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).
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.
News Article | April 26, 2016
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.
Hornstrup L.S.,Blegdamsvej |
Hornstrup L.S.,Copenhagen University |
Frikke-Schmidt R.,Blegdamsvej |
Frikke-Schmidt R.,Herlev Hospital |
And 8 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2013
Objective-Transthyretin can cause amyloidosis attributable to destabilization of transthyretin tetramers in plasma. We tested the hypothesis that genetic stabilization of transthyretin associates with reduced risk of vascular disease and increased life expectancy. Approach and Results-We included 68 602 participants from 2 prospective studies of the general population. We genotyped for 2 stabilizing genetic variants in the transthyretin gene (TTR), R104H and T119M, and determined the association of genotypes with plasma levels of transthyretin, measures of thyroid function, risk of vascular disease, and life expectancy. During a mean follow-up of 32 years, 10 636 participants developed vascular disease. We identified 321 heterozygotes for T119M (frequency, 0.47%); R104H was not detected. First, mean plasma transthyretin and thyroxine levels were increased by 17% (26 μg/mL) and 20% (19 nmol/L), respectively, in heterozygotes versus noncarriers (P=0.007 and P<0.0001), demonstrating functionality of this variant in the general population. Second, corresponding hazard ratios were 0.70 (95% confidence interval, 0.51-0.97) for all vascular diseases, 0.85 (0.59-1.23) for cardiovascular disease, 0.45 (0.25-0.81) for cerebrovascular disease, 0.47 (0.25-0.88) for ischemic cerebrovascular disease, and 0.31 (0.04-2.22) for hemorrhagic stroke. The cumulative incidence of cerebrovascular disease as a function of age was decreased in heterozygotes versus noncarriers (P=0.005). Third, median age at death from all causes, from vascular and cerebrovascular diseases, and after diagnosis of vascular disease, and median age at diagnosis of vascular disease, was increased by 5 to 10 years in heterozygotes versus noncarriers (P=0.002-0.05). Conclusions-These results are compatible with an association between genetic stabilization of transthyretin and decreased risk of cerebrovascular disease, and with increased life expectancy in the general population. © 2013 American Heart Association, Inc.
Perell K.,Blegdamsvej |
Perell K.,Center for Genomic Medicine |
Vincent M.,Copenhagen University |
Vainer B.,Copenhagen University |
And 8 more authors.
Molecular Oncology | Year: 2015
Identification of the primary tumor site in patients with metastatic cancer is clinically important, but remains a challenge. Hence, efforts have been made towards establishing new diagnostic tools. Molecular profiling is a promising diagnostic approach, but tissue heterogeneity and inadequacy may negatively affect the accuracy and usability of molecular classifiers. We have developed and validated a microRNA-based classifier, which predicts the primary tumor site of liver biopsies, containing a limited number of tumor cells. Concurrently we explored the influence of surrounding normal tissue on classification. MicroRNA profiling was performed using quantitative Real-Time PCR on formalin-fixed paraffin-embedded samples. 278 primary tumors and liver metastases, representing nine primary tumor classes, as well as normal liver samples were used as a training set. A statistical model was applied to adjust for normal liver tissue contamination. Performance was estimated by cross-validation, followed by independent validation on 55 liver core biopsies with a tumor content as low as 10%. A microRNA classifier developed, using the statistical contamination model, showed an overall classification accuracy of 74.5% upon independent validation. Two-thirds of the samples were classified with high-confidence, with an accuracy of 92% on high-confidence predictions. A classifier trained without adjusting for liver tissue contamination, showed a classification accuracy of 38.2%. Our results indicate that surrounding normal tissue from the biopsy site may critically influence molecular classification. A significant improvement in classification accuracy was obtained when the influence of normal tissue was limited by application of a statistical contamination model. © 2014 Federation of European Biochemical Societies.
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.
