143 results on '"Morten Hartvig Hansen"'
Search Results
2. Common phenotypic dynamics of tumor-infiltrating lymphocytes across different histologies upon checkpoint inhibition: impact on clinical outcome
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Iben Spanggaard, Inge Marie Svane, Sine Reker Hadrup, Morten Hartvig Hansen, Vinicius Araujo Barbosa de Lima, Annie Borch, Arianna Draghi, Ulrik Lassen, and Kristoffer Staal Rohrberg
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Adult ,Male ,0301 basic medicine ,Cancer Research ,Biopsy ,Programmed Cell Death 1 Receptor ,Immunology ,BTLA ,CD8-Positive T-Lymphocytes ,B7-H1 Antigen ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Immune system ,Neoplasms ,Tumor Microenvironment ,Humans ,Immunologic Factors ,Immunology and Allergy ,Medicine ,Molecular Targeted Therapy ,Genetics (clinical) ,Aged ,Transplantation ,Tumor microenvironment ,business.industry ,Tumor-infiltrating lymphocytes ,Cancer ,Cell Biology ,Middle Aged ,Gene signature ,medicine.disease ,Immune checkpoint ,Phenotype ,Treatment Outcome ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Immunotherapy ,business ,CD8 ,Follow-Up Studies - Abstract
Background Immune checkpoint inhibitors (ICIs) have revolutionized the cancer therapeutic landscape and our perception of interactions between the immune system and tumor cells. Despite remarkable progress, disease relapse and primary resistance are not uncommon. Understanding the biological processes that tumor-infiltrating lymphocytes (TILs) undergo during ICI, how this affects the tumor microenvironment (TME) and, ultimately, clinical outcome is, therefore, necessary to further improve treatment efficacy. Aim In the current study, we sought to characterize TILs from patients with metastatic solid tumors undergoing ICI correlating flowcytometric findings with clinical outcome. Methods In total, 20 patients with 10 different metastatic solid tumors treated with ICIs targeting programmed-cell death-1 (PD-1)/PD-L1 axis were included in this study. The phenotype of T cells deriving from biopsies obtained prior to treatment initiation and on-treatment was investigaded. Analyses were focused on T cells’ degree of differentiation and activity and how they correlate with transcriptomic changes in the TME. Results Data indicate that patients benefitting from ICIs accumulate CD8+central memory T cells. TILs developed an effector-like phenotype over time, which was also associated with a cytolytic gene signature. In terms of modulation of T-cell responses, we observed that high expression of checkpoint molecules pre-treatment (i.e., PD-1, lymphocyte activation gene-3 [LAG-3], B and T-lymphocyte attenuator [BTLA] and T-cell immunoglobulin and mucin domain containing-3 [TIM-3]) was associated with similar gene signature and correlated to treatment benefit. Increasing expression of LAG-3 and BTLA in the CD8 compartment and their co-expression with PD-1 during treatment were, however, a common feature for patients who failed to respond to ICIs. Conclusions Besides identifying immune profiles suggestive of response to ICI, our results provide a more nuanced picture regarding expression of checkpoint molecules that goes beyond T-cell anergy.
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- 2020
3. Qualitative yaw stability analysis of free-yawing downwind turbines
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Morten Hartvig Hansen, Gesine Wanke, and Torben J. Larsen
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Physics ,010504 meteorology & atmospheric sciences ,Renewable Energy, Sustainability and the Environment ,020209 energy ,lcsh:TJ807-830 ,lcsh:Renewable energy sources ,Energy Engineering and Power Technology ,02 engineering and technology ,Mechanics ,Wind direction ,01 natural sciences ,Turbine ,Wind speed ,Aerodynamic force ,Tilt (optics) ,0202 electrical engineering, electronic engineering, information engineering ,Torque ,Yaw bearing ,Ligand cone angle ,0105 earth and related environmental sciences - Abstract
This article qualitatively shows the yaw stability of a free-yawing downwind turbine and the ability of the turbine to align passively with the wind direction using a model with 2 degrees of freedom. An existing model of a Suzlon S111 upwind 2.1 MW turbine is converted into a downwind configuration with a 5∘ tilt and a 3.5∘ downwind cone angle. The analysis shows that the static tilt angle causes a wind-speed-dependent yaw misalignment of up to −19∘ due to the projection of the torque onto the yaw bearing and the skewed aerodynamic forces caused by wind speed projection. With increased cone angles, the yaw stiffness can be increased for better yaw alignment and the stabilization of the free-yaw motion. The shaft length influences the yaw alignment only for high wind speeds and cannot significantly contribute to the damping of the free-yaw mode within the investigated range. Asymmetric flapwise blade flexibility is seen to significantly decrease the damping of the free-yaw mode, leading to instability at wind speeds higher than 19 m s−1. It is shown that this additional degree of freedom is needed to predict the qualitative yaw behaviour of a free-yawing downwind wind turbine.
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- 2019
4. Immune Cell Profiling of Peripheral Blood as Signature for Response During Checkpoint Inhibition Across Cancer Types
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Kristoffer Staal Rohrberg, Vinicius Araujo Barbosa de Lima, Inge Marie Svane, Ulrik Lassen, Sine Reker Hadrup, Iben Spanggaard, and Morten Hartvig Hansen
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Oncology ,Cancer Research ,medicine.medical_specialty ,Cell type ,T cell ,immune signature ,clinical outcome ,Peripheral blood mononuclear cell ,lcsh:RC254-282 ,Immune system ,SDG 3 - Good Health and Well-being ,Internal medicine ,medicine ,Original Research ,Tumor microenvironment ,business.industry ,Cancer ,prediction ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immune checkpoint ,medicine.anatomical_structure ,PBMCs ,immune checkpoint inhibition ,business ,CD8 - Abstract
Despite encouraging results with immune checkpoint inhibition (ICI), a large fraction of cancer patients still does not achieve clinical benefit. Finding predictive markers in the complexity of the tumor microenvironment is a challenging task and often requires invasive procedures. In our study, we looked for putative variables related to treatment benefit among immune cells in peripheral blood across different tumor types treated with ICIs. For that, we included 33 patients with different solid tumors referred to our clinical unit for ICI. Peripheral blood mononuclear cells were isolated at baseline, 6 and 20 weeks after treatment start. Characterization of immune cells was carried out by multi-color flow cytometry. Response to treatment was assessed radiologically by RECIST 1.1. Clinical outcome correlated with a shift towards an effector-like T cell phenotype, PD-1 expression by CD8+T cells, low levels of myeloid-derived suppressor cells and classical monocytes. Dendritic cells seemed also to play a role in terms of survival. From these findings, we hypothesized that patients responding to ICI had already at baseline an immune profile, here called ‘favorable immune periphery’, providing a higher chance of benefitting from ICI. We elaborated an index comprising cell types mentioned above. This signature correlated positively with the likelihood of benefiting from the treatment and ultimately with longer survival. Our study illustrates that patients responding to ICI seem to have a pre-existing immune profile in peripheral blood that favors good outcome. Exploring this signature can help to identify patients likely to achieve benefit from ICI.
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- 2021
5. Therapeutic Cancer Vaccination With a Peptide Derived From the Calreticulin Exon 9 Mutations Induces Strong Cellular Immune Responses in Patients With CALR-Mutant Chronic Myeloproliferative Neoplasms
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Guy Wayne Novotny, Morten Orebo Holmström, Daniel El Fassi, Hans Carl Hasselbalch, Inge Marie Svane, Jacob Handlos Grauslund, Uffe Klausen, Mette Borg Clausen, Morten Hartvig Hansen, Claudia Schöllkopf, Nicolas Chatain, Steffen Koschmieder, Nicolai Grønne Jørgensen, Julie Westerlin Kjeldsen, Mads Hald Andersen, Özcan Met, Marie Fredslund Breinholt, Jesper Petersen, Lise Mette Rahbek Gjerdrum, Lasse Kjær, Vibe Skov, and Stine Emilie Weis-Banke
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0301 basic medicine ,Cancer Research ,Vaccination schedule ,medicine.medical_treatment ,lcsh:RC254-282 ,myeloproliferative neoplasms ,calreticulin ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Antigen ,medicine ,cancer immune therapy ,Original Research ,biology ,business.industry ,Essential thrombocythemia ,ELISPOT ,neo-antigen ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Vaccination ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,business ,Calreticulin ,Adjuvant ,cancer vaccines - Abstract
Frontiers in oncology 11, 637420 (2021). doi:10.3389/fonc.2021.637420 special issue: "Novel Treatment Strategies for Myeloproliferative Neoplasms / Edited by Ken-Hong Lim, Shinobu Matsuura, Bing Xu", Published by Frontiers Media, Lausanne
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- 2021
6. Wind turbine aero-servo-elasticity and dynamics
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Morten Hartvig Hansen
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Vibration ,Wind power ,Modal ,Computer science ,business.industry ,Mechanical engineering ,Elasticity (economics) ,business ,Aeroelasticity ,Turbine ,Servo - Abstract
In this chapter, we cover the derivation of aero-servo-elastic models of wind turbines, the modal dynamics of two- and three -bladed turbines, and the aeroelastic stability of their operational states. Knowledge of the modal properties and the aeroelastic stability limits are fundamental requirements for a good turbine design without resonance and self-induced vibrations.
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- 2019
7. Modal properties and stability of bend–twist coupled wind turbine blades
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Alexander R. Stäblein, Morten Hartvig Hansen, and David Robert Verelst
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Leading edge ,Engineering ,Turbine blade ,020209 energy ,lcsh:TJ807-830 ,lcsh:Renewable energy sources ,Energy Engineering and Power Technology ,02 engineering and technology ,7. Clean energy ,01 natural sciences ,Turbine ,Wind speed ,010305 fluids & plasmas ,law.invention ,Physics::Fluid Dynamics ,law ,Deflection (engineering) ,0103 physical sciences ,0202 electrical engineering, electronic engineering, information engineering ,Stiffness matrix ,Renewable Energy, Sustainability and the Environment ,business.industry ,Stall (fluid mechanics) ,Structural engineering ,Aeroelasticity ,business - Abstract
Coupling between bending and twist has a significant influence on the aeroelastic response of wind turbine blades. The coupling can arise from the blade geometry (e.g. sweep, prebending, or deflection under load) or from the anisotropic properties of the blade material. Bend–twist coupling can be utilized to reduce the fatigue loads of wind turbine blades. In this study the effects of material-based coupling on the aeroelastic modal properties and stability limits of the DTU 10 MW Reference Wind Turbine are investigated. The modal properties are determined by means of eigenvalue analysis around a steady-state equilibrium using the aero-servo-elastic tool HAWCStab2 which has been extended by a beam element that allows for fully coupled cross-sectional properties. Bend–twist coupling is introduced in the cross-sectional stiffness matrix by means of coupling coefficients that introduce twist for flapwise (flap–twist coupling) or edgewise (edge–twist coupling) bending. Edge–twist coupling can increase or decrease the damping of the edgewise mode relative to the reference blade, depending on the operational condition of the turbine. Edge–twist to feather coupling for edgewise deflection towards the leading edge reduces the inflow speed at which the blade becomes unstable. Flap–twist to feather coupling for flapwise deflections towards the suction side increase the frequency and reduce damping of the flapwise mode. Flap–twist to stall reduces frequency and increases damping. The reduction of blade root flapwise and tower bottom fore–aft moments due to variations in mean wind speed of a flap–twist to feather blade are confirmed by frequency response functions.
