323 research outputs found
Human biodistribution and radiation dosimetry of novel PET probes targeting the deoxyribonucleoside salvage pathway
PurposeDeoxycytidine kinase (dCK) is a rate-limiting enzyme in deoxyribonucleoside salvage, a metabolic pathway involved in the production and maintenance of a balanced pool of deoxyribonucleoside triphosphates (dNTPs) for DNA synthesis. dCK phosphorylates and therefore activates nucleoside analogs such as cytarabine, gemcitabine, decitabine, cladribine, and clofarabine that are used routinely in cancer therapy. Imaging probes that target dCK might allow stratifying patients into likely responders and nonresponders with dCK-dependent prodrugs. Here we present the biodistribution and radiation dosimetry of three fluorinated dCK substrates, (18)F-FAC, L: -(18)F-FAC, and L: -(18)F-FMAC, developed for positron emission tomography (PET) imaging of dCK activity in vivo.MethodsPET studies were performed in nine healthy human volunteers, three for each probe. After a transmission scan, the radiopharmaceutical was injected intravenously and three sequential emission scans acquired from the base of the skull to mid-thigh. Regions of interest encompassing visible organs were drawn on the first PET scan and copied to the subsequent scans. Activity in target organs was determined and absorbed dose estimated with OLINDA/EXM. The standardized uptake value was calculated for various organs at different times.ResultsRenal excretion was common to all three probes. Bone marrow had higher uptake for L: -(18)F-FAC and L: -(18)F-FMAC than (18)F-FAC. Prominent liver uptake was seen in L: -(18)F-FMAC and L: -(18)F-FAC, whereas splenic activity was highest for (18)F-FAC. Muscle uptake was also highest for (18)F-FAC. The critical organ was the bladder wall for all three probes. The effective dose was 0.00524, 0.00755, and 0.00910Â mSv/MBq for (18)F-FAC, L: -(18)F-FAC, and L: -(18)F-FMAC, respectively.ConclusionThe biodistribution of (18)F-FAC, L: -(18)F-FAC, and L: -(18)F-FMAC in humans reveals similarities and differences. Differences may be explained by different probe affinities for nucleoside transporters, dCK, and catabolic enzymes such as cytidine deaminase (CDA). Dosimetry demonstrates that all three probes can be used safely to image the deoxyribonucleoside salvage pathway in humans
Generalized Weyl solutions in d=5 Einstein-Gauss-Bonnet theory: the static black ring
We argue that the Weyl coordinates and the rod-structure employed to
construct static axisymmetric solutions in higher dimensional Einstein gravity
can be generalized to the Einstein-Gauss-Bonnet theory. As a concrete
application of the general formalism, we present numerical evidence for the
existence of static black ring solutions in Einstein-Gauss-Bonnet theory in
five spacetime dimensions. They approach asymptotically the Minkowski
background and are supported against collapse by a conical singularity in the
form of a disk. An interesting feature of these solutions is that the
Gauss-Bonnet term reduces the conical excess of the static black rings.
Analogous to the Einstein-Gauss-Bonnet black strings, for a given mass the
static black rings exist up to a maximal value of the Gauss-Bonnet coupling
constant . Moreover, in the limit of large ring radius, the suitably
rescaled black ring maximal value of and the black string maximal
value of agree.Comment: 43 pages, 14 figure
Einstein-Gauss-Bonnet black strings
We construct uniform black-string solutions in Einstein-Gauss-Bonnet gravity
for all dimensions between five and ten and discuss their basic properties.
Closed form solutions are found by taking the Gauss-Bonnet term as a
perturbation from pure Einstein gravity. Nonperturbative solutions are
constructed by solving numerically the equations of the model. The
Gregory-Laflamme instability of the black strings is explored via linearized
perturbation theory. Our results indicate that new qualitative features occur
for , in which case stable configurations exist for large enough values of
the Gauss-Bonnet coupling constant. For other dimensions, the black strings are
dynamically unstable and have also a negative specific heat. We argue that this
provides an explicit realization of the Gubser-Mitra conjecture, which links
local dynamical and thermodynamic stability. Nonuniform black strings in
Einstein-Gauss-Bonnet theory are also constructed in six spacetime dimensions.Comment: 33 pages, 11 figure
Abnormalities in Osteoclastogenesis and Decreased Tumorigenesis in Mice Deficient for Ovarian Cancer G Protein-Coupled Receptor 1
Ovarian cancer G protein-coupled receptor 1 (OGR1) has been shown to be a proton sensing receptor in vitro. We have shown that OGR1 functions as a tumor metastasis suppressor gene when it is over-expressed in human prostate cancer cells in vivo. To examine the physiological functions of OGR1, we generated conditional OGR1 deficient mice by homologous recombination. OGR1 deficient mice were viable and upon gross-inspection appeared normal. Consistent with in vitro studies showing that OGR1 is involved in osteoclastogenesis, reduced osteoclasts were detected in OGR1 deficient mice. A pH-dependent osteoclasts survival effect was also observed. However, overall abnormality in the bones of these animals was not observed. In addition, melanoma cell tumorigenesis was significantly inhibited in OGR1 deficient mice. OGR1 deficient mice in the mixed background produced significantly less peritoneal macrophages when stimulated with thioglycolate. These macrophages also showed altered extracellular signal-regulated kinases (ERK) activation and nitric oxide (NO) production in response to lipopolysaccharide. OGR1-dependent pH responses assessed by cAMP production and cell survival in macrophages or brown fat cells were not observed, presumably due to the presence of other proton sensing receptors in these cells. Our results indicate that OGR1's role in osteoclastogenesis is not strong enough to affect overall bone development and its role in tumorigenesis warrants further investigation. The mice generated can be potentially used for several disease models, including cancers or osteoclast-related diseases
Rotating black holes with equal-magnitude angular momenta in d=5 Einstein-Gauss-Bonnet theory
We construct rotating black hole solutions in Einstein-Gauss-Bonnet theory in
five spacetime dimensions. These black holes are asymptotically flat, and
possess a regular horizon of spherical topology and two equal-magnitude angular
momenta associated with two distinct planes of rotation. The action and global
charges of the solutions are obtained by using the quasilocal formalism with
boundary counterterms generalized for the case of Einstein-Gauss-Bonnet theory.
