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  • 51. Beckman, Claes
    et al.
    Jörgen, Thaung
    Göteborgs Universitet.
    Johan, Sjöstrand
    Göteborgs Universitet.
    In vitro Lens Scatter Measurements and Glare Testing1994In: The Association for Research in Vision and Ophthalmology Annual Meeting. Sarasota, Florida, May 1-6, 1994. Abstracts. Investigative Ophthalmology & Visual Science March 1994, Vol.35, 1254-2383., 1994, Vol. 35, p. 1803-Conference paper (Refereed)
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    fulltext
  • 52.
    Bedri, Sahl Khalid
    et al.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Inst, Ctr Mol Med, Stockholm, Sweden..
    Nilsson, Ola B.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Inst, Ctr Mol Med, Stockholm, Sweden.;Advice Foretagsassistans & Stockholm AB, TCER AB, Stockholm, Sweden..
    Fink, Katharina
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Inst, Ctr Mol Med, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Neurol, Stockholm, Sweden..
    Månberg, Anna
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Affin Prote, SciLifeLab, Stockholm, Sweden..
    Hamsten, Carl
    Karolinska Inst, Dept Med, Immunol & Allergy Unit, Stockholm, Sweden..
    Ayoglu, Burcu
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Affin Prote, SciLifeLab, Stockholm, Sweden..
    Manouchehrinia, Ali
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Inst, Ctr Mol Med, Stockholm, Sweden..
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Affin Prote, SciLifeLab, Stockholm, Sweden..
    Olsson, Tomas
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Inst, Ctr Mol Med, Stockholm, Sweden..
    Hillert, Jan
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Inst, Ctr Mol Med, Stockholm, Sweden..
    Grönlund, Hans
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Inst, Ctr Mol Med, Stockholm, Sweden..
    Glaser, Anna
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Inst, Ctr Mol Med, Stockholm, Sweden..
    Plasma protein profiling reveals candidate biomarkers for multiple sclerosis treatment2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 5, article id e0217208Article in journal (Refereed)
    Abstract [en]

    Multiple sclerosis (MS) treatment options have improved significantly over the past decades, but the consequences of MS can still be devastating and the needs for monitoring treatment surveillance are considerable. In the current study we used affinity proteomics technology to identify potential biomarkers which could ultimately be used to as facilitate treatment decisions. We profiled the intra-individual changes in the levels of 59 target proteins using an antibody suspension bead array in serial plasma samples from 44 MS patients during treatment with natalizumab followed by fingolimod. Nine proteins showed decreasing plasma levels during natalizumab treatment, with PEBP1 and RTN3 displaying the most significant changes. Protein levels remained stable during fingolimod treatment for both proteins. The decreasing PEBP1 levels during natalizumab treatment could be validated using ELISA and replicated in an independent cohort. These results support the use of this technology as a high throughput method of identifying potentially useful biomarkers of MS treatment.

  • 53. Belliato, M.
    et al.
    Caneva, L.
    Aina, A.
    Degani, A.
    Mongodi, S.
    Prahl Wittberg, Lisa
    KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW. KTH, School of Engineering Sciences (SCI), Centres, BioMEx. KTH, School of Engineering Sciences (SCI), Mechanics.
    Pellegrini, C.
    Broman, L. M.
    Iotti, G. A.
    An experimental model of veno-venous arterial extracorporeal membrane oxygenation2019In: International Journal of Artificial Organs, ISSN 0391-3988, E-ISSN 1724-6040Article in journal (Refereed)
    Abstract [en]

    Introduction: Veno-venous arterial extracorporeal membrane oxygenation is a hybrid-modality of extracorporeal membrane oxygenation combining veno-venous and veno-arterial extracorporeal membrane oxygenation. It may be applied to patients with both respiratory and cardio-circulatory failure. Aim: To describe a computational spreadsheet regarding an ex vivo experimental model of veno-venous arterial extracorporeal membrane oxygenation to determine the return of cannula pairs in a single pump–driven circuit. Methods: We developed an ex vivo model of veno-venous arterial extracorporeal membrane oxygenation with a single pump and two outflow cannulas, and a glucose solution was used to mimic the features of blood. We maintained a fixed aortic impedance and physiological pulmonary resistance. Both flow and pressure data were collected while testing different pairs of outflow cannulas. Six simulations of different cannula pairs were performed, and data were analysed by a custom-made spreadsheet, which was able to predict the flow partition at different flow levels. Results: In all simulations, the flow in the arterial cannula gradually increased differently depending on the cannula pair. The best cannula pair was a 19-Fr/18-cm arterial with a 17-Fr/50-cm venous cannula, where we observed an equal flow split and acceptable flow into the arterial cannula at a lower flow rate of 4 L/min. Conclusion: Our computational spreadsheet identifies the suitable cannula pairing set for correctly splitting the outlet blood flow into the arterial and venous return cannulas in a veno-venous arterial extracorporeal membrane oxygenation configuration without the use of external throttles. Several limitations were reported regarding fixed aortic impedance, central venous pressure and the types of cannulas tested; therefore, further studies are mandatory to confirm our findings.

  • 54.
    Bendazzoli, Simone
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems.
    Brusini, Irene
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging. Karolinska Inst, Dept Neurobiol Care Sci & Soc, Alfred Nobels Alle 23,D3, S-14152 Huddinge, Sweden..
    Damberg, Peter
    Karolinska Inst, Dept Clin Neurosci, Tomtebodavagen 18A P1 5, S-17177 Stockholm, Sweden..
    Smedby, Örjan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Andersson, Leif
    Uppsala Univ, Dept Med Biochem & Microbiol, Sci Life Lab Uppsala, Biomedicinskt Ctr BMC, Husargatan 3, S-75237 Uppsala, Sweden..
    Wang, Chunliang
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Automatic rat brain segmentation from MRI using statistical shape models and random forest2019In: MEDICAL IMAGING 2019: IMAGE PROCESSING / [ed] Angelini, ED Landman, BA, SPIE-INT SOC OPTICAL ENGINEERING , 2019, article id 1094920Conference paper (Refereed)
    Abstract [en]

    In MRI neuroimaging, the shimming procedure is used before image acquisition to correct for inhomogeneity of the static magnetic field within the brain. To correctly adjust the field, the brain's location and edges must first be identified from quickly-acquired low resolution data. This process is currently carried out manually by an operator, which can be time-consuming and not always accurate. In this work, we implement a quick and automatic technique for brain segmentation to be potentially used during the shimming. Our method is based on two main steps. First, a random forest classifier is used to get a preliminary segmentation from an input MRI image. Subsequently, a statistical shape model of the brain, which was previously generated from ground-truth segmentations, is fitted to the output of the classifier to obtain a model-based segmentation mask. In this way, a-priori knowledge on the brain's shape is included in the segmentation pipeline. The proposed methodology was tested on low resolution images of rat brains and further validated on rabbit brain images of higher resolution. Our results suggest that the present method is promising for the desired purpose in terms of time efficiency, segmentation accuracy and repeatability. Moreover, the use of shape modeling was shown to be particularly useful when handling low-resolution data, which could lead to erroneous classifications when using only machine learning-based methods.

  • 55.
    Benfeitas, Rui
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nielsen, Jens
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Mardinoglu, A.
    New challenges to study heterogeneity in cancer redox metabolism2017In: Frontiers in Cell and Developmental Biology, ISSN 2296-634X, Vol. 5, no JUL, article id 65Article in journal (Refereed)
    Abstract [en]

    Reactive oxygen species (ROS) are important pathophysiological molecules involved in vital cellular processes. They are extremely harmful at high concentrations because they promote the generation of radicals and the oxidation of lipids, proteins, and nucleic acids, which can result in apoptosis. An imbalance of ROS and a disturbance of redox homeostasis are now recognized as a hallmark of complex diseases. Considering that ROS levels are significantly increased in cancer cells due to mitochondrial dysfunction, ROS metabolism has been targeted for the development of efficient treatment strategies, and antioxidants are used as potential chemotherapeutic drugs. However, initial ROS-focused clinical trials in which antioxidants were supplemented to patients provided inconsistent results, i.e., improved treatment or increased malignancy. These different outcomes may result from the highly heterogeneous redox responses of tumors in different patients. Hence, population-based treatment strategies are unsuitable and patient-tailored therapeutic approaches are required for the effective treatment of patients. Moreover, due to the crosstalk between ROS, reducing equivalents [e.g., NAD(P)H] and central metabolism, which is heterogeneous in cancer, finding the best therapeutic target requires the consideration of system-wide approaches that are capable of capturing the complex alterations observed in all of the associated pathways. Systems biology and engineering approaches may be employed to overcome these challenges, together with tools developed in personalized medicine. However, ROS- and redox-based therapies have yet to be addressed by these methodologies in the context of disease treatment. Here, we review the role of ROS and their coupled redox partners in tumorigenesis. Specifically, we highlight some of the challenges in understanding the role of hydrogen peroxide (H2O2), one of the most important ROS in pathophysiology in the progression of cancer. We also discuss its interplay with antioxidant defenses, such as the coupled peroxiredoxin/thioredoxin and glutathione/glutathione peroxidase systems, and its reducing equivalent metabolism. Finally, we highlight the need for system-level and patient-tailored approaches to clarify the roles of these systems and identify therapeutic targets through the use of the tools developed in personalized medicine. © 2017 Benfeitas, Uhlen, Nielsen and Mardinoglu.

  • 56.
    Bennati, Paolo
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering.
    Dasu, A.
    Colarieti-Tosti, Massimiliano
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Lönn, Gustaf
    KTH, School of Technology and Health (STH), Medical Engineering.
    Larsson, David
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging.
    Fabbri, A.
    Galasso, M.
    Cinti, M. N.
    Pellegrini, R.
    Pani, R.
    Preliminary study of a new gamma imager for on-line proton range monitoring during proton radiotherapy2017In: Journal of Instrumentation, ISSN 1748-0221, E-ISSN 1748-0221, Vol. 12, no 5, article id C05009Article in journal (Refereed)
    Abstract [en]

    We designed and tested new concept imaging devices, based on a thin scintillating crystal, aimed at the online monitoring of the range of protons in tissue during proton radiotherapy. The proposed crystal can guarantee better spatial resolution and lower sensitivity with respect to a thicker one, at the cost of a coarser energy resolution. Two different samples of thin crystals were coupled to a position sensitive photo multiplier tube read out by 64 independent channels electronics. The detector was equipped with a knife-edge Lead collimator that defined a reasonable field of view of about 10 cm in the target. Geant4 Monte Carlo simulations were used to optimize the design of the experimental setup and assess the accuracy of the results. Experimental measurements were carried out at the Skandion Clinic, the recently opened proton beam facility in Uppsala, Sweden. PMMA and water phantoms studies were performed with a first prototype based on a round 6.0 mm thick Cry019 crystal and with a second detector based on a thinner 5 × 5 cm2, 2.0 mm thick LFS crystal. Phantoms were irradiated with mono-energetic proton beams whose energy was in the range between 110 and 160 MeV. According with the simulations and the experimental data, the detector based on LFS crystal seems able to identify the peak of prompt-gamma radiation and its results are in fair agreement with the expected shift of the proton range as a function of energy. The count rate remains one of the most critical limitations of our system, which was able to cope with only about 20% of the clinical dose rate. Nevertheless, we are confident that our study might provide the basis for developing a new full-functional system.

