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  • 1.
    Almstedt, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University.
    Rosén, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Gloger, Marleen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Hekmati, Neda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Koltowska, Katarzyna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Krona, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Real-time evaluation of glioblastoma treatments in patient-specific zebrafish xenograftsManuscript (preprint) (Other academic)
  • 2. Carlsson, J
    et al.
    Gedda, L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Grönvik, C
    Hartman, T
    Lindström, A
    Lindström, P
    Lundqvist, H
    Lövqvist, A
    Malmqvist, J
    Olsson, P
    Strategy for boron neutron capture therapy against tumor cells with over-expression of the epidermal growth factor-receptor.1994In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 30, no 1, p. 105-15Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Gliomas, squamous carcinomas and different adenocarcinomas from breast, colon and prostate might have an increased number of epidermal growth factor (EGF) receptors. The receptors are, in these cases, candidates for binding of receptor specific toxic conjugates that might inactivate cellular proliferation. The purpose of this study was to evaluate whether it is reasonable to try ligand-dextran based conjugates for therapy.

    METHODS AND MATERIALS: EGF or TGF alpha were conjugated to dextran and binding, internalization, retention and degradation of eight types of such conjugates were analyzed in EGF-receptor amplified glioma cells. The conjugates were labelled with radioactive nuclides to allow detection and two of the conjugates were carrying boron in the form of carboranyl amino acids or aminoalkyl-carboranes. Comparative binding tests, applying 125I-EGF, were made with cultured breast, colon and prostate adenocarcinoma, glioma and squamous carcinoma cells. Some introductory tests to label with 76Br for positron emission tomography and with 131I for radionuclide therapy were also made.

    RESULTS: The dextran part of the conjugates did not prevent receptor specific binding. The amount of receptor specific binding varied between the different types of conjugates and between the tested cell types. The dextran part improved intracellular retention and radioactive nuclides were retained for at least 20-24 h. The therapeutical effect improved when 131I was attached to EGF-dextran instead of native EGF.

    CONCLUSION: The improved cellular retention of the ligand-dextran conjugates is an important property since it gives extended exposure time when radionuclides are applied and flexibility in the choice of time for application of neutrons in boron neutron capture therapy (BNCT). It is possible that ligand-dextran mediated BNCT might allow, if the applied neutron fields covers rather wide areas around the primary tumor, locally spread cells that otherwise would escape treatment to be inactivated.

  • 3.
    Ebai, Tonge
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Parallel protein detection by solid-phase proximity ligation assay with real-time PCR or sequencing2015In: Current Protocol in Molecular Biology, ISSN 1934-3647, Vol. 109, no 20Article in journal (Refereed)
    Abstract [en]

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

  • 4.
    Eriksson, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Moreno, R
    Milenova, I. Yoanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Liljenfeldt, L
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Dieterich, L C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Christiansson, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karlsson, H
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ullenhag, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mangsbo, Sara M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Alemany, R
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Activation of myeloid and endothelial cells by CD40L gene therapy supports T-cell expansion and migration into the tumor microenvironment2017In: Gene Therapy, ISSN 0969-7128, E-ISSN 1476-5462, Vol. 24, no 2, p. 92-103Article in journal (Refereed)
    Abstract [en]

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

  • 5.
    Gao, Xiang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Yang, Ting
    Liu, Ming
    Peleli, Maria
    Zollbrecht, Christa
    Weitzberg, Eddie
    Lundberg, Jon O.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlstrom, Mattias
    NADPH Oxidase in the Renal Microvasculature Is a Primary Target for Blood Pressure-Lowering Effects by Inorganic Nitrate and Nitrite2015In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 65, no 1, p. 161-+Article in journal (Refereed)
    Abstract [en]

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

  • 6.
    Hammond, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    A DNA-mediated search for optimal combinations of protein bindersManuscript (preprint) (Other academic)
  • 7.
    Hirvonen, M. Karoliina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Assay development for in situ detection of autophagy-related protein-protein interactions for characterization of colorectal cancer2015Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
    Abstract [en]

