Synthesis and pre-clinical evaluation of a [18F] fluoromethyl-tanaproget derivative for imaging of progesterone receptor expression

The estrogen receptor (ER) and progesterone receptor (PR) are over-expressed in ∼50% of breast cancer lesions, and used as biomarkers to stratify patients for endocrine therapy. Currently, immunohistochemical (IHC) assessment of these lesions from a core-needle biopsy in deep-sited metastases has limitations associated with sampling error and lack of standardization. An alternative solution is positron emission tomography (PET)-based probes, which are inherently quantitative and capable of imaging the entire tumor, including metastases. This work features the synthesis and biological evaluation of a novel fluorinated derivative of tanaproget, a high affinity non-steroidal PR ligand, as a candidate for imaging PR expression in vivo. Radiolabeling of the candidate was achieved in a 15% ± 4 radiochemical yield (non-decay corrected) in one step from [18F]fluoromethyltosylate in 30 min. Cell uptake studies showed a significant difference between the radioligand uptake in PR+ and PR- cell lines; however, in vivo imaging was confounded by defluorination hypothesized to occur via iminium salt formation. Investigation into high affinity, metabolically stable non-steroidal PR ligands is currently ongoing

Mobility Disability in Older Adults: At the Intersection of People and Places

Mobility disability is associated with poor lower body function among older adults. This study examines whether specific types of neighborhood characteristics moderate that association

Flux-Line Lattice Structures in Untwinned YBa2Cu3O

A small angle neutron scattering study of the flux-line lattice in a large single crystal of untwinned YBa2Cu3O is presented. In fields parallel to the c-axis, diffraction spots are observed corresponding to four orientations of a hexagonal lattice, distorted by the a-b anisotropy. A value for the anisotropy, the penetration depth ratio, of 1.18(2) was obtained. The high quality of the data is such that second order diffraction is observed, indicating a well ordered FLL. With the field at 33 degrees to c a field dependent re-orientation of the lattice is observed around 3T.Comment: 4 pages, 4 figure

Ground State Vortex Lattice Structures in d-wave Superconductors

We show in a realistic $d_{x^{2}-y^{2}}$ symmetry gap model for a cuprate superconductor that the clean vortex lattice has discontinuous structural transitions (at and near T=0), as a function of the magnetic field $B$ along the c-axis. The transitions arise from the singular nonlocal and anisotropic susceptibility of the $d_{x^{2}-y^{2}}$ superconductor to the perturbation caused by supercurrents associated with vortices. The susceptibility, due to virtual Dirac quasiparticle-hole excitation, is calculated carefully, and leads to a ground state transition for the triangular lattice from an orientation along one of the crystal axis to one at 45$^o$ to them, i.e, along the gap zero direction. The field scale is seen to be 5 Tesla $\sim (\Delta_{0}/ta)^{2}\Phi_{0}$, where $\Delta_{0}$ is the gap maximum, $t$ is the nearest neighbour hopping, $a$ is the lattice constant, and $\Phi_{0}$ is the flux quantum. At much higher fields ($\sim 28T$) there is a discontinuous transition to a centred square structure. The source of the differences from existing calculations, and experimental observability are discussed, the latter especially in view of the very small (a few degrees $K$ per vortex) differences in the ground state energy.Comment: To be published in Phys. Rev.

Effect of pathology type and severity on the distribution of MRI signal intensities within the degenerated nucleus pulposus: application to idiopathic scoliosis and spondylolisthesis

<p>Abstract</p> <p>Background</p> <p>Disc degeneration is characterized by a loss of cellularity, degradation of the extracellular matrix, and, as a result, morphological changes and biomechanical alterations. We hypothesized that the distribution of the MR signal intensity within the nucleus zone of the intervertebral disc was modified according to the pathology and the severity of the pathology. The objective of this study was to propose new parameters characterizing the distribution of the signal intensity within the nucleus zone of lumbar intervertebral discs, and to quantify these changes in patients suffering from spondylolisthesis or idiopathic scoliosis.</p> <p>Methods</p> <p>A retrospective study had been performed on T2-weighted MR images of twenty nine patients suffering from spondylolisthesis and/or scoliosis. The high intensity zone of the nucleus pulposus was semi-automatically detected. The distance "DX" between the center weighted by the signal intensity and the geometrical center was quantified. The sum of the signal intensity on the axis perpendicular to the longitudinal axis of the disc was plotted for each position of the longitudinal axis allowing defining the maximum sum "SM" and its position "PSM".</p> <p>Results</p> <p>"SM" was clearly higher and "PSM" was more shifted for scoliosis than for spondylolisthesis. A two-way analysis of variance showed that the differences observed on "DX" were not attributed to the pathology nor its severity, the differences observed on "SM" were attributed to the pathology but not to its severity, and the differences observed on "PSM" were attributed to both the pathology and its severity.</p> <p>Conclusions</p> <p>The technique proposed in this study showed significant differences in the distribution of the MR signal intensity within the nucleus zone of intervertebral discs due to the pathology and its severity. The dependence of the "PSM" parameter to the severity of the pathology suggests this parameter as a predictive factor of the pathology progression. This new technique should be useful for the early diagnosis of intervertebral disc pathologies as it highlights abnormal patterns in the MRI signal for low severity of the pathology.</p

Genetic factors associated with patient-specific warfarin dose in ethnic Indonesians

<p>Abstract</p> <p>Background</p> <p><it>CYP2C9 </it>and <it>VKORC1 </it>are two major genetic factors associated with inter-individual variability in warfarin dose. Additionally, genes in the warfarin metabolism pathway have also been associated with dose variance. We analyzed Single Nucleotide Polymorphisms (SNPs) in these genes to identify genetic factors that might confer warfarin sensitivity in Indonesian patients.</p> <p>Methods</p> <p>Direct sequencing method was used to identify SNPs in <it>CYP2C9, VKORC1, CYP4F2, EPHX1, PROC </it>and <it>GGCX </it>genes in warfarin-treated patients. Multiple linear regressions were performed to model the relationship warfarin daily dose requirement with genetic and non-genetic variables measured and used to develop a novel algorithm for warfarin dosing.</p> <p>Results</p> <p>From the 40 SNPs analyzed, <it>CYP2C9 </it>rs17847036 and <it>VKORC1 </it>rs9923231 showed significant association with warfarin sensitivity. In our study population, no significant correlation could be detected between <it>CYP2C9*3, CYP2C9C</it>-65 (rs9332127), <it>CYP4F2 </it>rs2108622, <it>GGCX </it>rs12714145, <it>EPHX1 </it>rs4653436 and <it>PROC </it>rs1799809 with warfarin sensitivity.</p> <p>Conclusions</p> <p><it>VKORC1 </it>rs9923231 AA and <it>CYP2C9 </it>rs17847036 GG genotypes were associated with low dosage requirements of most patients (2.05 ± 0.77 mg/day and 2.09 ± 0.70 mg/day, respectively). <it>CYP2C9 </it>and <it>VKORC1 </it>genetic variants as well as non-genetic factors such as age, body weight and body height account for 15.4% of variance in warfarin dose among our study population. Additional analysis of this combination could allow for personalized warfarin treatment in ethnic Indonesians.</p