Analytical Validation of Variants to Aid in Genotype-Guided Therapy for Oncology

The Clinical Laboratory Improvement Amendments (CLIA) of 1988 requires that pharmacogenetic genotyping methods need to be established according to technical standards and laboratory practice guidelines before testing can be offered to patients. Testing methods for variants in ABCB1, CBR3, COMT, CYP3A7, C8ORF34, FCGR2A, FCGR3A, HAS3, NT5C2, NUDT15, SBF2, SEMA3C, SLC16A5, SLC28A3, SOD2, TLR4, and TPMT were validated in a CLIA-accredited laboratory. As no known reference materials were available, DNA samples that were from Coriell Cell Repositories (Camden, NJ) were used for the analytical validation studies. Pharmacogenetic testing methods developed here were shown to be accurate and 100% analytically sensitive and specific. Other CLIA-accredited laboratories interested in offering pharmacogenetic testing for these genetic variants, related to genotype-guided therapy for oncology, could use these publicly available samples as reference materials when developing and validating new genetic tests or refining current assays

Las biozonas de nummulitidos del Paleoceno Superior-Eoceno Inferior de la Cuenca Pirenaica

A nummulitid biozonation for the Upper Paleocene-Lower Eocene Pyrenean Basin is proposed in this work, The main contributions are: a) a new biozone proposed for the early Thanetian, b) a better characterization of the late Thanetian biozone, and c) the recognition of  two different biozones within the Lower Ilerdian.The nummulitid biozones established for the Pyrenean Upper Paleocene-Lower Eocene interval were correlated with the corresponding larger foraminiferal biozones Shallow Benthic Zones (SBZ) and integrated in the standard Paleocene-Eocene Time Scale on the basis of magnetostratigraphic data from the Pyrenean Basin and by correlation with the biozonation of calcareous nannoplankton and planktonic foraminifera in the Eastern and Central part of Tethys.The new biozones defined for tbe Pyrenean Upper Paleocene-Lower Eocene are: Nummulites heberti-Ranikothalia sindensis (early Thanetian), N. catari-Assilina yvettae-A. azilensis (late Thanetian), N. gamardensis-A. dandotica (early Ilerdian l), N. bigurdensis-A. aff. Prisca (early Ilerdian 2), N. carcasonensis-A. arenensis (middle Ilerdian l), N. exilis-A. leymeriei (middle Ilerdian 2), N. involutus-A. pomeroli (late Ilerdian), N. planulatus-N. burdigalensis burdigalensis-A. placentula (early Cuisian), N. praelaevigatus-N, cantabricus-A. laxispira (middle Cuisian), and N. manfredi-N. campesinus-A. mnior (late Cuisian)

Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study

BACKGROUND: Family studies and heritability estimates provide evidence for a genetic contribution to variation in the human life span. METHODS:We conducted a genome wide association study (Affymetrix 100K SNP GeneChip) for longevity-related traits in a community-based sample. We report on 5 longevity and aging traits in up to 1345 Framingham Study participants from 330 families. Multivariable-adjusted residuals were computed using appropriate models (Cox proportional hazards, logistic, or linear regression) and the residuals from these models were used to test for association with qualifying SNPs (70, 987 autosomal SNPs with genotypic call rate [greater than or equal to]80%, minor allele frequency [greater than or equal to]10%, Hardy-Weinberg test p [greater than or equal to] 0.001).RESULTS:In family-based association test (FBAT) models, 8 SNPs in two regions approximately 500 kb apart on chromosome 1 (physical positions 73,091,610 and 73, 527,652) were associated with age at death (p-value < 10-5). The two sets of SNPs were in high linkage disequilibrium (minimum r2 = 0.58). The top 30 SNPs for generalized estimating equation (GEE) tests of association with age at death included rs10507486 (p = 0.0001) and rs4943794 (p = 0.0002), SNPs intronic to FOXO1A, a gene implicated in lifespan extension in animal models. FBAT models identified 7 SNPs and GEE models identified 9 SNPs associated with both age at death and morbidity-free survival at age 65 including rs2374983 near PON1. In the analysis of selected candidate genes, SNP associations (FBAT or GEE p-value < 0.01) were identified for age at death in or near the following genes: FOXO1A, GAPDH, KL, LEPR, PON1, PSEN1, SOD2, and WRN. Top ranked SNP associations in the GEE model for age at natural menopause included rs6910534 (p = 0.00003) near FOXO3a and rs3751591 (p = 0.00006) in CYP19A1. Results of all longevity phenotype-genotype associations for all autosomal SNPs are web posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007. CONCLUSION: Longevity and aging traits are associated with SNPs on the Affymetrix 100K GeneChip. None of the associations achieved genome-wide significance. These data generate hypotheses and serve as a resource for replication as more genes and biologic pathways are proposed as contributing to longevity and healthy aging