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- 2017
8. Dendritic cell vaccination in combination with docetaxel for patients with metastatic castration-resistant prostate cancer: A randomized phase II study
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Per Kongsted, Rikke Andersen, Eva Ellebaek, Lisa Sengeløv, Trine Zeeberg Iversen, Özcan Met, Henriette Lindberg, Troels Holz Borch, Inge Marie Svane, and Morten Hartvig Hansen
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Combination therapy ,medicine.medical_treatment ,Immunology ,Docetaxel ,Cancer Vaccines ,Immunotherapy, Adoptive ,Transplantation, Autologous ,Disease-Free Survival ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Immunology and Allergy ,Neoplasm Metastasis ,Genetics (clinical) ,Aged ,Aged, 80 and over ,Transplantation ,Chemotherapy ,business.industry ,ELISPOT ,Common Terminology Criteria for Adverse Events ,Dendritic Cells ,Cell Biology ,Immunotherapy ,Middle Aged ,medicine.disease ,Combined Modality Therapy ,Prostatic Neoplasms, Castration-Resistant ,Treatment Outcome ,030220 oncology & carcinogenesis ,Taxoids ,Cancer vaccine ,business ,030215 immunology ,medicine.drug - Abstract
Background aims We investigated whether the addition of an autologous dendritic cell–based cancer vaccine (DCvac) induces an immune response in patients with metastatic castration-resistant prostate cancer treated with docetaxel. Methods Forty-three patients were randomized 1:1 to receive up to 10 cycles of docetaxel alone, 75 mg/m 2 every 3 weeks or in combination with DCvac. Monocytes were harvested following a leukapheresis procedure, matured ex vivo and subsequently transfected with messenger RNA encoding multiple tumor-associated antigens (TAAs). DCvac was administered intradermally twice through treatment cycles 1–4 and once through treatment cycles 5–10. Immune cell composition and antigen-specific responses were analyzed using flow cytometry, ELISpot and delayed type hypersensitivity (DTH) tests. Toxicity was graded according to Common Terminology Criteria for Adverse Events version 3.0. Progression-free survival (PFS) and disease-specific survival (DSS) was calculated using the Kaplan-Meier method. Results Prostate-specific antigen responses were similar in patients treated with docetaxel alone and combination therapy (58% versus 38%; P = 0.21). PFS and DSS were comparable: 5.5 versus 5.7 months ( P = 0.62, log rank) and 21.9 versus 25.1 months ( P = 0.60, log rank). Nine (50%) and 14 (78%) patients treated with docetaxel and DCvac had a TAA-specific or vaccine-specific immune response in the ELISpot and DTH analysis, respectively. Vaccine induced toxicity was limited to local reactions. Decline in myeloid-derived suppressor cells at the third treatment cycle was found to be an independent predictor of DSS. Conclusions The addition of DCvac was safe. Immune responses were detected in approximately half of the patients investigated.
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- 2017
9. Comparison of a coupled near- and far-wake model with a free-wake vortex code
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Taeseong Kim, Vasilis A. Riziotis, Helge Aagaard Madsen, Morten Hartvig Hansen, and Georg Pirrung
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Airfoil ,Engineering ,Renewable Energy, Sustainability and the Environment ,business.industry ,020209 energy ,Computation ,lcsh:TJ807-830 ,lcsh:Renewable energy sources ,Energy Engineering and Power Technology ,02 engineering and technology ,Aerodynamics ,Mechanics ,Structural engineering ,Vorticity ,Wake ,01 natural sciences ,010305 fluids & plasmas ,Vibration ,Physics::Fluid Dynamics ,0103 physical sciences ,0202 electrical engineering, electronic engineering, information engineering ,business ,Wake turbulence ,Numerical stability - Abstract
This paper presents the integration of a near-wake model for trailing vorticity, which is based on a prescribed-wake lifting-line model proposed by Beddoes(1987), with a blade element momentum (BEM)-based far-wake model and a 2-D shed vorticity model. The resulting coupled aerodynamics model is validated against lifting-surface computations performed using a free-wake panel code. The focus of the description of the aerodynamics model is on the numerical stability, the computation speed and the accuracy of unsteady simulations. To stabilize the near-wake model, it has to be iterated to convergence, using a relaxation factor that has to be updated during the computation. Further, the effect of simplifying the exponential function approximation of the near-wake model to increase the computation speed is investigated in this work. A modification of the dynamic inflow weighting factors of the far-wake model is presented that ensures good induction modeling at slow timescales. Finally, the unsteady airfoil aerodynamics model is extended to provide the unsteady bound circulation for the near-wake model and to improve the modeling of the unsteady behavior of cambered airfoils. The model comparison with results from a free-wake panel code and a BEM model is centered around the NREL 5 MW reference turbine. The response to pitch steps at different pitching speeds is compared. By means of prescribed vibration cases, the effect of the aerodynamic model on the predictions of the aerodynamic work is investigated. The validation shows that a BEM model can be improved by adding near-wake trailed vorticity computation. For all prescribed vibration cases with high aerodynamic damping, results similar to those obtained by the free-wake model can be achieved in a small fraction of computation time with the proposed model. In the cases with low aerodynamic damping, the addition of trailed vorticity modeling shifts the results closer to those obtained by using the free-wake code, but differences remain.
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- 2017
10. Fundamental aeroelastic properties of a bend–twist coupled blade section
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Georg Pirrung, Alexander R. Stäblein, and Morten Hartvig Hansen
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Engineering ,Turbine blade ,020209 energy ,Aeroelastic stability ,02 engineering and technology ,law.invention ,Physics::Fluid Dynamics ,law ,0202 electrical engineering, electronic engineering, information engineering ,medicine ,Stiffness matrix ,Bend–twist coupling ,business.industry ,Mechanical Engineering ,Stiffness ,Stall (fluid mechanics) ,Aerodynamics ,Structural engineering ,Aeroelasticity ,Aerodynamic force ,Aeroelastic response ,Aerofoil section ,Flutter ,medicine.symptom ,business - Abstract
The effects of bend–twist coupling on the aeroelastic modal properties and stability limits of a two-dimensional blade section in attached flow are investigated. Bend–twist coupling is introduced in the stiffness matrix of the structural blade section model. The structural model is coupled with an unsteady aerodynamic model in a linearised state–space formulation. A numerical study is performed using structural and aerodynamic parameters representative for wind turbine blades. It is shown that damping of the edgewise mode is primarily influenced by the work of the lift which is close to antiphase, making the stability of the mode sensitive to changes in the stiffness matrix. The aerodynamic forces increase the stiffness of the flapwise mode for flap–twist coupling to feather for downwind deflections. The stiffness reduces and damping increases for flap–twist to stall. Edge–twist coupling is prone to an edgetwist flutter instability at much lower inflow speeds than the uncoupled blade section. Flap–twist coupling results in a moderate reduction of the flutter speed for twist to feather and divergence for twist to stall.
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- 2017
11. Modal dynamics of structures with bladed isotropic rotors and its complexity for two-bladed rotors
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Morten Hartvig Hansen
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Engineering ,Renewable Energy, Sustainability and the Environment ,Nacelle ,business.industry ,Antisymmetric relation ,020209 energy ,lcsh:TJ807-830 ,Mathematical analysis ,Isotropy ,lcsh:Renewable energy sources ,Energy Engineering and Power Technology ,02 engineering and technology ,Mass matrix ,01 natural sciences ,Turbine ,010305 fluids & plasmas ,Physics::Fluid Dynamics ,Modal ,Control theory ,0103 physical sciences ,0202 electrical engineering, electronic engineering, information engineering ,business ,Fourier series ,Eigenvalues and eigenvectors - Abstract
The modal dynamics of structures with bladed isotropic rotors is analyzed using Hill's method. First, analytical derivation of the periodic system matrix shows that isotropic rotors with more than two blades can be represented by an exact Fourier series with 3/rev (three per rotor revolution) as the highest order. For two-bladed rotors, the inverse mass matrix has an infinite Fourier series with harmonic components of decreasing norm; thus, the system matrix can be approximated by a truncated Fourier series of predictable accuracy. Second, a novel method for automatically identifying the principal solutions of Hill's eigenvalue problem is introduced. The corresponding periodic eigenvectors can be used to compute symmetric and antisymmetric components of the two-bladed rotor motion, as well as the additional forward and backward whirling components for rotors with more than two blades. To illustrate the use of these generic methods, a simple wind turbine model is set up with three degrees of freedom for each blade and seven degrees of freedom for the nacelle and drivetrain. First, the model parameters are tuned such that the low-order modal dynamics of a three-bladed 10 MW turbine from previous studies is recaptured. Second, one blade is removed, leading to larger and higher harmonic terms in the system matrix. These harmonic terms lead to modal couplings for the two-bladed turbine that do not exist for the three-bladed turbine. A single mode of a two-bladed turbine will also have several resonance frequencies in both the ground-fixed and rotating frames of reference, which complicates the interpretation of simulated or measured turbine responses.
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- 2016
12. Modal dynamics of a three-bladed tri-rotor wind turbine
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Xuping Zhang, A. Yde, Morten Hartvig Hansen, Oliver Tierdad Filsoof, and Peter Bøttcher
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Modal ,Rotor (electric) ,law ,business.industry ,Dynamics (mechanics) ,Structural engineering ,business ,Turbine ,Geology ,law.invention - Published
- 2019
13. Tumor miRNA expression profile is related to vestibular schwannoma growth rate
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Rehannah Borup, Finn Cilius Nielsen, Hjalte Sass, Per Cayé-Thomasen, and Morten Hartvig Hansen
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Adult ,Male ,Genomics ,Schwannoma ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Mirna expression ,microRNA ,medicine ,Biomarkers, Tumor ,Gene silencing ,Humans ,Gene ,Vestibular system ,business.industry ,Gene Expression Profiling ,Neuroma, Acoustic ,Middle Aged ,medicine.disease ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,Cancer research ,Surgery ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Our objective was to investigate if the tumor microRNA (miRNA) expression profile was related to tumor growth rate. Growth-related miRNAs might be potential targets for future therapeutic intervention. Tumor tissue was sampled during surgery of patients with a sporadic vestibular schwannoma. Tumor growth rate was determined by tumor measurement on the two latest pre-operative MRI scans. Tumor miRNA expression was analyzed using the Affymetrix Gene Chip® protocol, and CEL files were generated using GeneChip® Command Console® Software and normalized using Partek Genomics Suite 6.5. The CEL files were analyzed using the statistical software program R. Principal component analysis, affected gene ontology analysis, and analysis of miRNA expression fold changes were used for analysis of potential relations between miRNA expression profile and tumor growth rate. Tumor miRNA expression is related to the growth rate of sporadic vestibular schwannomas. Rapid tumor growth is associated with deregulation of several miRNAs, including upregulation of miR-29abc, miR-19, miR-340-5p, miR-21, and miR-221 and downregulation of miR-744 and let-7b. Gene ontologies affected by the deregulated miRNAs included neuron development and differentiation, gene silencing, and negative regulation of various biological processes, including cellular and intracellular signaling and metabolism.
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- 2019
14. Inflammation induced PD-L1-specific T cells
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Mia Aabroe Jørgensen, Shamaila Munir, Christina Friese, Per thor Straten, Trine Hilkjær Petersen, Morten Hartvig Hansen, Mads Hald Andersen, Özcan Met, Mia Thorup Lundsager, and Charlotte M. Bonefeld
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Cancer Research ,Physiology ,Cell ,anti-regulatory T cells ,lcsh:Medicine ,Inflammation ,ifn-γ ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Peripheral blood mononuclear cell ,IDO ,pd-l1 ,In vivo ,PD-L1 ,medicine ,Immune homeostasis ,lcsh:QH301-705.5 ,anti-regulatory t-cells ,News and Thoughts ,biology ,Chemistry ,lcsh:R ,t-cell immunity ,Cell biology ,Treg ,medicine.anatomical_structure ,lcsh:Biology (General) ,inflammation ,biology.protein ,Molecular Medicine ,Local environment ,immunotherapy ,medicine.symptom ,anti-tregs ,CD8 - Abstract
PD-L1-specific T cells are a natural part of the T-cell repertoire in humans. Hence, we have previously described spontaneous CD8+ and CD4+ T-cell reactivity against PD-L1 in the peripheral blood of patients with various cancers as well as in healthy donors. It is well described that the expression of the PD-L1 protein is introduced in cells by pro-inflammatory cytokines, e.g. IFN-γ. In the current study, we were able to directly link inflammation with PD-L1-specific T cells by showing that inflammatory mediators such as IFN-γ generate measurable numbers of PD-L1-specific T cells in human PBMCs as well as in in vivo models. These PD-L1-specific T cells can vigorously modulate the cell compartments of the local environment. PD-L1-specific T cells may be important for immune homeostasis by sustaining the ongoing inflammatory response by the suppression of regulatory cell function both directly and indirectly.
