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  • 1.
    Aronsson, Christopher
    et al.
    Laboratory of Molecular Materials, Division of Biophysics and Bioengineering, Department of Physics, Chemistry and Biology, Linköping University, Sweden.
    Jury, Michael
    Laboratory of Molecular Materials, Division of Biophysics and Bioengineering, Department of Physics, Chemistry and Biology, Linköping University, Sweden.
    Naeimipour, Sajjad
    Laboratory of Molecular Materials, Division of Biophysics and Bioengineering, Department of Physics, Chemistry and Biology, Linköping University, Sweden.
    Boroojeni, Fatemeh Rasti
    Laboratory of Molecular Materials, Division of Biophysics and Bioengineering, Department of Physics, Chemistry and Biology, Linköping University, Sweden.
    Christoffersson, Jonas
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Division of Biotechnology, Department of Physics, Chemistry and Biology, Linköping University, Sweden.
    Lifwergren, Philip
    Laboratory of Molecular Materials, Division of Biophysics and Bioengineering, Department of Physics, Chemistry and Biology, Linköping University, Sweden.
    Mandenius, Carl-Fredrik
    Division of Biotechnology, Department of Physics, Chemistry and Biology, Linköping University, Sweden.
    Selegård, Robert
    Laboratory of Molecular Materials, Division of Biophysics and Bioengineering, Department of Physics, Chemistry and Biology, Linköping University, Sweden.
    Aili, Daniel
    Laboratory of Molecular Materials, Division of Biophysics and Bioengineering, Department of Physics, Chemistry and Biology, Linköping University, Sweden.
    Dynamic peptide-folding mediated biofunctionalization and modulation of hydrogels for 4D bioprinting2020Inngår i: Biofabrication, ISSN 1758-5082, E-ISSN 1758-5090, Vol. 12, nr 3, artikkel-id 035031Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hydrogels are used in a wide range of biomedical applications, including three-dimensional (3D) cell culture, cell therapy and bioprinting. To enable processing using advanced additive fabrication techniques and to mimic the dynamic nature of the extracellular matrix (ECM), the properties of the hydrogels must be possible to tailor and change over time with high precision. The design of hydrogels that are both structurally and functionally dynamic, while providing necessary mechanical support is challenging using conventional synthesis techniques. Here, we show a modular and 3D printable hydrogel system that combines a robust but tunable covalent bioorthogonal cross-linking strategy with specific peptide-folding mediated interactions for dynamic modulation of cross-linking and functionalization. The hyaluronan-based hydrogels were covalently cross-linked by strain-promoted alkyne-azide cycloaddition using multi-arm poly(ethylene glycol). In addition, a de novo designed helix-loop-helix peptide was conjugated to the hyaluronan backbone to enable specific peptide-folding modulation of cross-linking density and kinetics, and hydrogel functionality. An array of complementary peptides with different functionalities was developed and used as a toolbox for supramolecular tuning of cell-hydrogel interactions and for controlling enzyme-mediated biomineralization processes. The modular peptide system enabled dynamic modifications of the properties of 3D printed structures, demonstrating a novel route for design of more sophisticated bioinks for four-dimensional bioprinting. © 2020 The Author(s). Published by IOP Publishing Ltd.

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  • 2.
    Asplund, Annika
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Pradip, Arvind
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden / Novo Nordisk A/S, Bagsværd, Denmark.
    van Giezen, Mariska
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Aspegren, Anders
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Choukair, Helena
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Rehnström, Marie
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Jacobsson, Susanna
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Ghosheh, Nidal
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    El Hajjam, Dorra
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Holmgren, Sandra
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden / Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Larsson, Susanna
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Benecke, Jörg
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Butron, Mariela
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Wigander, Annelie
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Noaksson, Karin
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. AstraZeneca R&D, GMD CVMD GMed, Mölndal, Sweden.
    Björquist, Petter
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden / NovaHep AB, Gothenburg, Sweden.
    Edsbagge, Josefina
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Küppers-Munther, Barbara
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Takara Bio Europe AB (former Cellartis AB), Arvid Wallgrens Backe 20, 413 46, Gothenburg, Sweden.
    One Standardized Differentiation Procedure Robustly Generates Homogenous Hepatocyte Cultures Displaying Metabolic Diversity from a Large Panel of Human Pluripotent Stem Cells2016Inngår i: Stem Cell Reviews, ISSN 1550-8943, E-ISSN 1558-6804, Vol. 12, nr 1, s. 90-104Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human hepatocytes display substantial functional inter-individual variation regarding drug metabolizing functions. In order to investigate if this diversity is mirrored in hepatocytes derived from different human pluripotent stem cell (hPSC) lines, we evaluated 25 hPSC lines originating from 24 different donors for hepatic differentiation and functionality. Homogenous hepatocyte cultures could be derived from all hPSC lines using onestandardized differentiation procedure. To the best of our knowledge this is the first report of a standardized hepatic differentiation procedure that is generally applicable across a large panel of hPSC lines without any adaptations to individual lines. Importantly, with regard to functional aspects, such as Cytochrome P450 activities, we observed that hepatocytes derived from different hPSC lines displayed inter-individual variation characteristic for primary hepatocytes obtained from different donors, while these activities were highly reproducible between repeated experiments using the same line. Taken together, these data demonstrate the emerging possibility to compile panels of hPSC-derived hepatocytes of particular phenotypes/genotypes relevant for drug metabolism and toxicity studies. Moreover, these findings are of significance for applications within the regenerative medicine field, since our stringent differentiation procedure allows the derivation of homogenous hepatocyte cultures from multiple donors which is a prerequisite for the realization of future personalized stem cell based therapies.

