Everolimus is an immunosuppressant used as rejection prophylaxis in patients undergoing transplants. It requires blood concentration-guided dosing and is extensively metabolized. It was the goal to ...assess the crossreactivity of the major everolimus metabolites in the blood of patients undergoing kidney graft with the Innofluor Certican Assay (Seradyn, Inc., Indianapolis, IN), a clinical assay used to quantify the concentrations of everolimus in patients' blood samples. The three main hydroxy metabolites of everolimus (46-, 24-, and 25-hydroxy everolimus) and all other minor hydroxylated and demethylated metabolites were generated using pooled human liver microsomes and purified using semipreparative high-performance liquid chromatography with ultraviolet detection. Structures were confirmed using liquid chromatography-mass spectrometry/ion trap mass spectrometry and analysis of the fragmentation patterns. Blank blood samples were spiked with the isolated metabolites to determine the specific crossreactivity with the immunoassay. Crossreactivity testing with the immunoassay showed 1% or less for 46-hydroxy and 24-hydroxy everolimus and 6% or less crossreactivity for 25-hydroxy everolimus at therapeutically relevant concentrations. Crossreactivity testing of the minor metabolites showed crossreactivities of 16.3% for 45-hydroxy, 33.0% for 12-hydroxy, 18.3% for 11-hydroxy, 15.3% for 14-hydroxy, 38.7% for OH-piperidine I, 46.3% for OH-piperidine II, 43% for 39-O-desmethyl, 142% for 27-O-desmethyl, and 68% for 40-O-desethylhydroxy everolimus (sirolimus).
A
bstract
A search for evidence of physics beyond the Standard Model in final states with multiple high-transverse-momentum jets is performed using 20.3 fb
−1
of proton-proton collision data at
s
=
8
...TeV recorded by the ATLAS detector at the LHC. No significant excess of events beyond Standard Model expectations is observed, and upper limits on the visible cross sections for non-Standard Model production of multi-jet final states are set. A wide variety of models for black hole and string ball production and decay are considered, and the upper limit on the cross section times acceptance is as low as 0.16 fb at the 95% confidence level. For these models, excluded regions are also given as function of the main model parameters.
Does Crop Determine Culture? Hahn, Barbara; Saraiva, Tiago; Rhode, Paul W. ...
Agricultural history,
07/2014, Letnik:
88, Številka:
3
Journal Article
Recenzirano
Drawn from a plenary discussion at the 2013 Agricultural History Society's annual meeting in Banff, five scholars examine the relationships of specific crops to their surrounding cultures. The ...question “does crop determine culture?” provided opportunities to explore crop determinism and interrogate the relationships between particular crops and their production methods. The question intended to avoid the narrow association of “culture” with cultivation techniques, and each scholar discussed agricultural production methods in ways that included elements of their wider contexts. As usually happens in the history of technology, these historians spoke of cultivation methods that both reflect and shape those phenomena more often classified as social, cultural, political, or economic, rather than narrowly technological. The plenary ends with a call for readers to answer the organizing question for themselves, in their own studies of agriculture and its environments.
The Th1 cytokines IL-2 and IFN-γ, which inhibit T cell proliferation and promote activation induced cell death, may be required to diminish alloreactive T cell numbers and to foster tolerance across ...full allogeneic barriers. However, we hypothesized that these cytokines might be dispensable when the alloreactive T cell clone size is relatively small, as is seen in recipients of minor-mismatched grafts. We show that alloreactive T cell clone size of C57BL/6 mice against multiple minor-mismatched 129X1/sv mice was ∼4–9-fold smaller than that against MHC-mismatched BALB/c mice. In the MHC-mismatched combination, CD28-B7 blockade by CTLA4Ig induced long-term graft survival in wild-type recipients, but this treatment was ineffective in
IFNγ
–/–
or
IL-2
–/–
recipients. In contrast, in the minor-mismatched combination, CTLA4Ig induced long-term allograft survival in wild-type,
IFNγ
–/–
, and
IL-2
–/–
recipients. Bcl-x
L
transgenic animals, which are defective in "passive" T cell death, are likewise sensitive to the effects of CTLA4Ig only in the setting of the minor-mismatch grafts. Therefore, the alloreactive T cell clone size is an important determinant affecting the need for Th1 cytokines and T cell death in tolerance induction. These data have implications for the design of tolerance strategies in transplant recipients with varying degrees of MHC mismatching.
In primary cultures of human hepatocytes, paclitaxel (Taxol), at pharmacological concentrations, was demonstrated to induce immunoreactive cytochrome P4503A (CYP3A). The magnitude of the inductive ...response of the hepatocytes to Taxol varied in five separate cultures. In general, exposure to increasing concentrations of Taxol (0.2 to 10 μM) resulted in increases in immunoreactive CYP3A. In four of the cultures, treatment of hepatocytes with the lowest concentration of Taxol tested (0.2 μM) resulted in approximately two-fold increases in CYP3A. In the other culture, however, a six-fold increase in CYP3A was observed at 0.2 μM. Taxol was almost as effective as rifampicin in inducing CYP3A in two of the cultures, but less effective than rifampicin in two other cultures. CYP3A4 mRNA was increased by Taxol. Increases in CYP3A4 mRNA correlated with increases in the levels of immunoreactive CYP3A. These results demonstrate that Taxol is a potent inducer of CYP3A in human hepatocytes. The clinical significance of these findings is discussed.
The main building blocks of the ATLAS Inner Tracker (ITk) Strip Detector, to be installed for the High-Luminosity Upgrade of the Large Hadron Collider (HL-LHC), are modules that host sensors and ...front-end ASICs. Carbon-fibre substructures provide mechanical support to up to 14 modules per side. An End-of-Substructure (EoS) card on each substructure side connects up to 28 differential data lines at 640 Mbit/s from the module to low-powered GigaBit Transceivers (lpGBT) ASICs for data serialisation and uses 10 GBit/s optical links to transmit signals to the off-detector systems via the Versatile Link PLUS (VL+) transceiver module, VTRx+. Prototype EoS cards have been designed and extensively tested using lpGBT and VTRx+ prototypes. The status of the electronics design and recent results of tests of electrical and data processing performance based on these prototypes are presented.
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