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

  • 8.
    Hollmark, M
    et al.
    Division of Medical Radiation Physics, Department of Oncology-Pathology, Karolinska Institutet and Stockholm University.
    Edgren, M
    Kundrát, P
    Lind, B
    A comparison of radiobiological models for light ion therapyManuscript (preprint) (Other academic)
  • 9.
    Kamali-Moghaddam, Masood
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Löf, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Oliveir, Felipe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Wik, Lotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Wu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Yan, Junhong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Advanced Molecular Tools for Proteomic Analyses of Microvesicles2014In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 23, p. 102-102Article in journal (Other academic)
  • 10.
    Kupferschmidt, Natalia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials. Nanologica AB, SE-11428 Stockholm, Sweden.
    Csikasz, Robert
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Ballell, Lluis
    Diseases of the Developing World, GlaxoSmithKline, Madrid, Spanien.
    Bengtsson, Tore
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Garcia-Bennett, Alfonso E.
    Stockholm Univ, Arrhenius Lab, MMK, Dept Mat & Environm Chem, S-10691 Stockholm, Sweden.
    Large pore mesoporous silica induced weight loss in obese mice2013In: Nanomedicine, ISSN 1743-5889, E-ISSN 1748-6963, Vol. 9, no 9, p. 1353-1362Article in journal (Refereed)
    Abstract [en]

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

  • 11.
    Kühnemund, Malte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Science for life laboratory.
    Wei, Qingshan
    Department of Bioengineering, University of California Los Angeles (UCLA).
    Darai, Eva
    Science for life laboratory, Stockholm University.
    Wang, Y
    Department of Bioengineering, University of California Los Angeles (UCLA).
    Hernandez-Neuta, Ivan
    Science for life laboratory, Stockholm University.
    Tseng, D
    Department of Bioengineering, University of California Los Angeles (UCLA).
    Ahlford, Annika
    Science for life laboratory, Stockholm University.
    Ozcan, Aydogan
    Department of Bioengineering, University of California Los Angeles (UCLA).
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Science for life laboratory, Stockholm University.
    In situ detection of KRAS point mutations and targeted DNA sequencing with a mobile phoneManuscript (preprint) (Other academic)
  • 12.
    Matar, Amal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Considering a Baby? Responsible Screening for the Future: Ethical and social implications for implementation and use of preconception expanded carrier screening in Sweden2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Preconception expanded carrier screening is a novel technology that involves the offer of a screening test for many recessive diseases (via an expanded screening panel) to prospective parents, with no priori risk. Test positive couples have a number of reproductive choices; prenatal diagnosis and aborting affected fetus, IVF and preimplantation genetic diagnosis, sperm or ovum donation or simply accept the risk. The test had been piloted in studies and can potentially be implemented in Europe. Therefore, it seemed pertinent to evaluate stakeholders’ perspectives on ethical and social implications of implementing and using preconception ECS in Sweden.

    Two main stakeholders were examined; healthcare professionals and health policymaking experts, via a mix of qualitative methods for data collection and data analysis. In Study I, we employed in-depth interviews to collect data and content analysis to analyze it. In Studies III and IV, expert interviews were used to gather data while thematic analysis was utilized to interpret it. Furthermore, in Study II, an ethical concept namely; reproductive autonomy, was critically discussed within a setting that expects a couple to make a conjoint reproductive decision about preconception ECS, while each partner still upholds his or her individual autonomy.

    The main findings of the empirical studies (Studies I, III and IV) echo to a great extent the prevailing ethical and social debates associated with the novel technology. Respondents expressed concerns with reproductive autonomy, medicalization, prioritization of health resources, discrimination and long term societal changes. Furthermore, respondents emphasized the importance to observe Swedish values, such as human dignity, equality and solidarity, when assessing a preconception ECS program. In addition, they described practicalities of implementation and political considerations that are pertinent to the Swedish context. Finally, some respondents recognized the advantages of reduced suffering and decrease in fetal anomalies and abortion as a consequence of preconception ECS.

    Study II, proposed a notion of couple autonomy, where certain demands if met, a couple’s reproductive decision can be accepted by healthcare staff as autonomous.

    The findings, in this thesis, steer towards non implementation of preconception ECS in its current status within the publicly-funded healthcare system in Sweden. This is because healthcare providers and experts were of the opinion that it would not solve a medical need, threaten Swedish values and use up resources extensively.

