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  • 1. Alrifaiy, Ahmed
    et al.
    Borg, Johan
    Lindahl, Olof A.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Department of Computer Science, Electrical and Space Engineering, Luleå University of Technology; CMTF, Centre for Biomedical Engineering and Physics, Luleå and Umeå, Sweden; Department of Engineering Sciences and Mathematics, Luleå University of Technology.
    Ramser, Kerstin
    A lab-on-a-chip for hypoxic patch clamp measurements combined with optical tweezers and spectroscopy-first investigations of single biological cells2015In: Biomedical engineering online, ISSN 1475-925X, Vol. 14, 36Article in journal (Refereed)
    Abstract [en]

    The response and the reaction of the brain system to hypoxia is a vital research subject that requires special instrumentation. With this research subject in focus, a new multifunctional lab-on-a-chip (LOC) system with control over the oxygen content for studies on biological cells was developed. The chip was designed to incorporate the patch clamp technique, optical tweezers and absorption spectroscopy. The performance of the LOC was tested by a series of experiments. The oxygen content within the channels of the LOC was monitored by an oxygen sensor and verified by simultaneously studying the oxygenation state of chicken red blood cells (RBCs) with absorption spectra. The chicken RBCs were manipulated optically and steered in three dimensions towards a patch-clamp micropipette in a closed microfluidic channel. The oxygen level within the channels could be changed from a normoxic value of 18% O-2 to an anoxic value of 0.0-0.5% O-2. A time series of 3 experiments were performed, showing that the spectral transfer from the oxygenated to the deoxygenated state occurred after about 227 +/- 1 s and a fully developed deoxygenated spectrum was observed after 298 +/- 1 s, a mean value of 3 experiments. The tightness of the chamber to oxygen diffusion was verified by stopping the flow into the channel system while continuously recording absorption spectra showing an unchanged deoxygenated state during 5400 +/- 2 s. A transfer of the oxygenated absorption spectra was achieved after 426 +/- 1 s when exposing the cell to normoxic buffer. This showed the long time viability of the investigated cells. Successful patching and sealing were established on a trapped RBC and the whole-cell access (Ra) and membrane (Rm) resistances were measured to be 5.033 +/- 0.412 M Omega and 889.7 +/- 1.74 M Omega respectively.

  • 2.
    Arndt, Anton
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Laboratory for Biomechanics and Motor Control.
    The evolution of running shoes2012Conference paper (Other academic)
  • 3.
    Arndt, Anton
    et al.
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Laboratory for Biomechanics and Motor Control.
    Lundgren, Paul
    Liu, Anmin
    Nester, Christopher
    Maiwald, Christian
    Jones, Richard
    Lundberg, Arne
    The effect of a midfoot cut in the outer sole of a shoe on intrinsic foot kinematics during walking.2013In: Footwear Science, ISSN 1942-4280, Vol. 5, no 1, 63-69 p.Article in journal (Refereed)
    Abstract [en]

    Modifications in shoe outer soles are frequently made with the intention of altering biomechanics of the foot inside the shoe. These modifications are however, generally based upon intuition with little or no scientific data for support. The purpose of this study was to quantify changes in intrinsic foot segmental kinematics between walking in a neutral shoe and a shoe modified with a clear cut forming a break underneath the midfoot, approximating the Lisfrancs joint.

    Five healthy male subjects participated in the study. Intracortical pins were inserted under sterile conditions and local anaesthetic in nine different bones of the foot and shank. The subjects performed 10 walking trials in both a neutral, standard, flatsoled, flexible walking shoe and in the same shoe with an approximately 1 cm deep cut aligned with the subjects’ Lisfrancs joint. Material tests showed that the cut reduced midfoot shoe bending stiffness by 23% to 38% and torsional stiffness by 23% to 28%. A helical axis approach was applied for calculating the 3D rotations about relevant joints.

    Kinematic trajectories in the sagittal, frontal, and transverse planes were normalised to the stance phase for seven selected joints to compare rotation patterns when wearing the two shoe conditions. Although one out of 21 ranges of motion (ROM) showed a significant difference, there is strong reason to regard this as the result of a type 1 error. Apart from this no differences in ROM occurred between the shoe conditions.

    The low subject number reduced the statistical power of the results. However, the study indicated that outer sole modifications that may be assumed to have clear effects upon foot kinematics, do not necessarily do so.

  • 4.
    Bass, Tarek
    KTH, School of Biotechnology (BIO), Protein Technology.
    Evaluating the therapeutic potential of a dimeric HER3-binding affibody construct in comparison with a monoclonal antibody, seribantumab.Manuscript (preprint) (Other academic)
    Abstract [en]

    A number of monoclonal antibodies targeting HER3 are currently under clinical investigation as potential cancer therapeutics. We have earlier generated high affinity (low picomolar) affibody molecules targeting HER3. These are small, 58 amino acid, non-immunoglobulin based scaffold proteins that have proved suitable for tumor targeting applications, previously primarily for molecular imaging purposes. Our high affinity HER3-binding affibody molecule has demonstrated to have anti-proliferative capacity on HER3-positive tumor cells. When formatted as a bivalent construct, in which the two affibody moieties are flanking a small albumin-binding domain (ABD), we have recently demonstrated that tumor growth could be delayed in mice for HER3-positive xenografts. In this study, we have modified the construct further and reduced the size. In a comparative study, we evaluated safety, the capacity to delay tumor growth in mice with BxPC-3 xenografts, and mouse survival. Our novel construct was compared to the HER3-specific monoclonal antibody seribantumab (MM-121), presently in clinical development. They were found to be equally potent in their therapeutic effects and in their safety profile. We conclude that this format of bivalent HER3-binding affibody molecules seems promising for further evaluation as candidate therapeutics for treatment of HER3-overexpressing tumors.

  • 5.
    Bass, Tarek
    KTH, School of Biotechnology (BIO), Protein Technology.
    Affibody molecules targeting HER3 for cancer therapy2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The development of targeted therapy has contributed tremendously to the treatment of patients with cancer. The use of highly specific affinity proteins to target cancer cells has become a standard in treatment strategies for several different cancers. In light of this, many cancer cell markers are investigated for their potential use in diagnostics and therapy. One such marker is the human epidermal growth factor receptor 3, HER3. It has been established as an important contributor to many cancer types. The function of HER3 is to relay cell growth signals from outside of the cell to the inside. Interfering with- and inhibit- ing the function of HER3 has emerged as an interesting strategy for cancer therapeutics. The studies presented in this thesis aim to target HER3 with small, engineered affinity domain proteins for therapeutic purposes. Monomeric affibody molecules have previously been engineered to bind and inhibit HER3 in vitro. Due to the relatively low expression of HER3, an increase in valency appears promising to strengthen the therapeutic potential. Affibody molecules targeting the receptor were thus linked to form bivalent and bispecific constructs and evaluated both in vitro and in vivo. In the first study of this thesis affibody molecules specific for HER3 and HER2 were fused to an albumin binding domain to form bivalent and bispecific construct. The constructs inhibited ligand-induced receptor phos- phorylation of both HER2 and HER3 more efficiently than monomeric affibody molecules. A second approach to enhance the potential of affibody molecules in tumor targeting is described in the second study, where monomeric HER3-binding affibody molecules were engineered to increase their affinity for HER3. The resulting variants showed a 20-fold in- creased affinity and higher capacity to inhibit cancer cell growth. Combining the findings of the first two studies, the third study describes the evaluation of a HER3-targeting bivalent affibody construct for potential application as a therapeutic. Here, the bivalent construct inhibited cancer cell growth in vitro and was found to slow down tumor growth in mice, while being well tolerated and showing no visible toxicity. The fourth study built upon these findings and compares a very similar bivalent construct to the clinically-investigated HER3-specific monoclonal antibody seribantumab. The affibody construct showed very comparable efficacy with the antibody in terms of decreasing tumor growth rate and ex- tending mouse survival. Collectively, these works describe for the first time the use of alternative affinity protein constructs with therapeutic potential targeting HER3.

  • 6. Bello, M. A.
    et al.
    Ruiz-León, Y.
    Sandoval-Sierra, J. V.
    Rezinciuc, Svetlana
    KTH, School of Biotechnology (BIO), Glycoscience.
    Diéguez-Uribeondo, J.
    Scanning electron microscopy (SEM) protocols for problematic plant, oomycete, and fungal samples2017In: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, Vol. 2017, no 120, e55031Article in journal (Refereed)
    Abstract [en]

    Common problems in the processing of biological samples for observations with the scanning electron microscope (SEM) include cell collapse, treatment of samples from wet microenvironments and cell destruction. Using young floral tissues, oomycete cysts, and fungi spores (Agaricalesas examples, specific protocols to process delicate samples are described here that overcome some of the main challenges in sample treatment for image capture under the SEM. Floral meristems fixed with FAA (Formalin-Acetic-Alcohol) and processed with the Critical Point Dryer (CPD) did not display collapsed cellular walls or distorted organs. These results are crucial for the reconstruction of floral development. A similar CPD-based treatment of samples from wet microenvironments, such as the glutaraldehyde-fixed oomycete cysts, is optimal to test the differential growth of diagnostic characteristics (e.g., the cyst spines) on different types of substrates. Destruction of nurse cells attached to fungi spores was avoided after rehydration, dehydration, and the CPD treatment, an important step for further functional studies of these cells. The protocols detailed here represent low-cost and rapid alternatives for the acquisition of good-quality images to reconstruct growth processes and to study diagnostic characteristics.

