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  • Engineering  (9)
  • Engineering General  (9)
  • IDENTIFICATION  (3)
  • 1
    Keywords: VARIANTS ; BREAST-CANCER ; IDENTIFICATION ; PREDICTION ; BRCA2 ; GENOME-WIDE ASSOCIATION ; MULTIPLE LOCI
    Abstract: Background: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer. Methods: We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history. Results: The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2-5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). Conclusions: Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. Impact: We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs.
    Type of Publication: Journal article published
    PubMed ID: 25837820
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  • 2
    Keywords: TOOL ; RISK ; ANTIGEN ; IDENTIFICATION ; DUAL ROLE ; TRANSLATION ; ANTIANGIOGENIC ACTIVITY ; susceptibility loci ; MICRORNA EXPRESSION ; VAMP8
    Abstract: Prostate cancer is the second most common malignancy among men worldwide. Genome-wide association studies have identified 100 risk variants for prostate cancer, which can explain approximately 33% of the familial risk of the disease. We hypothesized that a comprehensive analysis of genetic variations found within the 3' untranslated region of genes predicted to affect miRNA binding (miRSNP) can identify additional prostate cancer risk variants. We investigated the association between 2,169 miRSNPs and prostate cancer risk in a large-scale analysis of 22,301 cases and 22,320 controls of European ancestry from 23 participating studies. Twenty-two miRSNPs were associated (P 〈 2.3 x 10(-5)) with risk of prostate cancer, 10 of which were within 7 genes previously not mapped by GWAS studies. Further, using miRNA mimics and reporter gene assays, we showed that miR-3162-5p has specific affinity for the KLK3 rs1058205 miRSNP T-allele, whereas miR-370 has greater affinity for the VAMP8 rs1010 miRSNP A-allele, validating their functional role. SIGNIFICANCE: Findings from this large association study suggest that a focus on miRSNPs, including functional evaluation, can identify candidate risk loci below currently accepted statistical levels of genome-wide significance. Studies of miRNAs and their interactions with SNPs could provide further insights into the mechanisms of prostate cancer risk.
    Type of Publication: Journal article published
    PubMed ID: 25691096
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  • 3
    Keywords: EXPRESSION ; IDENTIFICATION ; C-MYC ; TUMOR-SUPPRESSOR ; STATISTICAL-METHODS ; GLYCOGEN-SYNTHASE KINASE-3 ; RNAi ; THERAPEUTIC TARGET ; DNA-BINDING PROTEIN ; SPINDLE DYNAMICS
    Abstract: Neuroblastoma is the most common extra-cranial solid tumor of early childhood. Standard therapies are not effective in case of poor prognosis and chemotherapy resistance. To improve drug therapy, it is imperative to discover new targets that play a substantial role in tumorigenesis of neuroblastoma. The mitotic machinery is an attractive target for therapeutic interventions and inhibitors can be developed to target mitotic entry, spindle apparatus, spindle activation checkpoint, and mitotic exit. We present an elaborate analysis pipeline to determine cancer specific therapeutic targets by first performing a focused gene expression analysis to select genes followed by a gene knockdown screening assay of live cells. We interrogated gene expression studies of neuroblastoma tumors and selected 240 genes relevant for tumorigenesis and cell cycle. With these genes we performed time-lapse screening of gene knockdowns in neuroblastoma cells. We classified cellular phenotypes and used the temporal context of the perturbation effect to determine the sequence of events, particularly the mitotic entry preceding cell death. Based upon this phenotype kinetics from the gene knockdown screening, we inferred dynamic gene functions in mitosis and cell proliferation. We identified six genes (DLGAP5, DSCC1, SMO, SNRPD1, SSBP1, and UBE2C) with a vital role in mitosis and these are promising therapeutic targets for neuroblastoma. Images and movies of every time point of all screened genes are available at https://ichip.bioquant.uni-heidelberg.de.