    List of papers
    1. Swedish healthcare providers' perceptions of preconception expanded carrier screening (ECS)—a qualitative study
    Open this publication in new window or tab >>Swedish healthcare providers' perceptions of preconception expanded carrier screening (ECS)—a qualitative study
    2016 (English)In: Journal of Community Genetics, ISSN 1868-6001, Vol. 7, no 3, p. 203-214Article in journal (Refereed) Published
    Abstract [en]

    Reproductive autonomy, medicalization, and discrimination against disabled and parental responsibility are the main ongoing ethical debates concerning reproductive genetic screening. To examine Swedish healthcare professionals’ views on preconception expanded carrier screening (ECS), a qualitative study involving academic and clinical institutions in Sweden was conducted in September 2014 to February 2015. Eleven healthcare professionals including clinicians, geneticists, a midwife, and a genetic counselor were interviewed in depth using a semi-structured interview guide. The questionnaire was constructed after reviewing the main literature and meetings with relevant healthcare providers. The interviews were recorded, transcribed verbatim, and content analyzed for categories and subcategories. Participants nurtured many ethical and non-ethical concerns regarding preconception ECS. Among the ethical concerns were the potential for discrimination, medicalization, concerns with prioritization of healthcare resources, and effects on reproductive freedom. The effects of implementation of preconception ECS, its stakeholders, regulations, and motivation are some of non-ethical concerns. These concerns, if not addressed, may affect the uptake and usage of carrier screening within Swedish healthcare system. As this is a qualitative study with a small non-random sample size, the findings cannot be generalized. The participants had little to no working experience with expanded screening panels. Moreover, the interviews were conducted in English, a second language for the participants, which might have limited the expression of their views. However, the authors claim that the findings may be pertinent to similar settings in other Scandinavian countries.

    Place, publisher, year, edition, pages
    Springer, 2016
    Keywords
    reproductiion, autonomy, expanded carrier screening
    National Category
    Obstetrics, Gynecology and Reproductive Medicine Public Health, Global Health, Social Medicine and Epidemiology
    Identifiers
    urn:nbn:se:uu:diva-294966 (URN)10.1007/s12687-016-0268-2 (DOI)000386778700004 ()27225888 (PubMedID)
    Available from: 2016-05-31 Created: 2016-05-31 Last updated: 2019-01-11Bibliographically approved
    2. Couple autonomy in preconception expanded carrier screening
    Open this publication in new window or tab >>Couple autonomy in preconception expanded carrier screening
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Preconception Expanded Carrier Screening (ECS) is a genetic test offered to a general population or to couples who have no known risk of recessive and X-linked genetic diseases and are interested in becoming parents. A test may screen for carrier status of several autosomal recessive diseases at one go. Such a program has been piloted in the Netherlands and may become a reality in more European countries in the future. The ethical rationale for such tests is that they would enhance reproductive autonomy. The dominant conception of autonomy is individual-based. However, at the clinic, people deciding on preconception ECS will be counselled together and are expected to make a joint decision, as a couple. The aim of the present study was to develop an understanding of autonomous decisions made by couples in the context of reproductive technologies in general and of preconception ECS in particular. A further aim was to shed light on what occurs in reproductive clinics and to suggest concrete implications for the approach of healthcare professionals in those clinics. Discussion: Based on the shift in emphasis from individual autonomy to relational autonomy, a notion of couple autonomy was suggested and some features of this concept were outlined. First, that both partners are individually autonomous and that the decision is reached through a communicative process. In this process each partner should feel free to express his or her concerns and preferences, so no one partner dominates the discussion. Further, there should be adequate time for the couple to negotiate possible differences and conclude that the decision is right for them. The final decision should be reached through consensus of both partners without coercion, manipulation or miscommunication. Through concrete examples, the suggested notion of couple autonomy was applied to diverse clinical situations. Conclusions: A notion of couple autonomy can be fruitful for healthcare professionals by facilitating the ways in which close ones are vital for the decision-making concerning preconception ECS. A normative implication for healthcare staff is to allow the necessary time for decision-making and to promote a dialogue that can increase the power of the weaker part in a relationship.