  • 3.
    Bauzá-Thorbrügge, Marco
    et al.
    Unit for Metabolic Physiology, Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden.
    Vujičić, Milica
    Unit for Metabolic Physiology, Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden.
    Chanclón, Belén
    Unit for Metabolic Physiology, Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden.
    Palsdottir, Vilborg
    Unit for Endocrine Physiology, Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden.
    Pillon, Nicolas J.
    Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
    Benrick, Anna
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering. Unit for Metabolic Physiology, Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden.
    Wernstedt Asterholm, Ingrid
    Unit for Metabolic Physiology, Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden.
    Adiponectin stimulates Sca1+CD34-adipocyte precursor cells associated with hyperplastic expansion and beiging of brown and white adipose tissue2024Inngår i: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 151, artikkel-id 155716Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The adipocyte hormone adiponectin improves insulin sensitivity and there is an inverse correlation between adiponectin levels and type-2 diabetes risk. Previous research shows that adiponectin remodels the adipose tissue into a more efficient metabolic sink. For instance, mice that overexpress adiponectin show increased capacity for hyperplastic adipose tissue expansion as evident from smaller and metabolically more active white adipocytes. In contrast, the brown adipose tissue (BAT) of these mice looks “whiter” possibly indicating reduced metabolic activity. Here, we aimed to further establish the effect of adiponectin on adipose tissue expansion and adipocyte mitochondrial function as well as to unravel mechanistic aspects in this area. Methods: Brown and white adipose tissues from adiponectin overexpressing (APN tg) mice and littermate wildtype controls, housed at room and cold temperature, were studied by histological, gene/protein expression and flow cytometry analyses. Metabolic and mitochondrial functions were studied by radiotracers and Seahorse-based technology. In addition, mitochondrial function was assessed in cultured adiponectin deficient adipocytes from APN knockout and heterozygote mice. Results: APN tg BAT displayed increased proliferation prenatally leading to enlarged BAT. Postnatally, APN tg BAT turned whiter than control BAT, confirming previous reports. Furthermore, elevated adiponectin augmented the sympathetic innervation/activation within adipose tissue. APN tg BAT displayed reduced metabolic activity and reduced mitochondrial oxygen consumption rate (OCR). In contrast, APN tg inguinal white adipose tissue (IWAT) displayed enhanced metabolic activity. These metabolic differences between genotypes were apparent also in cultured adipocytes differentiated from BAT and IWAT stroma vascular fraction, and the OCR was reduced in both brown and white APN heterozygote adipocytes. In both APN tg BAT and IWAT, the mesenchymal stem cell-related genes were upregulated along with an increased abundance of Lineage−Sca1+CD34− “beige-like” adipocyte precursor cells. In vitro, the adiponectin receptor agonist Adiporon increased the expression of the proliferation marker Pcna and decreased the expression of Cd34 in Sca1+ mesenchymal stem cells. Conclusions: We propose that the seemingly opposite effect of adiponectin on BAT and IWAT is mediated by a common mechanism; while reduced adiponectin levels are linked to lower adipocyte OCR, elevated adiponectin levels stimulate expansion of adipocyte precursor cells that produce adipocytes with intrinsically higher metabolic rate than classical white but lower metabolic rate than classical brown adipocytes. Moreover, adiponectin can modify the adipocytes' metabolic activity directly and by enhancing the sympathetic innervation within a fat depot. 

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  • 4.
    Brackmann, Christian
    et al.
    Chalmers University of Technology, Molecular Microscopy, Department of Chemical and Biological Engineering, Göteborg, Sweden.
    Esguerra, Maricris
    Sahlgrenska Academy at University of Gothenburg, Institute of Clinical Sciences, Department of Surgery, Göteborg, Sweden.
    Olausson, Daniel
    Sahlgrenska Academy at University of Gothenburg, Institute of Clinical Sciences, Department of Surgery, Göteborg, Sweden.
    Delbro, Dick
    Sahlgrenska Academy at University of Gothenburg, Institute of Clinical Sciences, Department of Surgery, Göteborg, Sweden.
    Krettek, Alexandra
    Sahlgrenska Academy at University of Gothenburg, Institute of Medicine, Department of Internal Medicine, Göteborg, Sweden.
    Gatenholm, Paul
    Chalmers University of Technology, Polymer Science, Department of Chemical and Biological Engineering, Göteborg, Sweden.
    Enejder, Annika
    Chalmers University of Technology, Molecular Microscopy, Department of Chemical and Biological Engineering, Göteborg, Sweden.
    Coherent anti-Stokes Raman scattering microscopy of human smooth muscle cells in bioengineered tissue scaffolds2011Inngår i: Journal of Biomedical Optics, ISSN 1083-3668, E-ISSN 1560-2281, Vol. 16, nr 2, artikkel-id 021115Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The integration of living, human smooth muscle cells in biosynthesized cellulose scaffolds was monitored by nonlinear microscopy toward contractile artificial blood vessels. Combined coherent anti-Stokes Raman scattering (CARS) and second harmonic generation (SHG) microscopy was applied for studies of the cell interaction with the biopolymer network. CARS microscopy probing CH(2)-groups at 2845 cm(-1) permitted three-dimensional imaging of the cells with high contrast for lipid-rich intracellular structures. SHG microscopy visualized the fibers of the cellulose scaffold, together with a small signal obtained from the cytoplasmic myosin of the muscle cells. From the overlay images we conclude a close interaction between cells and cellulose fibers. We followed the cell migration into the three-dimensional structure, illustrating that while the cells submerge into the scaffold they extrude filopodia on top of the surface. A comparison between compact and porous scaffolds reveals a migration depth of <10 μm for the former, whereas the porous type shows cells further submerged into the cellulose. Thus, the scaffold architecture determines the degree of cell integration. We conclude that the unique ability of nonlinear microscopy to visualize the three-dimensional composition of living, soft matter makes it an ideal instrument within tissue engineering.

  • 5.
    Chaudhari, Aditi
    et al.
    University of Gothenburg.
    Ejeskär, Katarina
    Högskolan i Skövde, Institutionen för hälsa och lärande. Högskolan i Skövde, Forskningsspecialiseringen Hälsa och Lärande.
    Wettergren, Yvonne
    University of Gothenburg, Sahlgrenska University Hospital/Östra.
    Kahn, Ronald
    Joslin Diabetes Center and Harvard Medical School, United States.
    Rotter Sopasakis, Victoria
    University of Gothenburg / Joslin Diabetes Center and Harvard Medical School, United states.
    Hepatic deletion of p110α and p85α results in insulin resistance despite sustained IRS1-associated phosphatidylinositol kinase activity2017Inngår i: F1000 Research, E-ISSN 2046-1402, Vol. 6, artikkel-id 1600Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Class IA phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is an integral mediator of insulin signaling. The p110 catalytic and p85 regulatory subunits of PI3K are the products of separate genes, and while they come together to make the active heterodimer, they have opposing roles in insulin signaling and action. Deletion of hepatic p110α results in an impaired insulin signal and severe insulin resistance, whereas deletion of hepatic p85α results in improved insulin sensitivity due to sustained levels of phosphatidylinositol (3,4,5)-trisphosphate. Here, we created mice with combined hepatic deletion of p110α and p85α (L-DKO) to study the impact on insulin signaling and whole body glucose homeostasis.Methods: Six-week old male flox control and L-DKO mice were studied over a period of 18 weeks, during which weight and glucose levels were monitored, and glucose tolerance tests, insulin tolerance test and pyruvate tolerance test were performed. Fasting insulin, insulin signaling mediators, PI3K activity and insulin receptor substrate (IRS)1-associated phosphatidylinositol kinase activity were examined at 10 weeks. Liver, muscle and white adipose tissue weight was recorded at 10 weeks and 25 weeks.Results: The L-DKO mice showed a blunted insulin signal downstream of PI3K, developed markedly impaired glucose tolerance, hyperinsulinemia and had decreased liver and adipose tissue weights. Surprisingly, however, these mice displayed normal hepatic glucose production, normal insulin tolerance, and intact IRS1-associated phosphatidylinositol kinase activity without compensatory upregulated signaling of other classes of PI3K.Conclusions: The data demonstrate an unexpectedly overall mild metabolic phenotype of the L-DKO mice, suggesting that lipid kinases other than PI3Ks might partially compensate for the loss of p110α/p85α by signaling through other nodes than Akt/Protein Kinase B.