  • 7. Bengtsson, Erik
    et al.
    Nerjovaj, Pashtrik
    Wangefjord, Sakarias
    Nodin, Björn
    Eberhard, Jakob
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Borgquist, Signe
    Jirström, Karin
    HMG-CoA reductase expression in primary colorectal cancer correlates with favourable clinicopathological characteristics and an improved clinical outcome2014In: Diagnostic Pathology, ISSN 1746-1596, Vol. 9, no 1, 78- p.Article in journal (Refereed)
    Abstract [en]

    Background: An association between tumor-specific HMG-CoA reductase (HMGCR) expression and good prognosis has previously been demonstrated in breast and ovarian cancer. In this study, the expression, clinicopathological correlates and prognostic value of HMGCR expression in colorectal cancer was examined. Findings: Immunohistochemical expression of HMGCR was assessed in tissue microarrays with primary tumours from 557 incident cases of colorectal cancer in the Malmo Diet and Cancer Study. Pearson's Chi Square test was applied to explore the associations between HMGCR expression and clinicopathological factors and other investigative biomarkers. Kaplan Meier analysis and Cox proportional hazards modeling were used to assess the relationship between HMGCR expression and cancer-specific survival (CSS) according to negative vs positive HMGCR expression. A total number of 535 (96.0%) tumours were suitable for analysis, of which 61 (11.4%) were HMGCR negative. Positive cytoplasmic HMGCR expression was associated with distant metastasis-free disease at diagnosis (p = 0.002), lack of vascular invasion (p = 0.043), microsatellite-instability (p = 0.033), expression of cyclin D1 (p = <0.001) and p21 (p = <0.001). Positive HMGCR expression was significantly associated with a prolonged CSS in unadjusted Cox regression analysis in the entire cohort (HR = 1.79; 95% CI 1.20-2.66) and in Stage III-IV disease (HR = 1.71; 95% CI 1.09-2.68), but not after adjustment for established clinicopathological parameters. Conclusions: Findings from this prospective cohort study demonstrate that HMGCR is differentially expressed in colorectal cancer and that positive expression is associated with favourable tumour characteristics and a prolonged survival in unadjusted analysis. The utility of HMGCR as a predictor of response to neoadjuvant or adjuvant statin treatment in colorectal cancer merits further study. Virtual slides: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2115647072103464.

  • 8.
    Bernzen, Noel
    Halmstad University, School of Business, Engineering and Science.
    Noellator: Vinterrollator2016Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Idag är det en hög andel av äldre personer, främst kvinnor, som använder rollatorer. De blir allt fler med tiden, då genomsnittsåldern av befolkningen blir allt högre. För att öka livskvalitet för de äldre, är det rekommenderat att promenera utomhus så ofta som möjligt, exempelvis med hjälp av en rollator. Ett problem som uppstår är att ingen rollator är anpassad för användning under vintern. I detta examensarbete har ett rollator-koncept tagits fram, speciellt anpassat för ”fyra årstider”. Detta innebär att konceptet har allt som en vanligt rollator har men även tillbehör som är användarvänliga i vilket väder som helst, såväl vid snö- som isförhållanden. Det innebär en komplettering med specialdesignade tillbehör som är enkla att byta oberoende av väderslag. En årstidsoberoende rollator blir dyrare än en vanligt rollator, men samtidigt skapas ett hjälpmedel som gör det lättare för användaren att vara en del av samhället och förbättra sin hälsa, vilket faktiskt är såväl viktigt som aktuellt

  • 9.
    Cedersund, G
    Linköping University, Department of Electrical Engineering. Linköping University, The Institute of Technology.
    Elimination of the initial value parameters when identifying a system close to a Hopf bifurcation.2006In: IEE Proceedings - Systems Biology, ISSN 1741-2471, E-ISSN 1741-248X, Vol. 153, no 6, 448-456 p.Article in journal (Refereed)
    Abstract [en]

    One of the biggest problems when performing system identification of biological systems is that it is seldom possible to measure more than a small fraction of the total number of variables. If that is the case, the initial state, from where the simulation should start, has to be estimated along with the kinetic parameters appearing in the rate expressions. This is often done by introducing extra parameters, describing the initial state, and one way to eliminate them is by starting in a steady state. We report a generalisation of this approach to all systems starting on the centre manifold, close to a Hopf bifurcation. There exist biochemical systems where such data have already been collected, for example, of glycolysis in yeast. The initial value parameters are solved for in an optimisation sub-problem, for each step in the estimation of the other parameters. For systems starting in stationary oscillations, the sub-problem is solved in a straight-forward manner, without integration of the differential equations, and without the problem of local minima. This is possible because of a combination of a centre manifold and normal form reduction, which reveals the special structure of the Hopf bifurcation. The advantage of the method is demonstrated on the Brusselator.

  • 10.
    Cheddad, Abbas
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Hörnblad, Andreas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Prunskaite-Hyyryläinen, Renata
    Oulu Center for Cell-Matrix Research, Biocenter Oulu, Laboratory of Developmental Biology and Department of Medical Biochemistry and Molecular Biology, Institute of Biomedicine, University of Oulu, Finland.
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Georgsson, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Computing Science.
    Vainio, Seppo
    Oulu Center for Cell-Matrix Research, Biocenter Oulu, Laboratory of Developmental Biology and Department of Medical Biochemistry and Molecular Biology, Institute of Biomedicine, University of Oulu, Finland.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Improving signal detection in emission optical projection tomography via single source multi-exposure image fusion2013In: Optics Express, ISSN 1094-4087, Vol. 21, no 14, 16584-16604 p.Article in journal (Refereed)
    Abstract [en]

    We demonstrate a technique to improve structural data obtained from Optical Projection Tomography (OPT) using Image Fusion (IF) and contrast normalization. This enables the visualization of molecular expression patterns in biological specimens with highly variable contrast values. In the approach, termed IF-OPT, different exposures are fused by assigning weighted contrasts to each. When applied to projection images from mouse organs and digital phantoms our results demonstrate the capability of IF-OPT to reveal high and low signal intensity details in challenging specimens. We further provide measurements to highlight the benefits of the new algorithm in comparison to other similar methods.

  • 11. Chen, Ye
    et al.
    Wang, Aiguo
    Ding, Huitong
    Que, Xia
    Li, Yabo
    An, Ning
    Jiang, Lili
    Umeå University, Faculty of Science and Technology, Department of Computing Science.
    A global learning with local preservation method for microarray data imputation2016In: Computers in Biology and Medicine, ISSN 0010-4825, E-ISSN 1879-0534, Vol. 77, 76-89 p.Article in journal (Refereed)
    Abstract [en]

    Microarray data suffer from missing values for various reasons, including insufficient resolution, image noise, and experimental errors. Because missing values can hinder downstream analysis steps that require complete data as input, it is crucial to be able to estimate the missing values. In this study, we propose a Global Learning with Local Preservation method (GL2P) for imputation of missing values in microarray data. GL2P consists of two components: a local similarity measurement module and a global weighted imputation module. The former uses a local structure preservation scheme to exploit as much information as possible from the observable data, and the latter is responsible for estimating the missing values of a target gene by considering all of its neighbors rather than a subset of them. Furthermore, GL2P imputes the missing values in ascending order according to the rate of missing data for each target gene to fully utilize previously estimated values. To validate the proposed method, we conducted extensive experiments on six benchmarked microarray datasets. We compared GL2P with eight state-of-the-art imputation methods in terms of four performance metrics. The experimental results indicate that GL2P outperforms its competitors in terms of imputation accuracy and better preserves the structure of differentially expressed genes. In addition, GL2P is less sensitive to the number of neighbors than other local learning-based imputation. methods.