    National Category
    Other Medical Biotechnology
    Identifiers
    urn:nbn:se:uu:diva-366363 (URN)
    Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2019-01-11Bibliographically approved
    3. "A perfect society": Swedish policymakers' ethical and social views on preconception expanded carrier screening
    Open this publication in new window or tab >>"A perfect society": Swedish policymakers' ethical and social views on preconception expanded carrier screening
    2019 (English)In: Journal of Community Genetics, ISSN 1868-310X, E-ISSN 1868-6001, Vol. 10, no 2, p. 267-280Article in journal (Refereed) Published
    Abstract [en]

    To improve healthcare policymaking, commentators have recommended the use of evidence, health technology assessment, priority setting, and public engagement in the process of policymaking. Preconception expanded carrier screening, according to the World Health Organization’s definition, is a novel health technology and therefore warrants assessment, part of which involves evaluating ethical and social implications. We examined ten Swedish policymakers’ perspectives on ethical and social aspects of preconception expanded screening through in-depth expert interviewing, using a semi-structured questionnaire. Respondents were affiliated to governmental and non-governmental institutions that directly influence healthcare policymaking in Sweden. The interviews were recorded, transcribed verbatim, and analyzed via inductive thematic analysis method, which generated seven themes and several subthemes. Policymakers harbored concerns regarding the economics, Swedish and international political respects, implementation procedures, and societal effects, which included long-term ones. Moreover, participants detailed the role of public engagement, research, and responsibility in regard to preconception expanded carrier screening implementation. Since this is a qualitative study, with a small non-random sample, the results may not be generalizable to all policymakers in Sweden. However, the results give a profound insight into the process and interpretative knowledge of experts, in the Swedish milieu and the extent of readiness of Sweden to implement a preconception expanded carrier screening program.

    Keywords
    Preconception, Expanded carrier screening, Genetic, Policymakers, Reproductive decision-making, Ethics, Social effects
    National Category
    Other Medical Biotechnology Other Health Sciences Medical Ethics
    Identifiers
    urn:nbn:se:uu:diva-362390 (URN)10.1007/s12687-018-0389-x (DOI)000463053900011 ()30259298 (PubMedID)
    Available from: 2018-10-04 Created: 2018-10-04 Last updated: 2019-04-25Bibliographically approved
    4. Values and value conflicts in implementation and use of preconception expanded carrier screening: an expert interview study
    Open this publication in new window or tab >>Values and value conflicts in implementation and use of preconception expanded carrier screening: an expert interview study
    2019 (English)In: BMC Medical Ethics, ISSN 1472-6939, E-ISSN 1472-6939, Vol. 20, article id 25Article in journal (Refereed) Published
    Abstract [en]

    Background: Endeavors have been made to found and incorporate ethical values in most aspects of healthcare, including health technology assessment. Health technologies and their assessment are value-laden and could trigger problems with dissemination if they contradict societal norms. Per WHO definition, preconception expanded carrier screening is a new health technology that warrants assessment. It is a genetic test offered to couples who have no known risk of recessive genetic diseases and are interested pregnancy. A test may screen for carrier status of several autosomal recessive diseases and X-linked at one go. The technique has been piloted in the Netherlands and is discussed in other countries. The aim of the study was to examine values and value conflicts that healthcare experts recounted in relation to the discussion of implementation and use of preconception ECS in Sweden.

    Methods: We interviewed ten experts, who were associated with influencing health policymaking in Sweden. We employed systematizing expert interviews, which endeavor to access experts' specialist knowledge. There were four female and six male informants, of which four were physicians, three bioethicists, one a legal expert, one a theologian and one a political party representative in the parliament. The participants functioned as members of two non-governmental bodies and three governmental organizations. We employed thematic analysis to identify themes, categories and subcategories.

    Results: Two main themes surfaced: values and value conflicts. The main categories of Respect for persons, Solidarity, Human dignity, Do no harm, Health and Love formed the first theme, while values conflicting with autonomy and integrity respectively, constituted the second theme. Concepts relating to respect for persons were the most commonly mentioned among the participants, followed by notions alluding to solidarity. Furthermore, respondents discussed values conflicting with Swedish healthcare ones such as equality and solidarity.

