| 1. |
- Wang, Zhaoming, et al.
(författare)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 2. |
- Rothman, Nathaniel, et al.
(författare)
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A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 978-984
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Tidskriftsartikel (refereegranskat)abstract
- We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.
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| 3. |
- Benson, Tyler W, et al.
(författare)
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Glycoprotein VI is Critical for the Detection and Progression of Abdominal Aortic Aneurysms.
- 2023
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Ingår i: bioRxiv : the preprint server for biology.
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Tidskriftsartikel (refereegranskat)abstract
- UNLABELLED: A common feature in patients with abdominal aortic aneurysms (AAA) is the formation of a nonocclusive intraluminal thrombus (ILT) in regions of aortic dilation. Platelets are known to maintain hemostasis and propagate thrombosis through several redundant activation mechanisms, yet the role of platelet activation in the pathogenesis of AAA associated ILT is still poorly understood. Thus, we sought to investigate how platelet activation impacts the pathogenesis of AAA. Using RNA-sequencing, we identify that the platelet-associated transcripts are significantly enriched in the ILT compared to the adjacent aneurysm wall and healthy control aortas. We found that the platelet specific receptor glycoprotein VI (GPVI) is among the top enriched genes in AAA ILT and is increased on the platelet surface of AAA patients. Examination of a specific indicator of platelet activity, soluble GPVI (sGPVI), in two independent AAA patient cohorts is highly predictive of a AAA diagnosis and associates more strongly with aneurysm growth rate when compared to D-dimer in humans. Finally, intervention with the anti-GPVI antibody (J) in mice with established aneurysms blunted the progression of AAA in two independent mouse models. In conclusion, we show that levels of sGPVI in humans can predict a diagnosis of AAA and AAA growth rate, which may be critical in the identification of high-risk patients. We also identify GPVI as a novel platelet-specific AAA therapeutic target, with minimal risk of adverse bleeding complications, where none currently exist.KEY POINTS: Soluble glycoprotein VI, which is a platelet-derived blood biomarker, predicts a diagnosis of AAA, with high sensitivity and specificity in distinguishing patients with fast from slow-growing AAA.Blockade of glycoprotein VI in mice with established aneurysms reduces AAA progression and mortality, indicating therapeutic potential.
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| 4. |
- Larsson, Anna-Carin, et al.
(författare)
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Solid state 31P and 207Pb MAS NMR studies on polycrystalline O,O′-dialkyldithiophosphate lead(II) complexes
- 2005
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Ingår i: Journal of magnetic resonance. - : Elsevier BV. - 1090-7807 .- 1096-0856. ; 177:1, s. 56-66
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Tidskriftsartikel (refereegranskat)abstract
- A number of lead(II) O,O′-dialkyldithiophosphate complexes were studied by 13C, 31P, and 207Pb MAS NMR. Simulations of 31P chemical shift anisotropy using spinning sideband analysis reveal a linear relationship between the SPS bond angle and the principal values δ22 and δ33 of the 31P chemical shift tensor. The 31P CSA data were used to assign ligands with different structural functions. In the cases of Adiethyldithiophosphate and di-iso-butyldithiophosphate lead(II) complexes, 2J (31P, 207Pb)-couplings were resolved and used to confirm the suggested assignment of the ligands. The SIMPSON computer program was used to calculate 31P and 207Pb spectral sideband patterns.
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| 5. |
- Rusanova, Daniela, et al.
(författare)
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Formation of {Cu6[S2P(OC2H5)2]6} on Cu2S Surfaces from Aqueous Solutions of the KS2P(OC2H5)2 Collector: Scanning Electron Microscopy and Solid-State 31P Cross-Polarization/Magic Angle Spinning and Static 65Cu NMR Studies
- 2005
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Ingår i: Langmuir. - : American Chemical Society (ACS). - 0743-7463 .- 1520-5827. ; 21:10, s. 4420-4424
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Tidskriftsartikel (refereegranskat)abstract
- The interactions of synthetic chalcocite surfaces with diethyldithiophosphate, potassium salt, K[S2P(OC2H5)2], were studied by means of 31P cross-polarization/magic angle spinning (CP/MAS) NMR spectroscopy and scanning electron microscopy (SEM). To identify the species formed on the Cu2S surfaces, a polycrystalline {CuI6[S2P(OC2H5)2]6} cluster was synthesized and analyzed by SEM, powder X-ray diffraction techniques and solid-state 31P CP/MAS NMR and static 65Cu NMR spectroscopy. 31P chemical shift anisotropy (CSA) parameters, CS and CS, were estimated and used for assigning the bridging type of diethyldithiophosphate ligands in the {CuI6[S2P(OC2H5)2]6} cluster. The latter data were compared to 31P CSA parameters estimated from the spinning sideband patterns in 31P NMR spectra of the collector-treated mineral surfaces: formation of polycrystalline {CuI6[S2P(OC2H5)2]6} on the Cu2S surfaces is suggested. The second-order quadrupolar line shape of 65Cu was simulated, and the NMR interaction parameters, CQ and Q, for the copper(I) diethyldithiophosphate cluster were obtained.