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- 2019
15. Changes in design driving load cases: Operating an upwind turbine with a downwind rotor configuration
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Leonardo Bergami, Morten Hartvig Hansen, Gesine Wanke, and Torben J. Larsen
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Design loads basis ,Fatigue loads ,Renewable Energy, Sustainability and the Environment ,Tower shadow ,business.industry ,Rotor (electric) ,Structural engineering ,Design load ,Turbine ,law.invention ,Extreme loads ,Downwind rotor ,law ,Bending moment ,Environmental science ,business - Abstract
This work considers the design driving load cases from a full design load basis analysis on an upwind turbine changed into a downwind configuration. The upwind turbine is a commercial class IIIA 2.1-MW turbine, manufactured by Suzlon. The downwind turbine shows an increase in the normalized tower clearance by 6%, compared with the upwind concept. Removing the blade prebend increases the normalized minimum tower clearance by 17% in the downwind configuration compared with the upwind configuration. The extreme loads on the longitudinal tower bottom bending moment are seen to generally increase by 17% because of the overhanging gravity moment of the rotor-nacelle assembly. The extreme blade root bending moments are reduced by 10% flapwise, because of the coning of the rotor in downwind direction. The fatigue loads suffer from the tower shadow, leading to an overall increase of the fatigue loads in the blades with up to 5% in flapwise direction in the downwind configuration. Because of blade deflection and coning direction, the downwind configuration shows a 0.75% lower annual energy production. Removing the prebend increases the annual energy production loss to 1.66%.
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- 2019
16. Non-invasive biomarkers derived from the extracellular matrix associate with response to immune checkpoint blockade (anti-CTLA-4) in metastatic melanoma patients
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Inge Marie Svane, Christina Jensen, Morten Hartvig Hansen, Nicholas Willumsen, Morten A. Karsdal, Daniel H. Madsen, and Henrik Schmidt
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0301 basic medicine ,Oncology ,Male ,Cancer Research ,medicine.medical_treatment ,Vimentin ,Stroma ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Immunology and Allergy ,CTLA-4 Antigen ,Neoplasm Metastasis ,Melanoma ,Aged, 80 and over ,biology ,Extracellular matrix ,Middle Aged ,Prognosis ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Combined Modality Therapy ,Treatment Outcome ,030220 oncology & carcinogenesis ,Disease Progression ,Molecular Medicine ,Biomarker (medicine) ,Female ,Immunotherapy ,Collagen ,Antibody ,medicine.drug ,Research Article ,Adult ,medicine.medical_specialty ,Immunology ,Ipilimumab ,Enzyme-Linked Immunosorbent Assay ,lcsh:RC254-282 ,03 medical and health sciences ,Immune checkpoint inhibitors ,Internal medicine ,medicine ,Humans ,Aged ,Neoplasm Staging ,Pharmacology ,Liquid biopsy ,Proportional hazards model ,business.industry ,medicine.disease ,Immune checkpoint ,030104 developmental biology ,biology.protein ,business ,Progressive disease ,Biomarkers - Abstract
Background Excessive extracellular matrix (ECM) remodeling and a reactive stroma can affect T-cell infiltration and T-cell activity in the tumor and hereby influence response to immune checkpoint inhibitors (ICI). In the pursuit of finding biomarkers that predict treatment response, we evaluated the association between serum biomarkers of collagen and vimentin turnover and outcomes in metastatic melanoma patients treated with the anti-CTLA-4 antibody ipilimumab (IPI). Methods Type III collagen formation (PRO-C3), MMP-degraded type I, type III and type IV collagens (C1M, C3M and C4M), and citrullinated and MMP-degraded vimentin (VICM) were measured with ELISAs in serum from metastatic melanoma patients before (n = 66) and 3 weeks after (n = 52) initiation of IPI treatment. Biomarker levels were associated with Disease Control Rate (DCR) and survival outcomes. Results We found that baseline levels of PRO-C3 (p = 0.011), C1M (p = 0.003), C3M (p = 0.013) and C4M (p = 0.027) were significantly elevated in patients with progressive disease (PD). Univariate Cox regression analysis identified high PRO-C3 (p = 0.021) and C4M (p = 0.008) as predictors of poor overall survival (OS) and the biomarkers remained significant when evaluated with other covariates (PRO-C3 (p = 0.049) and C4M (p = 0.046)). Multivariate analysis identified VICM as a predictor of longer OS (p = 0.026). Similarly, a high C3M/PRO-C3 ratio predicted for increased OS (p = 0.034). Only C3M (p = 0.003) and VICM (p
- Published
- 2018
17. A novel methodology for analyzing modal dynamics of multi-rotor wind turbines
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Oliver Tierdad Filsoof, Xuping Zhang, Morten Hartvig Hansen, Peter Bøttcher, and Anders Yde
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Acoustics and Ultrasonics ,Computer science ,Modal analysis ,02 engineering and technology ,01 natural sciences ,Turbine ,law.invention ,0203 mechanical engineering ,law ,0103 physical sciences ,010301 acoustics ,Campbell diagram ,Wind power ,Rotor (electric) ,business.industry ,Mechanical Engineering ,Multi-rotor wind turbine ,Structural engineering ,Condensed Matter Physics ,High-fidelity model ,System dynamics ,Nonlinear system ,020303 mechanical engineering & transports ,Modal ,Linear time-invariant model ,Mechanics of Materials ,business - Abstract
A multi-rotor wind turbine (MRWT) is accepted as a novel solution in reducing the rotor size without decreasing the energy harvesting capability compared to a single-rotor wind turbine (SRWT). However, there is no systematic methodology available for obtaining the modal properties of MRWTs. This paper presents a novel methodology and systematic modeling method of modal dynamics with comprehensive numerical simulations and analyses of MRWTs. In the methodology, Coleman transformation is employed to convert the nonlinear time-variant dynamics formulation of a MRWT into a set of linear time-invariant dynamic equations. Using HAWC2 and HAWCStab2 a method to establishing high-fidelity linear time-invariant dynamic models is presented. The structural modal dynamics of a tri-rotor wind turbine is systematically investigated by using modal analysis theory and interpreting the rotor speed-dependent dynamics visualized in a Campbell diagram. The investigation shows that rotor modes on a MRWT have similar behavior as for a SRWT and that low torsional stiffness of the rotor attachment point affects the first flapwise backward whirling modes by decreasing the corresponding natural frequencies. Moreover, the low torsional stiffness results in a delayed splitting of the asymmetric flapwise rotor modes. The simulations and analyses result verified the proposed dynamic modeling method. The major contributions in this paper provide the essential insights and guidance in the design of MRWTs but also for SRWT with slender towers.
- Published
- 2021
18. The role of dendritic cells in cancer
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Mads Hald Andersen and Morten Hartvig Hansen
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0301 basic medicine ,Immunology ,Adaptive Immunity ,Biology ,Dinoprostone ,03 medical and health sciences ,0302 clinical medicine ,Antigens, CD ,T-Lymphocyte Subsets ,Immunity ,Neoplasms ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,Myeloid Cells ,Prostaglandin E2 ,beta Catenin ,Tumor microenvironment ,Follicular dendritic cells ,Cancer ,Dendritic Cells ,Acquired immune system ,medicine.disease ,Immunity, Innate ,Phenotype ,030104 developmental biology ,Cyclooxygenase 2 ,030220 oncology & carcinogenesis ,Disease Progression ,Tumor Escape ,Integrin alpha Chains ,Biomarkers ,CD8 ,Signal Transduction ,medicine.drug - Abstract
Though present in low numbers, dendritic cells (DCs) are recognized as major players in the control of cancer by adaptive immunity. The roles of cytotoxic CD8+ T-cells and Th1 helper CD4+ T-cells are well-documented in murine models of cancer and associated with a profound prognostic impact when infiltrating human tumors, but less information is known about how these T-cells gain access to the tumor or how they are primed to become tumor-specific. Here, we highlight recent findings that demonstrate a vital role of CD103+ DCs, which have been shown to be experts in cross-priming and the induction of anti-tumor immunity. We also focus on two different mediators that impair the function of tumor-associated DCs: prostaglandin E2 and β-catenin. Both of these mediators seem to be important for the exclusion of T-cells in the tumor microenvironment and may represent key pathways to target in optimized treatment regimens against cancer.
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- 2016
19. High-fidelity linear time-invariant model of a smart rotor with adaptive trailing edge flaps
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Morten Hartvig Hansen and Leonardo Bergami
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Frequency response ,Engineering ,Turbine blade ,Renewable Energy, Sustainability and the Environment ,business.industry ,020209 energy ,Linear model ,02 engineering and technology ,Structural engineering ,Aeroelasticity ,Turbine ,law.invention ,LTI system theory ,law ,Control theory ,Control system ,0202 electrical engineering, electronic engineering, information engineering ,Trailing edge ,business - Abstract
A high-fidelity linear time-invariant model of the aero-servo-elastic response of a wind turbine with trailing-edge flaps is presented and used for systematic tuning of an individual flap controller. The model includes the quasi-steady aerodynamic effects of trailing-edge flaps on wind turbine blades and is integrated in the linear aeroelastic code HAWCStab2. The dynamic response predicted by the linear model is validated against non-linear simulations, and the quasi-steady assumption does not cause any significant response bias for flap deflection with frequencies up to 2–3 Hz. The linear aero-servo-elastic model support the design, systematic tuning and model synthesis of smart rotor control systems. As an example application, the gains of an individual flap controller are tuned using the Ziegler–Nichols method for the full-order poles. The flap controller is based on feedback of inverse Coleman transformed and low-pass filtered flapwise blade root moments to the cyclic flap angles through two proportional-integral controllers. The load alleviation potential of the active flap control, anticipated by the frequency response of the linear closed-loop model, is also confirmed by non-linear time simulations. The simulations report reductions of lifetime fatigue damage up to 17% at the blade root and up to 4% at the tower bottom. Copyright © 2016 John Wiley & Sons, Ltd.
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- 2016
20. PD-L1-specific T cells
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Shamaila Munir Ahmad, Troels Holz Borch, Morten Hartvig Hansen, and Mads Hald Andersen
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Cancer Research ,medicine.drug_class ,T-Lymphocytes ,medicine.medical_treatment ,Immunology ,Epitopes, T-Lymphocyte ,Monoclonal antibody ,Cancer Vaccines ,B7-H1 Antigen ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Antigen ,Neoplasms ,Tumor Microenvironment ,medicine ,Humans ,Immunology and Allergy ,IL-2 receptor ,Tumor microenvironment ,business.industry ,Immunotherapy ,Acquired immune system ,Immune checkpoint ,Oncology ,030220 oncology & carcinogenesis ,business ,030215 immunology - Abstract
Recently, there has been an increased focus on the immune checkpoint protein PD-1 and its ligand PD-L1 due to the discovery that blocking the PD-1/PD-L1 pathway with monoclonal antibodies elicits striking clinical results in many different malignancies. We have described naturally occurring PD-L1-specific T cells that recognize both PD-L1-expressing immune cells and malignant cells. Thus, PD-L1-specific T cells have the ability to modulate adaptive immune reactions by reacting to regulatory cells. Thus, utilization of PD-L1-derived T cell epitopes may represent an attractive vaccination strategy for targeting the tumor microenvironment and for boosting the clinical effects of additional anticancer immunotherapy. This review summarizes present information about PD-L1 as a T cell antigen, depicts the initial findings about the function of PD-L1-specific T cells in the adjustment of immune responses, and discusses future opportunities.