Use of portable FTIR spectrometers for detecting greenhouse gas emissions of the megacity Berlin - Part 1: Instrumental line shape characterisation and calibration of a quintuple of spectrometers

Several low resolution spectrometers were used to investigate the CO2 and CH4 emissions of the megacity Berlin. Before and after the campaign the instruments were tested side-by-side. An excellent level of agreement and stability was found between the different spectrometers: the drifts in XCO2 and XCH4 are within 0.005 and 0.035%, respectively. The instrumental line shape characteristics of all spectrometers were found to be close to nominal. Cross-calibration factors for XCH4 and XCO2 were established for each spectrometer. An empirical airmass correction factor has been applied. As a last calibration step, using a co-located TCCON spectrometer as a reference, a common factor has been derived for the low-resolution campaign spectrometers, which ensures that the records are compatible to the WMO in-situ scale. Finally as a first result of the Berlin campaign we show the excellent agreement of ground pressure values obtained from total column measurements and in situ records

The Bartonian-Priabonian marine record of the eastern South Pyrenean foreland basin (NE Spain): a new calibration of the larger foraminifers and calcareous nannofossil biozonation

This study presents a combined biostratigraphic (calcareous nannofossils, larger foraminifers) and magnetostratigraphic study of the Middle and Late Eocene marine units of the Igualada area, eastern Ebro Basin. The studied sections of Santa Maria de Miralles and La Tossa encompass the complete marine succession of the Santa Maria Group, where assemblages rich in larger foraminifers have been studied since the early 1950’s. A total of 224 paleomagnetic sites and 62 biostratigraphic samples were collected along a 1350m-thick section that ranges from chron C20n to chron C16n (∼43Ma to ∼36Ma). The resulting magnetostratigraphy-based chronology challenges existing chronostratigraphic interpretations of these units and results in a new calibration of the biostratigraphic zonations. The base of calcareous nannofossil Zone NP19-20 is pinned down to an older age than its presently accepted attribution, whereas the time span assigned to Zone NP18 is significantly reduced. A revised calibration of larger foraminifers indicates that Zone SBZ18, formerly assigned exclusively to the late Bartonian, extends its range to the earlymost Priabonian, the Bartonian stage being almost entirely represented by Zone SBZ17. A division of Zone SBZ18 into two subzones is proposed

Calibration and instrumental line shape characterization of a set of portable FTIR spectrometers for detecting greenhouse gas emissions

A comprehensive calibration procedure for mobile, low-resolution, solar-absorption FTIR spectrometers, used for greenhouse gases observations, is developed. These instruments commend themselves for campaign use and deployment at remote sites. The instrumental line shape (ILS) of each spectrometer has been thoroughly characterized by analyzing the shape of H2O signatures in open path spectra. A setup for the external source is suggested and the invariance of derived ILS parameters with regard to chosen path length is demonstrated. The instrumental line shape characteristics of all spectrometers were found to be close to nominal. Side-by-side solar observations before and after a campaign, which involved shipping of all spectrometers to a selected target site and back, are applied for verifying the temporal invariability of instrumental characteristics and for deriving intercalibration factors for XCO2 and XCH4, which take into account residual differences of instrumental characteristics. An excellent level of agreement and stability was found between the different spectrometers: the uncorrected biases in XCO2 and XCH4 are smaller than 0.01 and 0.15 %, respectively, and the drifts are smaller than 0.005 and 0.035 %. As an additional sensitive demonstration of the instrumental performance we show the excellent agreement of ground pressure values obtained from the total column measurements of O2 and barometric records. We find a calibration factor of 0.9700 for the spectroscopic measurements in comparison to the barometric records and a very small scatter between the individual spectrometers (0.02 %). As a final calibration step, using a co-located TCCON (Total Carbon Column Observation Network) spectrometer as a reference, a common scaling factor has been derived for the XCO2 and XCH4 products, which ensures that the records are traceable to the WMO in situ scale. © Author(s) 2015