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  • 6.
    Chaudhari, Aditi
    et al.
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Krumlinde, Daniel
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Lundqvist, Annika
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Akyürek, Levent M.
    Department of Medical Chemistry and Cell biology, University of Gothenburg, Sweden.
    Bandaru, Sashidhar
    Department of Medical Chemistry and Cell biology, University of Gothenburg, Sweden.
    Skålén, Kristina
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Ståhlman, Marcus
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Borén, Jan
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Wettergren, Yvonne
    Department of Surgery, University of Gothenburg, Sweden.
    Ejeskär, Katarina
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Department of Medical and Clinical Genetics, University of Gothenburg, Sweden.
    Rotter Sopasakis, Victoria
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    p110α hot spot mutations E545K and H1047R exert metabolic reprogramming independently of p110α kinase activity2015Inngår i: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 35, nr 19, s. 3258-3273Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit p110α is the most frequently mutated kinase in human cancer, and the hot spot mutations E542K, E545K, and H1047R are the most common mutations in p110α. Very little is known about the metabolic consequences of the hot spot mutations of p110α in vivo. In this study, we used adenoviral gene transfer in mice to investigate the effects of the E545K and H1047R mutations on hepatic and whole-body glucose metabolism. We show that hepatic expression of these hot spot mutations results in rapid hepatic steatosis, paradoxically accompanied by increased glucose tolerance, and marked glycogen accumulation. In contrast, wild-type p110α expression does not lead to hepatic accumulation of lipids or glycogen despite similar degrees of upregulated glycolysis and expression of lipogenic genes. The reprogrammed metabolism of the E545K and H1047R p110α mutants was surprisingly not dependent on altered p110α lipid kinase activity.

  • 7.
    Dahl-Halvarsson, Martin
    et al.
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sweden.
    Olive, Montse
    Institute of Neuropathology, Department of Pathology and Neuromuscular Unit, Department of Neurology, IDIBELL-Hospital de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.
    Pokrzywa, Malgorzata
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sweden.
    Norum, Michaela
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sweden.
    Ejeskär, Katarina
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Tajsharghi, Homa
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Impaired muscle morphology in a Drosophila model of myosin storage myopathy was supressed by overexpression of an E3 ubiquitin ligase2020Inngår i: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 13, nr 12, artikkel-id dmm047886Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Myosin is vital for body movement and heart contractility. Mutations in MYH7, encoding slow/ß-cardiac myosin heavy chain, are an important cause of hypertrophic and dilated cardiomyopathy, as well as skeletal muscle disease. A dominant missense mutation (R1845W) in MYH7 has been reported in several unrelated cases with myosin storage myopathy. We have developed a Drosophila model for a myosin storage myopathy in order to investigate the dose-dependent mechanisms underlying the pathological roles of R1845W mutation. This study shows that higher expression level of the mutated allele is concomitant with severe impairment of muscle function and progressively disrupted muscle morphology. The impaired muscle morphology associated with the mutant allele was supressed by expression of Abba/Thin, an E3 ubiquitin ligase.This Drosophila model recapitulates pathological features seen in myopathy patients with the R1845W mutation and severe ultrastructural abnormalities including extensive loss of thick filaments with selective A-band loss and preservation of I-band and Z-disks were observed in indirect flight muscles of flies with exclusive expression of mutant myosin. Further, the impaired muscle morphology associated with the mutant allele was supressed by expression of Abba/Thin, an E3 ubiquitin ligase. These findings suggest that modification of ubiquitin proteasome system may be beneficial in myosin storage myopathy by reducing the impact of MYH7 mutation in patients.

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  • 8.
    Delsing, Louise
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Institute of Neuroscience and Physiology, Department of Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Sweden / Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Mölndal, Sweden.
    Herland, Anna
    Division of Micro and Nanosystems, KTH Royal Institute of Technology, Stockholm, Sweden / AIMES, Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Falk, Anna
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Hicks, Ryan
    Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Mölndal, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Zetterberg, Henrik
    Institute of Neuroscience and Physiology, Department of Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Sweden / Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden / Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom / UK Dementia Research Institute at UCL, London, United Kingdom.
    Models of the blood-brain barrier using iPSC-derived cells2020Inngår i: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 107, artikkel-id 103533Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The blood-brain barrier (BBB) constitutes the interface between the blood and the brain tissue. Its primary function is to maintain the tightly controlled microenvironment of the brain. Models of the BBB are useful for studying the development and maintenance of the BBB as well as diseases affecting it. Furthermore, BBB models are important tools in drug development and support the evaluation of the brain-penetrating properties of novel drug molecules. Currently used in vitro models of the BBB include immortalized brain endothelial cell lines and primary brain endothelial cells of human and animal origin. Unfortunately, many cell lines and primary cells do not recreate physiological restriction of transport in vitro. Human-induced pluripotent stem cell (iPSC)-derived brain endothelial cells have proven a promising alternative source of brain endothelial-like cells that replicate tight cell layers with low paracellular permeability. Given the possibility to generate large amounts of human iPSC-derived brain endothelial cells they are a feasible alternative when modelling the BBB in vitro. iPSC-derived brain endothelial cells form tight cell layers in vitro and their barrier properties can be enhanced through coculture with other cell types of the BBB. Currently, many different models of the BBB using iPSC-derived cells are under evaluation to study BBB formation, maintenance, disruption, drug transport and diseases affecting the BBB. This review summarizes important functions of the BBB and current efforts to create iPSC-derived BBB models in both static and dynamic conditions. In addition, it highlights key model requirements and remaining challenges for human iPSC-derived BBB models in vitro.

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  • 9.
    Ehtesham, Ehtesham
    Högskolan i Skövde, Institutionen för vård och natur.
    Embryonic Gene Alterations in rats Caused by Exposure to Diabetes and/or Obesity2012Independent thesis Advanced level (degree of Master (One Year)), 20 poäng / 30 hpOppgave
    Abstract [en]

    There is ample evidence that both diabetes as well as obesity leads to various metabolic disturbances that leads to oxidative stress. Oxidative stress has been shown  to  be  associated  with  congenital  malformations  of  which  neural  tube defects  and  cardiac  malformations  are  more  common.  The  cellular  and molecular  mechanisms  through  which  oxidative  stress  induces  these  defects during the developmental stage are not well known. Previous work in this field suggests   that   oxidative   stress   results   in   lipid   peroxidation   and   altered expression  of  genes  that  have  key  roles  in  the  developmental  processes.  The present study aimed to investigate gene alterations in embryos from pregnant diabetic  or  obese  rats.  Embryos  and  adipose  tissue  obtained  from  the  locally bred  diabetic  and  obese  Sprague-Dawley  inbred  rat  strain  were  subjected  to Total  RNA  extraction  and  were  quantified  using  Real  time  PCR  for  relative gene expressions analysis. The present study showed that maternal diabetes as well  as  obesity  diminishes  the  antioxidative  defense  mechanisms  by  down regulating the gene expressions of the key reactive oxygen species scavenging enzymes   copper   zinc   superoxide   dismutase   and   manganese   superoxide dismutase  in  day  10  rat  embryos.  There  was  also  altered  embryonic  gene expression  for  several  developmental  genes  due  to  maternal  diabetes  at gestational day 11 and 13 in rat embryos.