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- 2016
21. Granzyme B Degraded Type IV Collagen Products in Serum Identify Melanoma Patients Responding to Immune Checkpoint Blockade
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Nicholas Willumsen, Daniel H. Madsen, Patrik Önnerfjord, Inge Marie Svane, Morten Hartvig Hansen, Christina Jensen, Dovile Sinkeviciute, Morten A. Karsdal, and Henrik Schmidt
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collagen ,0301 basic medicine ,Cancer Research ,T-cell infiltration ,medicine.medical_treatment ,immune checkpoint inhibitor ,Immune checkpoint inhibitor ,Type IV collagen ,0302 clinical medicine ,Medicine ,ipilimumab ,Melanoma ,biology ,Extracellular matrix ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.anatomical_structure ,Tumor microenvironment ,Oncology ,030220 oncology & carcinogenesis ,SURVIVAL ,biomarker ,immunotherapy ,Collagen ,Immunotherapy ,extracellular matrix ,PREDICTIVE BIOMARKER ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,melanoma ,tumor microenvironment ,Fibroblast ,business.industry ,fibrosis ,CANCER PROGRESSION ,Biomarker ,medicine.disease ,Fibrosis ,Ipilimumab ,Immune checkpoint ,Granzyme B ,030104 developmental biology ,Granzyme ,Cancer research ,biology.protein ,business ,MATRIX - Abstract
A T-cell permissive tumor microenvironment, characterized by the presence of activated T cells and low fibrotic activity is crucial for response to immune checkpoint inhibitors (ICIs). Granzyme B has been shown to promote T-cell migration through the basement membrane by the degradation of type IV collagen. In this study, we evaluated the biomarker potential of measuring granzyme B-mediated degradation of type IV collagen (C4G) in combination with a fibroblast activation biomarker (PRO-C3) non-invasively for identifying metastatic melanoma patients responding to the ICI ipilimumab. A monoclonal antibody was generated against C4G and used to develop a competitive electro-chemiluminescence immunoassay. C4G and PRO-C3 were measured in pretreatment serum from metastatic melanoma patients (n = 54). The C4G assay was found specific for a granzyme B-generated neo-epitope on type IV collagen. The objective response rate (ORR) was 2.6-fold higher (18% vs. 7%) in patients with high C4G levels (>, 25th percentile) vs. low levels (&le, 25th percentile). Likewise, high C4G levels at baseline were associated with longer overall survival (OS) (log-rank, p = 0.040, and hazard ratio (HR) = 0.48, 95%CI: 0.24&ndash, 0.98, p = 0.045). Combining high C4G with low PRO-C3 correlated with improved OS with a median OS of 796 days vs. 273 days (p = 0.0003) and an HR of 0.30 (95%CI: 0.15&ndash, 0.60, p = 0.0006). In conclusion, these results suggest that high granzyme B degraded type IV collagen (C4G) combined with low PRO-C3 quantified non-invasively has the potential to identify the responders to ICI therapy.
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- 2020
22. Abstract 3091: Liquid biopsy reflecting a T-cell permissive tumor microenvironment identifies metastatic melanoma patients responding to immune checkpoint inhibitor therapy
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Nicholas Willumsen, Henrik Schmidt, Daniel H. Madsen, Patrik Önnerfjord, Dovile Sinkeviciute, Morten A. Karsdal, Morten Hartvig Hansen, Inge Marie Svane, and Christina Jensen
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Cancer Research ,Tumor microenvironment ,business.industry ,T cell ,Ipilimumab ,medicine.disease ,Granzyme B ,Type IV collagen ,medicine.anatomical_structure ,Oncology ,Fibrosis ,medicine ,Cancer research ,Biomarker (medicine) ,Liquid biopsy ,business ,medicine.drug - Abstract
Background: Non-invasive biomarkers for predicting response to immune checkpoint inhibitors (ICI) are urgently needed. Crucial for response to ICI's is a T-cell permissive tumor microenvironment (hot tumor), characterized by presence of activated T-cells and low fibrotic activity. Activated T-cells release the protease granzyme B (GzB), which can cleave type IV collagen during tumor infiltration. We evaluated the potential of measuring GzB generated type IV collagen degradation fragments in a liquid biopsy for identifying metastatic melanoma (MM) patients responding to ipilimumab. Methods: A monoclonal antibody was raised against a GzB generated neo-epitope on type IV collagen (C4G), and used to develop a technically robust competitive electro-chemiluminescence immunoassay (ECLIA). C4G was measured in serum from MM patients (n=54) before initiation of ipilimumab treatment. C4G was combined with the fibrosis biomarker PRO-C3, measuring type III collagen formation. Biomarker levels were associated with objective response rate (ORR) and overall survival (OS) outcomes. Results: The C4G assay was specific for a neo-epitope on type IV collagen degradation fragments generated by GzB. The ORR was 2.6 fold higher (18% vs 7%) in patients with high C4G levels (>25th percentile) vs low levels (≤25th percentile). Likewise, high C4G levels at baseline were associated with longer OS, with a median OS of 646 days vs 290 days for low C4G levels (HR=0.48, 95%CI: 0.24-0.98, p=0.045). When combining high C4G with low PRO-C3, the HR dropped to 0.30 (95%CI: 0.15-0.60, p=0.0006), and remained significant when adjusted for the covariates age, lactate dehydrogenase levels and prior treatment (HR: 0.35, 95%CI: 0.18-0.72, p=0.004). Conclusions: A liquid biopsy measuring granzyme B degraded type IV collagen (C4G) as a surrogate of active immune infiltration into the tumor microenvironment is associated with response to the ICI therapy ipilimumab. When combining C4G with the fibrosis biomarker PRO-C3, patients with this special phenotype - low fibrosis and high immune infiltration - have an even better chance of responding compared to high C4G levels alone. If validated, this suggests that specific collagen remodeling biomarkers (C4G+PRO-C3) have potential for predicting response to ICI's in clinical cancer trials. Citation Format: Christina Jensen, Dovile Sinkeviciute, Daniel H. Madsen, Patrik Önnerfjord, Morten Hansen, Henrik Schmidt, Inge Marie Svane, Morten A. Karsdal, Nicholas Willumsen. Liquid biopsy reflecting a T-cell permissive tumor microenvironment identifies metastatic melanoma patients responding to immune checkpoint inhibitor therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3091.
- Published
- 2020
23. USEFULNESS OF LEFT ATRIAL SPECKLE TRACKING ECHOCARDIOGRAPHY IN PREDICTING RECURRENCE OF ATRIAL FIBRILLATION AFTER RADIOFREQUENCY ABLATION: A META-ANALYSIS
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Mats Christian Højbjerg Lassen, Samuel Soerensen, Gunnar Gislason, Kasper Djernæs, Kristoffer Grundtvig Skaarup, Jesper Hastrup Svendsen, Tor Biering-Sørensen, Anne Bjerg Nielsen, Arne Johannessen, Morten Hartvig Hansen, and James Hansen
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medicine.medical_specialty ,Radiofrequency ablation ,business.industry ,Speckle tracking echocardiography ,Atrial fibrillation ,medicine.disease ,law.invention ,Left atrial ,law ,Internal medicine ,Meta-analysis ,medicine ,Cardiology ,Cardiology and Cardiovascular Medicine ,business - Published
- 2020
24. LEFT ATRIAL FUNCTION ASSESSED BY SPECKLE TRACKING ECHOCARDIOGRAPHY PREDICTS RECURRENCE OF ATRIAL FIBRILLATION AFTER CATHETER ABLATION: A RACE ECHOCARDIOGRAPHIC SUB-STUDY
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Anne Bjerg Nielsen, James Hansen, Kasper Djernæs, Arne Johannessen, René Worck, Samuel Soerensen, Kristoffer Grundtvig Skaarup, Raúl San José Estépar, Morten Hartvig Hansen, and Tor Biering-Sørensen
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medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Catheter ablation ,Atrial fibrillation ,Speckle tracking echocardiography ,medicine.disease ,Left atrial ,Internal medicine ,2d speckle tracking ,medicine ,Cardiology ,Cardiology and Cardiovascular Medicine ,business - Abstract
Left atrial function assessed by 2D speckle tracking echocardiography has shown to predict recurrence of atrial fibrillation (AF) after catheter ablation (CA). However, no studies have used implantable loop recorders to verify recurrence. The purpose of this study was to evaluate the predictive
- Published
- 2020
25. Dynamic Modeling and Stability Analysis of a Dual-Rotor Wind Turbine
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Morten Hartvig Hansen, Xuping Zhang, Anders Yde, and Oliver Tierdad Filsoof
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Wind power ,Rotor (electric) ,law ,Computer science ,business.industry ,Control theory ,business ,Turbine ,Stability (probability) ,Dual (category theory) ,System dynamics ,law.invention - Abstract
Various modal analysis methods are available for single-rotor wind turbines, but there is no report and guidance on the modal property analysis of multi-rotor wind turbines. This paper presents a dynamic modeling method for the modal response analysis of a wind turbine with two three-bladed isotropic rotors. The equations of motion are derived using Lagrange’s equations and are further linearized at a steady-state equilibrium. To avoid using Floquet Theory to remove the periodic coefficients, multi-blade coordinates are utilized. Comparison between the numerical simulations and a high-fidelity model in HAWC2 shows agreements in terms of modal frequencies. The results shows that the whirling modes splits into symmetric and asymmetric rotor modes.
- Published
- 2018
26. Extracellular matrix and tissue derived metabolites in a liquid biopsy identifies endotypes of metastatic melanoma patients with differential response to immune checkpoint inhibitor treatment
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Morten Hartvig Hansen, Daniel H. Madsen, Morten A. Karsdal, I.M. Svane, Henrik Schmidt, Christina Jensen, Nicholas Willumsen, and C.L. Bager
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0301 basic medicine ,Oncology ,Endotype ,medicine.medical_specialty ,Metastatic melanoma ,business.industry ,Immune checkpoint inhibitors ,Cancer ,Ipilimumab ,Hematology ,medicine.disease ,Extracellular matrix ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Progression-free survival ,Liquid biopsy ,business ,medicine.drug - Abstract
Background The extracellular matrix (ECM) is a major component of tumors. Several recent findings link ECM composition with outcome in cancer patients treated with immune checkpoint inhibitors (ICIs). The aim here was to explore circulating ECM- and tissue-derived metabolites to enable clustering of patients with metastatic melanoma (MM) into putative endotypes and evaluate patient characteristics and outcome when treated with Ipilimumab accordingly. Methods Serum was collected from MM patients prior to treatment with Ipilimumab (n = 64). Wards hierarchical clustering of patients was based on 15 ECM- and tissue-derived metabolites measured in serum by ELISA. Identified clusters (endotypes) were compared to clinical characteristics and evaluated for associations with disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Results Three putative endotypes (cluster A, B, C) were identified including 14, 30 and 20 patients, respectively. Overall a stepwise increase in ECM metabolite median levels were detected from C-B-A with the largest absolute change seen from B-A. There was no difference between A, B, and C according to age, gender, lactate dehydrogenase levels, number of metastasized organs and whether patients were treated previously. At follow-up, the DCR was 0%, 60% and 45% in A, B, and C, respectively. Likewise, patients with endotype A had a median PFS/OS time of 69/85 days versus 174/520 and 165/589 days for endotype B and C. In support, endotype A predicted for poor survival outcomes (PFSAvsB+C:HR=3.9, 95%CI:2.0-7.6, p = 0.0001; OSAvsB+C:HR:2.5, 95%CI:1.2-4.9, p = 0.0108). Conclusions Hierarchical clustering of MM patients based on 15 ECM- and tissue-derived metabolites measured in a liquid biopsy identifies 3 putative endotypes. One endotype (A) seems to reflect patients with an overall high and differentiated ECM turnover profile. These patients experience poor outcome when treated with Ipilimumab. If validated, this supports a link between ECM remodeling and outcome in cancer patients treated with ICIs. Legal entity responsible for the study Nordic Bioscience. Funding Has not received any funding. Disclosure N. Willumsen: Full / Part-time employment: Nordic Bioscience. C.L. Bager: Full / Part-time employment: Nordic Bioscience. C. Jensen: Full / Part-time employment: Nordic Bioscience. M.A. Karsdal: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Nordic Bioscience. H. Schmidt: Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy: Incyte; Advisory / Consultancy: Novartis; Research grant / Funding (institution): MSD; Travel / Accommodation / Expenses: Roche. I.M. Svane: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy: Pierre Faber; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy: Incyte; Honoraria (self): Roche-Genentech; Travel / Accommodation / Expenses: Pfizer. All other authors have declared no conflicts of interest.
