Antitumor Activity of VB-111, a Novel Antiangiogenic Virotherapeutic, in Thyroid Cancer Xenograft Mouse Models

VB-111 is an engineered antiangiogenic adenovirus that expresses Fas-c in angiogenic blood vessels and has previously been shown to have significant antitumor activity in vitro and in vivo in Lewis lung carcinoma, melanoma, and glioblastoma models. To evaluate the efficacy of VB-111 in thyroid cancer, we conducted in vivo xenograft nude mouse studies using multiple thyroid cancer-derived cell lines models. VB-111 treatment resulted in 26.6% (P = 0.0596), 34.4% (P = 0.0046), and 37.6% (P = 0.0249) inhibition of tumor growth in follicular, papillary and anaplastic thyroid cancer models, respectively. No toxicity was observed in any model. All tumor types showed a consistent and significant reduction of CD-31 staining (P < 0.05), reflecting a reduction of angiogenic activity in the tumors, consistent with the intended targeting of the virus. A phase 2 clinical trial of VB-111 in patients with advanced differentiated thyroid cancer is ongoing

Unique cellular and mitochondrial defects mediate FK506-induced islet β-cell dysfunction

OBJECTIVE: Determine biological mechanisms involved in post transplantation diabetes mellitus caused by the immunosuppressant FK506. METHODS: INS-1 cells and isolated rat islets were incubated with vehicle or FK506 and harvested at 24 hr intervals. Cells were assessed for viability, apoptosis, proliferation, cell insulin secretion and content. Gene expression studies by microarray analysis, qPCR and motifADE analysis of the microarray data identified potential FK506-mediated pathways and regulatory motifs. Mitochondrial functions, including cell respiration, mitochondrial content and bioenergetics were assessed. RESULTS: Cell replication, viability, insulin secretion, oxygen consumption, and mitochondrial content were decreased (p < 0.05) 1.2-, 1.27-, 1.77-, 1.32-, and 1.43-fold, respectively after 48 hr FK506 treatment. Differences increased with time. FK506 (50 ng/ml) and Cyclosporine A (800 ng/ml) had comparable effects. FK 506 significantly decreased mitochondrial content and mitochondrial bioenergetics and showed a trend towards decreased oxygen consumption in isolated islets. Cell apoptosis and proliferation, mitochondrial DNA copy number and ATP/ADP ratios were not significantly affected. Pathway analysis of microarray data showed FK506 modification of pathways involving ATP metabolism, membrane trafficking and cytoskeleton remodeling. PGC1-α mRNA was down-regulated by FK506. MotifADE identified nuclear factor of activated T-cells (NFAT), an important mediator of β cell survival and function, as a potential factor mediating both up- and down-regulation of gene expression. CONCLUSIONS: At pharmacologically relevant concentrations FK506 decreases insulin secretion and reduces mitochondrial density and function without changing apoptosis rates, suggesting that post transplantation diabetes induced by FK506 may be mediated by its effects on mitochondrial function

The X/Ka Celestial Reference Frame

International audienceAn X/Ka-band (8.4/32 GHz) celestial reference frame has been constructed using single baselines from the combined NASA and ESA Deep Space Networks for approximately 100 sessions each of ∼24-hour duration. The frame solution has dramatically improved with respect to the last reported frame due to the inclusion of Southern NASA-ESA baselines, routine 2-Gbps data rates, and correction of instrumental delays by recently deployed Ka-band phase calibration tones. Comparisons with the S/X-band (2.3/8.4 GHz) ICRF-2 reference frame will be presented showing increasing agreement for 525 common sources. About 135 sources are located in the south polar cap (δ < −45◦) which became accessible for first time with the addition of the ESA station in Malargüe, Argentina to our project’s network. There is evidence for systematic errors at the 100 μas level. The known sources of error will be discussed.Frame tie precision with Gaia has been estimated in about ±7 μas (1-σ, per 3-D rotation com- ponent) using measured X/Ka position uncertainties and simulated Gaia uncertainties. Compared to X-band, Ka-band allows access to more compact radio source morphology and reduced core shift which should reduce these systematic errors compared to a tie of Gaia to S/X-band VLBI. However, there is a great deal of uncertainty in the offset between optical and radio centroids from effects such as optical host galaxy asymmetry which may ultimately limit the frame tie accuracy

ASTRA: Interdisciplinary study on enhancement of the end-to-end accuracy for spacecraft tracking techniques

Navigation of deep-space probes is accomplished through a variety of different radio observables, namely Doppler, ranging and Delta-Differential One-Way Ranging (Delta-DOR). The particular mix of observations used for navigation mainly depends on the available on-board radio system, the mission phase and orbit determination requirements. The accuracy of current ESA and NASA tracking systems is at level of 0.1 mais at 60 s integration time for Doppler, 1 to 5 m for ranging and 6 to 15 nrad for Delta-DOR measurements in a wide range of operational conditions. The ASTRA study, funded under ESA's General Studies Programme (GSP), addresses the ways to improve the end-to-end accuracy of Doppler, ranging and Delta-DOR systems by roughly a factor of 10. The target accuracies were set to 0.01 mm/s at 60 s integration time for Doppler, 20 cm for ranging and 1 nrad for Delta-DOR. The companies and universities that took part in the study were the University of Rome Sapienza, ALMASpace, BAE Systems and Thales Alenia Space Italy. The analysis of an extensive data set of radio-metric observables and dedicated tests of the ground station allowed consolidating the error budget for each measurement technique. The radio-metric data set comprises X/X, X/Ka and Ka/Ka range and Doppler observables from the Cassini and Rosetta missions. It includes also measurements from the Advanced Media Calibration System (AMCS) developed by JPL for the radio science experiments of the Cassini mission. The error budget for the three radio-metric observables was consolidated by comparing the statistical properties of the data set with the expected error models. The analysis confirmed the contribution from some error sources, but revealed also some discrepancies and ultimately led to improved error models. The error budget reassessment provides adequate information for building guidelines and strategies to effectively improve the navigation accuracies of future deep space missions. We report both on updated error budget for radio-metric observables and the system configurations proposed for the upgrade of ESA's tracking and orbit determination systems