  • 57.
    Bergenstråhle, Malin
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology.
    Thormann, Esben
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface Chemistry.
    Nordgren, Niklas
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface Chemistry.
    Berglund, Lars
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology.
    Force Pulling of Single Cellulose Chains at the Crystalline Cellulose-Liquid Interface: A Molecular Dynamics Study2009In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 25, no 8, p. 4635-4642Article in journal (Refereed)
    Abstract [en]

    Pulling single cellulose molecules from a crystalline cellulose surface has been modeled by molecular dynamics (MD) simulations of the experimental procedure used in atomic force microscopy (AFM). Specifically, the aim of the study was to investigate cellulose interactions at desorption. Simulations were performed in both water and the organic solvent cyclohexane. Moreover, the effects of initial octamer conformation and orientation with respect to the surface chains were studied. A strong effect from the solvent was observed. In cyclohexane, normal forces of 200-500 pN and energies of 43.5 +/- 6.0 kJ/mol glucose unit were required to pull off the octamer. The normal forces in water were substantially lower, around 58 pN, and the energies were 18.2 +/- 3.6 kJ/mol glucose unit. In addition, the lateral components of the pull-off force were shown to provide information on initial conformation and orientation. Hydrogen bonds between the octamer and surface were analyzed and found to be an important factor in the pull-off behavior. Altogether, it was shown that MD provides detailed information on the desorption processes that may be useful for the interpretation of AFM experiments.

  • 58.
    Berggren, Karl
    KTH, School of Engineering Sciences (SCI), Physics, Physics of Medical Imaging.
    Spectral image quality and applications in breast tomosynthesis2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In the 1970s, it was determined that screening mammography is an efficient tool in fighting the increasing number of women dying from breast cancer, and many countries have established screening programs since then. Mammography systems have improved substantially over the years with one of the major advances being the transition from x-ray film to digital x-ray detectors. Following this development, the number of women dying from breast cancer has decreased, but there is still much room for improvement. One technology that is changing the breast imaging landscape is breast tomosynthesis; tomographic imaging with in-plane resolution similar to that of mammography, albeit limited height resolution. Breast tomosynthesis is commonly implemented with flat-panel detectors, but line detectors in a slit-scanning geometry can also be used. The latter configuration allows for more complex detector technologies, such as spectral photon-counting detectors that enable single-shot spectral imaging. The combination of spectral imaging and tomosynthesis opens up for a range of new applications, but the slit scanning geometry, which differs substantially from that of flat-panel tomosynthesis systems, and the factors affecting image quality have not been well understood. This thesis aims at filling this gap. Image quality and the parameters that influence image quality in spectral photon-counting slit-scanning breast tomosynthesis are characterized and analyzed using cascaded-systems modelling and linear image quality metrics. In addition, the thesis goes into characterizing the x-ray properties of breast tissue, an important input parameter for accurate material decomposition of in-vivo tissue. Material decomposition with spectral imaging opens up a range of applications, such as accurate measurement of volumetric breast density and spectral lesion characterization for decision support as part of mammography screening, and contrast-enhanced K-edge imaging for diagnostics. Tomosynthesis combined with material decomposition has the potential to improve these methods further by, for instance, separating lesions or regions of interest from surrounding fibro-glandular tissue in quantitative 3D maps of breast tissue.

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  • 59.
    Berggren, Karl
    et al.
    KTH, School of Engineering Sciences (SCI), Physics, Physics of Medical Imaging. Philips Mammography Solutions, 164 40 Kista, Sweden.
    Cederstrom, Bjorn
    Lundqvist, Mats
    Fredenberg, Erik
    Cascaded systems analysis of shift-variant image quality in slit-scanning breast tomosynthesis2018In: Medical PhysicsArticle in journal (Refereed)
  • 60.
    Berggren, Karl
    et al.
    KTH, School of Engineering Sciences (SCI), Physics, Physics of Medical Imaging. Philips Mammorgaphy Solutions.
    Cederström, Björn
    Philips Mammography Solutions.
    Lundqvist, Mats
    Philips Mammography Solutions.
    Fredenberg, Erik
    Philips Research.
    Characterization of photon-counting multislit breast tomosynthesis2018In: Medical Physics, E-ISSN 2473-4209Article in journal (Refereed)
    Abstract [en]

    Purpose: It has been shown that breast tomosynthesis may improve sensitivity and specificity compared to two-dimensional mammography, resulting in increased detection-rate of cancers or lowered call-back rates. The purpose of this study is to characterize a spectral photon-counting multislit breast tomosynthesis system that is able to do single-scan spectral imaging with multiple collimated x-ray beams. The system differs in many aspects compared to conventional tomosynthesis using energyintegrating flat-panel detectors. Methods: The investigated system was a prototype consisting of a dual-threshold photon-counting detector with 21 collimated line detectors scanning across the compressed breast. A review of the system is done in terms of detector, acquisition geometry, and reconstruction methods. Three reconstruction methods were used, simple back-projection, filtered back-projection and an iterative algebraic reconstruction technique. The image quality was evaluated by measuring the modulation transfer-function (MTF), normalized noise-power spectrum, detective quantum-efficiency (DQE), and artifact spread-function (ASF) on reconstructed spectral tomosynthesis images for a total-energy bin (defined by a low-energy threshold calibrated to remove electronic noise) and for a high-energy bin (with a threshold calibrated to split the spectrum in roughly equal parts). Acquisition was performed using a 29 kVp W/Al x-ray spectrum at a 0.24 mGy exposure. Results: The difference in MTF between the two energy bins was negligible, that is, there was no energy dependence on resolution. The MTF dropped to 50% at 1.5 lp/mm to 2.3 lp/mm in the scan direction and 2.4 lp/mm to 3.3 lp/mm in the slit direction, depending on the reconstruction method. The full width at half maximum of the ASF was found to range from 13.8 mm to 18.0 mm for the different reconstruction methods. The zero-frequency DQE of the system was found to be 0.72. The fraction of counts in the high-energy bin was measured to be 59% of the total detected spectrum. Scantimes ranged from 4 s to 16.5 s depending on voltage and current settings. Conclusions: The characterized system generates spectral tomosynthesis images with a dual-energy photon-counting detector. Measurements show a high DQE, enabling high image quality at a low dose, which is beneficial for low-dose applications such as screening. The single-scan spectral images open up for applications such as quantitative material decomposition and contrast-enhanced tomosynthesis. 

  • 61.
    Berggren, Karl
    et al.
    KTH, School of Engineering Sciences (SCI), Physics, Physics of Medical Imaging. Philips Mammography Solutions.
    Cederström, Björn
    Philips Mammography Solutions.
    Lundqvist, Mats
    Philips.
    Fredenberg, Erik
    Philips Research.
    Technical Note: Comparison of first‐ and second‐generation photon‐counting slit‐scanning tomosynthesis systems2018In: Medical PhysicsArticle in journal (Refereed)
    Abstract [en]

    Purpose: Digital breast tomosynthesis (DBT) is an emerging tool for breast-cancer screening and diagnostics. The purpose of this study is to present a second-generation photon-counting slitscanning DBT system and compare it to the first-generation system in terms of geometry and image quality. The study presents the first image-quality measurements on the second-generation system. Method: The geometry of the new system is based on a combined rotational and linear motion, in contrast to a purely rotational scan motion in the first generation. In addition, the calibration routines have been updated. Image quality was measured in the center of the image field in terms of in-slice modulation transfer function (MTF), artifact spread function (ASF), and in-slice detective quantum efficiency (DQE). Images were acquired using a W/Al 29 kVp spectrum at 13 mAs with 2 mm Al additional filtration and reconstructed using simple back-projection. Result: The in-slice 50% MTF was improved in the chest-mammilla direction, going from 3.2 to 3.5 lp/mm, and the zero-frequency DQE increased from 0.71 to 0.77. The MTF and ASF were otherwise found to be on par for the two systems. The new system has reduced in-slice variation of the tomographic angle. Conclusions: The new geometry is less curved, which reduces in-slice tomographic-angle variation, and increases the maximum compression height, making the system accessible for a larger population. The improvements in MTF and DQE were attributed to the updated calibration procedures. We conclude that the second-generation system maintains the key features of the photon-counting system while maintaining or improving image quality and improving the maximum compression height. 

  • 62.
    Berggren, Karl
    et al.
    KTH, School of Engineering Sciences (SCI), Physics, Physics of Medical Imaging.
    Eriksson, Mikael
    Hall, Per
    Wallis, Matthew
    Fredenberg, Erik
    In-vivo measurement of the effective atomic number of breast skin using spectral mammography2018In: Article in journal (Refereed)
  • 63.
    Berggren, Karl
    et al.
    KTH, School of Engineering Sciences (SCI), Physics, Physics of Medical Imaging. Philips Healthcare, S-17141 Solna, Sweden.
    Lundqvist, Mats
    Cederstrom, Bjorn
    Danielsson, Mats
    KTH, School of Engineering Sciences (SCI), Physics, Physics of Medical Imaging.
    Fredenberg, Erik
    Physical characterization of photon-counting tomosynthesis2015Conference paper (Refereed)
    Abstract [en]

    Tomosynthesis is emerging as a next generation technology in mammography. Combined with photon-counting detectors with the ability for energy discrimination, a novel modality is enabled - spectral tomosynthesis. Further advantages of photon-counting detectors in the context of tomosynthesis include elimination of electronic noise, efficient scatter rejection (in some geometries) and no lag. Fourier-based linear-systems analysis is a well-established method for optimizing image quality in two-dimensional x-ray systems. The method has been successfully adapted to three-dimensional imaging, including tomosynthesis, but several areas need further investigation. This study focuses on two such areas: 1) Adaption of the methodology to photon-counting detectors, and 2) violation of the shift-invariance and stationarity assumptions in non-cylindrical geometries. We have developed a Fourier-based framework to study the image quality in a photon-counting tomosynthesis system, assuming locally linear, stationary, and shift-invariant system response. The framework includes a cascaded-systems model to propagate the modulation-transfer function (MTF) and noise-power spectrum (NPS) through the system. The model was validated by measurements of the MTF and NPS. High degrees of non-shift invariance and non-stationarity were observed, in particular for the depth resolution as the angle of incidence relative the reconstruction plane varied throughout the imaging volume. The largest effects on image quality in a given point in space were caused by interpolation from the inherent coordinate system of the x-rays to the coordinate system that was used for reconstruction. This study is part of our efforts to fully characterize the spectral tomosynthesis system, we intend to extend the model further to include the detective-quantum efficiency, observer modelling, and spectral effects.

