Selective targeting of IL-2 to NKG2D bearing cells for improved immunotherapy

Despite over 20 years of clinical use, IL-2 has not fulfilled expectations as a safe and effective form of tumour immunotherapy. Expression of the high affinity IL-2Rα chain on regulatory T cells mitigates the anti-tumour immune response and its expression on vascular endothelium is responsible for life threatening complications such as diffuse capillary leak and pulmonary oedema. Here we describe the development of a recombinant fusion protein comprised of a cowpox virus encoded NKG2D binding protein (OMCP) and a mutated form of IL-2 with poor affinity for IL-2Rα. This fusion protein (OMCP-mutIL-2) potently and selectively activates IL-2 signalling only on NKG2D-bearing cells, such as natural killer (NK) cells, without broadly activating IL-2Rα-bearing cells. OMCP-mutIL-2 provides superior tumour control in several mouse models of malignancy and is not limited by mouse strain-specific variability of NK function. In addition, OMCP-mutIL-2 lacks the toxicity and vascular complications associated with parental wild-type IL-2

'Round the Clock Observations of the Q0957+561 A,B Gravitationally Lensed Quasar

An observing campaign with 10 participating observatories has undertaken to monitor the optical brightness of the Q0957 gravitationally lensed quasar for 10 consecutive nights in January 2000. The resulting A image brightness curve has significant brightness fluctuations and makes a photometric prediction for the B image light curve for a second campaign planned for 12-21 March 2001. The ultimate purpose is to determine the gravitational lens time delay to a fraction of an hour, and to seek evidence for rapid microlensing.Comment: 8 pages, AASTeX 4.0, accepted by the Astrophysical Journa

Spatially hybrid computations for streamer discharges: II. Fully 3D simulations

We recently have presented first physical predictions of a spatially hybrid model that follows the evolution of a negative streamer discharge in full three spatial dimensions; our spatially hybrid model couples a particle model in the high field region ahead of the streamer with a fluid model in the streamer interior where electron densities are high and fields are low. Therefore the model is computationally efficient, while it also follows the dynamics of single electrons including their possible run-away. Here we describe the technical details of our computations, and present the next step in a systematic development of the simulation code. First, new sets of transport coefficients and reaction rates are obtained from particle swarm simulations in air, nitrogen, oxygen and argon. These coefficients are implemented in an extended fluid model to make the fluid approximation as consistent as possible with the particle model, and to avoid discontinuities at the interface between fluid and particle regions. Then two splitting methods are introduced and compared for the location and motion of the fluid-particle-interface in three spatial dimensions. Finally, we present first results of the 3D spatially hybrid model for a negative streamer in air

Permafrost is warming at a global scale

Permafrost warming has the potential to amplify global climate change, because when frozen sediments thaw it unlocks soil organic carbon. Yet to date, no globally consistent assessment of permafrost temperature change has been compiled. Here we use a global data set of permafrost temperature time series from the Global Terrestrial Network for Permafrost to evaluate temperature change across permafrost regions for the period since the International Polar Year (2007-2009). During the reference decade between 2007 and 2016, ground temperature near the depth of zero annual amplitude in the continuous permafrost zone increased by 0.39 ± 0.15 °C. Over the same period, discontinuous permafrost warmed by 0.20 ± 0.10 °C. Permafrost in mountains warmed by 0.19 ± 0.05 °C and in Antarctica by 0.37 ± 0.10 °C. Globally, permafrost temperature increased by 0.29 ± 0.12 °C. The observed trend follows the Arctic amplification of air temperature increase in the Northern Hemisphere. In the discontinuous zone, however, ground warming occurred due to increased snow thickness while air temperature remained statistically unchanged

Very Late Antigen-4 (α<inf>4</inf>β<inf>1</inf> Integrin) Targeted PET Imaging of Multiple Myeloma