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  • 10.
    Ejeskär, Katarina
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Department of Medical and Clinical Genetics, Gothenburg University, Gothenburg, Sweden.
    Vickes, Oscar
    Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Kuchipudi, Arunakar
    Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Wettergren, Yvonne
    Department of General Surgery, Gothenburg University, Gothenburg, Sweden.
    Uv, Anne
    Department of Medical and Clinical Genetics, Gothenburg University, Gothenburg, Sweden.
    Rotter Sopasakis, Victoria
    Department of Molecular and Clinical Medicine, Institute of Medicine, Wallenberg Laboratory, Gothenburg University, Gothenburg, Sweden.
    The unique non-catalytic C-terminus of p37delta-PI3K adds proliferative properties in vitro and in vivo2015Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 10, nr 5, artikkel-id e0127497Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The PI3K/Akt pathway is central for numerous cellular functions and is frequently deregulated in human cancers. The catalytic subunits of PI3K, p110, are thought to have a potential oncogenic function, and the regulatory subunit p85 exerts tumor suppressor properties. The fruit fly, Drosophila melanogaster, is a highly suitable system to investigate PI3K signaling, expressing one catalytic, Dp110, and one regulatory subunit, Dp60, and both show strong homology with the human PI3K proteins p110 and p85. We recently showed that p37δ, an alternatively spliced product of human PI3K p110δ, displayed strong proliferation-promoting properties despite lacking the catalytic domain completely. Here we functionally evaluate the different domains of human p37δ in Drosophila. The N-terminal region of Dp110 alone promotes cell proliferation, and we show that the unique C-terminal region of human p37δ further enhances these proliferative properties, both when expressed in Drosophila, and in human HEK-293 cells. Surprisingly, although the N-terminal region of Dp110 and the C-terminal region of p37δ both display proliferative effects, over-expression of full length Dp110 or the N-terminal part of Dp110 decreases survival in Drosophila, whereas the unique C-terminal region of p37δ prevents this effect. Furthermore, we found that the N-terminal region of the catalytic subunit of PI3K p110, including only the Dp60 (p85)-binding domain and a minor part of the Ras binding domain, rescues phenotypes with severely impaired development caused by Dp60 over-expression in Drosophila, possibly by regulating the levels of Dp60, and also by increasing the levels of phosphorylated Akt. Our results indicate a novel kinase-independent function of the PI3K catalytic subunit.

  • 11.
    Fetah, Alija
    Högskolan i Skövde, Institutionen för vård och natur.
    Mutations E688K and G569R within the NALP3 gene, associated with development of hereditary auto inflammatory disorders   2009Independent thesis Advanced level (degree of Master (One Year)), 20 poäng / 30 hpOppgave
    Abstract [en]

    Different mutations within the NALP3 gene are thought to be associated with development of several types of hereditary auto inflammatory disorders such as neonatal onset multisystem inflammatory disorder (NOMID) and muckle-wells syndrome (MWS). In this work two separate mutations E688K and G569R were supposed to be constructed by site-directed mutagenesis in the cloned wild type NALP3 genes and further expressed in bacterial and mammalian host cells for functional studies in protein -protein interaction models.

    Fulltekst (pdf)
    FULLTEXT02
  • 12.
    Fransson, S.
    et al.
    Department of Medical and Clinical Genetics, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg SE-405 30, Sweden.
    Uv, A.
    Department of Medical and Clinical Genetics, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg SE-405 30, Sweden.
    Eriksson, H.
    Department of Medical and Clinical Genetics, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg SE-405 30, Sweden.
    Andersson, M. K.
    Department of Pathology, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
    Wettergren, Y.
    Department of General Surgery, University of Gothenburg SE-40530 Gothenburg, Sweden.
    Bergo, M.
    Department of Medicine, Sahlgrenska Cancer Center, University of Gothenburg, SE-40530 Gothenburg, Sweden.
    Ejeskär, Katarina
    Högskolan i Skövde, Institutionen för vård och natur. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    p37δ is a new isoform of PI3K p110δ that increases cell proliferation and is overexpressed in tumors2012Inngår i: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 31, nr 27, s. 3277-3286Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The phosphatidylinositol 3-kinases (PI3Ks) regulate cell growth, proliferation and survival, and are frequently affected in human cancer. PI3K is composed of a catalytic subunit, p110, and a regulatory subunit, p85. The PI3K catalytic subunit p110δ is encoded by PIK3CD and contains p85- and RAS-binding domains, and a kinase domain. Here we present an alternatively spliced PIK3CD transcript encoding a previously unknown protein, p37δ, and demonstrate that this protein is expressed in human ovarian and colorectal tumors. p37δ retains the p85-binding domain and a fraction of the RAS-binding domain, lacks the catalytic domain, and has a unique carboxyl-terminal region. In contrast to p110δ, which stabilizes p85, p37δ promoted p85 sequestering. Despite the truncated RAS-binding domain, p37δ bound to RAS and we found a strong positive correlation between the protein levels of p37δ and RAS. Overexpressing p37δ, but not p110δ, increased the proliferation and invasive properties of HEK-293 cells and mouse embryonic fibroblasts. Cells overexpressing p37δ showed a quicker phosphorylation response of AKT and ERK1/2 following serum stimulation. Ubiquitous expression of human p37δ in the fruit fly increased body size, DNA content and phosphorylated ERK1/2 levels. Thus, p37δ appears to be a new tumor-specific isoform of p110δ with growth-promoting properties.

  • 13.
    Fransson, Susanne
    et al.
    Department of Medical and Clinical Genetics, Sahlgrenska Cancer Center, Gothenburg University, Gothenburg, Sweden.
    Abel, Frida
    Department of Medical and Clinical Genetics, Sahlgrenska Cancer Center, Gothenburg University, Gothenburg, Sweden.
    Kogner, Per
    Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden.
    Martinsson, Tommy
    Department of Medical and Clinical Genetics, Sahlgrenska Cancer Center, Gothenburg University, Gothenburg, Sweden.
    Ejeskär, Katarina
    Högskolan i Skövde, Institutionen för vård och natur. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Stage-dependent expression of PI3K/Akt‑pathway genes in neuroblastoma2013Inngår i: International Journal of Oncology, ISSN 1019-6439, E-ISSN 1791-2423, Vol. 42, nr 2, s. 609-616Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The phosphoinositide-3 kinase (PI3K) pathway plays a critical role in cancer cell growth and survival and has also been implicated in the development of the childhood cancer neuroblastoma. In neuroblastoma high mRNA expression of the PI3K catalytic isoform PIK3CD is associated to favorable disease. Yet, activation of Akt is associated with poor prognosis. Since the contribution of the numerous members of this pathway to neuroblastoma pathogenesis is mainly unknown, genes of the PI3K/Akt pathway were analyzed at the mRNA level through microarrays and quantitative real-time RT-PCR (TaqMan) and at the protein level using western blot analysis. Five genes showed lower mRNA expression in aggressive compared to more favorable neuroblastomas (PRKCZ, PRKCB1, EIF4EBP1, PIK3RI and PIK3CD) while the opposite was seen for PDGFRA. Clustering analysis shows that the expression levels of these six genes can predict aggressive disease. At the protein level, p110δ (encoded by PIK3CD) and p85α isomers (encoded by PIK3R1) were more highly expressed in favorable compared to aggressive neuroblastoma. Evaluation of the expression of these PI3K genes can predict aggressive disease, and indicates stage-dependent involvement of PI3K-pathway members in neuroblastoma.

