| 1. |
- Xu, Jianfeng, et al.
(författare)
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Synthesis of Conformationally Locked Carba-LNAs through Intramolecular Free-Radical Addition to C=N. Electrostatic and Steric Implication of the Carba-LNA Substituents in the Modified Oligos for Nuclease and Thermodynamic Stabilities
- 2009
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 74:17, s. 6534-6554
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Tidskriftsartikel (refereegranskat)abstract
- The syntheses of the hitherto unavailable parentfully unsubstituted carba-LNA and its C7'-amino and/or C6'-hydroxyl substituted derivatives, have been accomplished by the intramolecular 5-exo free-radical addition to a C4'-tethered C=N to give carba-LNAs with variable hydrophilic substituents at C6'/C7' (amino and/or hydroxyl). They have been introduced into isosequential antisense oligonucleotides (AONs) to examine how their relative electrostatic and steric effects in the minor groove of a putative AON-RNA duplex affect the target affinity, nuclease resistance, and RNase H elicitation. We show that 2'-oxygen in LNA is important in stabilizing the DNA/DNA and DNA/RNA duplexes vis-a-vis the unsubstituted carba-LNA and its other derivatives and that hydrophobic groups at C6'/C7' in both carba-LNA and carba-ENA relatively destabilize the AON/DNA duplex more profoundly than those in the AON/RNA duplexes. Two main factors affect the relative stabilities of AON/DNA versus AON/RNA duplexes: (i) hydration in the minor groove depending upon hydrophilicity vis-a-vis hydrophobicity of the substituents, and (ii) the relative size of the minor groove in the AON/DNA versus AON/RNA duplexes dictates the steric clash with the substituents depending upon their relative chiralities. We also show how the chirality and chemical nature of the C6'/C7' substituents affect the nuclease stability as well as the thermal stability and the RNase recruitment by AON/RNA duplexes.
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| 2. |
- Bailey-Wilson, Joan E, et al.
(författare)
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Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families
- 2012
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Ingår i: BMC Medical Genetics. - London : BioMed Central. - 1471-2350. ; 13, s. 46-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive.Methods: Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed.Results: Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded.Conclusions: Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.
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| 3. |
- Liu, Yi, et al.
(författare)
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Synthesis of 2',4' -Propylene-Bridged (Carba-ENA) Thymidine and Its Analogues : The Engineering of Electrostatic and Steric Effects at the Bottom of the Minor Groove for Nuclease and Thermodynamic Stabilities and Elicitation of RNase H
- 2010
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 75:21, s. 7112-7128
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Tidskriftsartikel (refereegranskat)abstract
- 2',4'-Propylene-bridged thymidine (carba-ENA-T) and five 8'-Me/NH2/OH modified carba-ENA-T analogues have been prepared through intramolecular radical addition to C=N of the tethered oxime-ether. These carba-ENA nucleosides have been subsequently incorporated into 15mer oligodeoxynucleotides (AON), and their affinity toward cDNA and RNA, nuclease resistance, and RNase H recruitment capability have been investigated in comparison with those of the native and ENA counterparts. These carba-ENAs modified AONs are highly RNA-selective since all of them led to slight thermal stabilization effect for the AON: RNA duplex, but quite large destabilization effect for the AON:DNA duplex. It was found that different C8' substituents (at the bottom of the minor groove) on carba-ENA-T only led to rather small variation of thermal stability of the AON:RNA duplexes. We, however, observed that the parent carba-ENA-T modified AONs exhibited higher nucleolytic stability than those of the ENA-T modified counterparts. The nucleolytic stability of carba-ENA-T modified AONs can be further modulated by C8' substituent to variable extents depending on not only the chemical nature but also the stereochemical orientation of the C8' substituents: Thus, (1) 8'S-Me on carba-ENA increases the nucleolytic stability but 8'R-Me leads to a decreased effect; (2) 8'R-OH on carba-ENA had little, if any, effect on nuclease resistance hut 8'S-OH resulted in significantly decreased nucleolytic stability; and (3) 8'-NH2 substituted carba-ENA leads to obvious loss in the nuclease resistance. The RNA strand in all of the carba-ENA derivatives modified AON:RNA hybrid duplexes can be digested by RNase HI with high efficiency, even at twice the rate of those of the native and ENA modified counterpart.
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| 4. |
- Schumacher, Fredrick R., et al.
(författare)
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Genome-wide association study identifies new prostate cancer susceptibility loci
- 2011
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Ingår i: Human Molecular Genetics. - London : IRL Press. - 0964-6906 .- 1460-2083. ; 20:19, s. 3867-3875
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding its etiology and factors that influence clinical outcome. Genome-wide association studies (GWAS) of PrCa have identified at least 30 distinct loci associated with small differences in risk. We conducted a GWAS in 2782 advanced PrCa cases (Gleason grade >= 8 or tumor stage C/D) and 4458 controls with 571 243 single nucleotide polymorphisms (SNPs). Based on in silico replication of 4679 SNPs (Stage 1, P < 0.02) in two published GWAS with 7358 PrCa cases and 6732 controls, we identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884, P = 4.3 x 10(-8)). We also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774, P = 8.6 x 10(-9)). The estimated per-allele odds ratios for these loci (1.14 for rs2292884 and 1.17 for rs902774) did not differ between advanced and non-advanced PrCa (case-only test for heterogeneity P = 0.72 and P = 0.61, respectively). Further studies will be needed to assess whether these or other loci are differentially associated with PrCa subtypes.
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