Sleep disruption, chronotype, shift work, and prostate cancer risk and mortality : a 30-year prospective cohort study of Finnish twins

Sleep disruption and shift work have been associated with cancer risk, but epidemiologic evidence for prostate cancer remains limited. We aimed to prospectively investigate the association between midlife sleep- and circadian-related parameters and later prostate cancer risk and mortality in a population-based cohort of Finnish twins. Data were drawn from the Older Finnish Twin Cohort and included 11,370 twins followed from 1981 to 2012. Over the study period, 602 incident cases of prostate cancer and 110 deaths from prostate cancer occurred. Cox regression was used to evaluate associations between midlife sleep duration, sleep quality, chronotype, and shift work with prostate cancer risk and prostate cancer-specific mortality. Within-pair co-twin analyses were employed to account for potential familial confounding. Compared to "definite morning" types, "somewhat evening" types had a significantly increased risk of prostate cancer (HR 1.3; 95 % CI 1.1, 1.6). Chronotype significantly modified the relationship between shift work and prostate cancer risk (p-interaction <0.001). We found no significant association between sleep duration, sleep quality, or shift work and prostate cancer risk in the overall analyses and no significant association between any sleep- or circadian-related parameter and risk in co-twin analyses. Neither sleep- nor circadian-related parameters were significantly associated with prostate cancer-specific mortality. The association between sleep disruption, chronotype, and shift work with prostate cancer risk and mortality has never before been studied in a prospective study of male twins. Our findings suggest that chronotype may be associated with prostate cancer risk and modify the association between shift work and prostate cancer risk. Future studies of circadian disruption and prostate cancer should account for this individual-level characteristic.Peer reviewe

Interaction of free-floating planets with a star-planet pair

The recent discovery of free-floating planets and their theoretical interpretation as celestial bodies, either condensed independently or ejected from parent stars in tight clusters, introduced an intriguing possibility. Namely, that some exoplanets are not condensed from the protoplanetary disk of their parent star. In this novel scenario a free-floating planet interacts with an already existing planetary system, created in a tight cluster, and is captured as a new planet. In the present work we study this interaction process by integrating trajectories of planet-sized bodies, which encounter a binary system consisting of a Jupiter-sized planet revolving around a Sun-like star. To simplify the problem we assume coplanar orbits for the bound and the free-floating planet and an initially parabolic orbit for the free-floating planet. By calculating the uncertainty exponent, a quantity that measures the dependence of the final state of the system on small changes of the initial conditions, we show that the interaction process is a fractal classical scattering. The uncertainty exponent is in the range (0.2-0.3) and is a decreasing function of time. In this way we see that the statistical approach we follow to tackle the problem is justified. The possible final outcomes of this interaction are only four, namely flyby, planet exchange, capture or disruption. We give the probability of each outcome as a function of the incoming planet's mass. We find that the probability of exchange or capture (in prograde as well as retrograde orbits and for very long times) is non-negligible, a fact that might explain the possible future observations of planetary systems with orbits that are either retrograde or tight and highly eccentric.Comment: 19 pages, 12 figure

Stability of prograde and retrograde planets in circular binary systems

We investigate the stability of prograde versus retrograde planets in circular binary systems using numerical simulations. We show that retrograde planets are stable up to distances closer to the perturber than prograde planets. We develop an analytical model to compute the prograde and retrograde mean motion resonances' locations and separatrices. We show that instability is due to single resonance forcing, or caused by nearby resonances' overlap. We validate our results regarding the role of single resonances and resonances' overlap on orbit stability, by computing surfaces of section of the CR3BP. We conclude that the observed enhanced stability of retrograde planets with respect to prograde planets is due to essential differences between the phase-space topology of retrograde versus prograde resonances (at p/q mean motion ratio, prograde resonance is of order p - q while retrograde resonance is of order p + q).Comment: 13 pages, 10 figures; to appear in MNRA

Structural Insights into Human Peroxisome Proliferator Activated Receptor Delta (PPAR-Delta) Selective Ligand Binding

Peroxisome proliferator activated receptors (PPARs δ, α and γ) are closely related transcription factors that exert distinct effects on fatty acid and glucose metabolism, cardiac disease, inflammatory response and other processes. Several groups developed PPAR subtype specific modulators to trigger desirable effects of particular PPARs without harmful side effects associated with activation of other subtypes. Presently, however, many compounds that bind to one of the PPARs cross-react with others and rational strategies to obtain highly selective PPAR modulators are far from clear. GW0742 is a synthetic ligand that binds PPARδ more than 300-fold more tightly than PPARα or PPARγ but the structural basis of PPARδ:GW0742 interactions and reasons for strong selectivity are not clear. Here we report the crystal structure of the PPARδ:GW0742 complex. Comparisons of the PPARδ:GW0742 complex with published structures of PPARs in complex with α and γ selective agonists and pan agonists suggests that two residues (Val312 and Ile328) in the buried hormone binding pocket play special roles in PPARδ selective binding and experimental and computational analysis of effects of mutations in these residues confirms this and suggests that bulky substituents that line the PPARα and γ ligand binding pockets as structural barriers for GW0742 binding. This analysis suggests general strategies for selective PPARδ ligand design

Application of 3D Zernike descriptors to shape-based ligand similarity searching

Background: The identification of promising drug leads from a large database of compounds is an important step in the preliminary stages of drug design. Although shape is known to play a key role in the molecular recognition process, its application to virtual screening poses significant hurdles both in terms of the encoding scheme and speed. Results: In this study, we have examined the efficacy of the alignment independent three-dimensional Zernike descriptor (3DZD) for fast shape based similarity searching. Performance of this approach was compared with several other methods including the statistical moments based ultrafast shape recognition scheme (USR) and SIMCOMP, a graph matching algorithm that compares atom environments. Three benchmark datasets are used to thoroughly test the methods in terms of their ability for molecular classification, retrieval rate, and performance under the situation that simulates actual virtual screening tasks over a large pharmaceutical database. The 3DZD performed better than or comparable to the other methods examined, depending on the datasets and evaluation metrics used. Reasons for the success and the failure of the shape based methods for specific cases are investigated. Based on the results for the three datasets, general conclusions are drawn with regard to their efficiency and applicability

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

The Adult Repetitive Behaviours Questionnaire-2 (RBQ-2A): A Self-Report Measure of Restricted and Repetitive Behaviours

In two studies we developed and tested a new self-report measure of restricted and repetitive behaviours (RRB) suitable for adults. In Study 1, The Repetitive Behaviours Questionnaire-2 for adults (RBQ-2A) was completed by a sample of 163 neurotypical adults. Principal components analysis revealed two components: Repetitive Motor Behaviours and Insistence on Sameness. In Study 2, the mean RBQ-2A scores of a group of adults with autism spectrum disorder (ASD; N = 29) were compared to an adult neurotypical group (N = 37). The ASD sample had significantly higher total and subscale scores. These results indicate that the RBQ-2A has utility as a self-report questionnaire measure of RRBs suitable for adults, with potential clinical application