  • 14.
    Fransson, Susanne
    et al.
    Sahlgrenska Cancer Center, University of Gothenburg, Sweden.
    Ejeskär, Katarina
    Högskolan i Skövde, Institutionen för vård och natur. Högskolan i Skövde, Forskningscentrum för Systembiologi. Sahlgrenska Cancer Center, University of Gothenburg, Sweden.
    High level of p37δ-mRNA relative to p110δ-mRNA in neuroblastoma tumors correlates with poor patient survival2013Inngår i: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 30, nr 4, artikkel-id 724Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Alterations in the PI3K/Akt pathway, a pathway that promotes proliferation and oncogenic transformation, are common in various cancers. In neuroblastoma, activation of Akt is correlated with aggressive disease although mutations in genes of this pathway are rare. Previous findings include a few mutations in PIK3CD, the gene encoding PI3K catalytic subunit delta, p110delta. We recently reported that an alternatively spliced form of p110delta, called p37delta, had cell proliferative properties and was over-expressed in ovarian and colorectal tumors. Here, we investigated p37delta in neuroblastoma primary tumors of different stages using qPCR (TaqMan) for gene expression analysis (46 samples) and Western blot for protein analysis (22 samples). Elevated levels of both p37delta-mRNA and p110delta-mRNA were detected in metastasizing neuroblastoma tumors compared to normal adrenal gland (P<0.05), and higher expression of p37delta-mRNA relative to p110delta-mRNA in neuroblastoma non-survivor patients compared to survivors (P<0.01). p37delta-Protein levels but not p110delta levels correlated with increased pAKT(T308) and pERK levels. The p37delta-mRNA levels did not correlate with the protein levels, indicating major regulation at the translational/protein level. Deregulation of signaling pathways is a hallmark of cancer development. Here, we show that p37delta, a kinase-dead isoform of the PI3K catalytic subunit p110delta, is over-expressed in neuroblastoma tumors, and that it correlates with the activation of both PI3K/Akt- and RAS-signaling pathways.

  • 15.
    Fransson, Susanne
    et al.
    Department of Medical and Clinical Genetics, Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden / Department of Medical and Clinical Genetics, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Kogner, Per
    Department of Women’s and Children’s Health, Childhood Cancer Research Unit, Karolinska Institutet, Stockholm, Sweden.
    Martinsson, Tommy
    Department of Medical and Clinical Genetics, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Ejeskär, Katarina
    Högskolan i Skövde, Institutionen för vård och natur. Högskolan i Skövde, Forskningscentrum för Systembiologi. Department of Medical and Clinical Genetics, Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Aggressive neuroblastomas have high p110alpha but low p110delta and p55alpha/p50alpha protein levels compared to low stage neuroblastomas2013Inngår i: Journal of Molecular Signaling, E-ISSN 1750-2187, Vol. 8, nr 1, artikkel-id 4Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The phosphoinositide 3-kinase (PI3K)/Akt pathway is involved in neuroblastoma development where Akt/PKB activation is associated with poor prognosis. PI3K activity subsequently activates Akt/PKB, and as mutations of PI3K are rare in neuroblastoma and high levels of PI3K subunit p110delta is associated with favorable disease with low p-Akt/PKB, the levels of other PI3K subunits could be important for Akt activation.Methods: Protein levels of Type IA PI3K catalytic and regulatory subunits were investigated together with levels of phosphorylated Akt/PKB and the PI3K negative regulator PTEN in primary neuroblastoma tumors. Relation between clinical markers and protein levels were evaluated through t-tests. Results: We found high levels of p-Akt/PKB correlating to aggressive disease and p-Akt/PKB (T308) showed inverse correlation to PTEN levels. The regulatory isomers p55alpha/p50alpha showed higher levels in favorable neuroblastoma as compared with aggressive neuroblastoma. The PI3K-subunit p110alpha was found mainly in advanced tumors while p110delta showed higher levels in favorable neuroblastoma.Conclusions: Activation of the PI3K/Akt pathway is seen in neuroblastoma tumors, however the contribution of the different PI3K isoforms is unknown. Here we show that p110alpha is preferentially expressed in aggressive neuroblastomas, with high p-Akt/PKB and p110delta is mainly detected in favorable neuroblastomas, with low p-Akt/PKB. This is an important finding as PI3K-specific inhibitors are suggested for enrollment in treatment of neuroblastoma patients.

  • 16.
    Ghosheh, Nidal
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Küppers-Munther, Barbara
    Takara Bio Europe AB, Gothenburg, Sweden.
    Asplund, Annika
    Takara Bio Europe AB, Gothenburg, Sweden.
    Andersson, Christian X.
    Takara Bio Europe AB, Gothenburg, Sweden.
    Björquist, Petter
    VeriGraft AB, Gothenburg, Sweden.
    Andersson, Tommy B.
    Cardiovascular Renal and Metabolism, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden / Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden.
    Carén, Helena
    Sahlgrenska Cancer Center, Department of Pathology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Simonsson, Stina
    Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Late Stage Cardiovascular, Renal, and Metabolism, R&D BioPharmaceuticals, AstraZeneca, Mölndal, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Human Pluripotent Stem Cell-Derived Hepatocytes Show Higher Transcriptional Correlation with Adult Liver Tissue than with Fetal Liver Tissue2020Inngår i: ACS Omega, E-ISSN 2470-1343, Vol. 5, nr 10, s. 4816-4827Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human pluripotent stem cell-derived hepatocytes (hPSC-HEP) display many properties of mature hepatocytes, including expression of important genes of the drug metabolizing machinery, glycogen storage, and production of multiple serum proteins. To this date, hPSC-HEP do not, however, fully recapitulate the complete functionality of in vivo mature hepatocytes. In this study, we applied versatile bioinformatic algorithms, including functional annotation and pathway enrichment analyses, transcription factor binding-site enrichment, and similarity and correlation analyses, to datasets collected from different stages during hPSC-HEP differentiation and compared these to developmental stages and tissues from fetal and adult human liver. Our results demonstrate a high level of similarity between the in vitro differentiation of hPSC-HEP and in vivo hepatogenesis. Importantly, the transcriptional correlation of hPSC-HEP with adult liver (AL) tissues was higher than with fetal liver (FL) tissues (0.83 and 0.70, respectively). Functional data revealed mature features of hPSC-HEP including cytochrome P450 enzymes activities and albumin secretion. Moreover, hPSC-HEP showed expression of many genes involved in drug absorption, distribution, metabolism, and excretion. Despite the high similarities observed, we identified differences of specific pathways and regulatory players by analyzing the gene expression between hPSC-HEP and AL. These findings will aid future intervention and improvement of in vitro hepatocyte differentiation protocol in order to generate hepatocytes displaying the complete functionality of mature hepatocytes. Finally, on the transcriptional level, our results show stronger correlation and higher similarity of hPSC-HEP to AL than to FL. In addition, potential targets for further functional improvement of hPSC-HEP were also identified. 