  • 64.
    Berglund, Emelie
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.
    Maaskola, Jonas
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.
    Schultz, Niklas
    Friedrich, Stefanie
    Marklund, Maja
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.
    Bergenstrahle, Joseph
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.
    Tarish, Firas
    Tanoglidi, Anna
    Vickovic, Sanja
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Larsson, Ludvig
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.
    Salmén, Fredrik
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Ogris, Christoph
    Wallenborg, Karolina
    Lagergren, Jens
    KTH, School of Electrical Engineering and Computer Science (EECS), Computational Science and Technology (CST).
    Ståhl, Patrik
    Sonnhammer, Erik
    Helleday, Thomas
    Lundeberg, Joakim
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Spatial maps of prostate cancer transcriptomes reveal an unexplored landscape of heterogeneity2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 2419Article in journal (Refereed)
    Abstract [en]

    Intra-tumor heterogeneity is one of the biggest challenges in cancer treatment today. Here we investigate tissue-wide gene expression heterogeneity throughout a multifocal prostate cancer using the spatial transcriptomics (ST) technology. Utilizing a novel approach for deconvolution, we analyze the transcriptomes of nearly 6750 tissue regions and extract distinct expression profiles for the different tissue components, such as stroma, normal and PIN glands, immune cells and cancer. We distinguish healthy and diseased areas and thereby provide insight into gene expression changes during the progression of prostate cancer. Compared to pathologist annotations, we delineate the extent of cancer foci more accurately, interestingly without link to histological changes. We identify gene expression gradients in stroma adjacent to tumor regions that allow for re-stratification of the tumor microenvironment. The establishment of these profiles is the first step towards an unbiased view of prostate cancer and can serve as a dictionary for future studies.

  • 65. Berglund, S.
    et al.
    Magalhaes, I.
    Gaballa, A.
    Vanherberghen, Bruno
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Uhlin, Michael
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cellular Biophysics. Karolinska Institutet, Sweden.
    Advances in umbilical cord blood cell therapy: the present and the future2017In: Expert Opinion on Biological Therapy, ISSN 1471-2598, E-ISSN 1744-7682, Vol. 17, no 6, p. 691-699Article, review/survey (Refereed)
    Abstract [en]

    Introduction: Umbilical cord blood (UCB), previously seen as medical waste, is increasingly recognized as a valuable source of cells for therapeutic use. The best-known application is in hematopoietic stem cell transplantation (HSCT), where UCB has become an increasingly important graft source in the 28 years since the first umbilical cord blood transplantation (UCBT) was performed. Recently, UCB has been increasingly investigated as a putative source for adoptive cell therapy. Areas covered: This review covers the advances in umbilical cord blood transplantation (UCBT) to overcome the limitation regarding cellular dose, immunological naivety and additional cell doses such as DLI. It also provides an overview regarding the progress in adoptive cellular therapy using UCB. Expert opinion: UCB has been established as an important source of stem cells for HSCT. Successful strategies to overcome the limitations of UCBT, such as the limited cell numbers and naivety of the cells, are being developed, including novel methods to perform in vitro expansion of progenitor cells, and to improve their homing to the bone marrow. Promising early clinical trials of adoptive therapies with UCB cells, including non-immunological cells, are currently performed for viral infections, malignant diseases and in regenerative medicine.

  • 66.
    Berglund, Sofia
    et al.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Karolinska Inst, Dept Clin Neurosci, Therapeut Immune Design, Stockholm, Sweden.;Karolinska Univ Hosp, Cell Therapy & Allogene Stem Cell Transplantat CA, Stockholm, Sweden..
    Watz, Emma
    Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden.;Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden..
    Remberger, Mats
    Uppsala Univ, Uppsala Univ Hosp, Dept Med Sci, Uppsala, Sweden.;KFUE, Uppsala, Sweden..
    Legert, Karin Garming
    Karolinska Inst, Dept Dent Med, Stockholm, Sweden..
    Axdorph-Nygell, Ulla
    Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden.;Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden..
    Sundin, Mikael
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden.;Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Pediat Hematol Immunol & Hematopoiet Cell Transpl, Stockholm, Sweden..
    Uhlin, Michael
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden.;Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden.
    Mattsson, Jonas
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Princess Margaret Canc Ctr, Div Med Oncol & Hematol, Toronto, ON, Canada.;Univ Toronto, Dept Med, Toronto, ON, Canada..
    Granulocyte transfusions could benefit patients with severe oral mucositis after allogeneic hematopoietic stem cell transplantation2019In: Vox Sanguinis, ISSN 0042-9007, E-ISSN 1423-0410, Vol. 114, no 7, p. 769-777Article in journal (Refereed)
    Abstract [en]

    Background and objectives Mucositis is a common complication after allogeneic hematopoietic stem cell transplantation (HSCT), and is caused by a combination of conditioning-induced mucosal damage and severe neutropenia. The symptoms include oral and abdominal pain, inability to swallow food and fluids, and severe diarrhoea. Severe mucositis is associated with increased risk of Graft-versus-Host disease and infection. Granulocyte transfusions (GCX) could be a treatment option, and our objective was to study its feasibility and potential benefits. Material and methods This retrospective, single-centre study included 30 patients receiving GCX because of severe oral mucositis after HSCT during 2005-2017. Clinical outcome, response to GCX, change in opiate administration and adverse events were studied. Results Twenty-seven patients received GCX from donors pre-treated with steroids and G-CSF, and three from donors pre-treated with steroids only. Overall response was 83% (24/29 evaluable patients). Fifteen patients reached a complete response. In 14 of 24 responders, a reduction of the administration of opiate pain relief was seen. In eight patients this reduction was >= 50% of the dose. Adverse events (AEs) were reported in 14 cases, and were mild to moderate, and well manageable with symptomatic treatment. No life-threatening or fatal AEs were recorded. Conclusions These results indicate that GCX could be a safe and effective treatment for oral mucositis after HSCT with the potential to reduce the necessity of opiate analgesic treatment in this disorder. No severe AEs were seen in this study, but the risk for severe pulmonary AEs after GCX needs to be considered.

  • 67. Berninger, Erik
    et al.
    Olofsson, Åke
    Leijon, Arne
    KTH, School of Electrical Engineering (EES), Communication Theory.
    Analysis of Click-Evoked Auditory Brainstem Responses Using Time Domain Cross-Correlations Between Interleaved Responses2014In: Ear and Hearing, ISSN 0196-0202, E-ISSN 1538-4667, Vol. 35, no 3, p. 318-329Article in journal (Refereed)
    Abstract [en]

    Objectives: The rapidly evolving field of early diagnostics after the introduction of newborn hearing screening requires rapid, valid, and objective methods, which have to be thoroughly evaluated in adults before use in infants. The aim was to study cross-correlation analysis of interleaved auditory brainstem responses (ABRs) in a wide dynamic range in normal-hearing adults. Off-line analysis allowed for comparison with psychoacoustical click threshold (PCT), pure-tone threshold, and determination of ABR input/output function. Specifically, nonfiltered and band-pass filtered ABRs were studied in various time segments along with time elapsed for ensemble of sweeps reaching a specific detection criterion. Design: Fourteen healthy normal-hearing subjects (18 to 35 years of age, 50% females) without any history of noise exposure participated. They all had pure-tone thresholds better than 20 dB HL (125 to 8000 Hz). ABRs were recorded in both ears using 100 sec clicks, from 71.5 dB nHL down to -18.5 dB nHL, in 10 dB steps (repetition rate, 39 Hz; time window, 15 msec; filter, 30 to 8000 Hz). The number of sweeps increased from 2000 at 71.5 dB nHL, up to 30000 at -18.5 dB nHL. Each sweep was stored in a data base for off-line analysis. Cross-correlation analysis between two subaverages of interleaved responses was performed in the time domain for nonfiltered and digitally band-pass filtered (300 to 1500 Hz) entire and time-windowed (1 to 11 and 5 to 11 msec) responses. PCTs were measured using a Bekesy technique with the same insert phone and stimulus as used for the ABR (repetition rate, 20 Hz). Time elapsed (approximate to number of accepted sweeps/repetition rate) for the ensemble of sweeps needed to reach a cross-correlation coefficient () of 0.70 (=3.7 dB signal-to-noise ratio [SNR]) was analyzed. Results: Mean cross-correlation coefficients exceeded 0.90 in both ears at stimulus levels 11.5 dB nHL for the entire nonfiltered ABR. At 1.5 dB nHL, mean(SD) was 0.53(0.32) and 0.44(0.40) for left and right ears, respectively (n = 14) (=0 dB SNR). In comparison, mean(SD) PCT was -1.9(2.9) and -2.5(3.2) dB nHL for left and right ears, respectively (n = 14), while mean pure-tone average (500 to 2000 Hz) was 2.5 dB HL (n = 28). Almost no effect of band-pass filtering or reduced analysis time window existed. Average time elapsed needed to reach = 0.70 was approximately 20 seconds or less at stimulus levels 41.5 dB nHL, and approximate to 30 seconds at 31.5 dB nHL. The average (interpolated) stimulus level corresponding to =0.70 for the entire nonfiltered ABR was 6.5 dB nHL (n = 28), which coincided with the estimated psychoacoustical threshold for single clicks. Conclusions: ABR could be identified in a short period of time using cross-correlation analysis between interleaved responses. The average stimulus level corresponding to 0 dB SNR in the entire nonfiltered ABR occurred at 1.5 dB nHL, 4 dB above the average PCT. The mean input/output function for the ensemble of sweeps required to reach = 0.70 increased monotonically with increasing stimulus level, in parallel with the ABR based on all sweeps (1.5 dB nHL). Time domain cross-correlation analysis of ABR might form the basis for automatic response identification and future threshold-seeking procedures.