PubMed | Center for Genomic Medicine, Copenhagen University and Blegdamsvej
Type: Journal Article | Journal: Molecular oncology | Year: 2014
Identification of the primary tumor site in patients with metastatic cancer is clinically important, but remains a challenge. Hence, efforts have been made towards establishing new diagnostic tools. Molecular profiling is a promising diagnostic approach, but tissue heterogeneity and inadequacy may negatively affect the accuracy and usability of molecular classifiers. We have developed and validated a microRNA-based classifier, which predicts the primary tumor site of liver biopsies, containing a limited number of tumor cells. Concurrently we explored the influence of surrounding normal tissue on classification. MicroRNA profiling was performed using quantitative Real-Time PCR on formalin-fixed paraffin-embedded samples. 278 primary tumors and liver metastases, representing nine primary tumor classes, as well as normal liver samples were used as a training set. A statistical model was applied to adjust for normal liver tissue contamination. Performance was estimated by cross-validation, followed by independent validation on 55 liver core biopsies with a tumor content as low as 10%. A microRNA classifier developed, using the statistical contamination model, showed an overall classification accuracy of 74.5% upon independent validation. Two-thirds of the samples were classified with high-confidence, with an accuracy of 92% on high-confidence predictions. A classifier trained without adjusting for liver tissue contamination, showed a classification accuracy of 38.2%. Our results indicate that surrounding normal tissue from the biopsy site may critically influence molecular classification. A significant improvement in classification accuracy was obtained when the influence of normal tissue was limited by application of a statistical contamination model.
Cheung G.,Blegdamsvej |
Vejlstrup N.,Blegdamsvej |
Ihlemann N.,Blegdamsvej |
Arnous S.,Blegdamsvej |
And 3 more authors.
International Journal of Cardiology | Year: 2013
Background Infective endocarditis (IE) following percutaneous pulmonary valve replacement (PPVR) with the Melody valve is rarely reported. Furthermore, there are challenges in this diagnosis; especially echocardiographic evidence of vegetation within the prosthesis may be difficult. Method and result This study is a retrospective review of all patients with Melody valve implantation in a tertiary centre. Between November 2006 and November 2012, 43 procedures were performed in 42 patients (mean age 25 years, 6-67 years). At a median follow-up of 27 months (2-66 months), six patients were suspected for IE. However, repeated transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) showed no evidence of IE and the patients were diagnosed as possible cases according to the modified Duke's criteria. Two patients did not respond to antibiotic treatment and underwent intra-cardiac echocardiography (ICE), which clearly demonstrated vegetations. These two cases required surgical explantation, while the other four patients were treated medically without complications. Conclusion IE after Melody valve implantation is uncommon, but difficult to verify since TTE and TEE often cannot demonstrate vegetations inside the stent. ICE should be considered in suspected cases of IE following PPVR with negative TTE and TEE examinations in order to early tailor the best treatment for the individual patient suspected for IE. © 2013 Elsevier Ireland Ltd.
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.
PubMed | Blegdamsvej
Type: | Journal: JIMD reports | Year: 2013
-Mannosidosis, OMIM #248500, is an autosomal recessive lysosomal storage disease caused by acidic -mannosidase deficiency. Treatment options include bone marrow transplantation (BMT) and, possibly in the future, enzyme replacement therapy. Brain magnetic resonance spectroscopy (MRS) enables non-invasive monitoring of cerebral treatment effect. Accumulated cerebral mannose-containing oligosaccharides were demonstrated by MRS in a patient who at age 2 years and 11 months received a BMT from a haploidentical non-carrier sibling. The cerebral mannose-containing oligosaccharides had disappeared as early as 9 months after BMT. MRS furthermore demonstrated the persistent treatment effect at regular intervals up to 5 years after BMT. MRS is a non-invasive tool that can demonstrate the effect of BMT treatment. Likewise, MRS may be used to demonstrate the cerebral effect of other potential treatments such as enzyme replacement therapy.