Improvement of biodistribution profile of a radiogallium-labeled, αvβ6 integrin-targeting peptide probe by incorporation of negatively charged amino acids

Objective Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Since αvβ6 integrin has been reported as a promising target for PDAC diagnosis, we previously developed H-Cys(mal-NOTA-67Ga)-(Gly)6-A20FMDV2-NH2 ([67Ga]CG6) as an αvβ6 integrin-targeting probe. Although [67Ga]CG6 specifically binds to αvβ6 integrin-positive xenografts, the uptake of [67Ga]CG6 in the organs surrounding the pancreas, such as the liver and spleen, was comparable to that in the αvβ6 integrin-positive xenografts. We hypothesized that the undesirable accumulation of [67Ga]CG6 in those organs was caused by the positive charges of [67Ga]CG6 (+ 3). In this study, we aimed to decrease [67Ga]CG6 uptake in the liver and spleen by reducing the electric charges of the probe. Methods We synthesized H-Cys(mal-NOTA-67Ga)-(Asp)6-A20FMDV2-NH2 ([67Ga]CD6) and evaluated its affinity to αvβ6 integrin via in vitro competitive binding assay. Isoelectric points of the probes were determined by electrophoresis. Biodistribution study, autoradiography, and immunostaining for β6 integrin were conducted using αvβ6 integrin-positive and negative tumor-bearing mice. Results In vitro competitive binding assay showed that the alteration of the linker had a negligible impact on the affinity of [67Ga]CG6 to αvβ6 integrin. The results of electrophoresis revealed that [67Ga]CG6 was positively charged whereas [67Ga]CD6 was negatively charged. In the biodistribution study, the uptake of [67Ga]CD6 in the αvβ6 integrin-positive xenografts was significantly higher than that in the αvβ6 integrin-negative ones at 60 and 120 min. The uptake of [67Ga]CD6 in the liver and spleen was more than two-fold lower than that of [67Ga]CG6 at both time points. In the immunohistochemistry study, the radioactivity accumulated areas in the autoradiogram of the αvβ6 integrin-positive xenograft roughly coincided with β6 integrin-expressing areas. Conclusion We have successfully reduced the nonspecific uptake in the liver and spleen by altering the linker amino acid from G6 to D6. [67Ga]CD6 overcame the drawbacks of [67Ga]CG6 in its biodistribution

Tracking the Complex Absorption in NGC 2110 with Two Suzaku Observations

We present spectral analysis of two Suzaku observations of the Seyfert 2 galaxy, NGC 2110. This source has been known to show complex, variable absorption which we study in depth by analyzing these two observations set seven years apart and by comparing to previously analyzed observations with the XMM-Newton and Chandra observatories. We find that there is a relatively stable, full-covering absorber with a column density of ~3$\times 10 ^{22}$ cm$^{-2}$, with an additional patchy absorber that is likely variable in both column density and covering fraction over timescales of years, consistent with clouds in a patchy torus or in the broad line region. We model a soft emission line complex, likely arising from ionized plasma and consistent with previous studies. We find no evidence for reflection from an accretion disk in this source with no contribution from relativistically broadened Fe Ka line emission nor from a Compton reflection hump.Comment: Accepted to ApJ: March, 201

Anti-cancer drugs and glutathione stimulate vanadate-induced trapping of nucleotide in multidrug resistance-associated protein (MRP)

AbstractMultidrug resistance-associated protein (MRP), a member of the ABC superfamily transporters, functions as an ATP-dependent efflux pump that extrudes cytotoxic drugs from the cells. Although glutathione has been considered to play an important role in the function of MRP, there is no convincing evidence that glutathione directly interacts with MRP. Here we demonstrate that vanadate-induced trapping of 8-azido-ATP in MRP was stimulated in the presence of glutathione, oxidized glutathione and the anti-cancer drugs VP-16 and vincristine. MRP in membrane from a human MRP cDNA transformant was specifically photolabeled with 8-azido-[α-32P]ATP by the vanadate-trapping technique. Vanadate and Mg2+ were required for trapping of nucleotides, and vanadate trapping of nucleotides was inhibited by excess ADP as well as ATP. These results suggest that a stable inhibitory complex MRP·MgADP·Vi, an analog of the MRP·MgADP·Pi transition state complex, is formed in the presence of vanadate. Glutathione as well as anti-cancer drugs would directly interact with MRP, and stimulate the formation of the transition state of the ATPase reaction of MRP