  • 68. Bersani, Cinzia
    et al.
    Huss, Mikael
    KTH, School of Biotechnology (BIO). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Giacomello, Stefania
    KTH, School of Biotechnology (BIO). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Xu, Li-Di
    Bianchi, Julie
    Eriksson, Sofi
    Jerhammar, Fredrik
    Alexeyenko, Andrey
    Vilborg, Anna
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lui, Weng-Onn
    Wiman, Klas G.
    Genome-wide identification of Wig-1 mRNA targets by RIP-Seq analysis2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 2, p. 1895-1911Article in journal (Refereed)
    Abstract [en]

    RNA-binding proteins (RBPs) play important roles in the regulation of gene expression through a variety of post-transcriptional mechanisms. The p53-induced RBP Wig-1 (Zmat3) binds RNA through its zinc finger domains and enhances stability of p53 and N-Myc mRNAs and decreases stability of FAS mRNA. To identify novel Wig-1-bound RNAs, we performed RNA-immunoprecipitation followed by high-throughput sequencing (RIP-Seq) in HCT116 and Saos-2 cells. We identified 286 Wig-1-bound mRNAs common between the two cell lines. Sequence analysis revealed that AU-rich elements (AREs) are highly enriched in the 3'UTR of these Wig-1-bound mRNAs. Network enrichment analysis showed that Wig-1 preferentially binds mRNAs involved in cell cycle regulation. Moreover, we identified a 2D Wig-1 binding motif in HIF1A mRNA. Our findings confirm that Wig-1 is an ARE-BP that regulates cell cycle-related processes and provide a novel view of how Wig-1 may bind mRNA through a putative structural motif. We also significantly extend the repertoire of Wig-1 target mRNAs. Since Wig-1 is a transcriptional target of the tumor suppressor p53, these results have implications for our understanding of p53-dependent stress responses and tumor suppression.

  • 69. Bertaccini, E. J.
    et al.
    Yoluk, Özge
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lindahl, Erik R.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Trudell, James Robert
    Department of Anesthesia, Stanford University School of Medicine, United States .
    Assessment of homology templates and an anesthetic binding site within the ?-aminobutyric acid receptor2013In: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175, Vol. 119, no 5, p. 1087-1095Article in journal (Refereed)
    Abstract [en]

    Background: Anesthetics mediate portions of their activity via modulation of the ?-aminobutyric acid receptor (GABAaR). Although its molecular structure remains unknown, significant progress has been made toward understanding its interactions with anesthetics via molecular modeling. Methods: The structure of the torpedo acetylcholine receptor (nAChR?), the structures of the ?4 and ?2 subunits of the human nAChR, the structures of the eukaryotic glutamate-gated chloride channel (GluCl), and the prokaryotic pH-sensing channels, from Gloeobacter violaceus and Erwinia chrysanthemi, were aligned with the SAlign and 3DMA algorithms. A multiple sequence alignment from these structures and those of the GABAaR was performed with ClustalW. The Modeler and Rosetta algorithms independently created three-dimensional constructs of the GABAaR from the GluCl template. The CDocker algorithm docked a congeneric series of propofol derivatives into the binding pocket and scored calculated binding affinities for correlation with known GABAaR potentiation EC50s. Results: Multiple structure alignments of templates revealed a clear consensus of residue locations relevant to anesthetic effects except for torpedo nAChR. Within the GABAaR models generated from GluCl, the residues notable for modulating anesthetic action within transmembrane segments 1, 2, and 3 converged on the intersubunit interface between ? and ? subunits. Docking scores of a propofol derivative series into this binding site showed strong linear correlation with GABAaR potentiation EC50. Conclusion: Consensus structural alignment based on homologous templates revealed an intersubunit anesthetic binding cavity within the transmembrane domain of the GABAaR, which showed a correlation of ligand docking scores with experimentally measured GABAaR potentiation.

  • 70.
    Birnbaum, Bernard A.
    et al.
    New York University.
    Noz, Marilyn E.
    New York University.
    Chapnick, Jeffrey V.
    New York University.
    Sanger, Joseph J.
    New York University.
    Megibow, Alec J.
    New York University.
    Maguire Jr., Gerald Q.
    Columbia University, Department of Computer Science.
    Weinreb, Jeffrey C.
    New York University.
    Kaminer, Evan M.
    New York University.
    Kramer, Elissa L.
    New York University.
    Hepatic hemangiomas: diagnosis with fusion of MR, CT, and Tc-99m-labeled red blood cell SPECT images1991In: Radiology, ISSN 0033-8419, E-ISSN 1527-1315, Vol. 181, no 2, p. 469-474Article in journal (Refereed)
    Abstract [en]

    A method of image analysis was developed for correlation of hemangiomas detected at computed tomography {(CT)} and/or magnetic resonance {(MR)} imaging with increased blood pool activity evident at single photon emission {CT} {(SPECT)} performed after labeling of red blood cells with technetium-99m. Image analysis was performed in 20 patients with 35 known hepatic hemangiomas. After section thickness and pixel sizes of the different studies were matched, intrinsic landmarks were chosen to identify anatomically corresponding locations. Regions of interest {(ROIs)} drawn on the {CT} and/or {MR} images were translated, rotated, and reprojected to match the areas of interest on the corresponding {SPECT} images by means of a two-dimensional polynomial-based warping algorithm. Analysis of {ROIs} on 30 {SPECT-MR} and 20 {SPECT-CT} pairs of registered images provided absolute confirmation that 34 suspected hemangiomas identified on {SPECT} images correlated exactly with lesions seen on {CT} and/or {MR} images. Accuracy of fusion was within an average of 1.5 pixels +/- 0.8 (+/- 1 standard deviation). The technique enabled diagnostic confirmation of hemangiomas as small as 1.0 cm and proved useful for evaluating lesions located adjacent to intrahepatic vessels.

  • 71.
    Birnbaum, Bernard A.
    et al.
    New York University.
    Noz, Marilyn E.
    New York University, Department of Radiology.
    Chapnick, Jeffrey V
    New York University.
    Sanger, Joseph J.
    New York University.
    Megibow, Alec J.
    New York University.
    Maguire Jr., Gerald Q.
    Columbia University, Computer Science.
    Weinreb, Jeffrey C.
    New York University.
    Kramer, Elissa L.
    New York University, Department of Radiology.
    Clinical Evaluation of Image Fusion Using MR Imaging, CT, and SPECT-RBC Images of Hepatic Hemangiomas1990In: Radiology, ISSN 0033-8419, E-ISSN 1527-1315, Vol. 177, p. P228-Article in journal (Refereed)
  • 72. Bjarnadottir, O.
    et al.
    Romero, Q.
    Bendahl, P-O
    Ryden, L.
    Rose, C.
    Loman, N.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Jirstrom, K.
    Grabau, D.
    Borgquist, S.
    Statin-induced decrease in proliferation depends on HMG-CoA reductase expression in breast cancer2012In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 72Article in journal (Other academic)
  • 73.
    Björkner, Eva
    et al.
    KTH, School of Computer Science and Communication (CSC), Speech, Music and Hearing, TMH.
    Sundberg, Johan
    KTH, School of Computer Science and Communication (CSC), Speech, Music and Hearing, TMH.
    Cleveland, T
    Stone, E
    Voice source differences between registers in female musical theater singers2006In: Journal of Voice, ISSN 0892-1997, E-ISSN 1873-4588, Vol. 20, no 2, p. 187-197Article in journal (Refereed)
    Abstract [en]

    Musical theater singing typically requires women to use two vocal registers. Our investigation considered voice source and subglottal pressure P-s characteristics of the speech pressure signal recorded for a sequence of /pae/ syllables sung at constant pitch and decreasing vocal loudness in each register by seven female musical theater singers. Ten equally spaced P-s values were selected, and the relationships between P-s and several parameters were examined; closed-quotient (Q(closed)), peak-to-peak pulse amplitude (Up-t-p), amplitude of the negative peak of the differentiated flow glottogram. ie, the maximum flow declination rate (MFDR), and the normalized amplitude quotient (NAQ) [Up-t-p/(TO*MFDR)], where TO is the fundamental period. P, was typically slightly higher in chest than in head register. As P, influences the measured glottogram parameters, these were also compared at an approximately identical P-s of 11 cm H2O. Results showed that for typical tokens, MFDR and Q(closed) were significantly greater, whereas Up-t-p and therefore NAQ were significantly lower in chest than in head.

  • 74. Björling, Gunilla
    et al.
    Axelsson, Sara
    Johansson, Unn-Britt
    Lysdahl, Michael
    Markström, Agneta
    Schedin, Ulla
    Aune, Ragnhild E.
    KTH, School of Industrial Engineering and Management (ITM), Materials Science and Engineering, Materials Process Science.
    Frostell, Claes
    Karlsson, Sigbritt
    Clinical use and material wear of polymeric tracheostomy tubes2007In: The Laryngoscope, ISSN 0023-852X, E-ISSN 1531-4995, Vol. 117, no 9, p. 1552-1559Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The objectives were to compare the duration of use of polymeric tracheostomy tubes, i.e., silicone (Si), polyvinyl chloride (PVC), and polyurethane (PU), and to determine whether surface changes in the materials could be observed after 30 days of patient use. METHODS: Data were collected from patient and technical records for all tracheostomized patients attending the National Respiratory Center in Sweden. In the surface study, 19 patients with long-term tracheostomy were included: six with Bivona TTS Si tubes, eight with Shiley PVC tubes, and five with Trachoe Twist PU tubes. All tubes were exposed in the trachea for 30 days before being analyzed by scanning electron microscopy (SEM) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). New tubes and tubes exposed in phosphate-buffered saline were used as reference. RESULTS: Si tubes are used for longer periods of time than those made of PVC (P < .0001) and PU (P = .021). In general, all polymeric tubes were used longer than the recommended 30-day period. Eighteen of the 19 tubes exposed in patients demonstrated, in one or more areas of the tube, evident surface changes. The morphologic changes identified by SEM correlate well with the results obtained by ATR-FTIR. CONCLUSIONS: Si tracheostomy tubes are in general used longer than those made of PVC and PU. Most of the tubes exposed in the trachea for 30 days suffered evident surface changes, with degradation of the polymeric chains as a result.