- Published
- 2019
27. PS1380 PEPTIDE VACCINATION AGAINST PD-L1 (IO103) IN MULTIPLE MYELOMA – A PHASE I FIRST IN HUMAN TRIAL
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Evelina Martinenaite, S.M. Ahmad, Morten Hartvig Hansen, I.M. Svane, L.M. Knudsen, Nicolai Grønne Jørgensen, J.H. Grauslund, Mads Hald Andersen, Özcan Met, and U. Klausen
- Subjects
chemistry.chemical_classification ,biology ,business.industry ,Peptide ,Hematology ,First in human ,medicine.disease ,Vaccination ,chemistry ,Phase (matter) ,PD-L1 ,biology.protein ,medicine ,Cancer research ,business ,Multiple myeloma - Published
- 2019
28. Butyrate and propionate inhibit antigen-specific CD8+ T cell activation by suppressing IL-12 production by antigen-presenting cells
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Claudia Nastasi, Andreas Willerslev-Olsen, Niels Ødum, Charlotte M. Bonefeld, Carsten Geisler, Simon Fredholm, Anders Woetmann, Mads Hald Andersen, and Morten Hartvig Hansen
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0301 basic medicine ,chemistry.chemical_classification ,Multidisciplinary ,Chemistry ,T cell ,lcsh:R ,lcsh:Medicine ,Dendritic cell ,Butyrate ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,Immune system ,Interleukin 12 ,medicine ,Propionate ,Cytotoxic T cell ,lcsh:Q ,Antigen-presenting cell ,lcsh:Science - Abstract
Short chain fatty acids (SCFAs), such as acetate, butyrate and propionate, are products of microbial macronutrients fermentation that distribute systemically and are believed to modulate host immune responses. Recent data have indicated that certain SCFAs, such as butyrate and propionate, directly modulate human dendritic cell (DC) function. Given the role of DCs in initiating and shaping the adaptive immune response, we now explore how SCFAs affect the activation of antigen-specific CD8+ T cells stimulated with autologous, MART1 peptide-pulsed DC. We show that butyrate reduces the frequency of peptide-specific CD8+ T cells and, together with propionate, inhibit the activity of those cells. On the contrary, acetate does not affect them. Importantly, butyrate and propionate inhibit the production of IL-12 and IL-23 in the DCs and exogenous IL-12 fully restores the activation of the MART-1-specific CD8+ T cells, whereas IL-23 has no effect. In conclusion, these results point to a pivotal role of butyrate and propionate in modulating CD8+ T cell activation via the inhibition of IL-12 secretion from DCs. These findings reveal a novel mechanism whereby bacterial fermentation products may modulate CD8+ T cell function with possible implications in anti-cancer immunotherapy.
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- 2017
29. Wind turbine fatigue damage evaluation based on a linear model and a spectral method
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Christian Bak, Lars Christian Henriksen, Carlo Tibaldi, and Morten Hartvig Hansen
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Engineering ,Renewable Energy, Sustainability and the Environment ,business.industry ,020209 energy ,02 engineering and technology ,Structural engineering ,Turbine ,Wind speed ,Power (physics) ,Control theory ,Frequency domain ,0202 electrical engineering, electronic engineering, information engineering ,Bending moment ,Rainflow-counting algorithm ,Time domain ,business - Abstract
Wind turbine multidisciplinary design optimization is currently the focus of several investigations because it has showed potential in reducing the cost of energy. This design approach requires fast methods to evaluate wind turbine loads with a sufficiently high level of fidelity. This paper presents a method to estimate wind turbine fatigue damage suited for optimization design applications. The method utilizes a high-order linear wind turbine model. The model comprehends a detailed description of the wind turbine and the controller. The fatigue is computed with a spectral method applied to power spectral densities of wind turbine sensor responses to turbulent wind. In this paper, the model is validated both in time domain and frequency domain with a nonlinear aeroservoelastic model. The approach is compared quantitatively against fatigue damage obtained from the power spectra of time series evaluated with nonlinear aeroservoelastic simulations and qualitatively against rainflow counting. Results are presented for three cases: load evaluation at normal operation in the full wind speed range, load change evaluation due to two different controller tunings at normal operation at three different wind speeds above rated and load dependency on the number of turbulence seeds used for their evaluation. For the full-range normal operation, the maximum difference between the two frequency domain-based estimates of the tower base lateral fatigue moments is 36%, whereas the differences for the other sensors are less than 15%. For the load variation evaluation, the maximum difference of the tower base longitudinal bending moment variation is 22%. Such large difference occurs only when the change in controller tuning has a low effect on the loads. Furthermore, results show that loads evaluated with the presented method are less dependent on the turbulent wind realization; therefore, less turbulence seeds are required compared with time-domain simulations to remove the dependency on the wind realization used to estimate loads. Copyright © 2015 John Wiley & Sons, Ltd.
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- 2015
30. Tumor infiltrating lymphocyte therapy for ovarian cancer and renal cell carcinoma
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Magnus Pedersen, Rikke Andersen, Inge Marie Svane, Morten Hartvig Hansen, Marie Christine Wulff Westergaard, and Marco Donia
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Oncology ,medicine.medical_specialty ,Adoptive cell transfer ,T cell ,medicine.medical_treatment ,Immunology ,Cell- and Tissue-Based Therapy ,Immunotherapy, Adoptive ,Lymphocytes, Tumor-Infiltrating ,Cancer immunotherapy ,Renal cell carcinoma ,Commentaries ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,Precision Medicine ,Carcinoma, Renal Cell ,Cells, Cultured ,Ovarian Neoplasms ,Pharmacology ,business.industry ,Tumor-infiltrating lymphocytes ,Melanoma ,Cancer ,medicine.disease ,medicine.anatomical_structure ,Female ,Ovarian cancer ,business - Abstract
Personalized cancer immunotherapy based on infusion of T cells holds the promise to specifically target a patient’s individual tumor. Accumulating evidence indicates that the T cells mediating these tumor regressions after cancer immunotherapies may primarily target patient-specific mutations expressed by the patients’ tumors and that the presence of these “neo-antigen” specific T-cells may be related to a high number of mutations in the tumor. In melanoma, treatment with autologous tumor-infiltrating lymphocytes (TILs) can mediate durable complete responses. Previous trials investigating TIL therapy in solid tumors other than melanoma have shown limited success, however none of these early trials used current preparative chemotherapy regimens, and the methods for in vitro lymphocyte expansion have changed considerably. New advances and understandings in T cell based immunotherapies have stimulated the interest in developing this approach for other indications. Here, we summarize the early clinical data in the field of adoptive cell transfer therapy (ACT) using tumor-infiltrating lymphocytes for patients with renal cell carcinoma (RCC) and ovarian cancer (OC). In addition we describe the major advances in the characterization and application of TIL therapy for patients with RCC and OC.
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- 2015
31. Frequent adaptive immune responses against arginase-1
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Evelina Martinenaite, Morten Orebo Holmström, Rasmus Erik Johansson Mortensen, Marco Donia, Shamaila Munir Ahmad, Inge Marie Svane, Morten Hartvig Hansen, Nicolai Grønne Jørgensen, Mads Hald Andersen, and Özcan Met
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0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,inflammation and cancer ,T cell ,Immunology ,Inflammation ,Biology ,immunomodulation ,lcsh:RC254-282 ,Epitope ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Antigen ,antigens ,medicine ,peptide vaccine ,Immunology and Allergy ,t cells ,models of immunostimulation ,Original Research ,Melanoma ,ELISPOT ,arginase ,models of anticancer vaccination ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,mdsc ,Cancer cell ,medicine.symptom ,lcsh:RC581-607 - Abstract
The enzyme arginase-1 reduces the availability of arginine to tumor-infiltrating immune cells, thus reducing T-cell functionality in the tumor milieu. Arginase-1 is expressed by some cancer cells and by immune inhibitory cells, such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), and its expression is associated with poor prognosis. In the present study, we divided the arginase-1 protein sequence into overlapping 20-amino-acid-long peptides, generating a library of 31 peptides covering the whole arginase-1 sequence. Reactivity towards this peptide library was examined in PBMCs from cancer patients and healthy individuals. IFNγ ELISPOT revealed frequent immune responses against multiple arginase-1-derived peptides. We further identified a hot-spot region within the arginase-1 protein sequence containing multiple epitopes recognized by T cells. Next, we examined in vitro-expanded tumor-infiltrating lymphocytes (TILs) isolated from melanoma patients, and detected arginase-1-specific T cells that reacted against epitopes from the hot-spot region. Arginase-1-specific CD4+T cells could be isolated and expanded from peripheral T cell pool of a patient with melanoma, and further demonstrated the specificity and reactivity of these T cells. Overall, we showed that arginase-1-specific T cells were capable of recognizing arginase-1-expressing cells. The activation of arginase-1-specific T cells by vaccination is an attractive approach to target arginase-1-expressing malignant cells and inhibitory immune cells. In the clinical setting, the induction of arginase-1-specific immune responses could induce or increase Th1 inflammation at the sites of tumors that are otherwise excluded due to infiltration with MDSCs and TAMs.
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- 2017
32. Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes
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Philippa Rabbitt, Richard L. Young, Tina Vilsbøll, Paul Hollington, Dayan de Fontgalland, Alice P. Liou, Ulrich Rohde, Morten Hartvig Hansen, Damien J. Keating, David P. Sonne, Emily W. Sun, David Wattchow, Jens F. Rehfeld, Emilie Bahne, Filip K. Knop, Steven L. Due, Jakob S. Hansen, Jens J. Holst, Margaret Jackson, and Luigi Sposato
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0301 basic medicine ,Adult ,Blood Glucose ,Male ,medicine.medical_specialty ,endocrine system ,endocrine system diseases ,medicine.drug_class ,030209 endocrinology & metabolism ,Type 2 diabetes ,Placebo ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Glucagon-Like Peptide 1 ,Internal medicine ,Diabetes mellitus ,medicine ,Humans ,Aged ,Aged, 80 and over ,business.industry ,digestive, oral, and skin physiology ,Australia ,nutritional and metabolic diseases ,General Medicine ,Middle Aged ,medicine.disease ,Receptor antagonist ,Postprandial Period ,Glucagon-like peptide-1 ,Metformin ,3. Good health ,030104 developmental biology ,Postprandial ,Endocrinology ,Diabetes Mellitus, Type 2 ,Female ,business ,Ex vivo ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug ,Research Article - Abstract
BACKGROUND. Metformin reduces plasma glucose and has been shown to increase glucagon-like peptide 1 (GLP-1) secretion. Whether this is a direct action of metformin on GLP-1 release, and whether some of the glucose-lowering effect of metformin occurs due to GLP-1 release, is unknown. The current study investigated metformin-induced GLP-1 secretion and its contribution to the overall glucose-lowering effect of metformin and underlying mechanisms in patients with type 2 diabetes. METHODS. Twelve patients with type 2 diabetes were included in this placebo-controlled, double-blinded study. On 4 separate days, the patients received metformin (1,500 mg) or placebo suspended in a liquid meal, with subsequent i.v. infusion of the GLP-1 receptor antagonist exendin9-39 (Ex9-39) or saline. During 240 minutes, blood was sampled. The direct effect of metformin on GLP-1 secretion was tested ex vivo in human ileal and colonic tissue with and without dorsomorphin-induced inhibiting of the AMPK activity. RESULTS. Metformin increased postprandial GLP-1 secretion compared with placebo (P = 0.014), and the postprandial glucose excursions were significantly smaller after metformin + saline compared with metformin + Ex9-39 (P = 0.004). Ex vivo metformin acutely increased GLP-1 secretion (colonic tissue, P < 0.01; ileal tissue, P < 0.05), but the effect was abolished by inhibition of AMPK activity. CONCLUSIONS. Metformin has a direct and AMPK-dependent effect on GLP-1–secreting L cells and increases postprandial GLP-1 secretion, which seems to contribute to metformin’s glucose-lowering effect and mode of action. TRIAL REGISTRATION. {"type":"clinical-trial","attrs":{"text":"NCT02050074","term_id":"NCT02050074"}}NCT02050074 (https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT02050074","term_id":"NCT02050074"}}NCT02050074). FUNDING. This study received grants from the A.P. Moller Foundation, the Novo Nordisk Foundation, the Danish Medical Association research grant, the Australian Research Council, the National Health and Medical Research Council, and Pfizer Inc.
