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Fadel T.R.,Yale University | Sharp F.A.,Yale University | Vudattu N.,Yale University | Ragheb R.,Yale University | And 9 more authors.
Nature Nanotechnology | Year: 2014

Clinical translation of cell therapies requires strategies that can manufacture cells efficiently and economically. One promising way to reproducibly expand T cells for cancer therapy is by attaching the stimuli for T cells onto artificial substrates with high surface area. Here, we show that a carbon nanotube-polymer composite can act as an artificial antigen-presenting cell to efficiently expand the number of T cells isolated from mice. We attach antigens onto bundled carbon nanotubes and combined this complex with polymer nanoparticles containing magnetite and the T-cell growth factor interleukin-2 (IL-2). The number of T cells obtained was comparable to clinical standards using a thousand-fold less soluble IL-2. T cells obtained from this expansion were able to delay tumour growth in a murine model for melanoma. Our results show that this composite is a useful platform for generating large numbers of cytotoxic T cells for cancer immunotherapy. © 2014 Macmillan Publishers Limited.

Hald B.O.,Blegdamsvej | Hendriksen M.G.,Universitetsparken 5 | Sorensen P.G.,Universitetsparken 5
Bioinformatics | Year: 2013

Motivation: Heterogeneity is a ubiquitous property of biological systems. Even in a genetically identical population of a single cell type, cell-to-cell differences are observed. Although the functional behavior of a given population is generally robust, the consequences of heterogeneity are fairly unpredictable. In heterogeneous populations, synchronization of events becomes a cardinal problem-particularly for phase coherence in oscillating systems. Results: The present article presents a novel strategy for construction of large-scale simulation programs of heterogeneous biological entities. The strategy is designed to be tractable, to handle heterogeneity and to handle computational cost issues simultaneously, primarily by writing a generator of the 'model to be simulated'. We apply the strategy to model glycolytic oscillations among thousands of yeast cells coupled through the extracellular medium. The usefulness is illustrated through (i) benchmarking, showing an almost linear relationship between model size and run time, and (ii) analysis of the resulting simulations, showing that contrary to the experimental situation, synchronous oscillations are surprisingly hard to achieve, underpinning the need for tools to study heterogeneity. Thus, we present an efficient strategy to model the biological heterogeneity, neglected by ordinary mean-field models. This tool is well posed to facilitate the elucidation of the physiologically vital problem of synchronization. © 2013 The Author. Published by Oxford University Press. All rights reserved.

News Article | April 26, 2016
Site: www.rdmag.com

All light sources work by absorbing energy – for example, from an electric current – and emit energy as light. But the energy can also be lost as heat and it is therefore important that the light sources emit the light as quickly as possible, before the energy is lost as heat. Superfast light sources can be used, for example, in laser lights, LED lights and in single-photon light sources for quantum technology. New research results from the Niels Bohr Institute show that light sources can be made much faster by using a principle that was predicted theoretically in 1954. The results are published in the scientific journal, Physical Review Letters. Researchers at the Niels Bohr Institute are working with quantum dots, which are a kind of artificial atom that can be incorporated into optical chips. In a quantum dot, an electron can be excited (i.e. jump up), for example, by shining a light on it with a laser and the electron leaves a 'hole'. The stronger the interaction between light and matter, the faster the electron decays back into the hole and the faster the light is emitted. But the interaction between light and matter is naturally very weak and it makes the light sources very slow to emit light and this can reduce energy efficiency. Already in 1954, the physicist Robert Dicke predicted that the interaction between light and matter could be increased by having a number of atoms that 'share' the excited state in a quantum superposition. Demonstrating this effect has been challinging so far because the atoms either come so close together that they bump into each other or they are so far apart that the quantum speed up does not work. Researchers at the Niels Bohr Institute have now finally demonstrated the effect experimentally, but in an entirely different physical system than Dicke had in mind. They have shown this so-called superradiance for photons emitted from a single quantum dot. "We have developed a quantum dot so that it behaves as if it was comprised of five quantum dots, which means that the light is five times stronger. This is due to the attraction between the electron and the hole. But what is special is that the quantum dot still only emits a single photon at a time. It is an outstanding single-photon source," said Søren Stobbe, an associate professor in the Quantum Photonic research group at the Niels Bohr Institute at the University of Copenhagen who led the project. The experiment was carried out in collaboration with Professor David Ritchie's research group at the University of Cambridge, who have made the quantum dots. Petru Tighineanu, a postdoc in the Quantum Photonics research group at the Niels Bohr Institute, has carried out the experiments and he explains the effect as such, that the atoms are very small and light is very 'big' because of its long wavelength, so the light almost cannot 'see' the atoms – like a lorry that is driving on a road and does not notice a small pebble. But if many pebbles become a larger stone, the lorry will be able to register it and then the interaction becomes much more dramatic. In the same way, light interacts much more strongly with the quantum dot if the quantum dot contains the special superradiant quantum state, which makes it look much bigger. The experiments were carried out in the group’s laboratories on Blegdamsvej in Copenhagen. "The increased light-matter interaction makes the quantum dots more robust in regards to the disturbances that are found in all materials, for example, acoustic oscillations. It helps to make the photons more uniform and is important for how large you can build future quantum computers," said Stobbe. He adds that it is actually the temperature, which is only a few degrees above absolute zero, that limits how fast the light emissions can remain in their current experiments. In the long term, they will study the quantum dots at even lower temperatures, where the effects could be very dramatic.