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| 6. |
- Rusanova, Daniela, et al.
(författare)
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Formation of Ο,Ο’-di-alkyl-dithiophosphate copper (I) complexes on the surface of synthetic chalcocite : NMR and SEM studies
- 2005
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Ingår i: Centenary of Flotation Symposium Proceedings. - : The Australian Institute of Mining and Metallurgy. - 9781920806316 ; , s. 581-590
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Konferensbidrag (refereegranskat)abstract
- The adsorption mechanism of three different 0,0'-di-alkyl-dithiophosphate (dtp) collectors, K[S22P(OR)2] with R = Et, i-Bu and i'-Amyl, on the surface of synthetic chalcocite (Cu2S)Was studied by means of solid-state 31P CP/MAS NMR spectroscopy. The morphology changes on the conditioned (Cu2S) surfaces, in the collector concentration range 0.1 - 10 mM, were also monitored with scanning electron microscope (SEM). In order to assign Cu(I)-dtp species on the surface of CU 2S, the corresponding bulk Cu(I)-dtp compounds, which are clusters of the monovalent copper containing either Cu6(antiprismatic) or Cu8(cubic) cores, were synthesised, and characterised by means of solid-state 31P CP/MAS and static 65Cu NMR. Further investigations on the crystal habits of the bulk systems were carried out by powder x-ray diffraction and SEM. A comparative analysis of the 31P chemical shift and chemical shift anisotropy (CSA) data estimated from the experimental NMR spectra of the polycrystalline bulk Cu(l) dialkyldithiophosphate complexes was used for assigning the 31P resonance lines in the NMR spectra of the collector treated CU2S powder samples. The species formed on the synthetic Cu2S surfaces were assigned to polycrystalline phases of: Cu6L6 with L = Et2dtp̄μ, Cu6L6, and Cu 8L6(S) with L = i'-Bu2dtp̄, and 3. Cu 8L6S) with L = i-Amyl2dtp̄. A heterophase autocatalytic step process of both formation and growth of solid Cu xLy (L = R2dtp, x = 6 or 8 and y = 6) complexes on the collector treated CU2S surface is proposed. A possible role of the oxidised form of dithiophosphate collectors, bis[di-alkyl-thiophosphoryl] -disulfane (disulfide), is discussed in terms of a specific self-redox reaction. The second order quadrupolar lineshapes in 65Cu NMR spectra were simulated and the interaction parameters, CQ and nQ, for the bulk dialkyldithiophosphato-copper(I) complexes were obtained
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| 7. |
- Rusanova, Daniela, et al.
(författare)
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Solid-state 31P CP/MAS and static 65Cu NMR characterization of polycrystalline copper(I) dialkyldithiophosphate clusters
- 2006
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Ingår i: Journal of magnetic resonance. - : Elsevier BV. - 1090-7807 .- 1096-0856. ; 179:1, s. 140-145
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Tidskriftsartikel (refereegranskat)abstract
- Polycrystalline tetra-nuclear Cu4[S2P(O-i-C3H7)2]4, hexa-nuclear Cu6[S2P(OC2H5)2]6, and octa-nuclear Cu8[S2P(O-i-C4H9)2]6(S) complexes were synthesized and analyzed by means of solid-state 31P CP/MAS and 65Cu static NMR spectroscopy. The symmetries of the electronic environments around each P-site were estimated from the 31P chemical shift anisotropy (CSA) parameters, Δaniso and η. The 65Cu chemical shift and quadrupolar splitting parameters obtained from the experimental 65Cu NMR spectra of the polycrystalline CuI-complexes are presented. A solid-state NMR approach for the elucidation of the stereochemistry of poly-nuclear Cu(I) dithiophosphate complexes, when the structural analysis of the systems by single-crystal X-ray diffraction is not readily available, is proposed.
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| 8. |
- Rusanova, Daniela, et al.