    Conclusions: The experts highlighted values and concepts that are distinctive of welfare states such as Sweden and delineated how preconception ECS could challenge such values. Moreover, the analysis revealed that certain values were deemed more substantive than others, judging by the extent and detail of inference; for example, respect for persons and solidarity were on top of the list.

    Keywords
    Moral values; intrinsic and extrinsic values; preconception expanded carrier screening; respect for persons; Solidarity; human dignity.
    National Category
    Other Medical Biotechnology
    Identifiers
    urn:nbn:se:uu:diva-366366 (URN)10.1186/s12910-019-0362-1 (DOI)000465408300001 ()31014326 (PubMedID)
    Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2019-05-10Bibliographically approved
  • 13.
    Matar, Amal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Couples Considering a Baby? Screen for the Future: Ethical and Implementation Aspects of Preconception Genetic Carrier Screening2016Licentiate thesis, comprehensive summary (Other academic)
    List of papers
    1. Swedish healthcare providers' perceptions of preconception expanded carrier screening (ECS)—a qualitative study
    Open this publication in new window or tab >>Swedish healthcare providers' perceptions of preconception expanded carrier screening (ECS)—a qualitative study
    2016 (English)In: Journal of Community Genetics, ISSN 1868-6001, Vol. 7, no 3, p. 203-214Article in journal (Refereed) Published
    Abstract [en]

    Reproductive autonomy, medicalization, and discrimination against disabled and parental responsibility are the main ongoing ethical debates concerning reproductive genetic screening. To examine Swedish healthcare professionals’ views on preconception expanded carrier screening (ECS), a qualitative study involving academic and clinical institutions in Sweden was conducted in September 2014 to February 2015. Eleven healthcare professionals including clinicians, geneticists, a midwife, and a genetic counselor were interviewed in depth using a semi-structured interview guide. The questionnaire was constructed after reviewing the main literature and meetings with relevant healthcare providers. The interviews were recorded, transcribed verbatim, and content analyzed for categories and subcategories. Participants nurtured many ethical and non-ethical concerns regarding preconception ECS. Among the ethical concerns were the potential for discrimination, medicalization, concerns with prioritization of healthcare resources, and effects on reproductive freedom. The effects of implementation of preconception ECS, its stakeholders, regulations, and motivation are some of non-ethical concerns. These concerns, if not addressed, may affect the uptake and usage of carrier screening within Swedish healthcare system. As this is a qualitative study with a small non-random sample size, the findings cannot be generalized. The participants had little to no working experience with expanded screening panels. Moreover, the interviews were conducted in English, a second language for the participants, which might have limited the expression of their views. However, the authors claim that the findings may be pertinent to similar settings in other Scandinavian countries.

    Place, publisher, year, edition, pages
    Springer, 2016
    Keywords
    reproductiion, autonomy, expanded carrier screening
    National Category
    Obstetrics, Gynecology and Reproductive Medicine Public Health, Global Health, Social Medicine and Epidemiology
    Identifiers
    urn:nbn:se:uu:diva-294966 (URN)10.1007/s12687-016-0268-2 (DOI)000386778700004 ()27225888 (PubMedID)
    Available from: 2016-05-31 Created: 2016-05-31 Last updated: 2019-01-11Bibliographically approved
    2. Couple autonomy in preconception expanded carrier screening
    Open this publication in new window or tab >>Couple autonomy in preconception expanded carrier screening
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Preconception Expanded Carrier Screening (ECS) is a genetic test offered to a general population or to couples who have no known risk of recessive and X-linked genetic diseases and are interested in becoming parents. A test may screen for carrier status of several autosomal recessive diseases at one go. Such a program has been piloted in the Netherlands and may become a reality in more European countries in the future. The ethical rationale for such tests is that they would enhance reproductive autonomy. The dominant conception of autonomy is individual-based. However, at the clinic, people deciding on preconception ECS will be counselled together and are expected to make a joint decision, as a couple. The aim of the present study was to develop an understanding of autonomous decisions made by couples in the context of reproductive technologies in general and of preconception ECS in particular. A further aim was to shed light on what occurs in reproductive clinics and to suggest concrete implications for the approach of healthcare professionals in those clinics. Discussion: Based on the shift in emphasis from individual autonomy to relational autonomy, a notion of couple autonomy was suggested and some features of this concept were outlined. First, that both partners are individually autonomous and that the decision is reached through a communicative process. In this process each partner should feel free to express his or her concerns and preferences, so no one partner dominates the discussion. Further, there should be adequate time for the couple to negotiate possible differences and conclude that the decision is right for them. The final decision should be reached through consensus of both partners without coercion, manipulation or miscommunication. Through concrete examples, the suggested notion of couple autonomy was applied to diverse clinical situations. Conclusions: A notion of couple autonomy can be fruitful for healthcare professionals by facilitating the ways in which close ones are vital for the decision-making concerning preconception ECS. A normative implication for healthcare staff is to allow the necessary time for decision-making and to promote a dialogue that can increase the power of the weaker part in a relationship.