  • 75.
    Blom, Hans
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Bernhem, Kristoffer
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Institutet, Sweden.
    Sodium pump organization in dendritic spines2016In: NEUROPHOTONICS, ISSN 2329-423X, Vol. 3, no 4, article id 041803Article in journal (Refereed)
    Abstract [en]

    Advancement in fluorescence imaging with the invention of several super-resolution microscopy modalities (e.g., PALM/STORM and STED) has opened up the possibility of deciphering molecular distributions on the nanoscale. In our quest to better elucidate postsynaptic protein distribution in dendritic spines, we have applied these nanoscopy methods, where generated results could help improve our understanding of neuronal functions. In particular, we have investigated the principal energy transformer in the brain, i.e., the Na+; K+-ATPase (or sodium pump), an essential protein responsible for maintaining resting membrane potential and a major controller of intracellular ion homeostasis. In these investigations, we have focused on estimates of protein amount, giving assessments of how variations may depend on labeling strategies, sample analysis, and choice of nanoscopic imaging method, concluding that all can be critical factors for quantification. We present a comparison of these results and discuss the influences this may have for homeostatic sodium regulation in neurons and energy consumption.

  • 76. Blomstedt, Yulia
    et al.
    Bhutta, Zulfiqar A.
    Dahlstrand, Johan
    Friberg, Peter
    Gostin, Lawrence O.
    Nilsson, Måns
    KTH, School of Architecture and the Built Environment (ABE), Sustainable development, Environmental science and Engineering.
    Sewankambo, Nelson K.
    Tomson, Goran
    Alfven, Tobias
    Partnerships for child health: capitalising on links between the sustainable development goals2018In: BMJ. British Medical Journal, E-ISSN 1756-1833, Vol. 360, article id k125Article in journal (Other academic)
  • 77. Blystad, I
    et al.
    Håkansson, I
    Tisell, A
    Ernerudh, J
    Smedby, Örjan
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Image Processing and Visualization. Linköping University.
    Lundberg, P
    Larsson, E-M
    Quantitative MRI for Analysis of Active Multiple Sclerosis Lesions without Gadolinium-Based Contrast Agent2015In: American Journal of Neuroradiology, ISSN 0195-6108, E-ISSN 1936-959XArticle in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Contrast-enhancing MS lesions are important markers of active inflammation in the diagnostic work-up of MS and in disease monitoring with MR imaging. Because intravenous contrast agents involve an expense and a potential risk of adverse events, it would be desirable to identify active lesions without using a contrast agent. The purpose of this study was to evaluate whether pre-contrast injection tissue-relaxation rates and proton density of MS lesions, by using a new quantitative MR imaging sequence, can identify active lesions.

    MATERIALS AND METHODS: Forty-four patients with a clinical suspicion of MS were studied. MR imaging with a standard clinical MS protocol and a quantitative MR imaging sequence was performed at inclusion (baseline) and after 1 year. ROIs were placed in MS lesions, classified as nonenhancing or enhancing. Longitudinal and transverse relaxation rates, as well as proton density were obtained from the quantitative MR imaging sequence. Statistical analyses of ROI values were performed by using a mixed linear model, logistic regression, and receiver operating characteristic analysis.

    RESULTS: Enhancing lesions had a significantly (P < .001) higher mean longitudinal relaxation rate (1.22 ± 0.36 versus 0.89 ± 0.24), a higher mean transverse relaxation rate (9.8 ± 2.6 versus 7.4 ± 1.9), and a lower mean proton density (77 ± 11.2 versus 90 ± 8.4) than nonenhancing lesions. An area under the receiver operating characteristic curve value of 0.832 was obtained.

    CONCLUSIONS: Contrast-enhancing MS lesions often have proton density and relaxation times that differ from those in nonenhancing lesions, with lower proton density and shorter relaxation times in enhancing lesions compared with nonenhancing lesions.

  • 78.
    Bohman, Mikael
    et al.
    KTH, School of Computer Science and Communication (CSC), Speech, Music and Hearing, TMH.
    Ternström, Sten
    KTH, School of Computer Science and Communication (CSC), Speech, Music and Hearing, TMH, Music Acoustics.
    Södersten, M.
    Karolinska University Hospital at Huddinge.
    The use of channel estimation techniques for investigating vocal stress in noisy environments2003In: Ultragarsas, ISSN 1392-2114, Vol. 3, no 48, p. 9-13Article in journal (Other academic)
  • 79.
    Bokrantz, Rasmus
    et al.
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Optimization and Systems Theory. RaySearch Laboratories, Sweden.
    Miettinen, Kaisa
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Optimization and Systems Theory. University of Jyväskylä, Finland.
    Projections onto the Pareto surface in multicriteria radiation therapy optimization2015In: Medical physics (Lancaster), ISSN 0094-2405, Vol. 42, no 10, p. 5862-5870Article in journal (Refereed)
    Abstract [en]

    Purpose: To eliminate or reduce the error to Pareto optimality that arises in Pareto surface navigation when the Pareto surface is approximated by a small number of plans. Methods: The authors propose to project the navigated plan onto the Pareto surface as a postprocessing step to the navigation. The projection attempts to find a Pareto optimal plan that is at least as good as or better than the initial navigated plan with respect to all objective functions. An augmented form of projection is also suggested where dose-volume histogram constraints are used to prevent that the projection causes a violation of some clinical goal. The projections were evaluated with respect to planning for intensity modulated radiation therapy delivered by step-and-shoot and sliding window and spot-scanned intensity modulated proton therapy. Retrospective plans were generated for a prostate and a head and neck case. Results: The projections led to improved dose conformity and better sparing of organs at risk (OARs) for all three delivery techniques and both patient cases. The mean dose to OARs decreased by 3.1 Gy on average for the unconstrained form of the projection and by 2.0 Gy on average when dose-volume histogram constraints were used. No consistent improvements in target homogeneity were observed. Conclusions: There are situations when Pareto navigation leaves room for improvement in OAR sparing and dose conformity, for example, if the approximation of the Pareto surface is coarse or the problem formulation has too permissive constraints. A projection onto the Pareto surface can identify an inaccurate Pareto surface representation and, if necessary, improve the quality of the navigated plan.

  • 80. Boman, K.
    et al.
    Larsson, A. H.
    Segersten, U.
    Kuteeva, E.
    Johannesson, H.
    Nodin, B.
    Eberhard, J.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Malmström, P-U
    Jirström, K.
    Membranous expression of podocalyxin-like protein is an independent factor of poor prognosis in urothelial bladder cancer2013In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 108, no 11, p. 2321-2328Article in journal (Refereed)
    Abstract [en]

    Background: Membranous expression of the anti-adhesive glycoprotein podocalyxin-like (PODXL) has previously been found to correlate with poor prognosis in several major cancer forms. Here we examined the prognostic impact of PODXL expression in urothelial bladder cancer. Methods: Immunohistochemical PODXL expression was examined in tissue microarrays with tumours from two independent cohorts of patients with urothelial bladder cancer: n = 100 (Cohort I) and n = 343 (Cohort II). The impact of PODXL expression on disease-specific survival (DSS; Cohort II), 5-year overall survival (OS; both cohorts) and 2-year progression-free survival (PFS; Cohort II) was assessed. Results: Membranous PODXL expression was significantly associated with more advanced tumour (T) stage and high-grade tumours in both cohorts, and a significantly reduced 5-year OS (unadjusted HR = 2.25 in Cohort I and 3.10 in Cohort II, adjusted HR = 2.05 in Cohort I and 2.18 in Cohort II) and DSS (unadjusted HR = 4.36, adjusted HR = 2.70). In patients with Ta and T1 tumours, membranous PODXL expression was an independent predictor of a reduced 2-year PFS (unadjusted HR = 6.19, adjusted HR = 4.60) and DSS (unadjusted HR = 8.34, adjusted HR = 7.16). Conclusion: Membranous PODXL expression is an independent risk factor for progressive disease and death in patients with urothelial bladder cancer.

  • 81. Borch, D. Zangger
    et al.
    Sundberg, Johan
    KTH, School of Computer Science and Communication (CSC), Speech, Music and Hearing, TMH.
    Some Phonatory and Resonatory Characteristics of the Rock, Pop, Soul, and Swedish Dance Band Styles of Singing2011In: Journal of Voice, ISSN 0892-1997, E-ISSN 1873-4588, Vol. 25, no 5, p. 532-537Article in journal (Refereed)
    Abstract [en]

    This investigation aims at describing voice function of four nonclassical styles of singing, Rock, Pop, Soul, and Swedish Dance Band. A male singer, professionally experienced in performing in these genres, sang representative tunes, both with their original lyrics and on the syllable /pae/. In addition, he sang tones in a triad pattern ranging from the pitch Bb2 to the pitch C4 on the syllable /pae/in pressed and neutral phonation. An expert panel was successful in classifying the samples, thus suggesting that the samples were representative of the various styles. Subglottal pressure was estimated from oral pressure during the occlusion for the consonant [p]. Flow glottograms were obtained from inverse filtering. The four lowest formant frequencies differed between the styles. The mean of the subglottal pressure and the mean of the normalized amplitude quotient (NAQ), that is, the ratio between the flow pulse amplitude and the product of period and maximum flow declination rate, were plotted against the mean of fundamental frequency. In these graphs, Rock and Swedish Dance Band assumed opposite extreme positions with respect to subglottal pressure and mean phonation frequency, whereas the mean NAQ values differed less between the styles.

  • 82. Borg, Jörgen
    et al.
    Holm, Lena
    Cassidy, J David
    Peloso, Paul M.
    Carroll, Linda J.
    von Holst, Hans
    Department of Neurosurgery, Karolinska Institutet, Stockholm, Sweden.
    Ericson, Kaj
    Diagnostic procedures in mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury2004In: Journal of Rehabilitation Medicine, ISSN 1650-1977, E-ISSN 1651-2081, Vol. 36, no 43, p. 61-75Article in journal (Refereed)
    Abstract [en]

    We examined diagnostic procedures in mild traumatic brain injury by a systematic literature search. After screening 38,806 abstracts, we critically reviewed 228 diagnostic studies and accepted 73 (32%). The estimated prevalence of intracranial CT scan abnormalities is 5% in patients presenting to hospital with a Glasgow Coma Scale score of 15 and 30% or higher in patients presenting with a score of 13. About 1% of all treated patients with mild traumatic brain injury require neurosurgical intervention. There is strong evidence that clinical factors can predict computerized tomography scan abnormalities and the need for intervention in adults, but no such evidence for mild traumatic brain injury in children. We found evidence that skull fracture is a risk factor for intracranial lesions, but the diagnostic accuracy of radiologically diagnosed skull fracture as an indication of intracranial lesions is poor. There is only a little evidence for the diagnostic validity of cognitive testing and other diagnostic tools for mild traumatic brain injury.