    Type of Publication: Journal article published
    PubMed ID: 23251412
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  • 4
    ISSN: 0748-8025
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: A set of non-linear and coupled equations governing the thermomechanical deformations of a viscoplastic body undergoing simple shearing deformations is integrated in time by using the forward-difference Galerkin finite-element (FDGFE) method and the Crank-Nicolson-Galerkin finite-element (CNGFE) method. In the latter scheme the number of unknown functions is increased so that the governing equations contain only first-order spatial derivatives. It is shown that the solutions obtained by the two methods agree qualitatively; however, the CNGFE method seems to introduce some damping into the system for non-polar materials, but none for dipolar materials.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Chichester [u.a.] : Wiley-Blackwell
    ISSN: 0029-5981
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: The coupled system of equations governing the thermomechanical deformations of a viscoelastic sheet while it is being cold rolled is solved numerically. The pertinent energy equation is solved by the finite difference method and the mechanical problem is solved by the finite element method using uniform first order rectangular elements. The developed computer program enables one to compute the complete deformation and temperature fields in the sheet. Results presented graphically include the temperature distribution, the stress distribution at the middle surface, the contact pressure distribution and the asymmetric surface deformation of the sheet.
    Additional Material: 8 Ill.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Chichester [u.a.] : Wiley-Blackwell
    ISSN: 0029-5981
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: The problem of cold rolling of a composite sheet which consists of alternate layers of viscoelastic and elastic materials is studied by the finite element method. Results computed and presented graphically include the pressure distribution at the contact surface, the normal stress distribution at the middle surface and the asymmetric deformation of the surface of the sheet in contact with the roller.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 0029-5981
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: Finite deformations of a nonlinear viscoelastic rubber layer bonded to a uniformly rotating rigid cylinder and indented by another rigid cylinder are studied by the finite element method. The problem formulation includes both material and geometric nonlinearities. The effect of the change in the thickness of the layer, its speed of rotation and its material properties on the pressure distribution at the contact surface, and other aspects of the deformation of the layer, are studied.
    Additional Material: 12 Ill.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 0029-5981
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: Equations governing the thermomechanical deformations of a block made of a viscoplastic material, and undergoing overall simple shearing deformations, are stiff in the sense that time scales associated with the heat conduction, viscous effects, strain hardening and strain-rate hardening may differ by several orders of magnitude as localization of the deformation initiates and proceeds. Because of the presence of high spatial gradients within the region of localization of the deformation, we also consider a viscoplasticity theory in which the strain gradient is taken as a kinematic variable. The Galerkin approximation of the pertinent initial-boundary-value problem yields an initial-value problem involving a set of coupled non-linear ordinary differential equations. The solution of these equations by the Crank-Nicolson, Adams-Moulton and the Gear methods reveals that the three methods give qualitatively similar results. However, quantitatively the results by the three methods differ somewhat, the difference being more for the dipolar theory.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 0029-5981
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: The coupled thermomechanical behaviour of a layer of thermorheologically simple material bonded to a uniformly rotating rigid cylinder and indented by another rigid cylinder is studied by the finite element method. The various approximations necessary to reduce the problem to one of tractable size and the computational methods used are discussed in some detail. The complete thermal, deformation and stress fields may be computed. Some results, computed for a grid using ‘rectangular’ elements, presented graphically include the temperature distribution, the stress distribution near the bond surface, the contact pressure distribution and the asymmetric surface deformation of the rubberlike layer.
    Additional Material: 8 Ill.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Chichester [u.a.] : Wiley-Blackwell
    ISSN: 0029-5981
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Notes: A finite element program capable of analysing finite plane strain deformations of incompressible rubberlike (Mooney-Rivlin) materials has been developed. Two problems, namely a long wall loaded uniformly in two directions and a thick-wall cylindrical pressure vessel loaded internally, have been solved. The computed values of displacements, strains, stresses and hydrostatic pressure agree very closely with their values obtained analytically.
    Additional Material: 8 Ill.
    Type of Medium: Electronic Resource
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