Bartels E.D.,Blegdamsvej | Christoffersen C.,Blegdamsvej | Lindholm M.W.,Roche Holding AG | Nielsen L.B.,Blegdamsvej | Nielsen L.B.,Copenhagen University
Circulation Research | Year: 2015

Rationale: Plasma cholesterol lowering is beneficial in patients with atherosclerosis. However, it is unknown how it affects entry and degradation of low-density lipoprotein (LDL) particles in the lesioned arterial wall. Objective: We studied the effect of lipid-lowering therapy on LDL permeability and degradation of LDL particles in atherosclerotic aortas of mice by measuring the accumulation of iodinated LDL particles in the arterial wall. Methods and Results: Cholesterol-fed, LDL receptor-deficient mice were treated with either an anti-Apob antisense oligonucleotide or a mismatch control antisense oligonucleotide once a week for 1 or 4 weeks before injection with preparations of iodinated LDL particles. The anti-Apob antisense oligonucleotide reduced plasma cholesterol by ≈90%. The aortic LDL permeability and degradation rates of newly entered LDL particles were reduced by ≈50% and ≈85% already after 1 week of treatment despite an unchanged pool size of aortic iodinated LDL particles. In contrast, the size, foam cell content, and aortic pool size of iodinated LDL particles of aortic atherosclerotic plaques were not reduced until after 4 weeks of treatment with the anti-Apob antisense oligonucleotide. Conclusions: Improved endothelial barrier function toward the entry of plasma LDL particles and diminished aortic degradation of the newly entered LDL particles precede plaque regression. © 2015 American Heart Association, Inc.

Lassen U.,Blegdamsvej | Chinot O.L.,Aix - Marseille University | McBain C.,Christie Hospital | Mau-Sorensen M.,Blegdamsvej | And 9 more authors.
Neuro-Oncology | Year: 2015

Background We conducted a phase 1 dose-escalation study of RO5323441, a novel antiplacental growth factor (PlGF) monoclonal antibody, to establish the recommended dose for use with bevacizumab and to investigate the pharmacokinetics, pharmacodynamics, safety/tolerability, and preliminary clinical efficacy of the combination. Methods Twenty-two participants with histologically confirmed glioblastoma in first relapse were treated every 2 weeks with RO5323441 (625 mg, 1250 mg, or 2500 mg) plus bevacizumab (10 mg/kg). A standard 3 + 3 dose-escalation trial design was used. Results RO5323441 combined with bevacizumab was generally well tolerated, and the maximum tolerated dose was not reached. Two participants experienced dose-limiting toxicities (grade 3 meningitis associated with spinal fluid leak [1250 mg] and grade 3 cerebral infarction [2500 mg]). Common adverse events included hypertension (14 participants, 64%), headache (12 participants, 55%), dysphonia (11 participants, 50%) and fatigue (6 participants, 27%). The pharmacokinetics of RO5323441 were linear, over-the-dose range, and bevacizumab exposure was unaffected by RO5323441 coadministration. Modulation of plasmatic angiogenic proteins, with increases in VEGFA and decreases in FLT4, was observed. Dynamic contrast-enhanced/diffusion-weighted MRI revealed large decreases in vascular parameters that were maintained through the dosing period. Combination therapy achieved an overall response rate of 22.7%, including one complete response, and median progression-free and overall survival of 3.5 and 8.5 months, respectively. Conclusion The toxicity profile of RO5323441 plus bevacizumab was acceptable and manageable. The observed clinical activity of the combination does not appear to improve on that obtained with single-agent bevacizumab in patients with recurrent glioblastoma. © 2015 The Author(s).

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