  • 83. Borg, Jörgen
    et al.
    Holm, Lena
    Peloso, Paul M.
    Cassidy, J. David
    Carroll, Linda J.
    von Holst, Hans
    Department of Neurosurgery, Karolinska Institutet, Stockholm, Sweden.
    Paniak, Chris
    Yates, David
    Non-surgical intervention and cost for mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury2004In: Journal of Rehabilitation Medicine, ISSN 1650-1977, E-ISSN 1651-2081, Vol. 36, no 43, p. 76-83Article in journal (Refereed)
    Abstract [en]

    We examined the evidence for non-surgical interventions and for economic costs for mild traumatic brain injury patients by a systematic search of the literature and a best-evidence synthesis. After screening 38,806 abstracts, we critically reviewed 45 articles on intervention and accepted 16 (36%). We reviewed 16 articles on economic costs and accepted 7 (44%). We found some evidence that early educational information can reduce long-term complaints and that this early intervention need not be intensive. Most cost studies were performed more than a decade ago. Indirect costs are probably higher than direct costs. Studies comparing costs for routine hospitalized observation vs the use of computerized tomography scan examination for selective hospital admission indicate that the latter policy reduces costs, but comparable clinical outcome of these policies has not been demonstrated. The sparse scientific literature in these areas reflects both conceptual confusion and limited knowledge of the natural history of mild traumatic brain injury.

  • 84.
    Bornefalk, Hans
    KTH, School of Engineering Sciences (SCI), Physics.
    Computer-aided detection and novel mammography imaging techniques2006Doctoral thesis, comprehensive summary (Other scientific)
    Abstract [en]

    This thesis presents techniques constructed to aid the radiologists in detecting breast cancer, the second largest cause of cancer deaths for western women. In the first part of the thesis, a computer-aided detection (CAD) system constructed for the detection of stellate lesions is presented. Different segmentation methods and an attempt to incorporate contra-lateral information are evaluated.

    In the second part, a new method for evaluating such CAD systems is presented based on constructing credible regions for the number of false positive marks per image at a certain desired target sensitivity. This method shows that the resulting regions are rather wide and this explains some of the difficulties encountered by other researchers when trying to compare CAD algorithms on different data sets. In this part an attempt to model the clinical use of CAD as a second look is also made and it shows that applying CAD in sequence to the radiologist in a routine manner, without duly altering the decision criterion of the radiologist, might very well result in suboptimal operating points.

    Finally, in the third part two dual-energy imaging methods optimized for contrast-enhanced imaging of breast tumors are presented. The first is based on applying an electronic threshold to a photon-counting digital detector to discriminate between high- and low-energy photons. This allows simultaneous acquisition of the high- and low-energy images. The second method is based on the geometry of a scanned multi-slit system and also allows single-shot contrast-enhanced dual-energy mammography by filtering the x-ray beam that reaches different detector lines differently.

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  • 85.
    Bornefalk, Hans
    KTH, School of Engineering Sciences (SCI), Physics, Medical Imaging.
    Synthetic Hounsfield units from spectral CT data2012In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 57, no 7, p. N83-N87Article in journal (Refereed)
    Abstract [en]

    Beam-hardening-free synthetic images with absolute CT numbers that radiologists are used to can be constructed from spectral CT data by forming 'dichromatic' images after basis decomposition. The CT numbers are accurate for all tissues and the method does not require additional reconstruction. This method prevents radiologists from having to relearn new rules-of-thumb regarding absolute CT numbers for various organs and conditions as conventional CT is replaced by spectral CT. Displaying the synthetic Hounsfield unit images side-by-side with images reconstructed for optimal detectability for a certain task can ease the transition from conventional to spectral CT.

  • 86.
    Bornefalk, Hans
    KTH, School of Engineering Sciences (SCI), Physics, Medical Imaging.
    XCOM intrinsic dimensionality for low-Z elements at diagnostic energies2012In: Medical physics (Lancaster), ISSN 0094-2405, Vol. 39, no 2, p. 654-657Article in journal (Refereed)
    Abstract [en]

    Purpose: To determine the intrinsic dimensionality of linear attenuation coefficients (LACs) from XCOM for elements with low atomic number (Z = 1-20) at diagnostic x-ray energies (25-120 keV). H-0(q), the hypothesis that the space of LACs is spanned by q bases, is tested for various q-values. Methods: Principal component analysis is first applied and the LACs are projected onto the first q principal component bases. The residuals of the model values vs XCOM data are determined for all energies and atomic numbers. Heteroscedasticity invalidates the prerequisite of i.i.d. errors necessary for bootstrapping residuals. Instead wild bootstrap is applied, which, by not mixing residuals, allows the effect of the non-i.i.d residuals to be reflected in the result. Credible regions for the eigenvalues of the correlation matrix for the bootstrapped LAC data are determined. If subsequent credible regions for the eigenvalues overlap, the corresponding principal component is not considered to represent true data structure but noise. If this happens for eigenvalues l and l + 1, for any l <= q, H-0(q) is rejected. Results: The largest value of q for which H-0(q) is nonrejectable at the 5%-level is q = 4. This indicates that the statistically significant intrinsic dimensionality of low-Z XCOM data at diagnostic energies is four. Conclusions: The method presented allows determination of the statistically significant dimensionality of any noisy linear subspace. Knowledge of such significant dimensionality is of interest for any method making assumptions on intrinsic dimensionality and evaluating results on noisy reference data. For LACs, knowledge of the low-Z dimensionality might be relevant when parametrization schemes are tuned to XCOM data. For x-ray imaging techniques based on the basis decomposition method (Alvarez and Macovski, Phys. Med. Biol. 21, 733-744, 1976), an underlying dimensionality of two is commonly assigned to the LAC of human tissue at diagnostic energies. The finding of a higher statistically significant dimensionality thus raises the question whether a higher assumed model dimensionality (now feasible with the advent of multibin x-ray systems) might also be practically relevant, i.e., if better tissue characterization results can be obtained.

  • 87.
    Bornefalk, Hans
    et al.
    KTH, School of Engineering Sciences (SCI), Physics, Medical Imaging.
    Danielsson, Mats
    KTH, School of Engineering Sciences (SCI), Physics, Medical Imaging.
    Photon-counting spectral computed tomography using silicon strip detectors: a feasibility study2010In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 55, no 7, p. 1999-2022Article in journal (Refereed)
    Abstract [en]

    We show how the spectral imaging framework should be modified to account for a high fraction of Compton interactions in low Z detector materials such as silicon. Using this framework, where deposited energies differ from actual photon energies, we compare the performance of a silicon strip detector, including the influence of scatter inside the detector and charge sharing but disregarding signal pileup, with an ideal energy integrating detector. We show that although the detection efficiency for silicon rapidly drops for the acceleration voltages encountered in clinical computed tomography practice, silicon detectors could perform on a par with ideal energy integrating detectors for routine imaging tasks. The use of spectrally sensitive detectors opens up the possibility for decomposition techniques such as k-edge imaging, and we show that the proposed modification of the spectral imaging framework is beneficial for such imaging tasks.

  • 88.
    Bornefalk, Hans
    et al.
    KTH, School of Engineering Sciences (SCI), Physics, Physics of Medical Imaging.
    Persson, Mats
    KTH, School of Engineering Sciences (SCI), Physics, Physics of Medical Imaging.
    Theoretical Comparison of the Iodine Quantification Accuracy of Two Spectral CT Technologies2014In: IEEE Transactions on Medical Imaging, ISSN 0278-0062, E-ISSN 1558-254X, Vol. 33, no 2, p. 556-565Article in journal (Refereed)
    Abstract [en]

    We compare the theoretical limits of iodine quantification for the photon counting multibin and dual energy technologies. Dual energy systems by necessity have to make prior assumptions in order to quantify iodine. We explicitly allow the multibin system to make the same assumptions and also allow them to be wrong. We isolate the effect of technology from imperfections and implementation issues by assuming both technologies to be ideal, i.e., without scattered radiation, unity detection efficiency and perfect energy response functions, and by applying the Cramer-Rao lower bound methodology to assess the quantification accuracy. When priors are wrong the maximum likelihood estimates will be biased and the mean square error of the quantification error is a more appropriate figure of merit. The evaluation assumes identical X-ray spectra for both methodologies and for that reason a sensitivity analysis is performed with regard to the assumed X-ray spectrum. We show that when iodine is quantified over regions of interest larger than 6 cm, multibin systems benefit by independent estimation of three basis functions. For smaller regions of interest multibin systems can increase quantification accuracy by making the same prior assumptions as dual energy systems.

  • 89.
    Bornefalk, Hans
    et al.
    KTH, School of Engineering Sciences (SCI), Physics, Physics of Medical Imaging.
    Persson, Mats
    KTH, School of Engineering Sciences (SCI), Physics, Physics of Medical Imaging.
    Danielsson, Mats
    KTH, School of Engineering Sciences (SCI), Physics, Physics of Medical Imaging.
    Necessary forward model specification accuracy for basis material decomposition in spectral CT2014In: Medical Imaging 2014: Physics of Medical Imaging, SPIE - International Society for Optical Engineering, 2014, p. 90332I-Conference paper (Refereed)
    Abstract [en]

    Material basis decomposition in the sinogram domain requires accurate knowledge of the forward model in spectral CT. Misspecifications over a certain limit will result in biased estimates and make quantum limited quantitative CT difficult. We present a method whereby users can determine the degree of allowed misspecification error in a spectral CT forward model, and still have quantification errors that are quantum limited.

  • 90. Borsics, Tamas
    et al.
    Lundberg, Emma
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Geerts, Dirk
    Koomoa, Dana-Lynn T.
    Koster, Jan
    Wester, Kenneth
    Bachmann, Andres S.
    Subcellular distribution and expression of prenylated Rab acceptor 1 domain family, member 2 (PRAF2) in malignant glioma: Influence on cell survival and migration2010In: Cancer Science, ISSN 1347-9032, E-ISSN 1349-7006, Vol. 101, no 7, p. 1624-1631Article in journal (Refereed)
    Abstract [en]

    Our previous studies revealed that the expression of the 19-kDa protein prenylated Rab acceptor 1 domain family, member 2 (PRAF2) is elevated in cancer tissues of the breast, colon, lung, and ovary, when compared to noncancerous tissues of paired samples. PRAF2 mRNA expression also correlated with several genetic and clinical features and is a candidate prognostic marker in the pediatric cancer neuroblastoma. The PRAF2-related proteins, PRAF1 and PRAF3, play multiple roles in cellular processes, including endo/exocytic vesicle trafficking and glutamate uptake. PRAF2 shares a high sequence homology with these family members, but its function remains unknown. In this study, we examined PRAF2 mRNA and protein expression in 20 different human cancer types using Affymetrix microarray and human tissue microarray (TMA) analyses, respectively. In addition, we investigated the subcellular distribution of PRAF2 by immunofluorescence microscopy and cell fractionation studies. PRAF2 mRNA and protein expression was elevated in several cancer tissues with highest levels in malignant glioma. At the molecular level, we detected native PRAF2 in small, vesicle-like structures throughout the cytoplasm as well as in and around cell nuclei of U-87 malignant glioma cells. We further found that monomeric and dimeric forms of PRAF2 are associated with different cell compartments, suggesting possible functional differences. Importantly, PRAF2 down-regulation by RNA interference significantly reduced the cell viability, migration, and invasiveness of U-87 cells. This study shows that PRAF2 expression is elevated in various tumors with exceptionally high expression in malignant gliomas, and PRAF2 therefore presents a candidate molecular target for therapeutic intervention. (Cancer Sci 2010).