  • 12.
    Chudinova, Ekaterina
    et al.
    Tomsk Polytechnic University, Tomsk, Russia.
    Surmeneva, Maria
    Tomsk Polytechnic University, Tomsk, Russia.
    Koptyug, Andrey
    Mid Sweden University, Faculty of Science, Technology and Media, Department of Quality Technology and Management, Mechanical Engineering and Mathematics.
    Skoglund, Per
    Mid Sweden University, Faculty of Science, Technology and Media, Department of Quality Technology and Management, Mechanical Engineering and Mathematics.
    Sharanova, A
    Tomsk Polytechnic University, Tomsk, Russia.
    Loza, K
    University of Duisburg-Essen, Germany.
    Epple, M
    University of Duisburg-Essen, Germany.
    Surmenev, Roman
    Tomsk Polytechnic University, Tomsk, Russia.
    Hydroxyapatite coating and silver nanoparticles assemblies on additively manufactured Ti6Al4V scaffolds2015Conference paper (Other academic)
  • 13.
    Danø, Sune
    et al.
    Copenhagen University.
    Madsen, Mads F
    Copenhagen University.
    Schmidt, Henning
    Chalmers Technical University.
    Cedersund, Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Reduction of a biochemical model with preservation of its basic dynamic properties.2006In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 273, no 21, 4862-4877 p.Article in journal (Refereed)
    Abstract [en]

    The complexity of full-scale metabolic models is a major obstacle for their effective use in computational systems biology. The aim of model reduction is to circumvent this problem by eliminating parts of a model that are unimportant for the properties of interest. The choice of reduction method is influenced both by the type of model complexity and by the objective of the reduction; therefore, no single method is superior in all cases. In this study we present a comparative study of two different methods applied to a 20D model of yeast glycolytic oscillations. Our objective is to obtain biochemically meaningful reduced models, which reproduce the dynamic properties of the 20D model. The first method uses lumping and subsequent constrained parameter optimization. The second method is a novel approach that eliminates variables not essential for the dynamics. The applications of the two methods result in models of eight (lumping), six (elimination) and three (lumping followed by elimination) dimensions. All models have similar dynamic properties and pin-point the same interactions as being crucial for generation of the oscillations. The advantage of the novel method is that it is algorithmic, and does not require input in the form of biochemical knowledge. The lumping approach, however, is better at preserving biochemical properties, as we show through extensive analyses of the models.

  • 14.
    Ebai, Tonge
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Parallel protein detection by solid-phase proximity ligation assay with real-time PCR or sequencing2015In: Current Protocol in Molecular Biology, ISSN 1934-3647, Vol. 109, no 20Article in journal (Refereed)
    Abstract [en]

    Proximity ligation assays are a group of protein detection techniques in which reagents with affinity for target proteins, typically antibodies, are coupled to short strands of DNA. DNA-modified affinity reagents are combined in assays constructed such that the coordinated binding of individual target molecules or complexes of interacting proteins by two or more of the reagents, followed by DNA ligation and/or polymerization reactions, gives rise to amplifiable DNA reporter strands. Proximity ligation assays have been shown to exhibit excellent sensitivity in single and multiplexed protein assays for individual or interacting proteins, both in solution and in situ. This unit describes procedures for developing solid-phase proximity ligation assays for soluble proteins using either real-time PCR or DNA sequencing as the readout. In addition, critical steps for assay optimization are discussed.

  • 15. Enroth, Stefan
    et al.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Gyllensten, Ulf
    Effects of Long-Term Storage Time and Original Sampling Month on Biobank Plasma Protein Concentrations2016In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 12, 309-314 p.Article in journal (Refereed)
    Abstract [en]

    The quality of clinical biobank samples is crucial to their value for life sciences research. A number of factors related to the collection and storage of samples may affect the biomolecular composition. We have studied the effect of long-time freezer storage, chronological age at sampling, season and month of the year and on the abundance levels of 108 proteins in 380 plasma samples collected from 106 Swedish women. Storage time affected 18 proteins and explained 4.8–34.9% of the observed variance. Chronological age at sample collection after adjustment for storage-time affected 70 proteins and explained 1.1–33.5% of the variance. Seasonal variation had an effect on 15 proteins and month (number of sun hours) affected 36 proteins and explained up to 4.5% of the variance after adjustment for storage-time and age. The results show that freezer storage time and collection date (month and season) exerted similar effect sizes as age on the protein abundance levels. This implies that information on the sample handling history, in particular storage time, should be regarded as equally prominent covariates as age or gender and need to be included in epidemiological studies involving protein levels.

  • 16.
    Eriksson, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Moreno, R
    Milenova, I. Yoanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Liljenfeldt, L
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Dieterich, L C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Christiansson, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karlsson, H
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ullenhag, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mangsbo, Sara M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Alemany, R
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Activation of myeloid and endothelial cells by CD40L gene therapy supports T-cell expansion and migration into the tumor microenvironment2017In: Gene Therapy, ISSN 0969-7128, E-ISSN 1476-5462, Vol. 24, no 2, 92-103 p.Article in journal (Refereed)
    Abstract [en]

    CD40 is an interesting target in cancer immunotherapy due to its ability to stimulate T-helper 1 immunity via maturation of dendritic cells and to drive M2 to M1 macrophage differentiation. Pancreatic cancer has a high M2 content that has shown responsive to anti-CD40 agonist therapy and CD40 may thus be a suitable target for immune activation in these patients. In this study, a novel oncolytic adenovirus armed with a trimerized membrane-bound extracellular CD40L (TMZ-CD40L) was evaluated as a treatment of pancreatic cancer. Further, the CD40L mechanisms of action were elucidated in cancer models. The results demonstrated that the virus transferring TMZ-CD40L had oncolytic capacity in pancreatic cancer cells and could control tumor progression. TMZ-CD40L was a potent stimulator of human myeloid cells and T-cell responses. Further, CD40L-mediated stimulation increased tumor-infiltrating T cells in vivo, which may be due to a direct activation of endothelial cells to upregulate receptors for lymphocyte attachment and transmigration. In conclusion, CD40L-mediated gene therapy is an interesting concept for the treatment of tumors with high levels of M2 macrophages, such as pancreatic cancer, and an oncolytic virus as carrier of CD40L may further boost tumor killing and immune activation.

  • 17.
    Gao, Xiang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Yang, Ting
    Liu, Ming
    Peleli, Maria
    Zollbrecht, Christa
    Weitzberg, Eddie
    Lundberg, Jon O.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlstrom, Mattias
    NADPH Oxidase in the Renal Microvasculature Is a Primary Target for Blood Pressure-Lowering Effects by Inorganic Nitrate and Nitrite2015In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 65, no 1, 161-+ p.Article in journal (Refereed)
    Abstract [en]

    Renal oxidative stress and nitric oxide (NO) deficiency are key events in hypertension. Stimulation of a nitrate-nitrite-NO pathway with dietary nitrate reduces blood pressure, but the mechanisms or target organ are not clear. We investigated the hypothesis that inorganic nitrate and nitrite attenuate reactivity of renal microcirculation and blood pressure responses to angiotensin II (ANG II) by modulating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and NO bioavailability. Nitrite in the physiological range (10(-7)-10(-5) mol/L) dilated isolated perfused renal afferent arterioles, which were associated with increased NO. Contractions to ANG II (34%) and simultaneous NO synthase inhibition (56%) were attenuated by nitrite (18% and 26%). In a model of oxidative stress (superoxide dismutase-1 knockouts), abnormal ANG II-mediated arteriolar contractions (90%) were normalized by nitrite (44%). Mechanistically, effects of nitrite were abolished by NO scavenger and xanthine oxidase inhibitor, but only partially attenuated by inhibiting soluble guanylyl cyclase. Inhibition of NADPH oxidase with apocynin attenuated ANG II-induced contractility (35%) similar to that of nitrite. In the presence of nitrite, no further effect of apocynin was observed, suggesting NADPH oxidase as a possible target. In preglomerular vascular smooth muscle cells and kidney cortex, nitrite reduced both basal and ANG II-induced NADPH oxidase activity. These effects of nitrite were also abolished by xanthine oxidase inhibition. Moreover, supplementation with dietary nitrate (10(-2) mol/L) reduced renal NADPH oxidase activity and attenuated ANG II-mediated arteriolar contractions and hypertension (99+/-2-146+/-2 mm Hg) compared with placebo (100+/-3-168+/-3 mm Hg). In conclusion, these novel findings position NADPH oxidase in the renal microvasculature as a prime target for blood pressure-lowering effects of inorganic nitrate and nitrite.

