Photoactivation of lysosomally sequestered sunitinib after angiostatic treatment causes vascular occlusion and enhances tumor growth inhibition

The angiogenesis inhibitor sunitinib is a tyrosine kinase inhibitor that acts mainly on the VEGF and PDGF pathways. We have previously shown that sunitinib is sequestered in the lysosomes of exposed tumor and endothelial cells. This phenomenon is part of the drug-induced resistance observed in the clinic. Here, we demonstrate that when exposed to light, sequestered sunitinib causes immediate destruction of the lysosomes, resulting in the release of sunitinib and cell death. We hypothesized that this photoactivation of sunitinib could be used as a vaso-occlusive vascular-targeting approach to treating cancer. Spectral properties of sunitinib and its lysosomal accumulation were measured in vitro. The human A2780 ovarian carcinoma transplanted onto the chicken chorioallantoic membrane (CAM) and the Colo-26 colorectal carcinoma model in Balb/c mice were used to test the effects of administrating sunitinib and subsequently exposing tumor tissue to light. Tumors were subsequently resected and subject to immunohistochemical analysis. In A2780 ovarian carcinoma tumors, treatment with sunitinib+light resulted in immediate specific angio-occlusion, leading to a necrotic tumor mass 24 h after treatment. Tumor growth was inhibited by 70% as compared with the control group (**P= 4; P = 0.0002). Histology revealed that photoactivation of sunitinib resulted in a change in tumor vessel architecture. The current results suggest that the spectral properties of sunitinib can be exploited for application against certain cancer indications

Submillimeter to centimeter excess emission from the Magellanic Clouds. II. On the nature of the excess

Dust emission at submm to cm wavelengths is often simply the Rayleigh-Jeans tail of dust particles at thermal equilibrium and is used as a cold mass tracer in various environments including nearby galaxies. However, well-sampled spectral energy distributions of the nearby, star-forming Magellanic Clouds have a pronounced (sub-)millimeter excess (Israel et al., 2010). This study attempts to confirm the existence of such a millimeter excess above expected dust, free-free and synchrotron emission and to explore different possibilities for its origin. We model NIR to radio spectral energy distributions of the Magellanic Clouds with dust, free-free and synchrotron emission. A millimeter excess emission is confirmed above these components and its spectral shape and intensity are analysed in light of different scenarios: very cold dust, Cosmic Microwave Background (CMB) fluctuations, a change of the dust spectral index and spinning dust emission. We show that very cold dust or CMB fluctuations are very unlikely explanations for the observed excess in these two galaxies. The excess in the LMC can be satisfactorily explained either by a change of the spectral index due to intrinsic properties of amorphous grains, or by spinning dust emission. In the SMC however, due to the importance of the excess, the dust grain model including TLS/DCD effects cannot reproduce the observed emission in a simple way. A possible solution was achieved with spinning dust emission, but many assumptions on the physical state of the interstellar medium had to be made. Further studies, using higher resolution data from Planck and Herschel, are needed to probe the origin of this observed submm-cm excess more definitely. Our study shows that the different possible origins will be best distinguished where the excess is the highest, as is the case in the SMC.Comment: 7 pages, 6 figures; accepted in A&

Planetary Detection Efficiency of the Magnification 3000 Microlensing Event OGLE-2004-BLG-343

OGLE-2004-BLG-343 was a microlensing event with peak magnification A_{max}=3000+/-1100, by far the highest-magnification event ever analyzed and hence potentially extremely sensitive to planets orbiting the lens star. Due to human error, intensive monitoring did not begin until 43 minutes after peak, at which point the magnification had fallen to A~1200, still by far the highest ever observed. As the light curve does not show significant deviations due to a planet, we place upper limits on the presence of such planets by extending the method of Yoo et al. (2004b), which combines light-curve analysis with priors from a Galactic model of the source and lens populations, to take account of finite-source effects. This is the first event so analyzed for which finite-source effects are important, and hence we develop two new techniques for evaluating these effects. Somewhat surprisingly, we find that OGLE-2004-BLG-343 is no more sensitive to planets than two previously analyzed events with A_{max}~100, despite the fact that it was observed at ~12 times higher magnification. However, we show that had the event been observed over its peak, it would have been sensitive to almost all Neptune-mass planets over a factor of 5 of projected separation and even would have had some sensitivity to Earth-mass planets. This shows that some microlensing events being detected in current experiments are sensitive to very low-mass planets. We also give suggestions on how extremely high-magnification events can be more promptly monitored in the future.Comment: 50 pages, 13 figures, published in The Astrophysical Journa