We discuss the general properties of these black holes and study their
dependence on the Gauss-Bonnet coupling constant . We argue that most
of the properties of the configurations are not affected by the higher
derivative terms. For fixed the set of black hole solutions terminates
at an extremal black hole with a regular horizon, where the Hawking temperature
vanishes and the angular momenta attain their extremal values. The domain of
existence of regular black hole solutions is studied. The near horizon geometry
of the extremal solutions is determined by employing the entropy function
formalism.Comment: 25 pages, 7 figure
Magnetothermodynamics of BPS baby skyrmions
The magnetothermodynamics of skyrmion type matter described by the gauged BPS
baby Skyrme model at zero temperature is investigated. We prove that the BPS
property of the model is preserved also for boundary conditions corresponding
to an asymptotically constant magnetic field. The BPS bound and the
corresponding BPS equations saturating the bound are found. Further, we show
that one may introduce pressure in the gauged model by a redefinition of the
superpotential. Interestingly, this is related to non-extremal type solutions
in the so-called fake supersymmetry method. Finally, we compute the equation of
state of magnetized BSP baby skyrmions inserted into an external constant
magnetic field and under external pressure , i.e., , where
is the "volume" (area) occupied by the skyrmions. We show that the BPS baby
skyrmions form a ferromagnetic medium.Comment: Latex, 39 pages, 14 figures. v2: New results and references added,
physical interpretation partly change
Inhibition of fatty acid metabolism ameliorates disease activity in an animal model of multiple sclerosis
Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system and a leading cause of neurological disability. The complex immunopathology and variable disease course of multiple sclerosis have limited effective treatment of all patients. Altering the metabolism of immune cells may be an attractive strategy to modify their function during autoimmunity. We examined the effect of inhibiting fatty acid metabolism in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Mice treated with an inhibitor of carnitine palmitoyltransferase 1 (CPT-1), the rate-limiting enzyme in the beta-oxidation of fatty acids, showed a reduction in disease severity as well as less inflammation and demyelination. Inhibition of CPT-1 in encephalitogenic T-cells resulted in increased apoptosis and reduced inflammatory cytokine production. These results suggest that disruption of fatty acid metabolism promotes downregulation of inflammation in the CNS and that this metabolic pathway is a potential therapeutic target for multiple sclerosis
Skyrmions, Skyrme stars and black holes with Skyrme hair in five spacetime dimension
We consider a class of generalizations of the Skyrme model to five spacetime dimensions (d = 5), which is de fined in terms of an O (5) sigma model. A special ansatz for the Skyrme field allows angular momentum to be present and equations of motion with a radial dependence only. Using it, we obtain: 1) everywhere regular solutions describing localised energy lumps (Skyrmions); 2) Self-gravitating, asymptotically flat, everywhere non-singular solitonic solutions (Skyrme stars), upon minimally coupling the model to Einstein's gravity; 3) both static and spinning black holes with Skyrme hair, the latter with rotation in two orthogonal planes, with both angular momenta of equal magnitude. In the absence of gravity we present an analytic solution that satisfies a BPS-type bound and explore numerically some of the non-BPS solutions. In the presence of gravity, we contrast the solutions to this model with solutions to a complex scalar field model, namely boson stars and black holes with synchronised hair. Remarkably, even though the two models present key differences, and in particular the Skyrme model allows static hairy black holes, when introducing rotation, the synchronisation condition becomes mandatory, providing further evidence for its generality in obtaining rotating hairy black holes
Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV
The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of âs = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pTâ„20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60â€pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2â€{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration
Measurement of the cross-section of high transverse momentum vector bosons reconstructed as single jets and studies of jet substructure in pp collisions at âs = 7 TeV with the ATLAS detector
This paper presents a measurement of the cross-section for high transverse momentum W and Z bosons produced in pp collisions and decaying to all-hadronic final states. The data used in the analysis were recorded by the ATLAS detector at the CERN Large Hadron Collider at a centre-of-mass energy of âs = 7 TeV;{\rm Te}{\rm V}4.6\;{\rm f}{{{\rm b}}^{-1}}{{p}_{{\rm T}}}\gt 320\;{\rm Ge}{\rm V}|\eta |\lt 1.9{{\sigma }_{W+Z}}=8.5\pm 1.7$ pb and is compared to next-to-leading-order calculations. The selected events are further used to study jet grooming techniques
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