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- 2017
33. Corrigendum: Differential CCR7 Targeting in Dendritic Cells by Three Naturally Occurring CC-Chemokines
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Anne Steen, Suzan Fares, Mette M. Rosenkilde, Simi Ali, Gertrud Malene Hjortø, Olav Larsen, Viktorija Daugvilaite, Christian Berg, and Morten Hartvig Hansen
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0301 basic medicine ,MAPK/ERK pathway ,Chemistry ,dendritic cell ,CCL19 ,Immunology ,CC chemokine ,tailless-CCL21 ,C-C chemokine receptor type 7 ,Dendritic cell ,Cell biology ,03 medical and health sciences ,ERK ,030104 developmental biology ,Immunology and Allergy ,Differential (mathematics) ,CCL21 ,CCR7 ,biased signaling - Published
- 2017
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34. Predictors of responses to immune checkpoint blockade in advanced melanoma
- Author
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Brigitte Dréno, Caroline Flament, Nicolas Jacquelot, B. Balme, Yaron Meirow, Mitchell P. Levesque, Jeffrey S. Weber, Christophe Borg, Lawrence Fong, Amir Khammari, Guido Kroemer, Sylvie Rusakiewicz, Morten Hartvig Hansen, Ignacio Melero, Gorana Tomasic, Henrik Schmidt, Meriem Messaoudene, Andrea Cavalcanti, Maria Paula Roberti, Sarah Jegou, Yoshinobu Koguchi, Stefan Michiels, Moshe Sade-Feldman, Michal Baniyash, Ana C. Anderson, Byoung S. Kwon, Lieping Chen, Aurélien Marabelle, David Enot, Arun Burra, Inge Marie Svane, Stéphane Dalle, A.M. Di Giacomo, Dirk Schadendorf, Nils Ternès, Laurence Zitvogel, Reinhard Dummer, Andressa L. Sodre, Serena S. Kwek, O Beatrix, Vijay K. Kuchroo, Alexander M.M. Eggermont, David M. Woods, Benjamin Weide, Mark J. Smyth, Michele Maio, Maha Ayyoub, François Aubin, Connie P.M. Duong, Michal Lotem, Immunologie des tumeurs et immunothérapie (UMR 1015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Université Paris-Saclay, Institut Gustave Roussy (IGR), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Microorganismes et physiopathologie intestinale (ERL INSERM U1157 - CNRS UMR 7203), Laboratoire des biomolécules (LBM UMR 7203), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC), Laura & Isaac Perlmutter Cancer Center [New York, NY, USA], New York University Langone Medical Center (NYU Langone Medical Center), NYU System (NYU)-NYU System (NYU), Department of Hematology and Oncology [Herlev, Denmark], Copenhagen University Hospital, The Lautenberg Center for General and Tumor Immunology [Jerusalem, Israel], The Hebrew University Hadassah Medical School -BioMedical Research institute Israel Canada of the Faculty of Medicine [Jerusalem, Israel], Division of Hematology-Oncology [San Francisco, CA, USA] (Department of Medicine), University of California [San Francisco] (UCSF), University of California-University of California, Department of Immunobiology [New Haven, CT, USA] (Yale School of Medicine), Yale University [New Haven], Eutilex Co., Ltd [Seoul, Korea], Section of Clinical Immunology, Allergy, and Rheumatology [New Orleans, LA, USA] (Department of Medicine), Tulane University Health Sciences Center [New Orleans, LA, USA], Evergrande Center for Immunologic Diseases [Boston, MA, USA] (Ann Romney Center for Neurologic Diseases), Brigham & Women's Hospital, Harvard Medical School, Department of Dermatology [Tubingen, Germany], University Medical Center [Tubingen, Germany], Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service d'Oncologie Médicale [CHRU Besançon], Centre d'Investigation Clinique de Besançon (Inserm CIC 1431), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Pathologie [CHU Lyon-Sud - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Département de biologie et pathologie médicales [Gustave Roussy], Division of Medical Oncology and Immunotherapy [Siena, Italy], University Hospital of Siena, Department of Dermatology [Heidelberg, Germany], University Duisburg-Essen [Germany]-University Hospital [Heidelberg, Germany]-Germany & German Cancer Consortium - DKTZ [Heidelberg, Germany], Division of Hepatology and Gene Therapy (CIMA), Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV)-Universidad de Navarra [Pamplona] (UNAV), Oncology Department [Pamplona, Spain], University Clinic of Navarra - CUN [Pamplona, Spain], Centro de Investigación Biomedica en Red de Oncologia [Pamplona, Spain] (CIBERO), Clinical and Translational Research in Skin Cancer (CRCINA-ÉQUIPE 2), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Department of Dermatology [Zürich, Switzerland], Universität Zürich [Zürich] = University of Zurich (UZH)-University hospital of Zurich [Zurich], Earle A. Chiles Research Institute [Portland, OR, USA], Providence Portland Medical Center-Robert W. Franz Cancer Research Center, Sharett Institute of Oncology [Jerusalem, Israel], Hadassah Medical Organization [Jerusalem, Israel], Department of Oncology [Aarhus, Denmark], Aarhus University Hospital, Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Sorbonne Paris Cité (USPC), Pôle de biologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Département de chirurgie générale [Gustave Roussy], Service de dermatologie, Département de médecine oncologique [Gustave Roussy], Immunology in Cancer and Infection Laboratory [Herston, QLD, Australia], QIMR Berghofer Medical Research Institute, School of Medicine [Herston, QLD, Australia], University of Southern Queensland (USQ), This work was supported by Institut National du Cancer INCa, ANR, Ligue contre le cancer (équipe labellisée de L.Z.) and Swiss Bridge Foundation, ISREC Foundation, LABEX OncoImmunology, la direction générale de l’offre de soins (DGOS), Université Paris-Sud, SIRIC SOCRATE (INCa/DGOS/INSERM 6043), PACRI network and PIA2 TORINO-LUMIERE. N.J. received a fellowship from Cancéropole Idf. M.J.S. was supported by a National Health and Medical Research Council of Australia Senior Principal Research Fellowship., Bernardo, Elizabeth, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (UR 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Universität Duisburg-Essen = University of Duisburg-Essen [Essen]-University Hospital [Heidelberg, Germany]-Germany & German Cancer Consortium - DKTZ [Heidelberg, Germany], Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE)
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_treatment ,Medizin ,General Physics and Astronomy ,0302 clinical medicine ,METASTATIC MELANOMA ,TUMOR-INFILTRATING LYMPHOCYTES ,lcsh:Science ,Cancer ,screening and diagnosis ,Multidisciplinary ,CD137 ,3. Good health ,Detection ,030220 oncology & carcinogenesis ,Patient Safety ,BREAST-CANCER PATIENTS ,Nivolumab ,Adjuvant ,CIRCULATING SOLUBLE FAS ,medicine.drug ,medicine.medical_specialty ,CELL LUNG-CANCER ,Science ,PROGNOSTIC IMPACT ,Clinical Trials and Supportive Activities ,Ipilimumab ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Immune system ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Clinical Research ,Internal medicine ,Journal Article ,STAGE-III MELANOMA ,medicine ,CLINICAL-SIGNIFICANCE ,business.industry ,UNTREATED MELANOMA ,General Chemistry ,Immune checkpoint ,Blockade ,4.1 Discovery and preclinical testing of markers and technologies ,030104 developmental biology ,COMBINED NIVOLUMAB ,Immunology ,lcsh:Q ,business ,CD8 - Abstract
Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs. Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB. Based on this assay, we retrospectively observed, in eight cohorts enrolling 190 MMel patients treated with ipilimumab, that PD-L1 expression on peripheral T cells was prognostic on overall and progression-free survival. Moreover, detectable CD137 on circulating CD8+ T cells was associated with the disease-free status of resected stage III MMel patients after adjuvant ipilimumab + nivolumab (but not nivolumab alone). These biomarkers should be validated in prospective trials in MMel., The clinical management of metastatic melanoma requires predictors of the response to checkpoint blockade. Here, the authors use immunological assays to identify potential prognostic/predictive biomarkers in circulating blood cells and in tumor-infiltrating lymphocytes from patients with resected stage III melanoma.
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- 2017
35. Optimized Markov Chain Monte Carlo for Signal Detection in MIMO Systems: An Analysis of the Stationary Distribution and Mixing Time
- Author
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Weiyu Xu, Alexandros G. Dimakis, Babak Hassibi, Morten Hartvig Hansen, and Haider Ali Jasim Alshamary
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FOS: Computer and information sciences ,Markov chain mixing time ,Markov chain ,Computer Science - Information Theory ,Information Theory (cs.IT) ,Markov chain Monte Carlo ,Markov model ,Continuous-time Markov chain ,Hybrid Monte Carlo ,Combinatorics ,symbols.namesake ,Coupling from the past ,Signal Processing ,symbols ,Markov property ,Statistical physics ,Electrical and Electronic Engineering ,Mathematics - Abstract
In this paper we introduce an optimized Markov Chain Monte Carlo (MCMC) technique for solving the integer least-squares (ILS) problems, which include Maximum Likelihood (ML) detection in Multiple-Input Multiple-Output (MIMO) systems. Two factors contribute to the speed of finding the optimal solution by the MCMC detector: the probability of the optimal solution in the stationary distribution, and the mixing time of the MCMC detector. Firstly, we compute the optimal value of the "temperature" parameter, in the sense that the temperature has the desirable property that once the Markov chain has mixed to its stationary distribution, there is polynomially small probability ($1/\mbox{poly}(N)$, instead of exponentially small) of encountering the optimal solution. This temperature is shown to be at most $O(\sqrt{SNR}/\ln(N))$, where $SNR$ is the signal-to-noise ratio, and $N$ is the problem dimension. Secondly, we study the mixing time of the underlying Markov chain of the proposed MCMC detector. We find that, the mixing time of MCMC is closely related to whether there is a local minimum in the lattice structures of ILS problems. For some lattices without local minima, the mixing time of the Markov chain is independent of $SNR$, and grows polynomially in the problem dimension; for lattices with local minima, the mixing time grows unboundedly as $SNR$ grows, when the temperature is set, as in conventional wisdom, to be the standard deviation of noises. Our results suggest that, to ensure fast mixing for a fixed dimension $N$, the temperature for MCMC should instead be set as $\Omega(\sqrt{SNR})$ in general. Simulation results show that the optimized MCMC detector efficiently achieves approximately ML detection in MIMO systems having a huge number of transmit and receive dimensions., Comment: 14 pages. arXiv admin note: substantial text overlap with arXiv:1203.2213
- Published
- 2014
36. MECHANISMS IN ENDOCRINOLOGY: Bile acid sequestrants in type 2 diabetes: potential effects on GLP1 secretion
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Filip K. Knop, David P. Sonne, and Morten Hartvig Hansen
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medicine.medical_specialty ,Bile acid ,Cholesterol ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,General Medicine ,Biology ,G protein-coupled bile acid receptor ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Nuclear receptor ,Biochemistry ,Internal medicine ,CYP27A1 ,medicine ,Farnesoid X receptor ,Receptor ,Lipid digestion - Abstract
Bile acid sequestrants have been used for decades for the treatment of hypercholesterolaemia. Sequestering of bile acids in the intestinal lumen interrupts enterohepatic recirculation of bile acids, which initiate feedback mechanisms on the conversion of cholesterol into bile acids in the liver, thereby lowering cholesterol concentrations in the circulation. In the early 1990s, it was observed that bile acid sequestrants improved glycaemic control in patients with type 2 diabetes. Subsequently, several studies confirmed the finding and recently – despite elusive mechanisms of action – bile acid sequestrants have been approved in the USA for the treatment of type 2 diabetes. Nowadays, bile acids are no longer labelled as simple detergents necessary for lipid digestion and absorption, but are increasingly recognised as metabolic regulators. They are potent hormones, work as signalling molecules on nuclear receptors and G protein-coupled receptors and trigger a myriad of signalling pathways in many target organs. The most described and well-known receptors activated by bile acids are the farnesoid X receptor (nuclear receptor) and the G protein-coupled cell membrane receptor TGR5. Besides controlling bile acid metabolism, these receptors are implicated in lipid, glucose and energy metabolism. Interestingly, activation of TGR5 on enteroendocrine L cells has been suggested to affect secretion of incretin hormones, particularly glucagon-like peptide 1 (GLP1 (GCG)). This review discusses the role of bile acid sequestrants in the treatment of type 2 diabetes, the possible mechanism of action and the role of bile acid-induced secretion of GLP1 via activation of TGR5.