  • 18.
    Hadrevi, Jenny
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.
    Turkina, Maria V
    Department of Clinical and Experimental Medicine, Linköpings universitet.
    Carlsson, Anders
    Division of Community Medicine, Department of Medical and Health Sciences, Linköpings universitet.
    Gerdle, Björn
    Division of Community Medicine, Department of Medical and Health Sciences, Linköpings universitet.
    Larsson, Britt
    Division of Community Medicine, Department of Medical and Health Sciences, Linköpings universitet.
    Hellström, Fredrik
    Department of Occupational and Public Health Sciences, Högskolan i Gävle.
    Ghafouri, Bijar
    Division of Community Medicine, Department of Medical and Health Sciences, Linköpings universitet.
    Myosin light chain and calcium regulating protein differences in chronic musculoskeletal neck and shoulder pain2016In: Journal of Integrated Omnics, ISSN 2182-0287, Vol. 6, no 1, 1-8 p.Article in journal (Refereed)
    Abstract [en]

    Proteomic screening analysis has detected myosin light chain (MLC) as a protein implied to be involved in chronic musculoskeletal neck and shoulder pain. Several analyses of MLC proteins have stated a difference in phosphorylation being the determining factor for protein activation hence altered contrability of the muscle in i.e. senescence. In continuation of a previous publication, this study is an attempt to analyze the different MLC isoforms by mass spectrometry and immune-analyses in myalgic and healthy trapezius muscle. In the present study no differences in phosphorylation level between the corresponding individual proteins were detected using LC-MSMS and immunoblotting; instead we assigned different isoforms of regulatory MLCs. To further elucidate the contrability: calcium (Ca2+) regulatory proteins, sarco(endo)plasmic reticulum Ca2+ ATPase 1 (SERCA-1) and calsequestrine (CSQ) were analyzed by western blot. The analysis revealed a significantly increased abundance of SERCA-1 protein in the myalgic muscle and a significantly increased abundance of CSQ in healthy muscle. Myalgic muscle contraction patterns have in previous studies shown to differ from healthy muscle which may be connected to the Ca2+ availability in the muscle. Here we present the proteomic characterization of differences in Ca2+ regulating proteins and particularly regulatory MLCs in trapezius muscle of women with chronic musculoskeletal neck and shoulder pain.

  • 19.
    Hammond, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    A DNA-mediated search for optimal combinations of protein bindersManuscript (preprint) (Other academic)
  • 20.
    Hasmats, Johanna
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Analysis of genetic variations in cancer2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aim of this thesis is to apply recently developed technologies for genomic variation analyses, and to ensure quality of the generated information for use in preclinical cancer research.

    Faster access to a patients’ full genomic sequence for a lower cost makes it possible for end users such as clinicians and physicians to gain a more complete understanding of the disease status of a patient and adjust treatment accordingly. Correct biological interpretation is important in this context, and can only be provided through fast and simple access to relevant high quality data.

    Therefore, we here propose and validate new bioinformatic strategies for biomarker selection for prediction of response to cancer therapy. We initially explored the use of bioinformatic tools to select interesting targets for toxicity in carboplatin and paclitaxel on a smaller scale. From our findings we then further extended the analysis to the entire exome to look for biomarkers as targets for adverse effects from carboplatin and gemcitabine. To investigate any bias introduced by the methods used for targeting the exome, we analyzed the mutation profiles in cancer patients by comparing whole genome amplified DNA to unamplified DNA. In addition, we applied RNA-seq to the same patients to further validate the variations obtained by sequencing of DNA. The understanding of the human cancer genome is growing rapidly, thanks to methodological development of analysis tools. The next step is to implement these tools as a part of a chain from diagnosis of patients to genomic research to personalized treatment.

  • 21.
    Hellström, Fredrik
    et al.
    University of Gävle, Centre for Musculoskeletal Research. University of Gävle, Faculty of Health and Occupational Studies, Department of Occupational and Public Health Sciences, Occupational health science.
    Gouveia-Figueira, Sandra
    Department of Chemistry, Umeå University, Umeå; Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå.
    Nording, Malin
    Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå.
    Björklund, Martin
    University of Gävle, Centre for Musculoskeletal Research. University of Gävle, Faculty of Health and Occupational Studies, Department of Occupational and Public Health Sciences, Occupational health science. Department of Community Medicine and Rehabilitation, Umeå University, Umeå.
    Fowler, Christopher John
    Department of Community Medicine and Rehabilitation, Umeå universitet, Umeå.
    Association between plasma concentrations of linoleic acid-derived oxylipins and the perceived pain scores in an exploratory study in women with chronic neck pain2016In: BMC Musculoskeletal Disorders, ISSN 1471-2474, E-ISSN 1471-2474, Vol. 17, no 1, 103Article in journal (Refereed)
    Abstract [en]

    Background: Chronic musculoskeletal pain may be associated with changes in the balance of algogenic and anti-nociceptive compounds, and that such changes may be visible in plasma samples. We have undertaken an exploratory study to measure the levels of endocannabinoids, related N-acylethanolamines and oxylipins (primarily those derived from linoleic acid) in plasma samples from women with chronic neck pain (NP) and chronic widespread pain (CWP), and to investigate whether the observed levels are associated with the pain experienced by these women.

    Methods: Blood samples from 35 women with NP, 15 with CWP and 27 age-matched controls were analysed for the lipids using an ultra performance liquid chromatography coupled to tandem mass spectrometry method. Current pain ("NRSday") and the average pain during the last week ("NRSweek") were rated by the participants using a numerical rating scale.

    Results: There were no significant differences in the plasma concentrations of the fifteen lipids investigated between the pain subjects and the controls. However, significant correlations were seen for the NP group between the NRSday scores and the plasma concentrations of the linoleic acid derivatives 9- and 13- hydroxy-10E,12Zoctadecadienoic acid (Spearman's rho values 0.51 [P=0.0016]) and 0.53 [P=0.0011], respectively).

    Conclusions: The data obtained in this exploratory study are consistent with a model whereby the underlying inflammatory nature of the musculoskeletal disorders leads both to an increase in the NRSday scores and the hydroxy-10E,12Z-octadecadienoic acid levels, and these increases further influence the perceived pain of in the NP subjects.

  • 22.
    Hirvonen, M. Karoliina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Assay development for in situ detection of autophagy-related protein-protein interactions for characterization of colorectal cancer2015Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
    Abstract [en]

    Every year, more than a million people are diagnosed with colorectal cancer (CRC) that develops in the large intestine. It is one of the most studied cancers in the world but still more knowledge about how this cancer develops and acts is needed in order to use more effective ways to treat CRC. Autophagy is a vital mechanism in cells that is also suggested to maintain cancer cell survival. In normal cells, it plays an important role by removing damaged cells and organelles as well as eliminating pathogens. Under metabolic stress this mechanism is induced to provide enough nutrients and energy for the cell to survive. Cancer cells are exposed to greater environmental stress than normal cells and therefore, cancer cells exhibit higher levels of autophagy suggesting it to be a crucial mechanism for their survival. Gaining a deeper understanding of this essential mechanism and its activation might provide new insights and improved treatments for the fight against colorectal cancer. In situ Proximity Ligation Assay (PLA) is a protein detection method that enables sensitive and specific detection of proteins and protein-protein interactions (PPIs) in cell lines and tissue samples. The method uses simultaneous recognition of two independent antigens on a protein or protein complex together with a rolling circle amplification (RCA) to form a rolling circle product (RCP) on top of the target. By using fluorescent oligonucleotides, RCP can be visualized and is seen as a bright spot that enables sensitive detection of the target at single-molecule resolution. The aim of this study was to develop assays to detect endogenous molecular events known to be biomarkers of autophagy in situ in order to study autophagy mechanism in CRC patient samples. We focused our research on two PPIs that were known to interact when autophagy is induced. The first investigated interaction was between microtubule-associated protein 1A/1B- light chain 3 (LC3) and sequestome-1 (SQSTM1), an interaction that occurs during autophagy initiation. The second interaction was between B-cell lymphoma 2 (Bcl-2) and Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3) that takes place during hypoxia-induced autophagy. To study whether these PPIs can be used as a detection method to monitor autophagy, we used a well- established cell model based on serum starvation and CoCl2 - an hypoxic mimetic- treatment of the intestinal cancer cell line Caco-2 in comparison to normal culture condition. According to isPLA quantification, detection of both PPIs was distinctly higher in treated cells compared to untreated cells giving promising results and suggesting that they can be potentially used as suitable assays to monitor these biomarkers of autophagy. For development of an improved protein detection method that enables the study of several PPIs simultaneously in a tissue sample (In situ Multiplexing), we conjugated directly a short oligonucleotide strand to the primary antibodies. These formed proximity probes could later be used in in situ for multiplexing. 