    National Category
    Other Medical Biotechnology
    Identifiers
    urn:nbn:se:uu:diva-366363 (URN)
    Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2019-01-11Bibliographically approved
  • 14.
    Matar, Amal
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Hansson, Mats G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Höglund, Anna T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    "A perfect society": Swedish policymakers' ethical and social views on preconception expanded carrier screening2019In: Journal of Community Genetics, ISSN 1868-310X, E-ISSN 1868-6001, Vol. 10, no 2, p. 267-280Article in journal (Refereed)
    Abstract [en]

    To improve healthcare policymaking, commentators have recommended the use of evidence, health technology assessment, priority setting, and public engagement in the process of policymaking. Preconception expanded carrier screening, according to the World Health Organization’s definition, is a novel health technology and therefore warrants assessment, part of which involves evaluating ethical and social implications. We examined ten Swedish policymakers’ perspectives on ethical and social aspects of preconception expanded screening through in-depth expert interviewing, using a semi-structured questionnaire. Respondents were affiliated to governmental and non-governmental institutions that directly influence healthcare policymaking in Sweden. The interviews were recorded, transcribed verbatim, and analyzed via inductive thematic analysis method, which generated seven themes and several subthemes. Policymakers harbored concerns regarding the economics, Swedish and international political respects, implementation procedures, and societal effects, which included long-term ones. Moreover, participants detailed the role of public engagement, research, and responsibility in regard to preconception expanded carrier screening implementation. Since this is a qualitative study, with a small non-random sample, the results may not be generalizable to all policymakers in Sweden. However, the results give a profound insight into the process and interpretative knowledge of experts, in the Swedish milieu and the extent of readiness of Sweden to implement a preconception expanded carrier screening program.

  • 15.
    Matar, Amal
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Hansson, Mats G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Höglund, Anna T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Couple autonomy in preconception expanded carrier screeningManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Preconception Expanded Carrier Screening (ECS) is a genetic test offered to a general population or to couples who have no known risk of recessive and X-linked genetic diseases and are interested in becoming parents. A test may screen for carrier status of several autosomal recessive diseases at one go. Such a program has been piloted in the Netherlands and may become a reality in more European countries in the future. The ethical rationale for such tests is that they would enhance reproductive autonomy. The dominant conception of autonomy is individual-based. However, at the clinic, people deciding on preconception ECS will be counselled together and are expected to make a joint decision, as a couple. The aim of the present study was to develop an understanding of autonomous decisions made by couples in the context of reproductive technologies in general and of preconception ECS in particular. A further aim was to shed light on what occurs in reproductive clinics and to suggest concrete implications for the approach of healthcare professionals in those clinics. Discussion: Based on the shift in emphasis from individual autonomy to relational autonomy, a notion of couple autonomy was suggested and some features of this concept were outlined. First, that both partners are individually autonomous and that the decision is reached through a communicative process. In this process each partner should feel free to express his or her concerns and preferences, so no one partner dominates the discussion. Further, there should be adequate time for the couple to negotiate possible differences and conclude that the decision is right for them. The final decision should be reached through consensus of both partners without coercion, manipulation or miscommunication. Through concrete examples, the suggested notion of couple autonomy was applied to diverse clinical situations. Conclusions: A notion of couple autonomy can be fruitful for healthcare professionals by facilitating the ways in which close ones are vital for the decision-making concerning preconception ECS. A normative implication for healthcare staff is to allow the necessary

    2

    time for decision-making and to promote a dialogue that can increase the power of the weaker part in a relationship.