Biomedical imaging techniques such as skeletal survey and 18F-fluorodeoxyglucose (FDG)/Positron Emission Tomography (PET) are frequently used to diagnose and stage multiple myeloma (MM) patients. However, skeletal survey has limited sensitivity as it can detect osteolytic lesions only after 30-50% cortical bone destruction, and FDG is a marker of cell metabolism that has limited sensitivity for intramedullary lesions in MM. Targeted, and non-invasive novel probes are needed to sensitively and selectively image the unique molecular signatures and cellular processes associated with MM. Very late antigen-4 (VLA-4; also called α4β1 integrin) is over-expressed on MM cells, and is one of the key mediators of myeloma cell adhesion to the bone marrow (BM) that promotes MM cell trafficking and drug resistance. Here we describe a proof-of-principle, novel molecular imaging strategy for MM tumors using a VLA-4 targeted PET radiopharmaceutical, 64Cu-CB-TE1A1P-LLP2A. Cell uptake studies in a VLA-4-positive murine MM cell line, 5TGM1, demonstrated receptor specific uptake (P<0.0001, block vs. non-block). Tissue biodistribution at 2 h of 64Cu-CB-TE1A1P-LLP2A in 5TGM1 tumor bearing syngeneic KaLwRij mice demonstrated high radiotracer uptake in the tumor (12±4.5%ID/g), and in the VLA-4 rich organs, spleen (8.8±1.0%ID/g) and marrow (11.6±2.0%ID/g). Small animal PET/CT imaging with 64Cu-CB-TE1A1P-LLP2A demonstrated high uptake in the 5TGM1 tumors (SUV 6.6±1.1). There was a 3-fold reduction in the in vivo tumor uptake in the presence of blocking agent (2.3±0.4). Additionally, 64Cu-CB-TE1A1P-LLP2A demonstrated high binding to the human MM cell line RPMI-8226 that was significantly reduced in the presence of the cold targeting agent. These results provide pre-clinical evidence that VLA-4-targeted imaging using 64Cu-CB-TE1A1P-LLP2A is a novel approach to imaging MM tumors. © 2013 Soodgupta et al

Preclinical Positron Emission Tomographic Imaging of Acute Hyperoxia Therapy of Chronic Hypoxia during Pregnancy

The goal of this work was to study the efficacy of the positron emission tomography (PET) tracers 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) and 64 Cu-diacetyl-bis(N4-methylthiosemicarbazone) ([ 64 Cu]ATSM) and in monitoring placental and fetal functional response to acute hyperoxia in late-term pregnant mice subjected to experimentally induced chronic hypoxia. E15 mice were maintained at 12% inspired oxygen for 72 hours and then imaged during oxygen inhalation with either [ 18 F]FDG to monitor nutrient transport or 64 Cu-ATSM to establish the presence of hypoxia. Computed tomography (CT) with contrast allowed clear visualization of both placentas and fetuses. The average ratio of fetal to placental [ 18 F]FDG uptake was 0.45 ± 0.1 for the hypoxic animals and 0.55 ± 0.1 for the normoxic animals, demonstrating a significant decrease ( p = .0002) in placental function in dams exposed to chronic hypoxic conditions. Hypoxic placentas and fetuses retained more 64 Cu-ATSM compared to normoxic placentas and fetuses. Herein we report first-in-mouse PET imaging of fetuses employing both tracers [ 18 F]FDG (metabolism) and 64 Cu-ATSM (hypoxia). [ 18 F]FDG PET/CT imaging allowed clear visualization of placental-fetal structures and supported quantification of tracer uptake, making this a sensitive tool for monitoring placental function in preclinical rodent models. These measurements illustrate the potentially irreversible damage generated by chronic exposure to hypoxia, which cannot be corrected by acute exposure to hyperoxia

Imaging of CD47 Expression in Xenograft and Allograft Tumor Models

CD47 functions as a marker of “self” by inhibiting phagocytosis of autologous cells. CD47 has been shown to be overexpressed by various tumor types as a means of escaping the antitumor immune response. The goal of this research was to investigate the utility of CD47 imaging using positron emission tomography (PET) in both human xenograft and murine allograft tumor models. Anti-CD47 antibodies were conjugated with p -isothiocyanatobenzyldesferrioxamine (Df-Bz-NCS) and labeled with 89 Zr. We employed xenograft and allograft small-animal models of cancer in biodistribution and PET imaging studies to investigate the specificity and PET imaging robustness of CD47. Ab-Df-Bz-NCS conjugates were labeled with 89 Zr with specific activity of 0.9 to 1.6 μCi/μg. Biodistribution studies in the xenograft and allograft model showed similar specific tumor uptake of the antihuman and antimouse CD47 antibodies. However, the tracer retention in the liver, spleen, and kidneys was significantly higher in the allograft-bearing animals, suggesting uptake mediated by the CD47 normally expressed throughout the reticular endothelial system. CD47, a marker of “self,” was evaluated as a diagnostic PET biomarker in xenograft and allograft cancer animal models. CD47 imaging is feasible, warranting further studies and immunoPET tracer development