  • 23.
    Hollmark, M
    et al.
    Division of Medical Radiation Physics, Department of Oncology-Pathology, Karolinska Institutet and Stockholm University.
    Edgren, M
    Kundrát, P
    Lind, B
    A comparison of radiobiological models for light ion therapyManuscript (preprint) (Other academic)
  • 24.
    Jonsson, Amanda
    et al.
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Song, Zhiyang
    Department of Clinical Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
    Nilsson, David
    Acreo Swedish ICT AB, SE-601 17 Norrköping, Sweden.
    Meyerson, Björn A.
    Department of Clinical Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
    Simon, Daniel
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Linderoth, Bengt
    Department of Clinical Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
    Berggren, Magnus
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Therapy using implanted organic bioelectronics2015In: Science Advances, ISSN 2375-2548, Vol. 1, no 4, e1500039Article in journal (Refereed)
    Abstract [en]

    Many drugs provide their therapeutic action only at specific sites in the body, but are administered in ways that cause the drug’s spread throughout the organism. This can lead to serious side effects. Local delivery from an implanted device may avoid these issues, especially if the delivery rate can be tuned according to the need of the patient. We turned to electronically and ionically conducting polymers to design a device that could be implanted and used for local electrically controlled delivery of therapeutics. The conducting polymers in our device allow electronic pulses to be transduced into biological signals, in the form of ionic and molecular fluxes, which provide a way of interfacing biology with electronics. Devices based on conducting polymers and polyelectrolytes have been demonstrated in controlled substance delivery to neural tissue, biosensing, and neural recording and stimulation. While providing proof of principle of bioelectronic integration, such demonstrations have been performed in vitro or in anesthetized animals. Here, we demonstrate the efficacy of an implantable organic electronic delivery device for the treatment of neuropathic pain in an animal model. Devices were implanted onto the spinal cord of rats, and 2 days after implantation, local delivery of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) was initiated. Highly localized delivery resulted in a significant decrease in pain response with low dosage and no observable side effects. This demonstration of organic bioelectronics-based therapy in awake animals illustrates a viable alternative to existing pain treatments, paving the way for future implantable bioelectronic therapeutics. Keywords

  • 25.
    Juntikka, Rickard
    et al.
    KTH, School of Engineering Sciences (SCI), Aeronautical and Vehicle Engineering, Lightweight Structures.
    Kleiven, Svein
    KTH, School of Technology and Health (STH), Neuronic Engineering (Closed 20130701).
    Hallström, Stefan
    KTH, School of Engineering Sciences (SCI), Aeronautical and Vehicle Engineering, Lightweight Structures.
    Optimization of single skin surfaces for head injury prevention - a comparison of optima calculated for global versus local injury thresholds2004In: International Journal of Crashworthiness, ISSN 1358-8265, E-ISSN 1754-2111, Vol. 9, no 4, 365-379 p.Article in journal (Refereed)
    Abstract [en]

    This paper describes optimizations of material properties for a bonnet-like plate using finite element calculations and the Euro-NCAP pedestrian head impact test. Four different head models were used for the impact simulations, a Euro-NCAP dummy head, a Hybrid III dummy head and two biomechanical head models exhibiting different mechanical properties for the brain tissue. The objective function was to minimize the displacement of the bonnet plate while satisfying constraints on the head injury criterion (HIC), the resultant contact force and, for the human head models, the strain in the brain tissue. An investigation was also conducted of the kinematics of the head models during impact, evaluating the energy distribution and the apparent mass. The analysis gave at hand that optimization of the plate with respect to impact with the Euro-NCAP and Hybrid III head models reached substantially, different results compared to impact with the biomechanical head models. For the latter case, the stiffness of the brain tissue influenced which constraints were active in the final solution. The investigation of the kinematics at impact showed that a substantial portion of energy was confined within the brain during impact for the biomechanical head models. The apparent mass at impact coincided with the actual mass for the rigid dummy heads while for the human head models it was roughly the mass of the skull only.

  • 26.
    Kamali-Moghaddam, Masood
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Löf, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Oliveir, Felipe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Wik, Lotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Wu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Yan, Junhong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Advanced Molecular Tools for Proteomic Analyses of Microvesicles2014In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 23, 102-102 p.Article in journal (Other academic)
  • 27.
    Karlheden, Rebecka
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Asthma, asthma medication and training intensity in Swedish competitive athletes: An internet-based survey2015Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 28. Katchy, Anne
    et al.
    Williams, Cecilia
    Profiling of estrogen-regulated microRNAs in breast cancer cells.2014In: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, no 84, e51285Article in journal (Refereed)
    Abstract [en]

    Estrogen plays vital roles in mammary gland development and breast cancer progression. It mediates its function by binding to and activating the estrogen receptors (ERs), ERα, and ERβ. ERα is frequently upregulated in breast cancer and drives the proliferation of breast cancer cells. The ERs function as transcription factors and regulate gene expression. Whereas ERα's regulation of protein-coding genes is well established, its regulation of noncoding microRNA (miRNA) is less explored. miRNAs play a major role in the post-transcriptional regulation of genes, inhibiting their translation or degrading their mRNA. miRNAs can function as oncogenes or tumor suppressors and are also promising biomarkers. Among the miRNA assays available, microarray and quantitative real-time polymerase chain reaction (qPCR) have been extensively used to detect and quantify miRNA levels. To identify miRNAs regulated by estrogen signaling in breast cancer, their expression in ERα-positive breast cancer cell lines were compared before and after estrogen-activation using both the µParaflo-microfluidic microarrays and Dual Labeled Probes-low density arrays. Results were validated using specific qPCR assays, applying both Cyanine dye-based and Dual Labeled Probes-based chemistry. Furthermore, a time-point assay was used to identify regulations over time. Advantages of the miRNA assay approach used in this study is that it enables a fast screening of mature miRNA regulations in numerous samples, even with limited sample amounts. The layout, including the specific conditions for cell culture and estrogen treatment, biological and technical replicates, and large-scale screening followed by in-depth confirmations using separate techniques, ensures a robust detection of miRNA regulations, and eliminates false positives and other artifacts. However, mutated or unknown miRNAs, or regulations at the primary and precursor transcript level, will not be detected. The method presented here represents a thorough investigation of estrogen-mediated miRNA regulation.

  • 29.
    Khorshidi, Mohammad Ali
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Live Single Cell Imaging and Analysis Using Microfluidic Devices2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Today many cell biological techniques study large cell populations where an average estimate of individual cells’ behavior is observed. On the other hand, single cell analysis is required for studying functional heterogeneities between cells within populations. This thesis presents work that combines the use of microfluidic devices, optical microscopy and automated image analysis to design various cell biological assays with single cell resolution including cell proliferation, clonal expansion, cell migration, cell-cell interaction and cell viability tracking. In fact, automated high throughput single cell techniques enable new studies in cell biology which are not possible with conventional techniques.

    In order to automatically track dynamic behavior of single cells, we developed a microwell based device as well as a droplet microfluidic platform. These high throughput microfluidic assays allow automated time-lapse imaging of encapsulated single cells in micro droplets or confined cells inside microwells. Algorithms for automatic quantification of cells in individual microwells and micro droplets are developed and used for the analysis of cell viability and clonal expansion. The automatic counting protocols include several image analysis steps, e.g. segmentation, feature extraction and classification. The automatic quantification results were evaluated by comparing with manual counting and revealed a high success rate. In combination these automatic cell counting protocols and our microfluidic platforms can provide statistical information to better understand behavior of cells at the individual level under various conditions or treatments in vitro exemplified by the analysis of function and regulation of immune cells. Thus, together these tools can be used for developing new cellular imaging assays with resolution at the single cell level.

    To automatically characterize transient migration behavior of natural killer (NK) cells compartmentalized in microwells, we developed a method for single cell tracking. Time-lapse imaging showed that the NK cells often exhibited periods of high motility, interrupted with periods of slow migration or complete arrest. These transient migration arrest periods (TMAPs) often overlapped with periods of conjugations between NK cells and target cells. Such conjugation periods sometimes led to cell-mediated killing of target cells. Analysis of cytotoxic response of NK cells revealed that a small sub-class of NK cells called serial killers was able to kill several target cells. In order to determine a starting time point for cell-cell interaction, a novel technique based on ultrasound was developed to aggregate NK and target cells into the center of the microwells. Therefore, these assays can be used to automatically and rapidly assess functional and migration behavior of cells to detect differences between health and disease or the influence of drugs.

    The work presented in this thesis gives good examples of how microfluidic devices combined with automated imaging and image analysis can be helpful to address cell biological questions where single cell resolution is necessary. 

  • 30.
    Kroon, Martin
    Royal Institute of Technology (KTH).
    Modeling of fibroblast-controlled strengthening and remodeling of uniaxially constrained collagen gels2010In: Journal of Biomechanical Engineering, ISSN 0148-0731, E-ISSN 1528-8951, Vol. 132, no 11, 111008Article in journal (Refereed)
    Abstract [en]

    A theoretical model for the remodeling of collagen gels is proposed. The collagen fabric is modeled as a network of collagen fibers, which in turn are composed of collagen fibrils. In the model, the strengthening of collagen fabric is accomplished by fibroblasts, which continuously recruit and attach more collagen fibrils to existing collagen fibers. The fibroblasts also accomplish a reorientation of collagen fibers. Fibroblasts are assumed to reorient collagen fibers toward the direction of maximum material stiffness. The proposed model is applied to experiments in which fibroblasts were inserted into a collagen gel. The model is able to predict the force-strain curves for the experimental collagen gels, and the final distribution of collagen fibers also agrees qualitatively with the experiments.

