The association among cytochrome P450 3A, progesterone receptor polymorphisms, plasma 17-alpha hydroxyprogesterone caproate concentrations, and spontaneous preterm birth

Background Infants born <37 weeks’ gestation are of public health concern since complications associated with preterm birth are the leading cause of mortality in children <5 years of age and a major cause of morbidity and lifelong disability. The administration of 17-alpha hydroxyprogesterone caproate reduces preterm birth by 33% in women with history of spontaneous preterm birth. We demonstrated previously that plasma concentrations of 17-alpha hydroxyprogesterone caproate vary widely among pregnant women and that women with 17-alpha hydroxyprogesterone caproate plasma concentrations in the lowest quartile had spontaneous preterm birth rates of 40% vs rates of 25% in those women with higher concentrations. Thus, plasma concentrations are an important factor in determining drug efficacy but the reason 17-alpha hydroxyprogesterone caproate plasma concentrations vary so much is unclear. Predominantly, 17-alpha hydroxyprogesterone caproate is metabolized by CYP3A4 and CYP3A5 enzymes. Objective We sought to: (1) determine the relation between 17-alpha hydroxyprogesterone caproate plasma concentrations and single nucleotide polymorphisms in CYP3A4 and CYP3A5; (2) test the association between progesterone receptor single nucleotide polymorphisms and spontaneous preterm birth; and (3) test whether the association between plasma concentrations of 17-alpha hydroxyprogesterone caproate and spontaneous preterm birth varied by progesterone receptor single nucleotide polymorphisms. Study Design In this secondary analysis, we evaluated genetic polymorphism in 268 pregnant women treated with 17-alpha hydroxyprogesterone caproate, who participated in a placebo-controlled trial to evaluate the benefit of omega-3 supplementation in women with history of spontaneous preterm birth. Trough plasma concentrations of 17-alpha hydroxyprogesterone caproate were measured between 25-28 weeks of gestation after a minimum of 5 injections of 17-alpha hydroxyprogesterone caproate. We extracted DNA from maternal blood samples and genotyped the samples using TaqMan (Applied Biosystems, Foster City, CA) single nucleotide polymorphism genotyping assays for the following single nucleotide polymorphisms: CYP3A4*1B, CYP3A4*1G, CYP3A4*22, and CYP3A5*3; and rs578029, rs471767, rs666553, rs503362, and rs500760 for progesterone receptor. We adjusted for prepregnancy body mass index, race, and treatment group in a multivariable analysis. Differences in the plasma concentrations of 17-alpha hydroxyprogesterone caproate by genotype were evaluated for each CYP single nucleotide polymorphism using general linear models. The association between progesterone receptor single nucleotide polymorphisms and frequency of spontaneous preterm birth was tested using logistic regression. A logistic model also tested interaction between 17-alpha hydroxyprogesterone caproate concentrations with each progesterone receptor single nucleotide polymorphism for the outcome of spontaneous preterm birth. Results The association between CYP single nucleotide polymorphisms *22, *1G, *1B, and *3 and trough plasma concentrations of 17-alpha hydroxyprogesterone caproate was not statistically significant (P =.68,.44,.08, and.44, respectively). In an adjusted logistic regression model, progesterone receptor single nucleotide polymorphisms rs578029, rs471767, rs666553, rs503362, and rs500760 were not associated with the frequency of spontaneous preterm birth (P =.29,.10,.76,.09, and.43, respectively). Low trough plasma concentrations of 17-alpha hydroxyprogesterone caproate were statistically associated with a higher frequency of spontaneous preterm birth (odds ratio, 0.78; 95% confidence ratio, 0.61–0.99; P =.04 for trend across quartiles), however no significant interaction with the progesterone receptor single nucleotide polymorphisms rs578029, rs471767, rs666553, rs503362, and rs500760 was observed (P =.13,.08,.10,.08, and.13, respectively). Conclusion The frequency of recurrent spontaneous preterm birth appears to be associated with trough 17-alpha hydroxyprogesterone caproate plasma concentrations. However, the wide variation in trough 17-alpha hydroxyprogesterone caproate plasma concentrations is not attributable to polymorphisms in CYP3A4 and CYP3A5 genes. Progesterone receptor polymorphisms do not predict efficacy of 17-alpha hydroxyprogesterone caproate. The limitations of this secondary analysis include that we had a relative small sample size (n = 268) and race was self-reported by the patients

