Meson-Baryon Form Factors in Chiral Colour Dielectric Model

The renormalised form factors for pseudoscalar meson-baryon coupling are computed in chiral colour dielectric model. This has been done by rearranging the Lippmann-Schwinger series for the meson baryon scattering matrix so that it can be expressed as a baryon pole term with renormalized form factors and baryon masses and the rest of the terms which arise from the crossed diagrams. Thus we are able to obtain an integral equation for the renormalized meson-baryon form factors in terms of the bare form factors as well as an expression for the meson self energy. This integral equation is solved and renormalized meson baryon form factors and renormalized baryon masses are computed. The parameters of the model are adjusted to obtain a best fit to the physical baryon masses. The calculations show that the renormalized form factors are energy-dependent and differ from the bare form factors primarily at momentum transfers smaller than 1 GeV. At nucleon mass, the change in the form factors is about 10% at zero momentum transfer. The computed form factors are soft with the equivalent monopole cut-off mass of about 500 MeV. The renormalized coupling constants are obtained by comparing the chiral colour dielectric model interaction Hamiltonian with the standard form of meson-nucleon interaction Hamiltonian. The ratio of $\Delta N\pi$ and $NN\pi$ coupling constants is found to be about 2.15. This value is very close to the experimental value.Comment: 16 pages, 7 postscript figure

Dihyperon in Chiral Colour Dielectric Model

The mass of dihyperon with spin, parity $J^{\pi}=0^{+}$ and isospin $I = 0$ is calculated in the framework of Chiral colour dielectric model. The wave function of the dihyperon is expressed as a product of two colour-singlet baryon clusters. Thus the quark wave functions within the cluster are antisymmetric. Appropriate operators are then used to antisymmetrize inter-cluster quark wave functions. The radial part of the quark wavefunctions are obtained by solving the the quark and dielectric field equations of motion obtained in the Colour dielectric model. The mass of the dihyperon is computed by including the colour magnetic energy as well as the energy due to meson interaction. The recoil correction to the dihyperon mass is incorporated by Peierls-Yoccoz technique. We find that the mass of the dihyperon is smaller than the $\Lambda-\Lambda$ threshold by over 100 MeV. The implications of our results on the present day relativistic heavy ion experiments is discussed.Comment: LaTeX, 13 page

Apolipoprotein E gene polymorphism is not a strong risk factor for diabetic nephropathy and retinopathy in Type I diabetes: case-control study

BACKGROUND: The gene encoding apolipoprotein E (APOE) has been proposed as a candidate gene for vascular complications in Type I diabetes. This study aimed to investigate the influence of three-allelic variations in the APOE gene for the development of diabetic retinopathy and nephropathy. RESULTS: Neither APOE alleles frequencies or APOE genotypes frequencies differed between Type I diabetic groups either with or without nephropathy. Similar results were found for patients with and without diabetic retinopathy. CONCLUSIONS: APOE gene polymorphism does not determine genetic susceptibility for the development of diabetic retinopathy in Type I diabetes patients. Association between APOE gene polymorphism and diabetic nephropathy may be weak or moderate, but not strong

Genome‐wide association study of INDELs identified four novel susceptibility loci associated with lung cancer risk