  • 31. Kumar, Abhinav
    et al.
    Bicer, Elif Melis
    Morgan, Anna Babin
    Pfeffer, Paul E.
    Monopoli, Marco
    Dawson, Kenneth A.
    Eriksson, Jonny
    Edwards, Katarina
    Lynham, Steven
    Arno, Matthew
    Behndig, Annelie F.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Somers, Graham
    Hassall, Dave
    Dailey, Lea Ann
    Forbes, Ben
    Mudway, Ian S.
    Enrichment of immunoregulatory proteins in the biomolecular corona of nanoparticles within human respiratory tract lining fluid2016In: Nanomedicine: Nanotechnology, Biology and Medicine, ISSN 1549-9634, E-ISSN 1549-9642, Vol. 12, no 4, 1033-1043 p.Article in journal (Refereed)
    Abstract [en]

    When inhaled nanoparticles deposit in the lungs, they transit through respiratory tract lining fluid (RTLF) acquiring a biomolecular corona reflecting the interaction of the RTLF with the nanomaterial surface. Label-free snapshot proteomics was used to generate semiquantitative profiles of corona proteins formed around silica (SiO2) and poly(vinyl) acetate (PVAc) nanoparticles in RTLF, the latter employed as an archetype drug delivery vehicle. The evolved PVAc corona was significantly enriched compared to that observed on SiO2 nanoparticles (698 vs. 429 proteins identified); however both coronas contained a substantial contribution from innate immunity proteins, including surfactant protein A, napsin A and complement (C1q and C3) proteins. Functional protein classification supports the hypothesis that corona formation in RTLF constitutes opsonisation, preparing particles for phagocytosis and clearance from the lungs. These data highlight how an understanding of the evolved corona is necessary for the design of inhaled nanomedicines with acceptable safety and tailored clearance profiles. From the Clinical Editor: Inhaled nanoparticles often acquire a layer of protein corona while they go through the respiratory tract. Here, the authors investigated the identity of these proteins. The proper identification would improve the understanding of the use of inhaled nanoparticles in future therapeutics. (C) 2016 Published by Elsevier Inc.

  • 32.
    Kupferschmidt, Natalia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials. Nanologica AB, SE-11428 Stockholm, Sweden.
    Csikasz, Robert
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Ballell, Lluis
    Diseases of the Developing World, GlaxoSmithKline, Madrid, Spanien.
    Bengtsson, Tore
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Garcia-Bennett, Alfonso E.
    Stockholm Univ, Arrhenius Lab, MMK, Dept Mat & Environm Chem, S-10691 Stockholm, Sweden.
    Large pore mesoporous silica induced weight loss in obese mice2013In: Nanomedicine, ISSN 1743-5889, E-ISSN 1748-6963, Vol. 9, no 9, 1353-1362 p.Article in journal (Refereed)
    Abstract [en]

    Background: There is a need for medical treatments to curb the rising rate of obesity. Weight reduction is correlated with a decrease in associated risk factors and cholesterol levels in humans. Amorphous silica particles have been found to exert a hypocholesterolemic effect in humans, making them popular dietary additives. Aim: To investigate the effect of mesoporous silica, which possess sharp pore size distributions, on: weight loss, cholesterol, triglycerides and glucose blood levels in obese mice. Materials & methods: Mesoporous silicas with differing pore size were mixed in the high-fat diet of obese mice. Results: Animals receiving large pore mesoporous silica with a high-fat diet show a significant reduction in body weight and fat composition, with no observable negative effects. Conclusion: Pore size is an important parameter for reduction of body weight and body fat composition by mesoporous silica, demonstrating promising signs for the treatment of obesity.

  • 33.
    Kühnemund, Malte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Science for life laboratory.
    Wei, Qingshan
    Department of Bioengineering, University of California Los Angeles (UCLA).
    Darai, Eva
    Science for life laboratory, Stockholm University.
    Wang, Y
    Department of Bioengineering, University of California Los Angeles (UCLA).
    Hernandez-Neuta, Ivan
    Science for life laboratory, Stockholm University.
    Tseng, D
    Department of Bioengineering, University of California Los Angeles (UCLA).
    Ahlford, Annika
    Science for life laboratory, Stockholm University.
    Ozcan, Aydogan
    Department of Bioengineering, University of California Los Angeles (UCLA).
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Science for life laboratory, Stockholm University.
    In situ detection of KRAS point mutations and targeted DNA sequencing with a mobile phoneManuscript (preprint) (Other academic)
  • 34.
    Larsen, Christian
    et al.
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Forchheimer, Robert
    Edman, Ludvig
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Tu, Deyu
    Design, fabrication and application of organic power converters: Driving light-emitting electrochemical cells from the AC mains2017In: Organic electronics, ISSN 1566-1199, E-ISSN 1878-5530, Vol. 45, 57-64 p.Article in journal (Refereed)
    Abstract [en]

    The design, fabrication and operation of a range of functional power converter circuits, based on diode configured organic field-effect transistors as the rectifying unit and capable of transforming a high AC input voltage to a selectable DC voltage, are presented. The converter functionality is demonstrated by selecting and tuning its constituents so that it can effectively drive a low-voltage organic electronic device, a light-emitting electrochemical cell (LEC), when connected to high-voltage AC mains. It is established that the preferred converter circuit for this task comprises an organic full-wave rectifier and a regulation resistor but is void of a smoothing capacitor, and that such a circuit connected to the AC mains (230 V, 50 Hz) successfully can drive an LEC to bright luminance (360 cd m(-2)) and high efficiency (6.4 cd A(-1)).

  • 35. Liu, Anmin
    et al.
    Nester, Christopher
    Jones, Richard
    Lundgren, Paul
    Lundberg, Arne
    Arndt, Anton
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Laboratory for Biomechanics and Motor Control.
    Wolf, Peter
    The Effect of an Antipronation Foot Orthosis on Ankle and Subtalar Kinematics2012In: Medicine & Science in Sports & Exercise, ISSN 0195-9131, E-ISSN 1530-0315, Vol. 44, no 12, 2384-91 p.Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION/PURPOSE:

    The aim of this study was to describe the effect of an anti pronation foot orthosis on motion of the heel relative to the leg and explore the individual contributions of the ankle and subtalar joints to this effect.

    METHODS:

    Five subjects were investigated using invasive intracortical pins to track the movement of the tibia, talus and calcaneus during walking with and without a foot orthosis.

    RESULTS:

    The anti pronation foot orthosis produced small and unsystematic reductions in eversion and abduction of the heel relative to the leg at various times during stance. Changes in calcaneus-tibia motion were comparable to those described in the literature (1-3°). Changes at both the ankle and subtalar joints contributed to this orthotic effect. However, the nature and scale of changes was highly variable between subjects. Peak angular position, range of motion and angular velocity in frontal and transverse planes were affected to different degrees in different subjects. In some cases changes occurred mainly at the ankle, in other cases changes occurred mainly at the subtalar joint.

    CONCLUSION:

    The changes in ankle and subtalar kinematics in response to the foot orthosis contradict existing orthotic paradigms that assume that changes occur only at the subtalar joint. The kinematic changes due to the orthosis are indicative of a strong interaction between the often common function of the ankle and subtalar joints.

  • 36.
    Lundin, Anton
    et al.
    Halmstad University, School of Business, Engineering and Science.
    Johansson, Frida
    Halmstad University, School of Business, Engineering and Science.
    OutDoor Office: Ett alternativ till konventionella mötesplatser2015Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 37.
    Lundström, Claes
    et al.
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, The Institute of Technology.
    Persson, Anders
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Radiology in Linköping.
    Characterizing visual analytics in diagnostic imaging2011In: EuroVA 2011: International Workshop on Visual Analytics, 2011, 1-4 p.Conference paper (Other academic)
    Abstract [en]

    Many necessary and desired improvements in healthcare are dependent on progress in medical imaging. As shown in this paper, the challenges targeted by visual analytics (VA) coincide with main challenges for radiologists' diagnostic work. Key prerequisites for VA in this application domain have been identified through analysis of a survey among 22 radiologists at a university hospital. Two major findings are that efficiency is perceived as the most challenging aspect of their diagnostic work and that an exploratory approach is necessary in everyday image review. The presented characterization constitutes a validated input for design of future VA research initiatives within medical imaging.

  • 38.
    Nilsonne, Åsa
    et al.
    Karolinska Institute.
    Sundberg, Johan
    KTH, Superseded Departments, Speech Transmission and Music Acoustics.
    Ternström, Sten
    KTH, Superseded Departments, Speech Transmission and Music Acoustics.
    Askenfelt, Anders
    KTH, School of Computer Science and Communication (CSC), Speech, Music and Hearing, TMH, Music Acoustics.
    Measuring the rate of change of voice fundamental frequency in fluent speech during mental depression1988In: The Journal of the Acoustical Society of America, Vol. 83, no 2, 716-728 p.Article in journal (Refereed)
    Abstract [en]

    A method of measuring the rate of change of fundamental frequency has been developed in an effort to find acoustic voice parameters that could be useful in psychiatric research. A minicomputer program was used to extract seven parameters from the fundamental frequency contour of tape‐recorded speech samples: (1) the average rate of change of the fundamental frequency and (2) its standard deviation, (3) the absolute rate of fundamental frequency change, (4) the total reading time, (5) the percent pause time of the total reading time, (6) the mean, and (7) the standard deviation of the fundamental frequency distribution. The method is demonstrated on (a) a material consisting of synthetic speech and (b) voice recordings of depressed patients who were examined during depression and after improvement.

