Pharmacogenomics of Novel Direct Oral Anticoagulants: Newly Identified Genes and Genetic Variants

Direct oral anticoagulants (DOAC) have shown an upward prescribing trend in recent years due to favorable pharmacokinetics and pharmacodynamics without requirement for routine coagulation monitoring. However, recent studies have documented inter-individual variability in plasma drug levels of DOACs. Pharmacogenomics of DOACs is a relatively new area of research. There is a need to understand the role of pharmacogenomics in the interpatient variability of the four most commonly prescribed DOACs, namely dabigatran, rivaroxaban, apixaban, and edoxaban. We performed an extensive search of recently published research articles including clinical trials and in-vitro studies in PubMed, particularly those focusing on genetic loci, single nucleotide polymorphisms (SNPs), and DNA polymorphisms, and their effect on inter-individual variation of DOACs. Additionally, we also focused on commonly associated drug-drug interactions of DOACs. CES1 and ABCB1 SNPs are the most common documented genetic variants that contribute to alteration in peak and trough levels of dabigatran with demonstrated clinical impact. ABCB1 SNPs are implicated in alteration of plasma drug levels of rivaroxaban and apixaban. Studies conducted with factor Xa, ABCB1, SLCOB1, CYP2C9, and VKORC1 genetic variants did not reveal any significant association with plasma drug levels of edoxaban. Pharmacokinetic drug-drug interactions of dabigatran are mainly mediated by p-glycoprotein. Strong inhibitors and inducers of CYP3A4 and p-glycoprotein should be avoided in patients treated with rivaroxaban, apixaban, and edoxaban. We conclude that some of the inter-individual variability of DOACs can be attributed to alteration of genetic variants of gene loci and drug-drug interactions. Future research should be focused on exploring new genetic variants, their effect, and molecular mechanisms that contribute to alteration of plasma levels of DOACs

Synthesis and physicochemical properties of spherical catalysts based on TiO2-SiO2/MxOy, where M - Co, Cr

Catalysts TiO2-SiO2 composition in the form of hollow spheres modified cobalt and chromium was obtained. Spatial structure of spherical samples after heat treatment was study by method of 3D microtomography. Status cations of transition elements and titanium was characterized by UV-Vis DRS. The catalysts were tested in the oxidation reaction of heptane

Entdeckung von fünf neuen Planeten

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Constraining recent lead pollution sources in the North Pacific using ice core stable lead isotopes

Trends and sources of lead (Pb) aerosol pollution in the North Pacific rim of North America from 1850 to 2001 are investigated using a high-resolution (subannual to annual) ice core record recovered from Eclipse Icefield (3017 masl; St. Elias Mountains, Canada). Beginning in the early 1940s, increasing Pb concentration at Eclipse Icefield occurs coevally with anthropogenic Pb deposition in central Greenland, suggesting that North American Pb pollution may have been in part or wholly responsible in both regions. Isotopic ratios (208Pb/207Pb and 206Pb/207Pb) from 1970 to 2001 confirm that a portion of the Pb deposited at Eclipse Icefield is anthropogenic, and that it represents a variable mixture of East Asian (Chinese and Japanese) emissions transported eastward across the Pacific Ocean and a North American component resulting from transient meridional atmospheric flow. Based on comparison with source material Pb isotope ratios, Chinese and North American coal combustion have likely been the primary sources of Eclipse Icefield Pb over the 1970–2001 time period. The Eclipse Icefield Pb isotope composition also implies that the North Pacific mid-troposphere is not directly impacted by transpolar atmospheric flow from Europe. Annually averaged Pb concentrations in the Eclipse Icefield ice core record show no long-term trend during 1970–2001; however, increasing 208Pb/207Pb and decreasing 206Pb/207Pb ratios reflect the progressive East Asian industrialization and increase in Asian pollutant outflow. The post-1970 decrease in North American Pb emissions is likely necessary to explain the Eclipse Icefield Pb concentration time series. When compared with low (lichen) and high (Mt. Logan ice core) elevation Pb data, the Eclipse ice core record suggests a gradual increase in pollutant deposition and stronger trans-Pacific Asian contribution with rising elevation in the mountains of the North Pacific rim

Dr. Benjamin Apthorp Gould

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Characterization of the monocyte-specific esterase (MSE) gene

Carboxylic esterases are widely distributed in hematopoietic cells. Monocytes express the esterase isoenzyme (termed 'monocyte-specific esterase', MSE) that can be inhibited by NaF in the alpha-naphthyl acetate cytochemical staining. We examined the expression of MSE in normal cells and primary and cultured leukemia-lymphoma cells. The MSE protein was demonstrated by isoelectric focusing (IEF); MSE mRNA expression was investigated by Northern blotting and reverse transcriptase-polymerase chain reaction (RT-PCR). The following samples were positive for MSE protein and Northern mRNA expression: 20/24 monocytic, 4/32 myeloid, and 1/20 erythroid-megakaryocytic leukemia cell lines, but none of the 112 lymphoid leukemia or lymphoma cell lines; of the normal purified cell populations only the monocytes were positive whereas, T, B cells, and granulocytes were negative; of primary acute (myelo) monocytic leukemia cells (CD14-positive, FAB M4/M5 morphology) 14/20 were Northern mRNA and 11/14 IEF protein positive. RT-PCR revealed MSE expression in 29/49 Northern-negative lymphoid leukemia-lymphoma cell lines. The RT-PCR signals in monocytic cell lines were on average 50-fold stronger than the mostly weak trace expression in lymphoid specimens. On treatment with various biomodulators, only all-trans retinoic acid significantly upregulated MSE message and protein levels but could not induce new MSE expression in several leukemia cell lines; lipopolysaccharide and interferon-gamma increased MSE expression in normal monocytes. Analysis of DNA methylation with sensitive restriction enzymes showed no apparent regulation of gene expression by differential methylation; the MSE gene is evolutionarily conserved among mammalian species; the half-life of the human MSE transcripts was about 5-6 h. The extent of MSE expression varied greatly among different monocytic leukemia samples. However, the MSE overexpression in a significant number of specimens was not associated with gene amplification, gross structural rearrangements or point mutations within the cDNA region. Taken together, the results suggest that MSE expression is not absolutely specific for, but strongly associated with cells of the monocytic lineage; MSE is either not expressed at all or expressed at much lower levels in cells from other lineages. The biological significance, if any, of rare MSE messages in lymphoid cells detectable only by the hypersensitive RT-PCR remains unclear. Further studies on the regulation of this gene and on the physiological function of the enzyme will no doubt be informative with respect to its striking overexpression in some malignant cells and to a possible role in the pathobiology of monocytic leukemias