Hole-doping of mechanically exfoliated graphene by confined hydration layers

By the use of non-contact atomic force microscopy (NC-AFM) and Kelvin probe force microscopy (KPFM), we measure the local surface potential of mechanically exfoliated graphene on the prototypical insulating hydrophilic substrate of CaF2(111). Hydration layers confined between the graphene and the CaF2 substrate, resulting from the graphene’s preparation under ambient conditions on the hydrophilic substrate surface, are found to electronically modify the graphene as the material’s electron density transfers from graphene to the hydration layer. Density functional theory (DFT) calculations predict that the first 2 to 3 water layers adjacent to the graphene hole-dope the graphene by several percent of a unit charge per unit cel

Structural analysis and atomic simulation of Ag/BN nanoparticle hybrids obtained by Ag ion implantation

International audienceThe present paper describes fabrication of Ag/BN nanoparticle hybrids by means of Ag ion implantation into the hollow BN nanoparticles (BNNPs) with a petal-like surface. The structural transformations occurring during Ag ion implantation into BNNPs are studied by low- and high-resolution transmission electron microscopy (TEM), high angle annular dark field scanning TEM (HAADF-STEM) paired with energy-dispersive X-ray (EDX) spectroscopy mapping. The experimental results are theoretically verified in the framework of the classical molecular dynamics (MD) method. Our results have demonstrated that by changing Ag ion energy in the range of 2-20 kV it is possible to selectively fabricate Ag/BNNP nanohybrids with crystalline or amorphous BNNP structures and various Ag NPs distributions over the BNNP thicknesses. © 2016 Elsevier Ltd

Graphene/Half-Metallic Heusler Alloy: A Novel Heterostructure towards High-Performance Graphene Spintronic Devices

A novel heterostructure consisting of single-layer graphene (SLG) and half-metallic Co2Fe(Ge0.5Ga0.5) (CFGG) Heusler alloy ferromagnet were synthesized, and the electronic properties of the interface were examined by depth-resolved X-ray magnetic circular dichroism spectroscopy. We found that in the SLG/CFGG heterostructure the SLG has a quasi-free-standing nature and the CFGG preserves the half-metallic ferromagnetism in the vicinity of the interface, which suggested that the SLG/CFGG heterostructure possesses distinctive advantages over other reported graphene/ferromagnet heterostructures for realizing high-performance spintronics devices

電子スピンを自在に操ることができる積層材料の創製

「夢の素材」と呼ばれるグラフェンは、その卓越したスピン伝導性から次世代スピントロニクス材料として注目されている[1,2]。しかし、現在のグラフェンスピントロニクス素子は、金属スピントロニクス素子と比較して性能が低く、特性向上が大きな課題になっている。グラフェンスピントロニクス素子の性能が低い原因の一つとして、従来の素子では、スピン偏極率が低い一般的な磁性材料(Co, Ni, Fe等)が使われてきたことが考えられる。我々は、一般的な磁性材料の代わりに、高スピン偏極率なハーフメタルホイスラー合金を用いることによるグラフェンスピントロニクス素子の高性能化の研究に取り組んでいる。本研究では、ホイスラー合金・グラフェンスピントロニクス素子の実現の鍵となる、グラフェンとホイスラー合金からなる積層材料の創製に成功した[3]。さらに、放射光分光を用いて積層材料の界面物性の調査を行った。QST高崎サイエンスフェスタ202