  • 91.
    Boutajangout, Allal
    et al.
    NYU, Ctr Cognit Neurol, Langone Hlth, New York, NY 10016 USA.;NYU, Dept Neurol, Langone Hlth, New York, NY 10016 USA.;NYU, Dept Psychiat, Langone Hlth, 550 1St Ave, New York, NY 10016 USA.;NYU, Langone Med Ctr, Dept Physiol & Neurosci, New York, NY USA..
    Lindberg, Hanna
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Awwad, Abdulaziz
    King Abdulaziz Univ, Sch Med, Jeddah, Saudi Arabia..
    Paul, Arun
    NYU, Ctr Cognit Neurol, Langone Hlth, New York, NY 10016 USA.;NYU, Dept Neurol, Langone Hlth, New York, NY 10016 USA..
    Baitalmal, Rabaa
    NYU, Ctr Cognit Neurol, Langone Hlth, New York, NY 10016 USA.;NYU, Dept Neurol, Langone Hlth, New York, NY 10016 USA..
    Almokyad, Ismail
    NYU, Ctr Cognit Neurol, Langone Hlth, New York, NY 10016 USA.;NYU, Dept Neurol, Langone Hlth, New York, NY 10016 USA..
    Hoiden-Guthenberg, Ingmarie
    Affibody AB, Solna, Sweden..
    Gunneriusson, Elin
    Affibody AB, Solna, Sweden..
    Frejd, Fredrik Y.
    Affibody AB, Solna, Sweden..
    Hard, Torleif
    Swedish Univ Agr Sci SLU, Dept Chem & Biotechnol, Uppsala, Sweden..
    Löfblom, John
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Ståhl, Stefan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Wisniewski, Thomas
    NYU, Ctr Cognit Neurol, Langone Hlth, New York, NY 10016 USA.;NYU, Dept Neurol, Langone Hlth, New York, NY 10016 USA.;NYU, Dept Psychiat, Langone Hlth, 550 1St Ave, New York, NY 10016 USA.;NYU, Sch Med, Dept Pathol, New York, NY 10016 USA..
    Affibody-Mediated Sequestration of Amyloid beta Demonstrates Preventive Efficacy in a Transgenic Alzheimer's Disease Mouse Model2019In: Frontiers in Aging Neuroscience, ISSN 1663-4365, E-ISSN 1663-4365, Vol. 11, article id 64Article in journal (Refereed)
    Abstract [en]

    Different strategies for treatment and prevention of Alzheimer's disease (AD) are currently under investigation, including passive immunization with anti-amyloid beta (anti-A beta) monoclonal antibodies (mAbs). Here, we investigate the therapeutic potential of a novel type of A beta-targeting agent based on an affibody molecule with fundamentally different properties to mAbs. We generated a therapeutic candidate, denoted Z(SYM73)-albumin-binding domain (ABD; 16.8 kDa), by genetic linkage of the dimeric Z(SYM73) affibody for sequestering of monomeric A beta-peptides and an ABD for extension of its in vivo half-life. Amyloid precursor protein (APP)/PS1 transgenic AD mice were administered with Z(SYM73)-ABD, followed by behavioral examination and immunohistochemistry. Results demonstrated rescued cognitive functions and significantly lower amyloid burden in the treated animals compared to controls. No toxicological symptoms or immunology-related side-effects were observed. To our knowledge, this is the first reported in vivo investigation of a systemically delivered scaffold protein against monomeric A beta, demonstrating a therapeutic potential for prevention of AD.

  • 92. Bragina, Olga
    et al.
    von Witting, Emma
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Garousi, Javad
    Zelchan, Roman
    Sandström, Mattias
    Orlova, Anna
    Medvedeva, Anna
    Doroshenko, Artem
    Vorobyeva, Anzhelika
    Lindbo, Sarah
    Borin, Jesper
    Tarabanovskaya, Natalya
    Hober, Sophia
    Chernov, Vladimir
    Tolmachev, Vladimir
    Phase I study of 99mTc-ADAPT6, a scaffold protein-based probe for visualization of HER2 expression in breast cancerManuscript (preprint) (Other academic)
    Abstract [en]

    Radionuclide molecular imaging of human epidermal growth factor (HER2) expression may be helpful to stratify breast and gastroesophageal cancer patients for HER2-targeting therapies. ADAPTs (albumin-binding domain derived affinity proteins) are a new type of small (46-59 amino acids) proteins useful as probes for molecular imaging. The aim of this first in-human study was to evaluate biodistribution, dosimetry, and safety of HER2-specific 99mTc-ADAPT6.

    METHODS. Twenty-two patients with HER2-positive (n=11) or HER2-negative (n=11) primary breast cancer were intravenously injected with 385125 MBq. The injected amount of protein was either 500 μg (n=11) or 1000 μg (n=11). Planar scintigraphy followed by SPECT imaging was performed after 2, 4, 6 and 24 h. An additional cohort received a dose of 250 μg, and the planar scintigraphy followed by SPECT imaging was performed after 2 h only.

    RESULTS. Injection of 99mTc-ADAPT6 was well tolerated for all doses evaluated in the study, and was not associated with any adverse effects. 99mTc-ADAPT6 cleared rapidly from the blood and the majority of tissues. The normal organs with the highest accumulation were kidney, liver and lung. The effective doses were determined to 0.0090.002 and 0.0100.003 mSv/MBq when injecting protein amounts of 500 and 1000 μg, respectively. Injection of 500 μg resulted in excellent discrimination between HER2-positive and HER2-negative tumors already 2 h after injection (tumor-to-contralateral breast ratio was 3719 vs 52, p < 0.01). The tumor-to-contralateral breast ratios for HER2-positive tumors were significantly (p < 0.5) higher for the injected  mass of 500 μg than for both 250 and 1000 μg. In one patient, the imaging using 99mTc-ADAPT6 revealed three bone metastases, which were not found at the time of diagnosis by CT or 99mTcpyrophosphate bone scan. MRI imaging confirmed this finding.

    CONCLUSION. Injections of 99mTc-ADAPT6 are safe and associated with low absorbed and effective doses. A protein dose of 500 μg is preferable for discrimination between tumors with high and low expression of HER2. 99mTc-ADAPT6 is a promising imaging probe for the stratification of patients for HER2-targeting therapy.

  • 93. Brandberg, J
    et al.
    Janerot-Sjöberg, B
    Hälsouniversitetet, Linköping University.
    Ask, P
    Increased accuracy of echocardiographic measurement of flow using automated spherical integration of multiple plane velocity vectors.1999In: Ultrasound in Medicine and Biology, ISSN 0301-5629, E-ISSN 1879-291X, Vol. 25, no 2, p. 249-57Article in journal (Refereed)
    Abstract [en]

    The calculation of blood flow in the heart by surface integration of velocity vectors (SIVV) using Doppler ultrasound is independent of the angle. Flow is normally calculated from velocity in a spherical thick shell with its center located at the ultrasound transducer. In a numerical simulation, we have shown that the ratio between minor and major axes of an elliptic flow area substantially influences the accuracy of the estimation of flow in a single scan plane. The accuracy of flow measurements by SIVV can be improved by calculating the mean of the values from more than one scan plane. We have produced an automated computer program that includes an antialiasing procedure. We confirmed an improvement of flow measurements in a pulsatile hydraulic flow model, the 95% confidence interval for single estimations being reduced from 20% to 10% (p < 0.05) using the newly developed software. We think that the SIVV method has important implications for clinical transthoracic echocardiography.

  • 94. Brennan, Donal J.
    et al.
    Laursen, Henriette
    O'Connor, Darran P.
    Borgquist, Signe
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics.
    Gallagher, William M.
    Ponten, Fredrik
    Millikan, Robert C.
    Ryden, Lisa
    Jirström, Karin
    Tumor-specific HMG-CoA reductase expression in primary premenopausal breast cancer predicts response to tamoxifen2011In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 13, no 1, p. R12-Article in journal (Refereed)
    Abstract [en]

    Introduction: We previously reported an association between tumor-specific 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) expression and a good prognosis in breast cancer. Here, the predictive value of HMG-CoAR expression in relation to tamoxifen response was examined. Methods: HMG-CoAR protein and RNA expression was analyzed in a cell line model of tamoxifen resistance using western blotting and PCR. HMG-CoAR mRNA expression was examined in 155 tamoxifen-treated breast tumors obtained from a previously published gene expression study (Cohort I). HMG-CoAR protein expression was examined in 422 stage II premenopausal breast cancer patients, who had previously participated in a randomized control trial comparing 2 years of tamoxifen with no systemic adjuvant treatment (Cohort II). Kaplan-Meier analysis and Cox proportional hazards modeling were used to estimate the risk of recurrence-free survival (RFS) and the effect of HMG-CoAR expression on tamoxifen response. Results: HMG-CoAR protein and RNA expression were decreased in tamoxifen-resistant MCF7-LCC9 cells compared with their tamoxifen-sensitive parental cell line. HMG-CoAR mRNA expression was decreased in tumors that recurred following tamoxifen treatment (P < 0.001) and was an independent predictor of RFS in Cohort I (hazard ratio = 0.63, P = 0.009). In Cohort II, adjuvant tamoxifen increased RFS in HMG-CoAR-positive tumors (P = 0.008). Multivariate Cox regression analysis demonstrated that HMG-CoAR was an independent predictor of improved RFS in Cohort II (hazard ratio = 0.67, P = 0.010), and subset analysis revealed that this was maintained in estrogen receptor (ER)-positive patients (hazard ratio = 0.65, P = 0.029). Multivariate interaction analysis demonstrated a difference in tamoxifen efficacy relative to HMG-CoAR expression (P = 0.05). Analysis of tamoxifen response revealed that patients with ER-positive/HMG-CoAR tumors had a significant response to tamoxifen (P = 0.010) as well as patients with ER-positive or HMG-CoAR-positive tumors (P = 0.035). Stratification according to ER and HMG-CoAR status demonstrated that ER-positive/HMG-CoAR-positive tumors had an improved RFS compared with ER-positive/HMG-CoAR-negative tumors in the treatment arm (P = 0.033); this effect was lost in the control arm (P = 0.138), however, suggesting that HMG-CoAR predicts tamoxifen response. Conclusions: HMG CoAR expression is a predictor of response to tamoxifen in both ER-positive and ER-negative disease. Premenopausal patients with tumors that express ER or HMG-CoAR respond to adjuvant tamoxifen.