A Candidate Active Galactic Nucleus with a Pure Soft Thermal X-ray Spectrum

We report the discovery of a candidate active galactic nucleus (AGN), 2XMM J123103.2+110648 at z = 0.13, with an X-ray spectrum represented purely by soft thermal emission reminiscent of Galactic black hole (BH) binaries in the disk-dominated state. This object was found in the second XMM serendipitous source catalogue as a highly variable X-ray source. In three separate observations, its X-ray spectrum can be represented either by a multicolor disk blackbody model with an inner temperature of kT_in~0.16-0.21 keV or a Wien spectrum Comptonized by an optically thick plasma with kT~0.14-0.18 keV. The soft X-ray luminosity in the 0.5--2 keV band is estimated to be (1.6-3.8)x10^42 erg/s. Hard emission above ~2 keV is not detected. The ratio of the soft to hard emission is the strongest among AGNs observed thus far. Spectra selected in high/low flux time intervals are examined in order to study spectral variability. In the second observation with the highest signal-to-noise ratio, the low energy (below 0.7 keV) spectral regime flattens when the flux is high, while the shape of the high energy part (1-1.7 keV) remains unchanged. This behavior is qualitatively consistent with being caused by strong Comptonization. Both the strong soft excess and spectral change consistent with Comptonization in the X-ray spectrum imply that the Eddington ratio is large, which requires a small BH mass (smaller than ~10^5M_solar.Comment: To Appear in ApJ, 8 pages, 7 figure

The truncated disk from Suzaku data of GX 339-4 in the extreme very high state

We report on the geometry of accretion disk and high energy coronae in the strong Comptonization state (the very high/steep power law/hard intermediate state) based on a Suzaku observation of the famous Galactic black hole GX 339-4. These data were taken just before the peak of the 2006-2007 outburst, and the average X-ray luminosity in the 0.7-200 keV band is estimated to be 2.9E38 erg/s for a distance of 8 kpc. We fit the spectrum with both simple (independent disk and corona) and sophisticated (energetically coupled disk and corona) models, but all fits imply that the underlying optically thick disk is truncated significantly before the innermost stable circular orbit around the black hole. We show this directly by a comparison with similarly broadband data from a disk dominated spectrum at almost the same luminosity observed by XMM-Newton and RXTE 3 days after the Suzaku observation. During the Suzaku observation, the QPO frequency changes from 4.3 Hz to 5.5 Hz, while the spectrum softens. The energetically coupled model gives a corresponding 5+/- 8 % decrease in derived inner radius of the disk. While this is not significant, it is consistent with the predicted change in QPO frequency from Lense-Thirring precession of the hot flow interior to the disk and/or a deformation mode of this flow, as a higher QPO frequency implies a smaller size scale for the corona. This is consistent with the truncated disk extending further inwards towards the black hole.Comment: Accepted to ApJ, 41 pages, 9 figures, 3 table

Radial volumetric imaging breath-hold examination (VIBE) with k-space weighted image contrast (KWIC) for dynamic gadoxetic acid (Gd-EOB-DTPA)-enhanced MRI of the liver: advantages over Cartesian VIBE in the arterial phase

To compare radial volumetric imaging breath-hold examination with k-space weighted image contrast reconstruction (r-VIBE-KWIC) to Cartesian VIBE (c-VIBE) in arterial phase dynamic gadoxetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (DCE-MRI) of the liver. We reviewed 53 consecutive DCE-MRI studies performed on a 3-T unit using c-VIBE and 53 consecutive cases performed using r-VIBE-KWIC with full-frame image subset (r-VIBEfull) and sub-frame image subsets (r-VIBEsub; temporal resolution, 2.5-3 s). All arterial phase images were scored by two readers on: (1) contrast-enhancement ratio (CER) in the abdominal aorta; (2) scan timing; (3) artefacts; (4) visualisation of the common, right, and left hepatic arteries. Mean abdominal aortic CERs for c-VIBE, r-VIBEfull, and r-VIBEsub were 3.2, 4.3 and 6.5, respectively. There were significant differences between each group (P < 0.0001). The mean score for c-VIBE was significantly lower than that for r-VIBEfull and r-VIBEsub in all factors except for visualisation of the common hepatic artery (P < 0.05). The mean score of all factors except for scan timing for r-VIBEsub was not significantly different from that for r-VIBEfull. Radial VIBE-KWIC provides higher image quality than c-VIBE, and r-VIBEsub features high temporal resolution without image degradation in arterial phase DCE-MRI. aEuro cent Radial VIBE-KWIC minimised artefact and produced high-quality and high-temporal-resolution images. aEuro cent Maximum abdominal aortic enhancement was observed on sub-frame images of r-VIBE-KWIC. aEuro cent Using r-VIBE-KWIC, optimal arterial phase images were obtained in over 90 %. aEuro cent Using r-VIBE-KWIC, visualisation of the hepatic arteries was improved. aEuro cent A two-reader study revealed r-VIBE-KWIC's advantages over Cartesian VIBE.ArticleEUROPEAN RADIOLOGY. 24(6):1290-1299 (2014)journal articl