Well‐characterized genes that affect warfarin metabolism (cytochrome P450 (CYP) 2C9) and sensitivity (vitamin K epoxide reductase complex 1 (VKORC1)) explain one‐third of the variability in ...therapeutic dose before the international normalized ratio (INR) is measured. To determine genotypic relevance after INR becomes available, we derived clinical and pharmacogenetic refinement algorithms on the basis of INR values (on day 4 or 5 of therapy), clinical factors, and genotype. After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P < 0.001) of warfarin dose. The clinical algorithm had an R2 of 48% (median absolute error (MAE): 7.0 mg/week) and the pharmacogenetic algorithm had an R2 of 63% (MAE: 5.5 mg/week) in the derivation set (N = 969). In independent validation sets, the R2 was 26–43% with the clinical algorithm and 42–58% when genotype was added (P = 0.002). After several days of therapy, a pharmacogenetic algorithm estimates the therapeutic warfarin dose more accurately than one using clinical factors and INR response alone.
Clinical Pharmacology & Therapeutics (2010) 87 5, 572–578. doi: 10.1038/clpt.2010.13
Excessive activation of G-protein-coupled receptor (GPCR) and receptor tyrosine kinase (RTK) pathways has been linked to prostate cancer metastasis. Rac activation by guanine nucleotide exchange ...factors (GEFs) plays an important role in directional cell migration, a critical step of tumor metastasis cascades. We found that the upregulation of P-Rex1, a Rac-selective GEF synergistically activated by Gbetagamma freed during GPCR signaling, and PIP3, generated during either RTK or GPCR signaling, strongly correlates with metastatic phenotypes in both prostate cancer cell lines and human prostate cancer specimens. Silencing endogenous P-Rex1 in metastatic prostate cancer PC-3 cells selectively inhibited Rac activity and reduced cell migration and invasion in response to ligands of both epidermal growth factor receptor and G-protein-coupled CXC chemokine receptor 4. Conversely, expression of recombinant P-Rex1, but not its 'GEF-dead' mutant, in non-metastatic prostate cancer cells, such as CWR22Rv1, increased cell migration and invasion through Rac-dependent lamellipodia formation. More importantly, using a mouse xenograft model, we showed that the expression of P-Rex1, but not its mutant, induced lymph node metastasis of CWR22Rv1 cells without an effect on primary tumor growth. Thus, by functioning as a coincidence detector of chemotactic signals from both GPCRs and RTKs, P-Rex1-dependent activation of Rac promotes prostate cancer metastasis.
A beam-normal single-spin asymmetry generated in the scattering of transversely polarized electrons from unpolarized nucleons is an observable related to the imaginary part of the two-photon exchange ...process. We report a 2% precision measurement of the beam-normal single-spin asymmetry in elastic electron-proton scattering with a mean scattering angle of θlab=7.9° and a mean energy of 1.149 GeV. The asymmetry result is Bn=−5.194±0.067(stat)±0.082 (syst) ppm. This is the most precise measurement of this quantity available to date and therefore provides a stringent test of two-photon exchange models at far-forward scattering angles (θlab→0) where they should be most reliable.
The Q(weak) experiment has measured the parity-violating asymmetry in ep elastic scattering at Q(2)=0.025(GeV/c)(2), employing 145 μA of 89% longitudinally polarized electrons on a 34.4 cm long ...liquid hydrogen target at Jefferson Lab. The results of the experiment's commissioning run, constituting approximately 4% of the data collected in the experiment, are reported here. From these initial results, the measured asymmetry is A(ep)=-279±35 (stat) ± 31 (syst) ppb, which is the smallest and most precise asymmetry ever measured in ep scattering. The small Q(2) of this experiment has made possible the first determination of the weak charge of the proton Q(W)(p) by incorporating earlier parity-violating electron scattering (PVES) data at higher Q(2) to constrain hadronic corrections. The value of Q(W)(p) obtained in this way is Q(W)(p)(PVES)=0.064±0.012, which is in good agreement with the standard model prediction of Q(W)(p)(SM)=0.0710±0.0007. When this result is further combined with the Cs atomic parity violation (APV) measurement, significant constraints on the weak charges of the up and down quarks can also be extracted. That PVES+APV analysis reveals the neutron's weak charge to be Q(W)(n)(PVES+APV)=-0.975±0.010.
► We asses accuracy and predictive potential of causal methods versus stepwise and PCA. ► The HITON-MB and First Order Utility (FOU) methods were the most accurate. ► The accuracy of some causal ...selection methods was comparable to stepwise regression. ► A new index for testing method reliability or robustness was developed. ► FOU reliability was high on data of known relationship and low on watershed data.
Hydrological predictions at a watershed scale are commonly based on extrapolation and upscaling of hydrological behavior at plot and hillslope scales. Yet, dominant hydrological drivers at a hillslope may not be as dominant at the watershed scale because of the heterogeneity of watershed characteristics. With the availability of quantifiable watershed data (watershed descriptors and streamflow indices), variable selection can provide insight into the dominant watershed descriptors that drive different streamflow regimes. Stepwise regression and principal components analysis have long been used to select descriptive variables for relating runoff to climate and watershed descriptors. Questions have remained regarding the robustness of the selected descriptors. This paper evaluates five new approaches: Grow-Shrink, GS; a variant of Incremental Association Markov Boundary, interIAMBnPC; Local Causal Discovery, LCD2; HITON Markov Blanket, HITON-MB; and First-Order Utility, FOU. We demonstrate their performance by quantifying their accuracy, consistency and predictive potential compared to stepwise regression and principal component analysis on two known functional relationships. The results show that the variables selected by HITON-MB and the first-order utility are the most accurate while variables selected by Stepwise regression, although not accurate have a high predictive potential. Therefore, a model with high predictive power may not necessary represent the underlying hydrological processes of a watershed system.