  • 16.
    Matar, Amal
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Hansson, Mats G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Höglund, Anna T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Values and value conflicts in implementation and use of preconception expanded carrier screening: an expert interview study2019In: BMC Medical Ethics, ISSN 1472-6939, E-ISSN 1472-6939, Vol. 20, article id 25Article in journal (Refereed)
    Abstract [en]

    Background: Endeavors have been made to found and incorporate ethical values in most aspects of healthcare, including health technology assessment. Health technologies and their assessment are value-laden and could trigger problems with dissemination if they contradict societal norms. Per WHO definition, preconception expanded carrier screening is a new health technology that warrants assessment. It is a genetic test offered to couples who have no known risk of recessive genetic diseases and are interested pregnancy. A test may screen for carrier status of several autosomal recessive diseases and X-linked at one go. The technique has been piloted in the Netherlands and is discussed in other countries. The aim of the study was to examine values and value conflicts that healthcare experts recounted in relation to the discussion of implementation and use of preconception ECS in Sweden.

    Methods: We interviewed ten experts, who were associated with influencing health policymaking in Sweden. We employed systematizing expert interviews, which endeavor to access experts' specialist knowledge. There were four female and six male informants, of which four were physicians, three bioethicists, one a legal expert, one a theologian and one a political party representative in the parliament. The participants functioned as members of two non-governmental bodies and three governmental organizations. We employed thematic analysis to identify themes, categories and subcategories.

    Results: Two main themes surfaced: values and value conflicts. The main categories of Respect for persons, Solidarity, Human dignity, Do no harm, Health and Love formed the first theme, while values conflicting with autonomy and integrity respectively, constituted the second theme. Concepts relating to respect for persons were the most commonly mentioned among the participants, followed by notions alluding to solidarity. Furthermore, respondents discussed values conflicting with Swedish healthcare ones such as equality and solidarity.

    Conclusions: The experts highlighted values and concepts that are distinctive of welfare states such as Sweden and delineated how preconception ECS could challenge such values. Moreover, the analysis revealed that certain values were deemed more substantive than others, judging by the extent and detail of inference; for example, respect for persons and solidarity were on top of the list.

  • 17.
    Matar, Amal
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Höglund, Anna T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Segerdahl, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Kihlbom, Ulrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Couple autonomy in preconception expanded carrier screeningManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Preconception Expanded Carrier Screening (ECS) is a genetic test offered to a general population or to couples who have no known risk of recessive and X-linked genetic diseases and are interested in becoming parents. A test may screen for carrier status of several autosomal recessive diseases at one go. Such a program has been piloted in the Netherlands and may become a reality in more European countries in the future. The ethical rationale for such tests is that they would enhance reproductive autonomy. The dominant conception of autonomy is individual-based. However, at the clinic, people deciding on preconception ECS will be counselled together and are expected to make a joint decision, as a couple. The aim of the present study was to develop an understanding of autonomous decisions made by couples in the context of reproductive technologies in general and of preconception ECS in particular. A further aim was to shed light on what occurs in reproductive clinics and to suggest concrete implications for the approach of healthcare professionals in those clinics. Discussion: Based on the shift in emphasis from individual autonomy to relational autonomy, a notion of couple autonomy was suggested and some features of this concept were outlined. First, that both partners are individually autonomous and that the decision is reached through a communicative process. In this process each partner should feel free to express his or her concerns and preferences, so no one partner dominates the discussion. Further, there should be adequate time for the couple to negotiate possible differences and conclude that the decision is right for them. The final decision should be reached through consensus of both partners without coercion, manipulation or miscommunication. Through concrete examples, the suggested notion of couple autonomy was applied to diverse clinical situations. Conclusions: A notion of couple autonomy can be fruitful for healthcare professionals by facilitating the ways in which close ones are vital for the decision-making concerning preconception ECS. A normative implication for healthcare staff is to allow the necessary time for decision-making and to promote a dialogue that can increase the power of the weaker part in a relationship.