Leptin augments coronary vasoconstriction and smooth muscle proliferation via a Rho kinase dependent pathway

Leptin has been implicated as a key upstream mediator of pathways associated with coronary vascular dysfunction and disease. The purpose of this investigation was to test the hypothesis that leptin modifies the coronary artery proteome and promotes increases in coronary smooth muscle contraction and proliferation via influences on Rho kinase signaling. Global proteomic assessment of coronary arteries from lean swine cultured with obese concentrations of leptin (30 ng/mL) for 3 days revealed significant alterations in the coronary artery proteome (68 proteins) and identified an association between leptin treatment and calcium signaling/contraction (four proteins) and cellular growth and proliferation (35 proteins). Isometric tension studies demonstrated that both acute (30 min) and chronic (3 days, serum-free media) exposure to obese concentrations of leptin potentiated depolarization-induced contraction of coronary arteries. Inhibition of Rho kinase significantly reduced leptin-mediated increases in coronary artery contractions. The effects of leptin on the functional expression of Rho kinase were time-dependent, as acute treatment increased Rho kinase activity while chronic (3 day) exposure was associated with increases in Rho kinase protein abundance. Proliferation assays following chronic leptin administration (8 day, serum-containing media) demonstrated that leptin augmented coronary vascular smooth muscle proliferation and increased Rho kinase activity. Inhibition of Rho kinase significantly reduced these effects of leptin. Taken together, these findings demonstrate that leptin promotes increases in coronary vasoconstriction and smooth muscle proliferation and indicate that these phenotypic effects are associated with alterations in the coronary artery proteome and dynamic effects on the Rho kinase pathway

Use of portable FTIR spectrometers for detecting greenhouse gas emissions of the megacity Berlin - Part 2: Observed time series of XCO₂ and XCH₄

Five portable Bruker EM27/SUN FTIR spectrometers have been used for the accurate and precise observation of column averaged abundances of CO2 and CH4 around the megacity Berlin. In the first part of this work (Frey et al., 2015) we have presented the various measures that were undertaken to ensure that the observations are consistent between sites, accurate and precise. Here, we present the recorded time series of XCH4 and XCO2 and demonstrate that the CO2 emissions of Berlin can be clearly identified in the observations. A simple dispersion model is applied which indicates a total strength of the Berlin source of about 0.8 t CO2 s-1. In the Supplement of this work, we provide the measured dataset and auxiliary data. We hope that the model community will exploit this unique dataset for state-of-the art inversion studies of CO2 and CH4 sources in the Berlin area

Application of portable FTIR spectrometers for detecting greenhouse gas emissions of the major city Berlin

Five portable Bruker EM27/SUN FTIR (Fourier transform infrared) spectrometers have been used for the accurate and precise observation of column-averaged abundances of CO2 and CH4 around the major city Berlin. In the work by Frey et al. (2015), a calibration procedure is developed and applied to the set of spectrometers used for the Berlin campaign. Here, we describe the observational setup of the campaign and aspects of the data analysis, and we present the recorded time series of XCH4 and XCO2. We demonstrate that the CO2 emissions of Berlin can be clearly identified in the observations. A simple dispersion model is applied which indicates a total strength of the Berlin source of about 0.8 t CO2 s-1. In the Supplement of this work, we provide the measured data set and auxiliary data. We hope that the model community will exploit this unique data set for state-of-the art inversion studies of CO2 and CH4 sources in the Berlin area. © Author(s) 2015