  • 95. Brodin, L A
    et al.
    Janerot-Sjöberg, B
    Hälsouniversitetet, Linköping University.
    [Hopeful future for echocardiography. Progress within both the function and perfusion areas].2000In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 97, no 46, p. 5302-4, 5307Article in journal (Refereed)
    Abstract [sv]

    Echocardiography is presently a feasible method for quantitative estimation of intracardiac flows, pressure levels and for hemodynamic evaluation of valvular disease. The evaluation of regional myocardial function is still based on subjective scrutiny, and no routine method for the estimation of myocardial blood flow is available. We present an overview of newly developed techniques that are beginning to gain purchase in clinical practice. The use of native second harmonic imaging to improve image quality and of tissue Doppler to provide objective measurements of regional myocardial function is discussed. This article describes the transformation of tissue Doppler information into parametric images as in strain rate imaging, and overviews the use of ultrasound contrast agents. Used together with new imaging modalities, myocardial contrast echocardiography holds promise for future quantification of myocardial blood volume and flow. Other emerging echocardiographic technologies discussed are non-invasive measurement of coronary flow reserve and three dimensional cineloop visualization, developed to increase our understanding of cardiovascular physiological and anatomical coupling.

  • 96.
    Brodén, Cyrus
    et al.
    Department of Surgery and Cancer, Imperial College London, St Mary’s Hospital, London, UK2Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital, Division of Orthopaedics, Stockholm, Sweden.
    Giles, Joshua W.
    Department of Mechanical Engineering, University of Victoria, Victoria, BC, Canada4Mechatronics in Medicine Laboratory, Mechanical Engineering, Imperial College London, London, UK.
    Popat, Ravi
    Department of Bioengineering, Imperial College London, London, UK.
    Fetherston, Shirley
    Department of Radiology, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK.
    Olivecrona, Henrik
    Karolinska Institutet, Sweden.
    Sandberg, Olof
    Sectra, Linköping, Sweden.
    Maguire Jr., Gerald Q.
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Communication Systems, CoS.
    Noz, Marilyn E.
    New York University, Department of Radiology.
    Sködenberg, Olof
    Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital, Division of Orthopaedics, Stockholm, Sweden.
    Emery, Roger
    Department of Surgery and Cancer, Imperial College London, St Mary’s Hospital, London, UK.
    Accuracy and precision of a CT method for assessing migration in shoulder arthroplasty: an experimental study2019In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455Article in journal (Refereed)
    Abstract [en]

    Background: Radiostereometric analysis (RSA) is the gold standard to measure early implant migration which is a predictive factor for implant survival. Purpose: To validate an alternative computed tomography (CT) technique to measure implant migration in shoulder arthroplasty. Material and Methods: A cadaver proximal humerus and a scapula, which had tantalum beads incorporated within them, were prepared to accept a short-stemmed humeral component and a two-pegged glenoid component of a commercial total shoulder arthroplasty (TSA) system. A five degree of freedom micrometer and goniometer equipped rig was used to translate and rotate the implant components relative to the respective bone to predetermined positions. Double CT examinations were performed for each position and CT motion analysis software (CTMA) was used to assess these movements. The accuracy and precision of the software was estimated using the rig’s micrometers and goniometers as the gold standard. The technique’s effective dose was also assessed. Results: The accuracy was in the range of 0.07–0.23 mm in translation and 0.22–0.71° in rotation. The precision was in the range of 0.08–0.15 mm in translation and 0.23–0.54° in rotation. The mean effective dose for the CT scans was calculated to be 0.27 mSv. Conclusion: In this experimental setting, accuracy, precision, and effective dose of the CTMA technique were found to be comparable to that of RSA. Therefore, we believe clinical studies are warranted to determine if CTMA is a suitable alternative to traditional RSA for migration measurements in TSA.

  • 97.
    Brodén, Cyrus
    et al.
    Department of Molecular Medicine and Surgery, Karolinska Institutet.
    Olivecrona, Henrik
    Department of Molecular Medicine and Surgery, Karolinska Institutet.
    Maguire Jr., Gerald Q.
    KTH, School of Information and Communication Technology (ICT), Communication Systems, CoS, Radio Systems Laboratory (RS Lab).
    Noz, Marilyn E.
    New York University, Department of Radiology.
    Zeleznik, Michael P.
    School of Computing, College of Engineering, University of Utah.
    Sköldenberg, Olof
    Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet.
    Accuracy and Precision of Three-Dimensional Low Dose CT Compared to Standard RSA in Acetabular Cups: An Experimental Study2016In: BioMed Research International, ISSN 2314-6133, E-ISSN 2314-6141, article id 5909741Article in journal (Refereed)
    Abstract [en]

    Background and Purpose. The gold standard for detection of implant wear and migration is currently radiostereometry (RSA). The purpose of this study is to compare a three-dimensional computed tomography technique (3D CT) to standard RSA as an alternative technique for measuring migration of acetabular cups in total hip arthroplasty.

    Materials and Methods. With tantalum beads, we marked one cemented and one uncemented cup and mounted these on a similarly marked pelvic model. A comparison was made between 3D CT and standard RSA for measuring migration. Twelve repeated stereoradiographs and CT scans with double examinations in each position and gradual migration of the implants were made. Precision and accuracy of the 3D CT were calculated.

    Results. The accuracy of the 3D CT ranged between 0.07 and 0.32 mm for translations and 0.21 and 0.82° for rotation. The precision ranged between 0.01 and 0.09 mm for translations and 0.06 and 0.29° for rotations, respectively. For standard RSA, the precision ranged between 0.04 and 0.09 mm for translations and 0.08 and 0.32° for rotations, respectively. There was no significant difference in precision between 3D CT and standard RSA. The effective radiation dose of the 3D CT method, comparable to RSA, was estimated to be 0.33 mSv.

    Interpretation. Low dose 3D CT is a comparable method to standard RSA in an experimental setting.

  • 98.
    Broome, M.
    Umeå Universitet.
    Acute effects of Angiotensin II on myocardial performance2001Other (Refereed)
    Abstract [en]

    Background: Specific angiotensin II (Ang II) receptors exist in many organs including peripheral blood vessels, cardiac myocytes and the central nervous system. This suggests multiple sites of actions for Ang II throughout the cardiovascular system. Cardiac effects of Ang II are not completely understood, though its prominent vasoconstrictor actions are well described. This study was designed to assess left ventricular function during administration of Ang II using relatively load-independent methods in a whole-animal model. Methods: Ang II was infused in incremental doses (0-200 µg/h) in anaesthetised instrumented pigs (n=10). Cardiac systolic and diastolic function was evaluated by analysis of the left ventricular pressure-volume relationship. Results: Heart rate (HR), mean arterial pressure (MAP) and systemic vascular resistance (SVR) increased dose-dependently with Ang II, while cardiac output (CO) remained unchanged. Systolic function indices end-systolic elastance (Ees) and preload recruitable stroke work (PRSW) demonstrated dose-dependent increases. The diastolic function parameter tau (t) did not change with increasing Ang II dose. Conclusion: Ang II infusion caused increases in contractility indices in anaesthetised pigs in the doses used in this study. The mechanisms for these systolic function effects may be a direct myocardial effect or modulated through changes in autonomic nervous system activity.

  • 99.
    Broome, M.
    Karolinska Institutet.
    Exogenous Angiotensin II - An experimental study of integrated circulatory effects in heart, splanchnic organs and kidney2001Other (Refereed)
    Abstract [en]

    Aim: Exogenous Angiotensin II (Ang II) is currently used for treatment of hypotensive vasodilated shock, despite limited context-specific information about regional circulatory or cardiac responses. We aimed to experimentally investigate sites of action and mechanisms for the cardiovascular acute effects of Ang II infusion with emphasis on regional circulatory control and myocardial systolic and diastolic function. Methods: In healthy anaesthetised pigs, perivascular ultrasound flowmetry, laser-doppler flowmetry and tissue micro-oximetry were employed regionally (kidney and splanchnic organs), while cardiac function was evaluated by left ventricular pressurevolume loop analysis as derived from continuous intracardiac conductance volumetry and tip-manometry. Ang II was administered either systemically (i.v.) or in the left coronary artery in a continuous, dose-variable regimen. Regional perfusion pressures were artificially controlled either by pharmacological (nitroprusside) modulation of systemic arterial pressure or by local arterial graded occlusion (perivascular clamp). Cardiac afterload was controlled by pharmacological (nitroprusside) vasodilation. Results: Ang II exerted similarly powerful vasoconstrictions in the splanchnic and renal circulations. However, the splanchnic vascular bed differed in its responsiveness to Ang II in the sense that concomitant artificial maintenance of systemic normotension fully inhibited the increase in splanchnic vascular tone. Further, splanchnic vasoconstriction by Ang II was potentiated by increases in local arterial pressure. Heart rate and systolic function indices increased dose-dependently by systemic administration of Ang II, regardless of prevailing afterload conditions. Diastolic function was impaired or unchanged. On the other hand, these cardiac effects could not be reproduced when Ang II was administered via the intracoronary route. Conclusions: In the splanchnic vascular bed, the vascular responses of Ang II are powerfully modulated by local vasomotor control. Thus, during concurrent increases in systemic arterial pressure, autoregulatory myogenic increases in vascular smooth muscle tone serves to potentiate the local vasoconstrictive actions of Ang II. This implies that blood pressure alterations have an important role for the prediction of changes in splanchnic vascular resistance during Ang II treatment. Cardiac effects of Ang II include increases in contractile function, but seem to be predominantly mediated via extracardiac structures and mechanisms. This implies that the integrity of remote mechanisms for control of myocardial function are important for the cardiac effects of Ang II treatment. Keywords: Renin-Angiotensin System, Angiotensin II, Angiotensin Amide, Nitroprusside, Swine, Conductance volumetry (non-MESH), Cardiac function, Systolic function, Diastolic function, Vasoconstriction, Splanchnic Circulation, Renal Circulation

  • 100.
    Broome, M.
    Karolinska Institutet.
    MEDIQ Anaesthesia Simulator2003Other (Other academic)
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