Functional Regeneration of Supraspinal Connections in a Patient With Transected Spinal Cord Following Transplantation of Bulbar Olfactory Ensheathing Cells With Peripheral Nerve Bridging

Treatment of patients sustaining a complete spinal cord injury remains an unsolved clinical problem because of the lack of spontaneous regeneration of injured central axons. A 38-year-old man sustained traumatic transection of the thoracic spinal cord at upper vertebral level Th9. At 21 months after injury, the patient presented symptoms of a clinically complete spinal cord injury (American Spinal Injury Association class A-ASIA A). One of the patient's olfactory bulbs was removed and used to derive a culture containing olfactory ensheathing cells and olfactory nerve fibroblasts. Following resection of the glial scar, the cultured cells were transplanted into the spinal cord stumps above and below the injury and the 8-mm gap bridged by four strips of autologous sural nerve. The patient underwent an intense pre- and postoperative neurorehabilitation program. No adverse effects were seen at 19 months postoperatively, and unexpectedly, the removal of the olfactory bulb did not lead to persistent unilateral anosmia. The patient improved from ASIA A to ASIA C. There was improved trunk stability, partial recovery of the voluntary movements of the lower extremities, and an increase of the muscle mass in the left thigh, as well as partial recovery of superficial and deep sensation. There was also some indication of improved visceral sensation and improved vascular autoregulation in the left lower limb. The pattern of recovery suggests functional regeneration of both efferent and afferent long-distance fibers. Imaging confirmed that the grafts had bridged the left side of the spinal cord, where the majority of the nerve grafts were implanted, and neurophysiological examinations confirmed the restitution of the integrity of the corticospinal tracts and the voluntary character of recorded muscle contractions. To our knowledge, this is the first clinical indication of the beneficial effects of transplanted autologous bulbar cells

A Jovian-mass Planet in Microlensing Event OGLE-2005-BLG-071

We report the discovery of a several-Jupiter mass planetary companion to the primary lens star in microlensing event OGLE-2005-BLG-071. Precise (<1%) photometry at the peak of the event yields an extremely high signal-to-noise ratio detection of a deviation from the light curve expected from an isolated lens. The planetary character of this deviation is easily and unambiguously discernible from the gross features of the light curve. Detailed modeling yields a tightly-constrained planet-star mass ratio of q=m_p/M=0.0071+/-0.0003. This is the second robust detection of a planet with microlensing, demonstrating that the technique itself is viable and that planets are not rare in the systems probed by microlensing, which typically lie several kpc toward the Galactic center.Comment: 4 pages. Minor changes. Accepted for publication in ApJ Letter

A novel D2O tracer method to quantify RNA turnover as a biomarker of de novo ribosomal biogenesis, in vitro, in animal models, and in human skeletal muscle

Current methods to quantify in vivo RNA dynamics are limited. Here, we developed a novel stable isotope (D2O) methodology to quantify RNA synthesis (i.e., ribosomal biogenesis) in cells, animal models, and humans. First, proliferating C2C12 cells were incubated in D2O-enriched media and myotubes ±50 ng/ml IGF-I. Second, rat quadriceps (untrained, n = 9; 7-wk interval-“like” training, n = 13) were collected after ~3-wk D2O (70 atom %) administration, with body-water enrichment monitored via blood sampling. Finally, 10 (23 ± 1 yr) men consumed 150-ml D2O followed by 50 ml/wk and undertook 6-wk resistance exercise (6 × 8 repetitions, 75% 1-repetition maximum 3/wk) with body-water enrichment monitored by saliva sampling and muscle biopsies (for determination of RNA synthesis) at 0, 3, and 6 wk. Ribose mole percent excess (r-MPE) from purine nucleotides was analyzed via GC-MS/MS. Proliferating C2C12 cell r-MPE exhibited a rise to plateau, whereas IGF-I increased myotube RNA from 76 ± 3 to 123 ± 3 ng/μl and r-MPE by 0.39 ± 0.1% (both P < 0.01). After 3 wk, rat quadriceps r-MPE had increased to 0.25 ± 0.01% (P < 0.01) and was greater with running exercise (0.36 ± 0.02%; P < 0.01). Human muscle r-MPE increased to 0.06 ± 0.01 and 0.13 ± 0.02% at 3/6 wk, respectively, equating to synthesis rates of ~0.8%/day, increasing with resistance exercise to 1.7 ± 0.3%/day (P < 0.01) and 1.2 ± 0.1%/day (P < 0.05) at 3/6 wk, respectively. Therefore, we have developed and physiologically validated a novel technique to explore ribosomal biogenesis in a multimodal fashion