    Fulltekst (pdf)
    fulltext
  • 17.
    González-King, Hernán
    et al.
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Rodrigues, Patricia G.
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Albery, Tamsin
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Tangruksa, Benyapa
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Gurrapu, Ramya
    AstraZeneca India Private Limited, Neville Tower 11th Floor, Ramanujan IT SEZ, Rajv Gandhi Salai (OMR), Taramani, Tamil Nadu, Chennai, India.
    Silva, Andreia M.
    Discovery Sciences, Oligo Assay Development, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden ; Anjarium Biosciences AG, Schlieren, Switzerland.
    Musa, Gentian
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Kardasz, Dominika
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Liu, Kai
    Discovery Sciences, Oligo Assay Development, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden ; Pharmaceutical Sciences, Advanced Drug Delivery, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Kull, Bengt
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Åvall, Karin
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Rydén-Markinhuhta, Katarina
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Incitti, Tania
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Sharma, Nitin
    AstraZeneca India Private Limited, Neville Tower 11th Floor, Ramanujan IT SEZ, Rajv Gandhi Salai (OMR), Taramani, Tamil Nadu, Chennai, India.
    Graneli, Cecilia
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Valadi, Hadi
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Petkevicius, Kasparas
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Carracedo, Miguel
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Tejedor, Sandra
    Högskolan i Skövde, Forskningsmiljön Systembiologi. Högskolan i Skövde, Institutionen för biovetenskap. Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Ivanova, Alena
    Discovery Sciences, Oligo Assay Development, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Heydarkhan-Hagvall, Sepideh
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Chief Medical Office, Global Patient Safety, AstraZeneca, Mölndal, Sweden.
    Menasché, Phillipe
    Department of Cardiovascular Surgery, Hôpital Européen Georges Pompidou, Université de Paris, PARCC, INSERM, Paris, France.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Dekker, Niek
    Discovery Sciences, Oligo Assay Development, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Wang, Quing -Dong
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Jennbacken, Karin
    Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
    Head-to-head comparison of relevant cell sources of small extracellular vesicles for cardiac repair: Superiority of embryonic stem cells2024Inngår i: Journal of Extracellular Vesicles, E-ISSN 2001-3078, Vol. 13, nr 5, artikkel-id e12445Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Small extracellular vesicles (sEV) derived from various cell sources have been demonstrated to enhance cardiac function in preclinical models of myocardial infarction (MI). The aim of this study was to compare different sources of sEV for cardiac repair and determine the most effective one, which nowadays remains limited. We comprehensively assessed the efficacy of sEV obtained from human primary bone marrow mesenchymal stromal cells (BM-MSC), human immortalized MSC (hTERT-MSC), human embryonic stem cells (ESC), ESC-derived cardiac progenitor cells (CPC), human ESC-derived cardiomyocytes (CM), and human primary ventricular cardiac fibroblasts (VCF), in in vitro models of cardiac repair. ESC-derived sEV (ESC-sEV) exhibited the best pro-angiogenic and anti-fibrotic effects in vitro. Then, we evaluated the functionality of the sEV with the most promising performances in vitro, in a murine model of MI-reperfusion injury (IRI) and analysed their RNA and protein compositions. In vivo, ESC-sEV provided the most favourable outcome after MI by reducing adverse cardiac remodelling through down-regulating fibrosis and increasing angiogenesis. Furthermore, transcriptomic, and proteomic characterizations of sEV derived from hTERT-MSC, ESC, and CPC revealed factors in ESC-sEV that potentially drove the observed functions. In conclusion, ESC-sEV holds great promise as a cell-free treatment for promoting cardiac repair following MI. 

    Fulltekst (pdf)
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  • 18.
    Gustafson, Deborah R.
    Högskolan i Skövde, Institutionen för hälsa och lärande. Högskolan i Skövde, Forskningsspecialiseringen Hälsa och Lärande. Department of Neurology, State University of New York Downstate Medical Center, New York, USA.
    Adipose Tissue Complexities in Dyslipidemias2019Inngår i: Dyslipidemia / [ed] Samy I. McFarlane, London: IntechOpen , 2019, s. 1-22Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    Adipose tissue is the largest organ in the human body and, in excess, contributes to dyslipidemias and the dysregulation of other vascular and metabolic processes. Adipose tissue is heterogeneous, comprised of several cell types based on morphology, cellular age, and endocrine and paracrine function. Adipose tissue depots are also regional, primarily due to sex differences and genetic variation. Adipose tissue is also characterized as subcutaneous vs. visceral. In addition, fatty deposits exist outside of adipose tissue, such as those surrounding the heart, or as infiltration of skeletal muscle. This review focuses on adipose tissue and its contribution to dyslipidemias. Dyslipidemias are defined as circulating blood lipid levels that are too high or altered. Lipids include both traditional and nontraditional species. Leaving aside traditional definitions, adipose tissue contributes to dyslipidemias in a myriad of ways. To address a small portion of this topic, we reviewed (a) adipose tissue location and cell types, (b) body composition, (c) endocrine adipose, (d) the fat-brain axis, and (e) genetic susceptibility. The influence of these complex aspects of adipose tissue on dyslipidemias and human health, illustrating that, once again, that adipose tissue is a quintessential, multifunctional tissue of the human body, will be summarized.

    Fulltekst (pdf)
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  • 19.
    Harsha Vardhan Reddy, Burri
    Högskolan i Skövde, Institutionen för vård och natur.
    Design, Synthesis and Biological testing of Novel ligands for Ghrelin Receptor2008Independent thesis Advanced level (degree of Master (One Year)), 20 poäng / 30 hpOppgave
    Abstract [en]

    Abstract

    G-protein coupled receptors (GPCRs) are having the high medical importance since almost half of the medicinal drugs are designed as modulators of receptor molecules. Crystal structure or NMR structures of GPCRs are very difficult to determine because all GPCRs are typically bound to the cell membrane and thus their molecular activation mechanism is still unclear. The recent publication of the crystal structure of the 2-adrenoreceptor will provide new insights in the field of GPCR research.

    Ghrelin is a peptide growth hormone which binds to the growth hormone secretagogue receptor (GHS-R) and stimulates the release of growth hormone. Based on the known ghrelin receptor binding core sequences wFwLL (upper letter and lower letter representative for L-form and D-form of the amino acids respectively), we prepared two novel peptide analogs with terminal S-(2-aminoethylsulfenyl) cysteine residues. These peptides were tested for their ability to suppress the binding of ghrelin to transfected COS7 cell-line (Kidney fibroblast line from the green African monkey) cells expressing the ghrelin wild-type receptor or certain mutants thereof. As a result we observed a significant reduction of the total number of binding sites accessible for ghrelin, which increased with the time the cells were incubated with our test compounds. This observations support our hypothesis that the peptides we tested form a covalent bond with free thiols located closely to the ligand binding-site of the receptor protein by disulfide thiol exchange which is an interesting target for development of anti-obesity drugs.