- Published
- 2014
37. Potential of power gain with improved yaw alignment
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Morten Hartvig Hansen and Knud Abildgaard Kragh
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Power gain ,Engineering ,Offshore wind power ,Wind power ,Renewable Energy, Sustainability and the Environment ,business.industry ,Nacelle ,Control theory ,Inflow ,Wind direction ,business ,Turbine ,Wind speed - Abstract
One of the primary criteria for extracting energy from the wind using horizontal axis upwind wind turbines is the ability to align the rotor axis with the dominating wind direction. The conventional way of estimating the direction of the incoming flow is by using transducers placed atop the nacelle and downwind of the rotor. Recent studies have suggested methods based on advanced upwind measurement technologies for estimating the inflow direction and improving the yaw alignment. In this study, the potential of increased power output with improved yaw alignment is investigated by assessing the performance of a current measurement and yaw control system. The performance is assessed by analyzing data containing upwind wind speed and direction measurements from a met mast, and yaw angle and power production measurements from an operating offshore wind turbine. The results of the analysis indicate that the turbine is operating with a wind speed-dependent yaw error distribution. The theoretical annual energy production loss due to the yaw error distribution of the existing system is estimated to approximately 0.2%. Copyright © 2014 John Wiley & Sons, Ltd.
- Published
- 2014
38. Corrigendum: Differential CCR7 Targeting in Dendritic Cells by Three Naturally Occurring CC-Chemokines
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Morten Hartvig Hansen, Christian Berg, Mette M. Rosenkilde, Suzan Fares, Olav Larsen, Viktorija Daugvilaite, Anne Steen, Simi Ali, and Gertrud Malene Hjortø
- Subjects
lcsh:Immunologic diseases. Allergy ,0301 basic medicine ,endocrine system ,Chemokine ,dendritic cell ,Immunology ,C-C chemokine receptor type 7 ,Biology ,03 medical and health sciences ,0302 clinical medicine ,CCL19 ,Immunology and Allergy ,Receptor ,Original Research ,biased signaling ,Polysialic acid ,Correction ,tailless-CCL21 ,Chemotaxis ,Dendritic cell ,Cell biology ,ERK ,030104 developmental biology ,Biochemistry ,biology.protein ,lcsh:RC581-607 ,CCR7 ,CCL21 ,030215 immunology - Abstract
The CCR7 ligands CCL19 and CCL21 are increasingly recognized as functionally different (biased). Using mature human dendritic cells (DCs), we show that CCL19 is more potent than CCL21 in inducing 3D chemotaxis. Intriguingly, CCL21 induces prolonged and more efficient ERK1/2 activation compared with CCL19 and a C-terminal truncated (tailless) CCL21 in DCs. In contrast, tailless-CCL21 displays increased potency in DC chemotaxis compared with native CCL21. Using a CCL21-specific antibody, we show that CCL21, but not tailless-CCL21, accumulates at the cell surface. In addition, removal of sialic acid from the cell surface by neuraminidase treatment impairs ERK1/2 activation by CCL21, but not by CCL19 or tailless-CCL21. Using standard laboratory cell lines, we observe low potency of both CCL21 and tailless-CCL21 in G protein activation and β-arrestin recruitment compared with CCL19, indicating that the tail itself does not improve receptor interaction. Chemokines interact with their receptors in a stepwise manner with ultimate docking of their N-terminus into the main binding pocket. Employing site-directed mutagenesis we identify residues in this pocket of selective CCL21 importance. We also identify a molecular switch in the top of TM7 important for keeping CCR7 in an inactive conformation (Tyr312), as introduction of the chemokine receptor-conserved Glu (or Ala) induces high constitutive activity. Summarized, we show that the interaction of the tail of CCL21 with polysialic acid is needed for strong ERK signaling, whereas it impairs CCL21-mediated chemotaxis and has no impact on receptor docking consistent with the current model of chemokine:receptor interaction. This indicates that future selective pharmacological targeting of CCL19 versus CCL21 should focus on a differential targeting of the main receptor pocket, while selective targeting of tailless-CCL21 versus CCL21 and CCL19 requires targeting of the glycosaminoglycan (GAG) interaction.
- Published
- 2016
39. Assessment of extracellular matrix and tissue derived metabolites in a liquid biopsy for identifying endotypes of metastatic melanoma patients with differential response to immune checkpoint inhibitor treatment
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Nicholas Willumsen, Daniel H. Madsen, Cecilie L. Bager, Inge Marie Svane, Morten A. Karsdal, Morten Hartvig Hansen, Christina Jensen, and Henrik Schmidt
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Extracellular matrix ,Cancer Research ,Oncology ,Metastatic melanoma ,business.industry ,Immune checkpoint inhibitors ,Cancer research ,Medicine ,Cancer ,Liquid biopsy ,business ,medicine.disease ,Immune checkpoint - Abstract
e14050 Background: The extracellular matrix (ECM) is a major component of tumors. Several recent findings link ECM composition with outcome in cancer patients treated with immune checkpoint inhibitors (ICIs). The aim here was to explore circulating ECM- and tissue-derived metabolites to enable clustering of patients with metastatic melanoma (MM) into putative endotypes and evaluate patient characteristics and outcome when treated with Ipilimumab accordingly. Methods: Serum was collected from MM patients prior to treatment with Ipilimumab (n = 64). Wards hierarchical clustering of patients was based on 15 ECM- and tissue-derived metabolites measured in serum by ELISA. Identified clusters (endotypes) were compared to clinical characteristics and evaluated for associations with disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Results: Three putative endotypes (cluster A, B, C) were identified including 14, 30 and 20 patients, respectively. Overall a stepwise increase in ECM metabolite median levels were detected from C-B-A with the largest absolute change seen from B-A. There was no difference between A, B, and C according to age, gender, lactate dehydrogenase levels, number of metastasized organs and whether patients were treated previously. At follow-up, the DCR was 0%, 60% and 45% in A, B, and C, respectively. Likewise, patients with endotype A had a median PFS/OS time of 69/85 days versus 174/520 and 165/589 days for endotype B and C. In support, endotype A predicted for poor survival outcomes (PFSAvsB+C:HR = 3.9, 95%CI:2.0-7.6, p = 0.0001; OSAvsB+C:HR:2.5, 95%CI:1.2-4.9, p = 0.0108). Conclusions: Hierarchical clustering of MM patients based on 15 ECM- and tissue-derived metabolites measured in a liquid biopsy identifies 3 putative endotypes. One endotype (A) seems to reflect patients with an overall high and differentiated ECM turnover profile. These patients experience poor outcome when treated with Ipilimumab. If validated, this supports a link between ECM remodeling and outcome in cancer patients treated with ICIs.
- Published
- 2019
40. Abstract A079: Secreted IL-12p70 from long-term activated dendritic cells is lost concomitant with their apoptosis and release of IL-10
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Laura Stentoft Carstensen, Morten Hartvig Hansen, Andreas Obers, and Inge Marie Svane
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Cancer Research ,Lipopolysaccharide ,business.industry ,Immunology ,Peripheral tolerance ,Acquired immune system ,Peripheral blood mononuclear cell ,chemistry.chemical_compound ,Interleukin 10 ,chemistry ,Immunity ,Apoptosis ,Medicine ,Secretion ,business - Abstract
The intimate balance between peripheral tolerance and adaptive immunity has profound implications in several disease settings. Interleukin-12 (IL-12) plays a major role in immunity to intracellular pathogens and cancer by controlling IFNγ-dependent adaptive immunity. The transient production of the bioactive IL-12p70 heterodimer and the concurrent expression of interleukin-10 (IL-10) serves as a myeloid checkpoint to avoid immunopathology. Here, long-term exposure to inflammatory stimuli was evaluated on monocyte-derived dendritic cells (DCs) activated with lipopolysaccharide (LPS) and gamma interferon (IFNγ). The secretion of IFNγ from co-cultures with allogeneic T-cells present in peripheral blood mononuclear cells from healthy volunteers served as a measure of T-cell activation.The secretion of IFNγ from co-cultures was progressively lost as exposure of DCs to inflammatory stimuli was extended from one up to four days prior to co-culture or following IL-12p70 antibody-mediated blockade. Most pronounced was the 12-fold reduction (N = 9 donor pairs) seen with four-day activated DCs. Furthermore, at four days of activation, a significant fraction of DCs underwent apoptosis concomitant with their increased release of IL-10 and a striking 10-fold drop in levels of IL-12p70 as compared with DCs activated one, two or three days. Furthermore, after four days of activation, DC-derived IL-12p70 was inversely correlated with IL-10 and with IFNγ derived from co-cultures. It is currently an open question whether IL-12p70 naturally degrades after four days of activation or whether apoptotic DCs actively stimulate the degradation of IL-12p70. Citation Format: Morten Hansen, Laura Stentoft Carstensen, Andreas Obers, Inge Marie Stentoft Svane. Secreted IL-12p70 from long-term activated dendritic cells is lost concomitant with their apoptosis and release of IL-10 [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A079.
- Published
- 2019
41. Sensor comparison study for load alleviating wind turbine pitch control
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Knud Abildgaard Kragh, Lars Christian Henriksen, and Morten Hartvig Hansen
- Subjects
Engineering ,Lidar ,Pitch control ,Renewable Energy, Sustainability and the Environment ,Control theory ,business.industry ,Comparison study ,business ,Turbine ,Automotive engineering - Published
- 2013
42. Open-loop frequency response analysis of a wind turbine using a high-order linear aeroelastic model
- Author
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Ivan Bergquist Sønderby and Morten Hartvig Hansen
- Subjects
Frequency response ,Engineering ,Renewable Energy, Sustainability and the Environment ,business.industry ,Drivetrain ,Aerodynamics ,Structural engineering ,Aeroelasticity ,Turbine ,Physics::Fluid Dynamics ,Aerodynamic force ,Pitch control ,Control theory ,Torque ,business - Abstract
Wind turbine controllers are commonly designed on the basis of low-order linear models to capture the aeroelastic wind turbine response due to control actions and disturbances. This paper characterizes the aeroelastic wind turbine dynamics that influence the open-loop frequency response from generator torque and collective pitch control actions of a modern non-floating wind turbine based on a high-order linear model. The model is a linearization of a geometrically non-linear finite beam element model coupled with an unsteady blade element momentum model of aerodynamic forces including effects of shed vorticity and dynamic stall. The main findings are that the lowest collective flap modes have limited influence on the response from generator torque to generator speed, due to large aerodynamic damping. The transfer function from collective pitch to generator speed is affected by two non-minimum phase zeros below the frequency of the first drivetrain mode. To correctly predict the non-minimum phase zeros, it is essential to include lateral tower and blade flap degrees of freedom. Copyright © 2013 John Wiley & Sons, Ltd.
- Published
- 2013
43. Load alleviation of wind turbines by yaw misalignment
- Author
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Knud Abildgaard Kragh and Morten Hartvig Hansen
- Subjects
Engineering ,Wind power ,Renewable Energy, Sustainability and the Environment ,business.industry ,Aerospace engineering ,business ,Marine engineering - Published
- 2013
44. Measurements of Brownian relaxation of magnetic nanobeads using planar Hall effect bridge sensors
- Author
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Giovanni Rizzi, T. Zardán Gómez de la Torre, Mattias Strömberg, Peter Svedlindh, Morten Hartvig Hansen, Frederik Westergaard Østerberg, and Maria Strømme
- Subjects
Materials science ,Conductometry ,Biomedical Engineering ,Biophysics ,Measure (physics) ,Nanotechnology ,Biosensing Techniques ,Sensitivity and Specificity ,Bridge (interpersonal) ,Diffusion ,Magnetics ,Biopolymers ,Electrochemistry ,Suspension (vehicle) ,Planar hall effect ,Immunomagnetic Separation ,business.industry ,Reproducibility of Results ,Equipment Design ,General Medicine ,Magnetic response ,equipment and supplies ,Brownian relaxation ,Equipment Failure Analysis ,Optoelectronics ,business ,human activities ,Biosensor ,Biotechnology - Abstract
We compare measurements of the Brownian relaxation response of magnetic nanobeads in suspension using planar Hall effect sensors of cross geometry and a newly proposed bridge geometry. We find that the bridge sensor yields six times as large signals as the cross sensor, which results in a more accurate determination of the hydrodynamic size of the magnetic nanobeads. Finally, the bridge sensor has successfully been used to measure the change in dynamic magnetic response when rolling circle amplified DNA molecules are bound to the magnetic nanobeads. The change is validated by measurements performed in a commercial AC susceptometer. The presented bridge sensor is, thus, a promising component in future lab-on-a-chip biosensors for detection of clinically relevant analytes, including bacterial genomic DNA and proteins.
