267 research outputs found
Motivic Zeta Functions of the Quartic and its Mirror Dual
We use a formula of Bultot to compute the motivic zeta function for the toric degeneration of the quartic K3 and its Gross-Siebert mirror dual degeneration. We check for this explicit example that the identification of the logarithm of the monodromy and the mirror dual Lefschetz operator works at an integral level
Population pharmacogenetic-based pharmacokinetic modeling of efavirenz, 7-hydroxy- and 8-hydroxyefavirenz
The purpose of this study was to determine the demographic and pharmacogenetic covariates that influence the disposition of efavirenz (EFV) and its major metabolites. A population pharmacokinetic (PK) model was developed from a randomized, cross-over, drug-interaction study in healthy male Korean subjects (n = 17). Plasma concentrations of EFV and its hydroxy-metabolites (0-120 hours) were measured by LC/MS/MS. Genomic DNA was genotyped for variants in the cytochrome P450 (CYP) 2A6, 2B6, 3A5, and MDR1 genes. A PK model was built in a stepwise procedure using nonlinear mixed effect modeling in NONMEM 7. The covariate model was built using the generalized additive modeling and forward selection-backward elimination. Model-based simulations were performed to predict EFV steady-state concentrations following 200, 400, and 600 mg daily oral dose among different CYP2B6 genotypes. The final model included only CYP2B6 genotype as a covariate that predicts EFV clearance through the formation of 8-OH EFV that represented 65% to 80% of EFV clearance. The total clearance of EFV in CYP2B6*6/*6 genotype was ∼30% lower than CYP2B6*1/*1 or CYP2B6*1/*6 alleles (P < .001). Clopidogrel reduced both formation and elimination clearances of 8-OH EFV by 22% and 19%, respectively (P = .033 and .041). Other demographics and genotype of accessory CYP pathways did not predict EFV or metabolites PK. CYP2B6 genotype was the only significant predictor of EFV disposition. The developed model may serve as the foundation for further exploration of pharmacogenetic-based dosing of EFV
INFLUENCE OF ZOLEDRONIC ACID ON ATRIAL ELECTROPHYSIOLOGICAL PARAMETERS ASSOCIATED WITH RISK OF ATRIAL FIBRILLATION
Coexistence of ferro- and antiferromagnetic order in Mn-doped NiMnGa
Ni-Mn-Ga is interesting as a prototype of a magnetic shape-memory alloy
showing large magnetic field induced strains. We present here results for the
magnetic ordering of Mn-rich Ni-Mn-Ga alloys based on both experiments and
theory. Experimental trends for the composition dependence of the magnetization
are measured by a vibrating sample magnetometer (VSM) in magnetic fields of up
to several tesla and at low temperatures. The saturation magnetization has a
maximum near the stoichiometric composition and it decreases with increasing Mn
content. This unexpected behaviour is interpreted via first-principles
calculations within the density-functional theory. We show that extra Mn atoms
are antiferromagnetically aligned to the other moments, which explains the
dependence of the magnetization on composition. In addition, the effect of Mn
doping on the stabilization of the structural phases and on the magnetic
anisotropy energy is demonstrated.Comment: 4 pages, 3 figure
1-Alpha, 25-dihydroxyvitamin D3 alters the pharmacokinetics of mycophenolic acid in renal transplant recipients by regulating two extrahepatic UDP-glucuronosyltransferases 1A8 and 1A10
Mycophenolic acid (MPA) is an important immunosuppressant broadly used in renal transplantation. However, the large inter-patient variability in mycophenolic acid (MPA) pharmacokinetics (PK) limits its use. We hypothesize that extrahepatic metabolism of MPA may have significant impact on MPA PK variability. Two intestinal UDP-glucuronosyltransferases 1A8 and 1A10 plays critical role in MPA metabolism. Both in silico and previous genome-wide analyses suggested that vitamin D (VD) may regulate intestinal UGT1A expression. We validated the VD response elements (VDREs) across the UGT1A locus with chromatin immunoprecipitation (ChIP) and luciferase reporter assays. The impact of 1-alpha,25-dihydroxyvitamin D3 (D3) on UGT1A8 and UGT1A10 transcription and on MPA glucuronidation was tested in human intestinal cell lines LS180, Caco-2 and HCT-116. The correlation between transcription levels of VD receptor (VDR) and the two UGT genes were examined in human normal colorectal tissue samples (n = 73). PK alterations of MPA following the parent drug, mycophenolate mofetil (MMF), and D3 treatment was assessed among renal transplant recipients (n = 10). Our ChIP assay validate three VDREs which were further demonstrated as transcriptional enhancers with the luciferase assays. D3 treatment significantly increased transcription of both UGT genes as well as MPA glucuronidation in cells. The VDR mRNA level was highly correlated with that of both UGT1A8 and UGT1A10 in human colorectal tissue. D3 treatment in patients led to about 40% reduction in both AUC0-12 and Cmax while over 70% elevation of total clearance of MPA. Our study suggested a significant regulatory role of VD on MPA metabolism and PK via modulating extrahepatic UGT activity
Effect of Transdermal Testosterone and Oral Progesterone on Drug-Induced QT Interval Lengthening in Older Men
Olaparib Induced Moderate Killing of ATM-Deficient Mantle Cell Lymphoma Cells In Vitro and In Vivo
The Ataxia Telangiectasia Mutated (ATM) gene is frequently inactivated in lymphoid malignancies such as and Mantle Cell Lymphoma (MCL) and is associated with defective apoptosis, especially in response to standard cytotoxic chemotherapy. ATM deficient cells exhibit impaired homologous recombination and the inability to correct double strand DNA breaks. Inhibition of poly (ADPribose) Polymerase (PARP), which is required for DNA double strand break repair, has been shown to sensitize ATM-deficient tumor cells to killing. We investigated in vitro and in vivo sensitivity to the PARP inhibitor olaparib in the ATM deficient mantle cell lymphoma cell line Granta-519. Olaparib monotherapy and in combination with cisplatin or bendamustine confirmed decreased proliferation in vitro. A Nonobese Diabetic/Severe Combined Immunodeficient (NOD/SCID) murine xenograft model with the Granta-519 cell line did not result in a significantly reduced tumor load following treatment with olaparib in vivo
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