(författare)
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Solid-state NMR and EXAFS spectroscopic characterization of infoPolycrystalline copper(I) O,O prime -Dialkvldithiophosphate cluster compounds : Formation of copper(I) O,O prime -diisobutyklithiophosphate compounds on the surface of synthetic chalcocite
- 2006
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Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 12:20, s. 5282-5292
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Tidskriftsartikel (refereegranskat)abstract
- A number of polycrystalline copper(I) O,O-dialkyldithiophosphate cluster compounds with Cu4, Cu6, and Cu8 cores were synthesized and characterized by using extended X-ray absorption fine-structure (EXAFS) spectroscopy. The structural relationship of these compounds is discussed. The polycrystalline copper(I) O,O-diisobutyldithiophosphate cluster compounds, [Cu8{S2P(OiBu)2}6(S)] and [Cu6{S2P(OiBu)2}6], were also characterized by using 31P CP/MAS NMR (CP = cross polarization, MAS = magic-angle spinning) and static 65Cu NMR spectroscopies (at different magnetic fields) and powder X-ray diffraction (XRD) analysis. Comparative analyses of the 31P chemical-shift tensor, and the 65Cu chemical shift and quadrupolar-splitting parameters, estimated from the experimental NMR spectra of the polycrystalline copper(I) cluster compounds, are presented. The adsorption mechanism of the potassium O,O-diisobutyldithiophosphate collector, K[S2P(OiBu)2], at the surface of synthetic chalcocite (Cu2S) was studied by means of solid-state 31P CP/MAS NMR spectroscopy and scanning electron microscopy (SEM). 31P NMR resonance lines from collector-treated chalcocite surfaces were assigned to a mixture of [Cu8{S2P(OiBu)2}6(S)] and [Cu6{S2P(OiBu)2}6] compounds.
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| 9. |
- Rusanova, Daniela, et al.
(författare)
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Solid-state static 65Cu and 31P CP/MAS NMR, and liquid-state EXAFS studies on copper(I) O,O′-dialkyldithiophosphate cluster compounds : formation of the copper(I) O,O′-di-iso-amyldithiophosphate cluster compound on the surface of synthetic chalcocite
- 2006
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Ingår i: Polyhedron. - : Elsevier BV. - 0277-5387 .- 1873-3719. ; 25:18, s. 3569-3580
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Tidskriftsartikel (refereegranskat)abstract
- Polycrystalline octa-nuclear copper(I) O,O′-di-i-propyl- and O,O′-di-i-amyldithiophosphate cluster compounds, {Cu8[S2P(OR)2]6(μ8-S)} where R = iPr and iAm, were synthesized and characterized by 31P CP/MAS NMR at 8.46 T and static 65Cu NMR at multiple magnetic field strengths (7.05, 9.4 and 14.1 T). The symmetries of the electronic environments around the P sites were estimated from the 31P chemical shift anisotropy (CSA) parameters, δaniso and η. Analyses of the 65Cu chemical shift and quadrupolar splitting parameters for these compounds are presented with the data being compared to those for the analogous octa-nuclear cluster compounds with R = nBu and iBu. The 65Cu transverse relaxation for the copper sites in {Cu8[S2P(OiPr)2]6(μ8-S)} and {Cu8[S2P(OiAm)2]6(μ8-S)} was found to be very different, with a relaxation time, T2, of 590 μs (Gaussian) and 90 μs (exponential), respectively. The structures of {Cu4[S2P(OiPr)2]4} and {Cu8[S2P(OiPr)2]6(μ8-S)} cluster compounds in the liquid- and the solid-state were studied by Cu K-edge EXAFS. The disulfide, [S2P(OiAm)2]2, was obtained and characterized by 31P{1H} NMR. The interactions of the disulfide and of the potassium O,O′-di-i-amyldithiophosphate salt with the surfaces of synthetic chalcocite (Cu2S) were probed using solid-state 31P NMR spectroscopy and only the presence of copper(I) dithiophosphate species with the {Cu8[S2P(OiAm)2]6(μ8-S)} structure was observed.
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| 10. |
- Rusanova, Daniela, et al.
(författare)
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Spectroscopic characterization of the polycrystalline copper(I) di-n-butyldithiophosphate cluster - Cu8[S2P(O-n-Bu)2]6(μ8-S): Solid-state 31P CP/MAS and static 65Cu NMR studies
- 2006
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Ingår i: Inorganica Chimica Acta. - : Elsevier BV. - 0020-1693 .- 1873-3255. ; 259:12, s. 3903-3910
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Tidskriftsartikel (refereegranskat)abstract
- A polycrystalline copper(I) O,O′-di-n-butyldithiophosphate cluster compound, Cu8[S2P(O-n-Bu)2]6(μ8-S), was synthesized and characterized by 31P CP/MAS NMR at 8.46 T and static 65Cu NMR at multiple magnetic field strengths (7.05, 9.4 and 14.1 T). The principal values of the 31P chemical shift tensor and the 65Cu chemical shift and quadrupolar splitting parameters are presented. The data are compared to those for the analogous octa-nuclear cluster compounds [Cu8(S2P(OEt)2)6(μ8-S)], [Cu8(S2P(O-n-Pr)2)6(μ8-S)] and [Cu8(S2P(O-i-Bu)2)6(μ8-S)]. The transverse relaxation time constant, T2, for the [Cu8(S2P(O-n-Bu)2)6(μ8-S)] cluster compound was found to be 160 ± 8 μs. Possible intra-molecular motions in the cluster structures in terms of size and branching of the hydrocarbon chains are discussed as reasons for the different 65Cu NMR responses of the systems.
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