Genome‐wide association studies (GWAS) have identified 45 susceptibility loci associated with lung cancer. Only less than SNPs, small insertions and deletions (INDELs) are the second most abundant genetic polymorphisms in the human genome. INDELs are highly associated with multiple human diseases, including lung cancer. However, limited studies with large‐scale samples have been available to systematically evaluate the effects of INDELs on lung cancer risk. Here, we performed a large‐scale meta‐analysis to evaluate INDELs and their risk for lung cancer in 23,202 cases and 19,048 controls. Functional annotations were performed to further explore the potential function of lung cancer risk INDELs. Conditional analysis was used to clarify the relationship between INDELs and SNPs. Four new risk loci were identified in genome‐wide INDEL analysis (1p13.2: rs5777156, Insertion, OR = 0.92, P = 9.10 × 10−8; 4q28.2: rs58404727, Deletion, OR = 1.19, P = 5.25 × 10−7; 12p13.31: rs71450133, Deletion, OR = 1.09, P = 8.83 × 10−7; and 14q22.3: rs34057993, Deletion, OR = 0.90, P = 7.64 × 10−8). The eQTL analysis and functional annotation suggested that INDELs might affect lung cancer susceptibility by regulating the expression of target genes. After conducting conditional analysis on potential causal SNPs, the INDELs in the new loci were still nominally significant. Our findings indicate that INDELs could be potentially functional genetic variants for lung cancer risk. Further functional experiments are needed to better understand INDEL mechanisms in carcinogenesis

Joint Analysis for Genome-Wide Association Studies in Family-Based Designs

In family-based data, association information can be partitioned into the between-family information and the within-family information. Based on this observation, Steen et al. (Nature Genetics. 2005, 683–691) proposed an interesting two-stage test for genome-wide association (GWA) studies under family-based designs which performs genomic screening and replication using the same data set. In the first stage, a screening test based on the between-family information is used to select markers. In the second stage, an association test based on the within-family information is used to test association at the selected markers. However, we learn from the results of case-control studies (Skol et al. Nature Genetics. 2006, 209–213) that this two-stage approach may be not optimal. In this article, we propose a novel two-stage joint analysis for GWA studies under family-based designs. For this joint analysis, we first propose a new screening test that is based on the between-family information and is robust to population stratification. This new screening test is used in the first stage to select markers. Then, a joint test that combines the between-family information and within-family information is used in the second stage to test association at the selected markers. By extensive simulation studies, we demonstrate that the joint analysis always results in increased power to detect genetic association and is robust to population stratification

Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites

APOE and Alzheimer disease: a major gene with semi-dominant inheritance

Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease

Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele

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

Particulate matter exposure during pregnancy is associated with birth weight, but not gestational age, 1962-1992: a cohort study

<p>Abstract</p> <p>Background</p> <p>Exposure to air pollutants is suggested to adversely affect fetal growth, but the evidence remains inconsistent in relation to specific outcomes and exposure windows.</p> <p>Methods</p> <p>Using birth records from the two major maternity hospitals in Newcastle upon Tyne in northern England between 1961 and 1992, we constructed a database of all births to mothers resident within the city. Weekly black smoke exposure levels from routine data recorded at 20 air pollution monitoring stations were obtained and individual exposures were estimated via a two-stage modeling strategy, incorporating temporally and spatially varying covariates. Regression analyses, including 88,679 births, assessed potential associations between exposure to black smoke and birth weight, gestational age and birth weight standardized for gestational age and sex.</p> <p>Results</p> <p>Significant associations were seen between black smoke and both standardized and unstandardized birth weight, but not for gestational age when adjusted for potential confounders. Not all associations were linear. For an increase in whole pregnancy black smoke exposure, from the 1^st(7.4 μg/m³) to the 25^th(17.2 μg/m³), 50^th(33.8 μg/m³), 75^th(108.3 μg/m³), and 90^th(180.8 μg/m³) percentiles, the adjusted estimated decreases in birth weight were 33 g (SE 1.05), 62 g (1.63), 98 g (2.26) and 109 g (2.44) respectively. A significant interaction was observed between socio-economic deprivation and black smoke on both standardized and unstandardized birth weight with increasing effects of black smoke in reducing birth weight seen with increasing socio-economic disadvantage.</p> <p>Conclusions</p> <p>The findings of this study progress the hypothesis that the association between black smoke and birth weight may be mediated through intrauterine growth restriction. The associations between black smoke and birth weight were of the same order of magnitude as those reported for passive smoking. These findings add to the growing evidence of the harmful effects of air pollution on birth outcomes.</p