and lung cancer share some degree of genetic basis. Cancer Epidemiol Biomarkers Prev; 26(9); 1427-35. ©2017 AACR

Genetic Variants in Epigenetic Pathways and Risks of Multiple Cancers in the GAME-ON Consortium.

Background: Epigenetic disturbances are crucial in cancer initiation, potentially with pleiotropic effects, and may be influenced by the genetic background. Methods: In a subsets (ASSET) meta-analytic approach, we investigated associations of genetic variants related to epigenetic mechanisms with risks of breast, lung, colorectal, ovarian and prostate carcinomas using 51,724 cases and 52,001 controls. False discovery rate-corrected P values (q values < 0.05) were considered statistically significant. Results: Among 162,887 imputed or genotyped variants in 555 candidate genes, SNPs in eight genes were associated with risk of more than one cancer type. For example, variants in BABAM1 were confirmed as a susceptibility locus for squamous cell lung, overall breast, estrogen receptor (ER)-negative breast, and overall prostate, and overall serous ovarian cancer; the most significant variant was rs4808076 [OR = 1.14; 95% confidence interval (CI) = 1.10-1.19; q = 6.87 × 10 -5 ]. DPF1 rs12611084 was inversely associated with ER-negative breast, endometrioid ovarian, and overall and aggressive prostate cancer risk (OR = 0.93; 95% CI = 0.91-0.96; q = 0.005). Variants in L3MBTL3 were associated with colorectal, overall breast, ER-negative breast, clear cell ovarian, and overall and aggressive prostate cancer risk (e.g., rs9388766: OR = 1.06; 95% CI = 1.03-1.08; q = 0.02). Variants in TET2 were significantly associated with overall breast, overall prostate, overall ovarian, and endometrioid ovarian cancer risk, with rs62331150 showing bidirectional effects. Analyses of subpathways did not reveal gene subsets that contributed disproportionately to susceptibility. Conclusions: Functional and correlative studies are now needed to elucidate the potential links between germline genotype, epigenetic function, and cancer etiology. Impact: This approach provides novel insight into possible pleiotropic effects of genes involved in epigenetic processes. Cancer Epidemiol Biomarkers Prev; 26(6); 816-25. ©2017 AACR

Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer.

The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility

Quantifying the Genetic Correlation between Multiple Cancer Types.

Background: Many cancers share specific genetic risk factors, including both rare high-penetrance mutations and common SNPs identified through genome-wide association studies (GWAS). However, little is known about the overall shared heritability across cancers. Quantifying the extent to which two distinct cancers share genetic origin will give insights to shared biological mechanisms underlying cancer and inform design for future genetic association studies.Methods: In this study, we estimated the pair-wise genetic correlation between six cancer types (breast, colorectal, lung, ovarian, pancreatic, and prostate) using cancer-specific GWAS summary statistics data based on 66,958 case and 70,665 control subjects of European ancestry. We also estimated genetic correlations between cancers and 14 noncancer diseases and traits.Results: After adjusting for 15 pair-wise genetic correlation tests between cancers, we found significant (P P = 0.003), lung and colorectal cancer (rg = 0.31, P = 0.001). We also found suggestive genetic correlations between lung and breast cancer (rg = 0.27, P = 0.009), and colorectal and breast cancer (rg = 0.22, P = 0.01). In contrast, we found no evidence that prostate cancer shared an appreciable proportion of heritability with other cancers. After adjusting for 84 tests studying genetic correlations between cancer types and other traits (Bonferroni-corrected P value: 0.0006), only the genetic correlation between lung cancer and smoking remained significant (rg = 0.41, P = 1.03 × 10-6). We also observed nominally significant genetic correlations between body mass index and all cancers except ovarian cancer.Conclusions: Our results highlight novel genetic correlations and lend support to previous observational studies that have observed links between cancers and risk factors.Impact: This study demonstrates modest genetic correlations between cancers; in particular, breast, colorectal, and lung cancer share some degree of genetic basis. Cancer Epidemiol Biomarkers Prev; 26(9); 1427-35. ©2017 AACR

Inherited variation in circadian rhythm genes and risks of prostate cancer and three other cancer sites in combined cancer consortia

Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to investigate such associations. We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology (GAME-ON) network. The major results for prostate cancer were replicated in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, and for colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we conducted gene-based and pathway-based analyses by applying the summary-based Adaptive Rank Truncated Product method (sARTP) on the summary association statistics for each SNP within the candidate gene regions. Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME-ON and PLCO, after Bonferroni correction (ppathway < 0.00625). The two most significant genes were NPAS2 (pgene = 0.0062) and AANAT (pgene = 0.00078); the latter being significant after Bonferroni correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm pathway in GAME-ON (ppathway = 0.021); this association was not confirmed in GECCO (ppathway = 0.76) or the combined data (ppathway = 0.17). No significant association was observed for ovarian and lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms.Grant sponsor: National Institute of Health; Grant numbers: U19 CA148127-01 (PI: Amos) and 1U19CA148127-02 (PI: Bickeb€oller); Grantsponsor:Canadian Cancer Society Research Institute; Grant number: 020214 (PI: Hung); Grant sponsor: National Institute of Health; Grantnumber:U19 CA148065; Grant sponsor: National Institute of Health; Grant number: U19 CA148065; Grant sponsor: National Institute ofHealth;Grant numbers: U19 CA148107; R01 CA81488, P30 CA014089; Grant sponsor: GAME-ON U19 initiative for prostate cancer; Grantnumber:U19 CA148537; Grant sponsor: National Institute of Health; Grant number: U19 CA148107; R01 CA81488, P30 CA014089; Grantsponsor: GAME-ON U19 initiative for prostate cancer; Grant number: U19 CA148537; Grant sponsor: National Institutes of Health;Grant number: U19 CA148112-01 (PI: Sellers) and R01-CA149429 (Phelan); Grant sponsors: National Cancer Institute, National Institutes of Health, US Department of Health and Human Services;Grant numbers: U01 CA137088 and R01 CA059045; Grant sponsors: RegionalCouncil of Pays de la Loire, the Groupement des Entreprises Franc¸aises dans la Lutte contre le Cancer (GEFLUC), the Association Anne deBretagne Genetique and the Ligue Regionale Contre le Cancer [(LRCC); ASTERISK: a Hospital Clinical Research Program (PHRC)];Grantsponsor:German Research Council; Grant numbers: BR 1704/6–1, BR 1704/6–3, BR 1704/6–4 and CH 117/1–1); Grant sponsor: GermanFederal Ministry of Education and Research;Grant numbers: 01KH0404 and 01ER0814; Grant sponsor: National Institutes of Health;Grant number: R01 CA48998 (to M.L.S.); Grant sponsor: National Institutes of Health; Grant numbers: P01 CA 055075, UM1 CA167552,R01 137178, R01 CA 151993 and P50 CA 127003;Grant sponsor: National Institutes of Health; Grant numbers: R01 CA137178, P01 CA087969, R01 CA151993 and P50 CA 127003);Grant sponsor: National Institutes of Health; Grant number: R01 CA042182; Grant sponsor:National Institutes of Health (through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer; see CFR section);Grant number: U01 CA074783; Grant sponsors: Ontario Research Fund, the Canadian Institutes of Health Research, and the OntarioInstitute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation (Additional funding towardgenetic analyses of OFCCR);Grant sponsors: National Cancer Institute [NIH, Division of Cancer Prevention, DHHS (PLCO: IntramuralResearch Program of the Division of Cancer Epidemiology and Genetics)];Grant sponsor: National Institutes of Health (NIH) and Genes,Environment, and Health Initiative [GEI (Lung Cancer and Smoking study)];Grant numbers: Z01 CP 010200, NIH U01 HG004446 andNIH GEI U01 HG 004438;Grant sponsor: GENEVA Coordinating Center provided assistance with genotype cleaning and general studycoordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping (For the lung study);Grantsponsor:National Institutes of Health; Grant number: R01 CA076366 (to PA Newcomb); Grant sponsor: .; Grant sponsor: NationalInstitutes of Health;Grant number: K05 CA154337; Grant sponsor: National Heart, Lung, and Blood Institute, National Institutes ofHealth, US Department of Health and Human Services;Grant numbers: HHSN268201100046C, HHSN268201100001C,HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C;Grant sponsor: Swedish CancerFoundation;Grant numbers: 09–0677, 11–484, 12–823; Grant sponsor: The Cancer Risk Prediction Center (CRisP; www.crispcenter.org), aLinneus Centre;Grant number: 70867902; Grant sponsor: Swedish Research Council; Grant numbers: K2010-70X-20430–04-3, 2014–2269;Grant sponsor: Canadian Institutes of Health Research (European Commission’s Seventh Framework Programme grant agreement; CRUKGWAS);Grant number:223175 (HEALTH-F2-2009–223175); Grant sponsor: Cancer Research UK; Grant numbers: C5047/A7357, C1287/A10118, C5047/A3354, C5047/A10692 and C16913/A6135;Grant sponsor: National Institute of Health (NIH; Cancer Post-Cancer GWASinitiative grant);Grant number: 1 U19 CA 148537–01 (the GAME-ON initiative); Grant sponsors: The Institute of Cancer Research and TheEveryman Campaign, The Prostate Cancer Research Foundation, Prostate Research Campaign UK (now Prostate Action), The Orchid Cancer Appeal,The National Cancer Research Network UK and The National Cancer Research Institute (NCRI) UK;Grant sponsor: NIHR (NIHR BiomedicalResearch Cent re at The In stitute of Cancer Research and The Royal Marsden NHS Foundation Trust);Grant sponsor: The National Health andMedical Research Council, Australia (The Prostate Cancer Program of Cancer Council Victoria);Grant numbers: 126402, 209057, 251533,396414, 450104, 504700, 504702, 504715, 623204, 940394 and 614296,);Grant sponsors: VicHealth, Cancer Council Victoria, The Pros tateCancer Foundation of Australia, The Whitten Foundation, PricewaterhouseCoopers, and Tattersa ll’s;Grant sponsor: National Human GenomeResearch Institute for their support (EAO, DMK, and EMK acknowledge the Intramural Program

Two Novel Susceptibility Loci for Prostate Cancer in Men of African Ancestry.

Prostate cancer incidence is 1.6-fold higher in African Americans than in other populations. The risk factors that drive this disparity are unknown and potentially consist of social, environmental, and genetic influences. To investigate the genetic basis of prostate cancer in men of African ancestry, we performed a genome-wide association meta-analysis using two-sided statistical tests in 10 202 case subjects and 10 810 control subjects. We identified novel signals on chromosomes 13q34 and 22q12, with the risk-associated alleles found only in men of African ancestry (13q34: rs75823044, risk allele frequency = 2.2%, odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.37 to 1.76, P = 6.10 × 10-12; 22q12.1: rs78554043, risk allele frequency = 1.5%, OR = 1.62, 95% CI = 1.39 to 1.89, P = 7.50 × 10-10). At 13q34, the signal is located 5' of the gene IRS2 and 3' of a long noncoding RNA, while at 22q12 the candidate functional allele is a missense variant in the CHEK2 gene. These findings provide further support for the role of ancestry-specific germline variation in contributing to population differences in prostate cancer risk