  • 18.
    Nowak, Christoph
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Sundstrom, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Ganna, Andrea
    Massachusetts General Hospital, Harvard Medical School and Broad Institute, Boston, Massachusetts.
    Shen, Xia
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm , Sweden.
    Broeckling, Corey D.
    Proteomics and Metabolomics Facility, Colorado State University, Fort Collins, Colorado, USA.
    Prenni, Jessica
    Proteomics and Metabolomics Facility, Colorado State University, Fort Collins, Colorado, USA.
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. School of Health and Social Studies, Dalarna University, Falun, Sweden.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
    Metabolite profiles during an oral glucose tolerance test reveal new associations with clamp-measured insulin sensitivityManuscript (preprint) (Other academic)
    Abstract [en]

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

  • 19.
    Tegler, Gustaf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Hall, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Wanhainen, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Björck, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Autoradiography screening of potential positron emission tomography tracers for asymptomatic abdominal aortic aneurysms2014In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 3, p. 229-235Article in journal (Refereed)
    Abstract [en]

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

  • 20.
    Tegler, Gustaf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Ericson, Katharina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Björck, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Wanhainen, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    4D-PET/CT with [11C]-PK11195 and [11C]-D-deprenyl does not identify the chronic inflammation in asymptomatic abdominal aortic aneurysms2013In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 45, no 4, p. 351-356Article in journal (Refereed)
    Abstract [en]

    Objectives

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

    Design

    Prospective clinical study.

    Materials/methods

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

    Results

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

    Conclusions

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

  • 21.
    Tegler, Gustaf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Wallgren, AnnaCarin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Wanhainen, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Björck, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    [18F]fluciclatide- Autoradiography study of angiogenesis in abdominal aortic aneurysm2013Manuscript (preprint) (Other academic)
  • 22.
    Thorslund, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nguyen, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Läräng, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Barkefors, Irmeli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kreuger, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    A disposable and multifunctional capsule for easy operation of microfluidic elastomer systems2011In: Journal of Micromechanics and Microengineering, ISSN 0960-1317, E-ISSN 1361-6439, Vol. 21, no 12, p. 127001-Article in journal (Refereed)
    Abstract [en]

    The global lab-on-chip and microfluidic markets for cell-based assays have been predicted to grow considerably, as novel microfluidic systems enable cell biologists to perform in vitro experiments at an unprecedented level of experimental control. Nevertheless, microfluidic assays must, in order to compete with conventional assays, be made available at easily affordable costs, and in addition be made simple to operate for users having no previous experience with microfluidics. We have to this end developed a multifunctional microfluidic capsule that can be mass-produced at low cost in thermoplastic material. The capsule enables straightforward operation of elastomer inserts of optional design, here exemplified with insert designs for molecular gradient formation in microfluidic cell culture systems. The integrated macro–micro interface of the capsule ensures reliable connection of the elastomer fluidic structures to an external perfusion system. A separate compartment in the capsule filled with superabsorbent material is used for internal waste absorption. The capsule assembly process is made easy by integrated snap-fits, and samples within the closed capsule can be analyzed using both inverted and upright microscopes. Taken together, the capsule concept presented here could help accelerate the use of microfluidic-based biological assays in the life science sector.

  • 23. Waligórski, Michael P R
    et al.
    Hollmark, Malin
    Gudowska, Irena
    Lesia, Jan
    Cellular parameters and RBE-LET dependences for modelling heavy-ion radiotherapy.2004In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 73 Suppl 2, p. S173-5Article in journal (Refereed)
    Abstract [en]

    Sets of four parameters (m, E0, sigma0 and kappa) of the cellular track structure model of Katz have been fitted to recently published data concerning human melanoma (AA) and mammalian (V79) cells exposed to a variety of lighter ions and to mixed ion-Co60 and ion-ion irradiation. Using these parameters, model predictions of V79 survival were verified against experimental data. RBE-LET dependences were calculated and compared with experimental data obtained for V79 cells after exposure to 3He, 12C and 20Ne ion beams. The presented track-segment approach used in track structure calculations, while satisfactory for heavier ions, may be of limited value for predicting the RBE-LET dependence of proton and helium radiotherapy beams in regions close to the distal range of these particles. We discuss the predictive capability of this model and propose standards in reporting cellular radiobiology data for application in modelling heavy ion beam radiotherapy.

1 - 23 of 23
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