    Fulltekst (pdf)
    FULLTEXT01
  • 20.
    Herring, Matthew
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Sweden ; Inflammatory Response and Infection Susceptibility Centre (iRiSC), Örebro University, Sweden.
    Persson, Alexander
    School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Sweden ; Inflammatory Response and Infection Susceptibility Centre (iRiSC), Örebro University, Sweden.
    Potter, Ryan
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Göteborg University, Sweden.
    Karlsson, Roger
    Nanoxis Consulting AB, Göteborg, Sweden ; Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, Göteborg University, Sweden ; Department of Clinical Microbiology, Sahlgrenska University Hospital, Region Västra Götaland, Göteborg, Sweden.
    Särndahl, Eva
    School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Sweden ; Inflammatory Response and Infection Susceptibility Centre (iRiSC), Örebro University, Sweden.
    Ejdebäck, Mikael
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Exposing kinetic disparities between inflammasome readouts using time-resolved analysis2024Inngår i: Heliyon, E-ISSN 2405-8440, Vol. 10, nr 11, artikkel-id e32023Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The NLRP3 inflammasome is an intracellular multiprotein complex described to be involved in both an effective host response to infectious agents and various diseases. Investigation into the NLRP3 inflammasome has been extensive in the past two decades, and often revolves around the analysis of a few specific readouts, including ASC-speck formation, caspase-1 cleavage or activation, and cleavage and release of IL-1β and/or IL-18. Quantification of these readouts is commonly undertaken as an endpoint analysis, where the presence of each positive outcome is assessed independently of the others. In this study, we apply time-resolved analysis of a human macrophage model (differentiated THP-1-ASC-GFP cells) to commonly accessible methods. This approach yields the additional quantifiable metrics time-resolved absolute change and acceleration, allowing comparisons between readouts. Using this methodological approach, we reveal (potential) discrepancies between inflammasome-related readouts that otherwise might go undiscovered. The study highlights the importance of time-resolved data in general and may be further extended as well as incorporated into other areas of research. 

    Fulltekst (pdf)
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  • 21.
    Hu, Chun
    et al.
    Xiamen Univ, Coll Med, Canc Res Ctr, Xiamen 361005, Peoples R China .
    Song, Gang
    Xiamen Univ, Coll Med, Canc Res Ctr, Xiamen 361005, Peoples R China .
    Zhang, Bing
    Xiamen Univ, Coll Med, Dept Basic Med, Xiamen 361005, Peoples R China.
    Liu, Zhongchen
    Xiamen Univ, Coll Med, Zhongshan Affiliated Hosp, Xiamen 361005, Peoples R China .
    Chen, Rong
    Wuhan Inst Technol, Minist Educ, Key Lab Green Chem Proc, Wuhan, Peoples R China and Wuhan Inst Technol, Minist Educ, Sch Chem Engn & Pharm, Wuhan, Peoples R China .
    Zhang, Hong
    Högskolan i Skövde, Institutionen för vård och natur. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Hu, Tianhui
    Xiamen Univ, Coll Med, Canc Res Ctr, Xiamen 361005, Peoples R China .
    Intestinal metabolite compound K of panaxoside inhibits the growth of gastric carcinoma by augmenting apoptosis via Bid-mediated mitochondrial pathway2012Inngår i: Journal of Cellular and Molecular Medicine (Print), ISSN 1582-1838, E-ISSN 1582-4934, Vol. 16, nr 1, s. 96-106Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Compound K (20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol, CK), an intestinal bacterial metabolite of panaxoside, has been shown to inhibit tumour growth in a variety of tumours. However, the mechanisms involved are largely unknown. We use human gastric carcinoma cell lines BGC823, SGC7901 and human gastric carcinoma xenograft in nude mice as models to study the mechanisms of CK in gastric cancers. We found that CK significantly inhibits the viabilities of BGC823 and SGC7901 cells in dose- and time-dependent manners. CK-induced BGC823 and SGC7901 cells apoptosis and cell cycle arrest in G2 phase by up-regulation of p21 and down-regulation of cdc2 and cyclin B1. Further studies show that CK induces apoptosis in BGC823 and SGC7901 cells mainly through mitochondria-mediated internal pathway, and that CK induces the translocation of nuclear Bid to mitochondria. Finally, we found that CK effectively inhibited the tumour formation of SGC7901 cells in nude mice. Our studies show that CK can inhibit the viabilities and induce apoptosis of human gastric carcinoma cells via Bid-mediated mitochondrial pathway.

  • 22.
    Jansson, Andreas
    et al.
    Högskolan i Skövde, Institutionen för vård och natur. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Pernestig, Anna-Karin
    Högskolan i Skövde, Institutionen för vård och natur. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Nilsson, Patric
    Högskolan i Skövde, Institutionen för vård och natur. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Jirstrand, Mats
    Fraunhofer-Chalmers Research Centre for Industrial Mathematics, Gothenburg, Sweden.
    Hornquist, Elisabeth Hultgren
    Univ Örebro, Sch Hlth & Med Sci, Dept Biomed, Örebro, Sweden.
    Toward Quantifying the Thymic Dysfunctional State in Mouse Models of Inflammatory Bowel Disease2013Inngår i: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 19, nr 4, s. 881-888Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Inflammatory bowel disease is characterized by a number of immunological alterations, not the least in the T-cell compartment. Numerous animal models of colitis have revealed aberrant thymocyte dynamics associated with skewed thymocyte development. The recent advancements in quantitative methods have proposed critical kinetic alterations in the thymocyte development during the progression of colitis. This review focuses on the aberrant thymocyte dynamics in G alpha i2-deficient mice as this mouse model provides most quantitative data of the thymocyte development associated with colitis. Herein, we discuss several dynamic changes during the progression of colitis and propose a hypothesis for the underlying causes for the skewed proportions of the thymocyte populations seen in the G alpha i2-deficient mice and in other mouse models of colitis.

  • 23.
    Johansson, Markus
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Sweden.
    Tangruksa, Benyapa
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Heydarkhan-Hagvall, Sepideh
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Jeppsson, Anders
    Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Sweden ; Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Data Mining Identifies CCN2 and THBS1 as Biomarker Candidates for Cardiac Hypertrophy2022Inngår i: Life, E-ISSN 2075-1729, Vol. 12, nr 5, artikkel-id 726Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cardiac hypertrophy is a condition that may contribute to the development of heart failure. In this study, we compare the gene-expression patterns of our in vitro stem-cell-based cardiac hypertrophy model with the gene expression of biopsies collected from hypertrophic human hearts. Twenty-five differentially expressed genes (DEGs) from both groups were identified and the expression of selected corresponding secreted proteins were validated using ELISA and Western blot. Several biomarkers, including CCN2, THBS1, NPPA, and NPPB, were identified, which showed significant overexpressions in the hypertrophic samples in both the cardiac biopsies and in the endothelin-1-treated cells, both at gene and protein levels. The protein-interaction network analysis revealed CCN2 as a central node among the 25 overlapping DEGs, suggesting that this gene might play an important role in the development of cardiac hypertrophy. GO-enrichment analysis of the 25 DEGs revealed many biological processes associated with cardiac function and the development of cardiac hypertrophy. In conclusion, we identified important similarities between ET-1-stimulated human-stem-cell-derived cardiomyocytes and human hypertrophic cardiac tissue. Novel putative cardiac hypertrophy biomarkers were identified and validated on the protein level, lending support for further investigations to assess their potential for future clinical applications. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