  • 39.
    Nowak, Christoph
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Sundstrom, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Ganna, Andrea
    Massachusetts General Hospital, Harvard Medical School and Broad Institute, Boston, Massachusetts.
    Shen, Xia
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm , Sweden.
    Broeckling, Corey D.
    Proteomics and Metabolomics Facility, Colorado State University, Fort Collins, Colorado, USA.
    Prenni, Jessica
    Proteomics and Metabolomics Facility, Colorado State University, Fort Collins, Colorado, USA.
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. School of Health and Social Studies, Dalarna University, Falun, Sweden.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
    Metabolite profiles during an oral glucose tolerance test reveal new associations with clamp-measured insulin sensitivityManuscript (preprint) (Other academic)
    Abstract [en]

    Impaired insulin sensitivity (IS) is a major risk factor for cardiovascular disease and type 2 diabetes. Metabolomic profiling during an oral glucose tolerance test (OGTT) can reveal early pathogenic alterations in healthy individuals. Our aim was to identify IS biomarkers and gain new pathophysiologic insights by applying untargeted metabolomics to repeated OGTT plasma samples in association with a hyperinsulinemic-euglycemic clamp assessment. We studied 192 metabolites identified by non-targeted liquid chromatography/mass spectrometry in plasma samples taken at 0, 30, and 120 min during an OGTT in 470 non-diabetic 71-yr-old men. Insulin sensitivity was associated with 35 metabolites at one or more time points in multivariable-adjusted linear regression. The trajectories of nine metabolites during the OGTT were related to IS, six of which (oleic and palmitoleic acid, decanoyl- and dodecanoylcarnitine, deoxycholate-glycine and hexose) showed no associations with IS in the baseline fasting state. The strongest effects were detected for medium-chain acylcarnitines, which increased between 30-120 min in insulin-resistant individuals compared to those with normal IS. In this large community sample, we identified novel associations between clamp-measured IS and metabolite profiles that became apparent only after an oral glucose challenge. Associations of differential medium-chain acylcarnitine and monounsaturated fatty acid trajectories with IS provide new insights into the pathogenesis of insulin resistance.

  • 40.
    Pardon, Gaspard
    et al.
    KTH, School of Electrical Engineering (EES), Micro and Nanosystems.
    Ladhani, Laila
    KTH, School of Electrical Engineering (EES), Micro and Nanosystems.
    Sandström, Niklas
    KTH, School of Electrical Engineering (EES), Micro and Nanosystems.
    Ettori, Maxime
    KTH, School of Electrical Engineering (EES), Micro and Nanosystems.
    Lobov, Gleb
    KTH, School of Electrical Engineering (EES), Micro and Nanosystems.
    van der Wijngaart, Wouter
    KTH, School of Electrical Engineering (EES), Micro and Nanosystems.
    Aerosol sampling using an electrostatic precipitator integrated with a microfluidic interface2015In: Sensors and actuators. B, Chemical, ISSN 0925-4005, Vol. 212, 344-352 p.Article in journal (Refereed)
    Abstract [en]

    In this work, the development of a point-of-care (PoC) system to capture aerosol from litres of air directly onto a microfluidic lab-on-chip for subsequent analysis is addressed. The system involves an electrostatic precipitator that uses corona charging and electrophoretic transport to capture aerosol droplets onto a microfluidic air-to-liquid interface for downstream analysis. A theoretical study of the governing geometric and operational parameters for optimal electrostatic precipitation is presented. The fabrication of an electrostatic precipitator prototype and its experimental validation using a laboratory-generated aerosolized dye is described. Collection efficiencies were comparable to those of a state-of-the-art Biosampler impinger, with the significant advantage of providing samples that are at least 10 times more concentrated. Finally, we discuss the potential of such a system for breath-based diagnostics.

  • 41.
    Petzold, Martin
    et al.
    University of Cologne, Germany.
    Barbabella, Francesco
    National Institute of Health and Science on Ageing (INRCA), Italy.
    Bobeth, Jan
    CURE - Center for Usability Research and Engineering, Austria.
    Kern, Dagmar
    Mayer, Christopher
    AIT Austrian Institute of Technology GmbH, Austria.
    Morandell, Martin
    AIT Austrian Institute of Technology GmbH, Austria.
    Towards an Ambient Assisted Living User Interaction Taxonomy2013In: CHI '13 Extended Abstracts of the ACM International Conference on Human Factors in Computing Systems, New York: ACM Press, 2013, 49-54 p.Conference paper (Refereed)
    Abstract [en]

    Extensive research in the field of ambient assisted living (AAL) provides profound knowledge about the design of AAL systems. However, more generic design characteristics for user interaction have not been formalized for this domain yet. Thus, we propose to develop a domain specific taxonomy for the design of user interaction in AAL systems. We adopted a systematic taxonomy development approach that combines an empirical and a pseudo-conceptual strategy. Six co-researchers from different disciplines conduct the iterative research process. Next to AAL systems existing taxonomies in the field of human-computer interaction are analyzed following the Delphi method. In this paper we present our research process and preliminary results from the first iteration. The final taxonomy allows classification and should support the analysis of user interaction utilized in AAL systems. Furthermore, it can deal as a practical design guideline.

  • 42. Ravichandran, R.
    et al.
    Åstrand, Carolina
    KTH, School of Biotechnology (BIO), Industrial Biotechnology.
    Patra, H. K.
    Turner, Anthony P. F.
    Chotteau, Véronique
    KTH, School of Biotechnology (BIO), Industrial Biotechnology.
    Phopase, J.
    Intelligent ECM mimetic injectable scaffolds based on functional collagen building blocks for tissue engineering and biomedical applications2017In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 7, no 34, 21068-21078 p.Article in journal (Refereed)
    Abstract [en]

    Hydrogels comprising natural extracellular matrix (ECM) components are very attractive as scaffolds for regenerative medicine applications due to their inherent biointeractive properties. Responsive materials that adapt to their surrounding environments and regulate transport of ions and bioactive molecules manifest significant advantages for biomedical applications. Although there are many exciting challenges, the opportunity to design, fabricate and engineer stimuli-responsive polymeric systems based on ECM components is particularly attractive for regenerative medicine. Here we describe a one-pot approach to fabricate in situ fast gellable intelligent ECM mimetic scaffolds, based on methacrylated collagen building blocks with mechanical properties that can be modulated in the kPa-MPa range and that are suitable for both soft and hard tissues. Physiochemical characterizations demonstrate their temperature and pH responsiveness, together with the structural and enzymatic resistance that make them suitable scaffolds for long-term use in regenerative medicine and biomedical applications. The multifunctionality of these hydrogels has been demonstrated as an in situ depot-forming delivery platform for the adjustable controlled release of proteins and small drug molecules under physiological conditions and as a structural support for adhesion, proliferation and metabolic activities of human cells. The results presented herein should be useful to the design and fabrication of tailor-made scaffolds with tunable properties that retain and exhibit sustained release of growth factors for promoting tissue regeneration.

  • 43.
    Shcherbina, Anna
    et al.
    Stanford University.
    Mattsson, C. Mikael
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences.
    Waggott, Daryl
    Stanford University.
    Salisbury, Heidi
    Stanford University.
    Christle, Jeffrey W
    Stanford University.
    Hastie, Trevor J
    Stanford University.
    Wheeler, Matthew
    Stanford University.
    Ashley, Euan A.
    Stanford University.
    Accuracy in wrist-worn, sensor-based measurements of heart rate and energy expenditure in a diverse cohort2016Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: The ability to measure activity and physiology through wrist-worn devices provides an opportunity for cardiovascular medicine. However, the accuracy of commercial devices is largely unknown. Objective: To assess the accuracy of seven commercially available wrist-worn devices in estimating heart rate (HR) and energy expenditure (EE) and to propose a wearable sensor evaluation framework. Methods: We evaluated the Apple Watch, Basis Peak, Fitbit Surge, Microsoft Band, Mio Alpha 2, PulseOn, and Samsung Gear S2. Participants wore devices while being simultaneously assessed with continuous telemetry and indirect calorimetry while sitting, walking, running, and cycling. Sixty volunteers (29 male, 31 female, age 38 +/- 11 years) of diverse age, height, weight, skin tone, and fitness level were selected. Error in HR and EE was computed for each subject/device/activity combination. Results: Devices reported the lowest error for cycling and the highest for walking. Device error was higher for males, greater body mass index, darker skin tone, and walking. Six of the devices achieved a median error for HR below 5% during cycling. No device achieved an error in EE below 20 percent. The Apple Watch achieved the lowest overall error in both HR and EE, while the Samsung Gear S2 reported the highest. Conclusions: Most wrist-worn devices adequately measure HR in laboratory-based activities, but poorly estimate EE, suggesting caution in the use of EE measurements as part of health improvement programs. We propose reference standards for the validation of consumer health devices (http://precision.stanford.edu/).