- Published
- 2013
45. Characterization of T-cell responses against IκBα in cancer patients
- Author
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Morten Hartvig Hansen, Shamaila Munir, Thomas Mørch Frøsig, Inge Marie Svane, and Mads Hald Andersen
- Subjects
T cell ,Immunology ,T cells ,Antigen ,antigens ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,inhibitor of κB ,biology ,business.industry ,Melanoma ,Cancer ,medicine.disease ,IκBα ,proteasome ,medicine.anatomical_structure ,Oncology ,Proteasome ,Granzyme ,CTL ,Cancer research ,biology.protein ,business ,Research Paper ,NFκB - Abstract
The nuclear factor κ light chain enhancer of activated B cells (NFκB) is constitutively active in most cancers, controlling multiple cellular processes including proliferation, invasion and resistance to therapy. NFκB is primarily regulated through the association with inhibitory proteins that are known as inhibitors of NFκB (IκBs). Increased NFκB activity in tumor cells has been correlated with decrease stability of IκB proteins, in particular IκBα. In responso to a large number of stimuli, IκB proteins are degraded by the proteasome. Cytotoxic T lymphocytes (CTLs) recognize HLA-restricted antigenic peptides that are generated by proteasomal degradation in target cells. In the present study, we demonstrate the presence of naturally occurring IκBα -specific T cells in the peripheral blood of patients suffering from several unrelated tumor types, i.e., breast cancer, malignant melanoma and renal cell carcinoma, but not of healthy controls. Furthermore, we show that such IBα-specific T cells are granzyme B-releasing, cytotoxic cells. Hence, the increased proteasomal degradation of IκBα in cancer induces IκBα-specific CTLs.
- Published
- 2012
46. A LIDAR-assisted model predictive controller added on a traditional wind turbine controller
- Author
-
Mahmood Mirzaei and Morten Hartvig Hansen
- Subjects
0209 industrial biotechnology ,Engineering ,Wind power ,business.industry ,020209 energy ,Open-loop controller ,PID controller ,Control engineering ,02 engineering and technology ,Turbine ,Wind speed ,Power (physics) ,020901 industrial engineering & automation ,Pitch control ,Control theory ,0202 electrical engineering, electronic engineering, information engineering ,business - Abstract
LIDAR-assisted collective pitch control shows promising results for load reduction in the full load operating region of horizontal axis wind turbines (WT). Utilizing LIDARs in WT control can be approached in different ways; One method is to design the WT controller from ground up based on the LIDAR measurements. Nevertheless, to make the LIDAR-assisted controller easily implementable on existing wind turbines, one can design a controller that is added to the original and existing WT controller. This add-on solution makes it easier to prove the applicability and performance of the LIDAR-assisted WT control and opens the market of retrofitting existing wind turbines with the new technology. In this paper, we suggest a model predictive controller (MPC) that is added to the basic gain scheduled PI controller of a WT to enhance the performance of the closed loop system using LIDAR measurements. The performance of the MPC controller is compared against two controllers. The controllers are 1) a gain scheduled PI controller and 2) a controller with the same feedback as controller no. 1 and an added feed-forward loop (FF+PI controller). Simulations are used to compare their performances. The simulation scenarios include the extreme operating gust and normal power production using stochastic wind field in the full load region. The results show superior performance compared to the PI controller and a performance marginally better compared to the FF+PI controller. The reason for a better performance against the PI controller is that the MPC controller employs the LIDAR wind speed measurements to predict and compensate future disturbances. The MPC controller is designed based on the closed loop model of the wind turbine including the pitch actuator and therefore an appropriate pitch signal is calculated, while the FF+PI controller employs filter and delay compensation to take the actuator dynamics into account.
- Published
- 2016
47. CCL22-specific T Cells: Modulating the immunosuppressive tumor microenvironment
- Author
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Marie Christine Wulff Westergaard, Shamaila Munir Ahmad, Mads Hald Andersen, Özcan Met, Stine Kiaer Larsen, Tobias Wirenfeldt Klausen, Marco Donia, Inge Marie Svane, Morten Hartvig Hansen, and Evelina Martinenaite
- Subjects
0301 basic medicine ,CD40 ,biology ,Immunology ,Natural killer T cell ,03 medical and health sciences ,Interleukin 21 ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Interleukin 12 ,Immunology and Allergy ,Cytotoxic T cell ,IL-2 receptor ,Antigen-presenting cell ,Interleukin 3 ,Original Research - Abstract
Tumor cells and tumor-infiltrating macrophages produce the chemokine CCL22, which attracts regulatory T cells (Tregs) into the tumor microenvironment, decreasing anticancer immunity. Here, we investigated the possibility of targeting CCL22-expressing cells by activating specific T cells. We analyzed the CCL22 protein signal sequence, identifying a human leukocyte antigen A2- (HLA-A2-) restricted peptide epitope, which we then used to stimulate peripheral blood mononuclear cells (PMBCs) to expand populations of CCL22-specific T cells in vitro. T cells recognizing an epitope derived from the signal-peptide of CCL22 will recognize CCL22-expressing cells even though CCL22 is secreted out of the cell. CCL22-specific T cells recognized and killed CCL22-expressing cancer cells. Furthermore, CCL22-specific T cells lysed acute monocytic leukemia cells in a CCL22 expression-dependent manner. Using the Enzyme-Linked ImmunoSPOT assay, we examined peripheral blood mononuclear cells from HLA-A2+ cancer patients and healthy volunteers for reactivity against the CCL22-derived T-cell epitope. This revealed spontaneous T-cell responses against the CCL22-derived epitope in cancer patients and in healthy donors. Finally, we performed tetramer enrichment/depletion experiments to examine the impact of HLA-A2-restricted CCL22-specific T cells on CCL22 levels among PMBCs. The addition or activation of CCL22-specific T cells decreased the CCL22 level in the microenvironment. Activating CCL22-specific T cells (e.g., by vaccination) may directly target cancer cells and tumor-associated macrophages, thereby modulating Treg recruitment into the tumor environment and augmenting anticancer immunity.
- Published
- 2016
48. Autocrine CCL19 blocks dendritic cell migration toward weak gradients of CCL21
- Author
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Gertrud Malene Hjortø, Mette M. Rosenkilde, Inge Marie Svane, Morten Hartvig Hansen, Niels Bent Larsen, Mads Hald Andersen, and Özcan Met
- Subjects
0301 basic medicine ,Male ,endocrine system ,Cancer Research ,Chemokine ,Immunology ,Biology ,Dinoprostone ,Monocytes ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Immunology and Allergy ,Humans ,Autocrine signalling ,Dendritic cell migration ,Genetics (clinical) ,Cells, Cultured ,Transplantation ,Chemokine CCL21 ,Chemotaxis ,CCL19 ,hemic and immune systems ,Cell Biology ,Dendritic Cells ,Cell biology ,030104 developmental biology ,Oncology ,biology.protein ,Chemokine CCL19 ,030215 immunology ,Chemotaxis assay ,Homing (hematopoietic) ,CCL21 - Abstract
Background aims Maturation of dendritic cells (DCs) induces their homing from peripheral to lymphatic tissues guided by CCL21. However, in vitro matured human monocyte-derived DC cancer vaccines injected intradermally migrate poorly to lymph nodes (LNs). In vitro maturation protocols generate DCs with high (type 1 DCs) or low (prostaglandin E 2 [PGE 2 ]-DCs) autocrine CCL19 levels, which may potentially interfere with LN homing of DCs. Methods. Employing a three-dimensional (3D) chemotaxis assay, chemokine competition/desensitization studies and short interfering RNA (siRNA) against CCL19, we analyzed the effect of autocrine CCL19 on in vitro migration of human DCs toward CCL21. Results. Using human monocyte-derived DCs in a 3D chemotaxis assay, we are the first to demonstrate that CCL19 more potently induces directed migration of human DCs compared with CCL21. When comparing migration of type 1 DCs and PGE 2 -DCs, migration of type 1 DCs was strikingly impaired compared with PGE 2 -DCs, but only toward low concentrations of CCL21. When type 1 DCs were cultured overnight in fresh culture medium (reducing autocrine CCL19 levels), a rescuing effect was observed on migration toward low concentrations of CCL21 in a 3D chemotaxis assay. Finally pre-incubation with CCL19 negatively affected PGE 2 -DC migration, whereas silencing of CCL19 by siRNA improved type 1 DC migration. Importantly, in both cases, the effect was observed only at low concentrations of CCL21. Conclusions. Our results demonstrate that autocrine CCL19 negatively affects DC migratory potential toward CCL21, the potency difference between CCL19 and CCL21 being the underlying cause. CCL19 secretion level of in vitro matured DCs is an important indicator of DC vaccine homing potential.
- Published
- 2016
49. Modal dynamics of structures with bladed isotropic rotors and its complexity for 2-bladed rotors
- Author
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Morten Hartvig Hansen
- Subjects
Physics::Fluid Dynamics - Abstract
The modal dynamics of structures with bladed isotropic rotors is analyzed using Hill's method. First, analytical derivation of the periodic system matrix shows that isotropic rotors with more than two blades can be represented by an exact Fourier series with 3/rev as the highest order. For 2-bladed rotors, the inverse mass matrix has an infinite Fourier series with harmonic components of decreasing norm, thus the system matrix can be approximated by a truncated Fourier series of predictable accuracy. Second, a novel method for automatically identifying the principal solutions of Hill's eigenvalue problem is introduced. The corresponding periodic eigenvectors can be used to compute symmetric and anti-symmetric components of the 2-bladed rotor motion, and the additional forward and backward whirling components for rotors with more than two blades. Finally, the generic methods are used on a simple wind turbine model consisting of three degrees of freedom for each blade and seven degrees of freedom for the nacelle and drivetrain. The modal dynamics of a 3-bladed 10MW turbine from previous studies is recaptured. Removing one blade, the larger and higher harmonic terms in the system matrix lead to resonant modal couplings for the 2-bladed turbine that do not exist for the 3-bladed turbine, and that excitation of a single mode of a 2-bladed turbine leads to responses at several frequencies in both the ground-fixed and rotating blade frames of reference which complicates the interpretation of simulated or measured turbine responses.
- Published
- 2016
50. Aeroservoelastic analysis of storm-ride-through control strategies for wind turbines
- Author
-
Carlo Tibaldi and Morten Hartvig Hansen
- Subjects
Wind power ,Computer science ,business.industry ,020209 energy ,Drivetrain ,02 engineering and technology ,Aerodynamics ,01 natural sciences ,Turbine ,Wind speed ,010305 fluids & plasmas ,Derating ,Control theory ,0103 physical sciences ,0202 electrical engineering, electronic engineering, information engineering ,Torque ,Pitch angle ,business ,Physics::Atmospheric and Oceanic Physics - Abstract
An investigation of a control strategy to allow wind turbines to operate at high wind speeds by derating the rotor speed and generator torque set-points is presented. The investigation analyzes the wind turbine aeroservoelastic behavior in the above rated operational range by computing the aerodynamic gains and closed-loop eigenvalue solutions using a high-fidelity linear model. A simple strategy to reduce the reference rotor speed based on a pitch angle feedback is presented and analyzed. It is shown that high aerodynamic gains for operation at high wind speeds requires special handling in the scheduling of the controller gains. The computed closed-loop modal frequencies and damping ratios show how most turbine modes become less damped as the rotor speed is derated, and at very high winds the frequency and damping of the first drivetrain torsion mode are significantly reduced. Possible resonance problems can also be seen from the computed frequencies, and these problems may be worsened by the decreased damping during storm-ride-through. Finally it is shown that the dynamics of the pitch feedback to the derated generator speed is significantly affected by the operational wind speed, resulting in a slow response at high wind speeds.
- Published
- 2016
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