Microlens OGLE-2005-BLG-169 Implies Cool Neptune-Like Planets are Common

We detect a Neptune mass-ratio (q~8e-5) planetary companion to the lens star in the extremely high-magnification (A~800) microlensing event OGLE-2005-BLG-169. If the parent is a main-sequence star, it has mass M~0.5 M_sun implying a planet mass of ~13 M_earth and projected separation of ~2.7 AU. When intensely monitored over their peak, high-magnification events similar to OGLE-2005-BLG-169 have nearly complete sensitivity to Neptune mass-ratio planets with projected separations of 0.6 to 1.6 Einstein radii, corresponding to 1.6--4.3 AU in the present case. Only two other such events were monitored well enough to detect Neptunes, and so this detection by itself suggests that Neptune mass-ratio planets are common. Moreover, another Neptune was recently discovered at a similar distance from its parent star in a low-magnification event, which are more common but are individually much less sensitive to planets. Combining the two detections yields 90% upper and lower frequency limits f=0.37^{+0.30}_{-0.21} over just 0.4 decades of planet-star separation. In particular, f>16% at 90% confidence. The parent star hosts no Jupiter-mass companions with projected separations within a factor 5 of that of the detected planet. The lens-source relative proper motion is \mu~7--10 mas/yr, implying that if the lens is sufficiently bright, I<23.8, it will be detectable by HST by 3 years after peak. This would permit a more precise estimate of the lens mass and distance, and so the mass and projected separation of the planet. Analogs of OGLE-2005-BLG-169Lb orbiting nearby stars would be difficult to detect by other methods of planet detection, including radial velocities, transits, or astrometry.Comment: Submitted to ApJ Letters, 9 text pages + 4 figures + 1 tabl

A Low-Mass Planet with a Possible Sub-Stellar-Mass Host in Microlensing Event MOA-2007-BLG-192

We report the detection of an extrasolar planet of mass ratio q ~ 2 x 10^(-4) in microlensing event MOA-2007-BLG-192. The best fit microlensing model shows both the microlensing parallax and finite source effects, and these can be combined to obtain the lens masses of M = 0.060 (+0.028 -0.021) M_sun for the primary and m = 3.3 (+4.9 -1.6) M_earth for the planet. However, the observational coverage of the planetary deviation is sparse and incomplete, and the radius of the source was estimated without the benefit of a source star color measurement. As a result, the 2-sigma limits on the mass ratio and finite source measurements are weak. Nevertheless, the microlensing parallax signal clearly favors a sub-stellar mass planetary host, and the measurement of finite source effects in the light curve supports this conclusion. Adaptive optics images taken with the Very Large Telescope (VLT) NACO instrument are consistent with a lens star that is either a brown dwarf or a star at the bottom of the main sequence. Follow-up VLT and/or Hubble Space Telescope (HST) observations will either confirm that the primary is a brown dwarf or detect the low-mass lens star and enable a precise determination of its mass. In either case, the lens star, MOA-2007-BLG-192L, is the lowest mass primary known to have a companion with a planetary mass ratio, and the planet, MOA-2007-BLG-192Lb, is probably the lowest mass exoplanet found to date, aside from the lowest mass pulsar planet.Comment: Accepted for publication in the Astrophysical Journal. Scheduled for the Sept. 1, 2008 issu