► We assess classification results based on selected variables by causal versus PCA and stepwise. ► Classification performance was higher for variables selected by causal selection methods. ► The ...HITON-MB selected variables that were unique to each of the three ecoregions. ► Variables such as MRVBF and MRRT gave better topographic variability than hypsometry. ► Hypsometry gave better classification in the Piedmont compared to other ecoregions.
Hydrological flow predictions in ungauged and sparsely gauged watersheds use regionalization or classification of hydrologically similar watersheds to develop empirical relationships between hydrologic, climatic, and watershed variables. The watershed classifications may be based on geographic proximity, regional frameworks such as ecoregions or classification using cluster analysis of watershed descriptors. General approaches used in classifying hydrologically similar watersheds use climatic and watershed variables or statistics of streamflow data. Use of climatic and watershed descriptors requires variable selection to minimize redundancy from a large pool of potential variables. This study compares classification performance of four variable groups to identify homogeneous watersheds in three Mid-Atlantic ecoregions (USA): Appalachian Plateau, Piedmont, and Ridge and Valley. The variable groups included: (1) variables that define watershed geographic proximity; (2) variables that define watershed hypsometry; (3) variables selected using causal selection algorithms; and (4) variables selected using principal component analysis (PCA) and stepwise regression. The classification results were compared to reference watersheds classified as homogeneous using three streamflow indices: Slope of flow duration curve; Baseflow index; and Streamflow elasticity using a similarity index (SI). Classification performance was highest using variables selected by causal algorithms (e.g., HITON-MB method, SI=0.71 for Appalachian Plateau, SI=0.90 for Piedmont, and SI=0.72 for Ridge and Valley) compared to variables selected by stepwise regression (SI=0.72 for Appalachian Plateau, SI=0.87 for Piedmont, and SI=0.64 for Ridge and Valley) and PCA (SI=0.71 for Appalachian Plateau, SI=0.76 for Piedmont, and SI=0.57 for Ridge and Valley).
The recently cloned human GLUT9 gene, which maps to chromosome 4p15.3-p16, consists of 12 exons coding for a 540-amino acid protein. Based on a sequence entry (NCBI accession number BC018897) and ...screening of expressed sequence tags, we have cloned an alternative splice variant of GLUT9 from human kidney cDNA. The RNA of this splice variant consists of 13 exons and codes for a putative protein of 512 amino acids (GLUT9DeltaN). The predicted proteins differ only in their N terminus, suggesting a different subcellular localization and possible physiological role. Screening human tissue RNA by reverse transcription-PCR showed that GLUT9 is expressed mainly in kidney, liver, placenta, and leukocytes, whereas GLUT9DeltaN was detected only in kidney and placenta. The GLUT9 protein localized by immunohistochemistry to human kidney proximal tubules, and subcellular fractionation of human kidney revealed the GLUT9 protein in plasma membranes and high density microsomal membranes. Treatment of kidney membrane proteins with peptide N-glycosidase F showed that GLUT9 and GLUT9DeltaN are expressed in vivo. Localization of GLUT9 and GLUT9DeltaN in three kidney-derived cell lines revealed a plasma membrane distribution for GLUT9 in COS-7 and HEK293 cells, whereas GLUT9DeltaN showed a perinuclear pattern and plasma membrane staining in COS-7 and HEK293 cells, respectively. In polarized Madin-Darby canine kidney cells, GLUT9 trafficked to the basolateral membrane, whereas GLUT9DeltaN localized to the apical membrane. Using heterologous expression of GLUT9 in Xenopus oocytes, GLUT9 appears to be a functional isoform with low affinity for deoxyglucose. Deoxyglucose transport mediated by GLUT9 was not inhibited by cytochalasin B. GLUT9 did not bind cytochalasin B as shown by a cytochalasin B binding assay, indicating a similar behavior of GLUT9 compared with GLUT5.
The recently completed Qweak experiment at Jefferson Laboratory made the first direct determination of the proton's weak charge, QpW, via a measurement of the parity-violating asymmetry in elastic ...electron-proton scattering at low four-momentum transfer. The Standard Model (SM) makes a precise prediction of QpW (SM) = 0.0710 ± 0.0007. A deviation from this prediction could be an indicator of new physics. A longitudinally polarized electron beam was scattered off a liquid hydrogen target and detected in eight azimuthally symmetric fused silica detectors. The small asymmetry, Aep = -279 ± 35 (stat) ±31 (syst) ppb, was measured by observing the difference in rates seen in the detectors when the helicity of the electron beam was rapidly reversed. The measured asymmetry is the most precise and smallest asymmetry ever measured in an e⃗p scattering experiment. Combining this asymmetry with previous parity- violating electron scattering (PVES) data, we obtained a value of QpW(PVES) = 0.064 ± 0.012, which agrees well with the SM value. The results of the experiment's commissioning run, which constitutes about 4% of the total data set, are reported here. Analysis of the remainder of the data set is ongoing and will significantly reduce the statistical and systematic uncertainties; several aspects of this analysis will be highlighted.
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