  • 44.
    Shildrick, Margrit
    Queens University, Belfast.
    Imagining the heart: incorporations, intrusions and identity2011In: Keynote address, 2011Conference paper (Other academic)
  • 45.
    Shildrick, Margrit
    Queens University, Belfast.
    Some Reflections on the Socio-cultural and Bioscientific Limits of Bodily Integrity2010In: Body & Society, ISSN 1357-034X, E-ISSN 1460-3632, Vol. 16, no 3, 11-22 p.Article in journal (Refereed)
  • 46.
    Shildrick, Margrit
    et al.
    Queens University, Belfast.
    McKeever, Patricia
    Bloorview Research Institute, University of Toronto.
    Abbey, Susan
    University Health Network, Toronto.
    Poole, Jennifer
    Ryerson University, Toronto.
    Ross, Heather
    University Health Network, Toronto.
    Troubling dimensions of heart transplantation2009In: Medical Humanities, ISSN 1468-215X, Vol. 35, no 1, 35-38 p.Article in journal (Refereed)
    Abstract [en]

    Heart transplantation is now the accepted therapy for end-stage heart failure that is resistant to medical treatment. Families of deceased donors routinely are urged to view the heart as a "gift of life" that will enable the donor to live on by extending and sustaining the life of a stranger. In contrast, heart recipients are encouraged to view the organ mechanistically--as a new pump that was rendered a spare, reusable part when a generous stranger died. Psychosocial and psychoanalytic research, anecdotal evidence and first-person accounts indicate that after transplant, many recipients experience unexpected changes or distress that cannot be understood adequately using biomedical explanatory models alone. In this paper it is argued that phenomenological philosophy offers a promising way to frame an ongoing empirical study that asks recipients to reflect on what it is like to incorporate the heart of another person. Merleau-Ponty and others have posited that any change to the body inevitably transforms the self. Hence, it is argued in this paper that replacing failing hearts with functioning hearts from deceased persons must be considered much more than a complex technical procedure. Acknowledging the disturbances to embodiment and personal identity associated with transplantation may explain adverse outcomes that heretofore have been inexplicable. Ultimately, a phenomenological understanding could lead to improvements in the consent process, preoperative teaching and follow-up care.

  • 47.
    Shildrick, Margrit
    et al.
    Linköping University, The Tema Institute, The Department of Gender Studies. Linköping University, Faculty of Arts and Sciences.
    Poole, Jennifer
    Ryerson University, Toronto, Canada.
    Ross, Heather
    University Health Network, Toronto, Canada.
    Mauthner, Oliver
    University Health Network, Toronto, Canada.
    Abbey, Susan
    University Health Network, Toronto, Canada.
    Life on the Heart Transplant Waiting List: Life on Hold? Life at All?2013Other (Other academic)
  • 48.
    Skouloudaki, Kassiani
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Developmental Biology.
    Walz, Gerd
    YAP1 Recruits c-Abl to Protect Angiomotin-Like 1 from Nedd4-Mediated Degradation2012In: PLoS ONE, ISSN 1932-6203, Vol. 7, no 4, e35735- p.Article in journal (Refereed)
    Abstract [en]

    Background: Tissue development and organ growth require constant remodeling of cell-cell contacts formed between epithelial cells. The Hippo signaling cascade curtails organ growth by excluding the transcriptional co-activator Yes Associated Protein 1 (YAP1) from the nucleus. Angiomotin family members recruit YAP1 to tight junctions [1], but whether YAP1 plays a specific role outside of the nucleus is currently unknown. Methodology/Principal Findings: The present study demonstrates that the E3 ubiquitin ligase Nedd4.2 targets Angiomotin-like 1 (AMOTL1), a family member that promotes the formation of epithelial tight junctions, for ubiquitin-dependent degradation. Unexpectedly, YAP1 antagonizes the function of Nedd4.2, and protects AMOTL1 against Nedd4.2-mediated degradation. YAP1 recruits c-Abl, a tyrosine kinase that binds and phosphorylates Nedd4.2 on tyrosine residues, thereby modifying its ubiquitin-ligase activity. Conclusions/Significance: Our results uncover a novel function for cytoplasmic YAP1. YAP1 recruits c-Abl to protect AMOTL1 against Nedd4.2-mediated degradation. Thus, YAP1, excluded from the nucleus, contributes to the maintenance of tight junctions.

  • 49.
    Tegler, Gustaf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Hall, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Wanhainen, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Björck, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Autoradiography screening of potential positron emission tomography tracers for asymptomatic abdominal aortic aneurysms2014In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 3, 229-235 p.Article in journal (Refereed)
    Abstract [en]

    Objective. The aetiology and early pathophysiological mechanisms of aortic aneurysm formation are still unknown and challenging to study in vivo. Positron emission tomography (PET) is a potentially valuable instrument for non-invasive in vivo pathophysiological studies. No specific tracer to identify the pathophysiological process of aneurysmal dilatation is yet available, however. The aim of this study was to explore if different PET tracers could be useful to image aneurysmal disease. Methods and results. Human aneurysmal aortic tissue, collected during elective resection of abdominal aortic aneurysm (AAA) of asymptomatic patients, was investigated in vitro by means of autoradiography with [Ga-68]CRP-binder targeting C-reactive protein, [C-11]DAA1106 targeting translocator protein (18 kDa), [C-11]D-deprenyl with unknown target receptor, [C-11] deuterium-L-deprenyl targeting astrocytes, [F-18]fluciclatide targeting integrin alpha(V)beta(3), [Ga-68]IMP461 and bi-specific antibody TF2 052107 targeting carcinoembryonic antigen, [F-18]F-metomidate targeting mitochondrial cytochrome P-450 species in the adrenal cortex, and [F-18]vorozole targeting aromatase. Of the investigated tracers, only [F-18]fluciclatide exhibited specific binding, whereas the other PET tracers failed to show specific uptake in the investigated tissue and are probably not useful for the intended purpose. Conclusion. It seems likely that alpha(V)beta(3) integrin expression in AAA can be visualized with PET and that the alpha(V)beta(3) selective tracer, [F-18]fluciclatide, may be suitable for in vivo molecular imaging of asymptomatic AAA. Additional evaluation of [F-18]fluciclatide and alpha(V)beta(3) integrin expression in AAA will be performed in vitro as well as in vivo.

  • 50.
    Tegler, Gustaf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Ericson, Katharina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Björck, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Wanhainen, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    4D-PET/CT with [11C]-PK11195 and [11C]-D-deprenyl does not identify the chronic inflammation in asymptomatic abdominal aortic aneurysms2013In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 45, no 4, 351-356 p.Article in journal (Refereed)
    Abstract [en]

    Objectives

    The aim of this study was to investigate the relevance of inflammation in the pathogenesis of abdominal aortic aneurysm (AAA) in vivo with two novel positron emission tomography (PET) tracers: [11C]-PK11195 which targets the translocator protein (18 kDa) expressed on macrophages and [11C]-d-deprenyl with a yet unknown target receptor expressed in chronic inflammation.

    Design

    Prospective clinical study.

    Materials/methods

    Five patients were examined with [11C]-PK11195-positron emission tomography/computed tomography (PET/CT) and 10 with [11C]-d-deprenyl-PET/CT. Nine large AAAs (54–66 mm) scheduled for repair and six small AAA (35–44 mm). All 15 patients were male and the AAAs were all asymptomatic. Regional activity was measured as standardised uptake values (SUVs) and retention index was calculated. Biopsies were taken from the aneurysm wall for histological examinations, in the nine patients operated on.

    Results

    No aortic uptake was recorded on the visual inspection, neither with [11C]-PK11195 nor with [11C]-d-deprenyl. For [11C]-PK11195 the median SUV of the AAA wall was 0.9 (range 0.8–1.0) and for [11C]-d-deprenyl, 0.7 (range 0.4–1.2). No increased uptake was seen in the aneurysmal infrarenal aorta compared with the non-aneurysmal suprarenal aorta. Histological examination of the aneurysm wall showed high inflammatory cell infiltration with lymphocytes and macrophages.

    Conclusions

    The chronic inflammation observed in the vessel wall was not detectable with [11C]-PK11195 and [11C]-d-deprenyl. In order to study the relevance of the inflammation in the pathogenesis of AAA in vivo other PET tracers need to be investigated.

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