Impact of Preindustrial Biomass-Burning Emissions on the Oxidation Pathways of Tropospheric Sulfur and Nitrogen

Ice core measurements (H2O2 and CH4/HCHO) and modeling studies indicate a change in the oxidation capacity of the atmosphere since the onset of the Industrial Revolution due to increases in fossil fuel burning emissions [e. g., Lelieveld et al., 2002; Hauglustaine and Brasseur, 2001; Wang and Jacob, 1998; Staffelbach et al., 1991]. The mass-independent fractionation (MIF) in the oxygen isotopes of sulfate and nitrate from a Greenland ice core reveal that biomass-burning events in North America just prior to the Industrial Revolution significantly impacted the oxidation pathways of sulfur and nitrogen species deposited in Greenland ice. This finding highlights the importance of biomass-burning emissions for atmospheric chemistry in preindustrial North America and warrants the inclusion of this impact in modeling studies estimating changes in atmospheric oxidant chemistry since the Industrial Revolution, particularly when using paleo-oxidant data as a reference for model evaluation

Seasonal variations of glaciochemical, isotopic and stratigraphic properties in Siple Dome (Antarctica) surface snow

Six snow-pit records recovered from Siple Dome, West Antarctica, during 1994 are used to study seasonal variations in chemical (major ion and H202), isotopic (deuterium) and physical stratigraphic properties during the 1988-94 period. Comparison of δD measurements and satellite-derived brightness temperature for the Siple Dome area suggests that most seasonal SD maxima occur within ±4 weeks of each 1 January. Several other chemical species (H2O2, non-sea-salt (nss) SO4 2-, methanesulfonic acid and NO3-) show coeval peaks with SD, together providing an accurate method for identifying summer accumulation. Sea-salt-derived species generally peak during winter/spring, but episodic input is noted throughout some years. No reliable seasonal signal is identified in species with continental sources (nssCa2+ nss Mg2+), NH4 + or nssCl-. Visible strata such as large depth-hoar layers (\u3e5 cm) are associated with summer accumulation and its metamorphosis, but smaller hoar layers and crusts are more difficult to interpret. A multi-parameter approach is found to provide the most accurate dating of these snow-pit records, and is used to determine annual layer thicknesses at each site Significant spatial accumulation variability exists on an annual basis, but mean accumulation in the sampled 10 km2 grid for the 1988-94 period is fairly uniform

Roadside verges and cemeteries: Comparative analysis of anthropogenic orchid habitats in the Eastern Mediterranean

Several important habitats have become threatened in the last few centuries in the Mediterranean Basin due to major changes adopted in land-use practices. The consequent loss of natural and seminatural orchid habitats leads to the appreciation of small anthropogenic habitats, such as cemeteries and roadside verges. Colonization of cemeteries and roadside verges by orchids has long been known, but no study to date compared the suitability of these two anthropogenic habitats for orchids. Therefore, in this paper our aim was to survey cemeteries and roadside verges and to compare these two habitats regarding their role in conserving Mediterranean terrestrial orchids. We conducted field surveys in three Mediterranean islands, Cyprus, Crete, and Lesbos, where both cemeteries and roadside verges were sampled on a geographically representative scale. We found a total of almost 7,000 orchid individuals, belonging to 77 species in the two anthropogenic habitat types. Roadside verges hosted significantly more individuals than cemeteries in Crete and Lesbos, and significantly more species across all three islands. Our results suggest that although cemeteries have a great potential conservation value in other parts of the world, intensive maintenance practices that characterized cemeteries in these three islands renders them unable to sustain valuable plant communities. On the other hand, roadside verges play a prominent role in the conservation of Mediterranean orchids in Cyprus and Greece. The pioneer status of roadside verges facilitates their fast colonization, while roads serve as ecological corridors in fragmented landscapes

Ab-initio transport theory for digital ferromagnetic heterostructures

MnAs/GaAs superlattices, made by $\delta$-doping GaAs with Mn, are known as digital ferromagnetic heterostructures. Here we present a theoretical density functional study of the electronic, magnetic and transport properties of such heterostructures. In the absence of intrinsic donors these systems show an half metallic density of states, with an exchange interaction much stronger than that of a random alloy with the same Mn concentration. {\it Ab initio} ballistic transport calculations show that the carriers with energies close to the Fermi energy are strongly confined within a few monolayers around the MnAs plane. This strong confinement is responsible for the large exchange coupling. Therefore the system can be described as a two dimensional half metal with large conductance in the MnAs plane and small conductance in the perpendicular direction