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  • 24.
    Johansson, Markus
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Sweden.
    Ulfenborg, Benjamin
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Andersson, Christian X.
    Takara Bio Europe AB, Gothenburg, Sweden.
    Heydarkhan-Hagvall, Sepideh
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals, R&D AstraZeneca, Gothenburg, Sweden.
    Jeppsson, Anders
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Sweden / Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Late-stage Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Cardiac hypertrophy in a dish: a human stem cell based model2020Inngår i: Biology open, ISSN 2046-6390, Vol. 9, nr 9, artikkel-id bio052381Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cardiac hypertrophy is an important and independent risk factor for the development of heart failure. To better understand the mechanisms and regulatory pathways involved in cardiac hypertrophy, there is a need for improved in vitro models. In this study, we investigated how hypertrophic stimulation affected human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs). The cells were stimulated with endothelin-1 (ET-1) for 8, 24, 48, 72, or 96 h. Parameters including cell size, ANP-, proBNP-, and lactate concentration were analyzed. Moreover, transcriptional profiling using RNA-sequencing was performed to identify differentially expressed genes following ET-1 stimulation. The results show that the CMs increase in size by approximately 13% when exposed to ET-1 in parallel to increases in ANP and proBNP protein and mRNA levels. Furthermore, the lactate concentration in the media was increased indicating that the CMs consume more glucose, a hallmark of cardiac hypertrophy. Using RNA-seq, a hypertrophic gene expression pattern was also observed in the stimulated CMs. Taken together, these results show that hiPSC-derived CMs stimulated with ET-1 display a hypertrophic response. The results from this study also provide new molecular insights about the underlying mechanisms of cardiac hypertrophy and may help accelerate the development of new drugs against this condition.

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  • 25.
    Jurcevic, Sanja
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Keane, Simon
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Borgmästars, Emmy
    Department of Surgical and Perioperative Sciences/Surgery, Umeå University, Sweden.
    Lubovac-Pilav, Zelmina
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Ejeskär, Katarina
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering. Högskolan i Skövde, Institutionen för biovetenskap.
    Bioinformatics analysis of miRNAs in the neuroblastoma 11q-deleted region reveals a role of miR-548l in both 11q-deleted and MYCN amplified tumour cells2022Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 12, nr 1, artikkel-id 19729Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neuroblastoma is a childhood tumour that is responsible for approximately 15% of all childhood cancer deaths. Neuroblastoma tumours with amplification of the oncogene MYCN are aggressive, however, another aggressive subgroup without MYCN amplification also exists; rather, they have a deleted region at chromosome arm 11q. Twenty-six miRNAs are located within the breakpoint region of chromosome 11q and have been checked for a possible involvement in development of neuroblastoma due to the genomic alteration. Target genes of these miRNAs are involved in pathways associated with cancer, including proliferation, apoptosis and DNA repair. We could show that miR-548l found within the 11q region is downregulated in neuroblastoma cell lines with 11q deletion or MYCN amplification. In addition, we showed that the restoration of miR-548l level in a neuroblastoma cell line led to a decreased proliferation of these cells as well as a decrease in the percentage of cells in the S phase. We also found that miR-548l overexpression suppressed cell viability and promoted apoptosis, while miR-548l knockdown promoted cell viability and inhibited apoptosis in neuroblastoma cells. Our results indicate that 11q-deleted neuroblastoma and MYCN amplified neuroblastoma coalesce by downregulating miR-548l.

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  • 26.
    Karlsson, Sandra
    Högskolan i Skövde, Institutionen för vård och natur.
    Expression analysis of genes involved in the development of endometrial adenocarcinoma in a rat model of human cancer2006Licentiatavhandling, monografi (Annet vitenskapelig)
  • 27.
    Karlsson, Sandra
    Högskolan i Skövde, Forskningscentrum för Systembiologi. Högskolan i Skövde, Institutionen för vård och natur.
    Gene Expression Patterns in a Rat Model of Human Endometrial Adenocarcinoma2008Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Endometrial cancer develops from the endometrium of the uterus and is the most common pelvic malignancy diagnosed in women in the western society. Similar to all cancer diseases, endometrial cancer is a disorder that results from complex patterns of genetic and epigenetic alterations involved in the malignant transformation. The BDII/Han rat model is unique for spontaneous hormonal carcinogenesis since more than 90% of the female virgins spontaneously develop endometrial cancer. The possibility to perform global gene expression profiling of tumor cells would likely provide important information of the genes and pathways that are aberrant in endometrial adenocarcinoma (EAC). The works in the present thesis have been focused on investigating the expression patterns in endometrial tumors.  The findings in this thesis involve the identification of a novel candidate tumor suppressor region of rat chromosome 10. This genomic segment contains 18 potential tumor suppressor genes. Preliminary microarray data analysis confirmed that this region might contain relevant candidate genes as the EACs on average had 3.8 times lower expression of Crk in comparison to the normal/premalignant endometrial tissue cultures. Furthermore, an expression analysis using qPCR, revealed a significant down-regulation of Myo1c and Hic.   We were also able to identify a group of genes associated with the TGF-Beta pathway that were differentially expressed between endometrial tumors and normal/pre-malignant endometrium. These results suggest that the TGF-Beta signaling pathway is disrupted in EAC. This has previously been demonstrated in human EAC, although this is the first report on aberrant expression of TGF-Beta downstream target genes.  Evaluation of Gpx3 down-regulation in the rat EAC cell lines revealed an almost complete loss of expression in a majority of the endometrial tumors. From methylation studies, we could conclude that the loss of expression of Gpx3 is correlated with biallelic hypermethylation in the Gpx3 promoter region. This result was confirmed with a demethylation study of EAC cell lines, where the Gpx3 mRNA expression was restored after treatment with a demethylation agent and a deacetylation inhibitor. We also showed that mRNA expression of the well-known oncogene, Met, was slightly higher in endometrial tumors with loss of Gpx3 expression. A likely consequence of loss of Gpx3 function is a higher amount of reactive oxygen species (ROS) in the cancer cell environment. Since it has been proposed that overproduction of ROS is required for the hypoxic activation of HIF-1, we suggest that loss of Gpx3 expression activates transcription of Met through induction of the transcription factor HIF-1. The loss of the protective properties of GPX3 most likely makes the endometrial cells more vulnerable to ROS damage and genome instability.  We extended the results obtained from the rat endometrial tumors to human material, and conducted expression analysis of GPX3 in 30 endometrial human tumors using qPCR. The results showed a uniformly down-regulation of GPX3 in 29 of the tumors, independent of tumor grade. We thus concluded that the down-regulation of GPX3 probably occurs at an early stage of EAC and therefore contributes to the EAC carcinogenesis. These results suggest that there are important clinical implications of GPX3 expression in EAC, both as a biomarker for EAC and as a potential target for therapeutics.

     

  • 28.
    Kashash, Hadeel
    Högskolan i Skövde, Institutionen för hälsa och lärande.
    Effects of missense mutation of Unc45B on sarcomeric structure of rat cardiomyocytes2018Independent thesis Basic level (degree of Bachelor), 20 poäng / 30 hpOppgave
    Abstract [en]

    UNC-45B is a crucial chaperone protein that aids in myosin folding and assembly and is an essential component for sarcomeric organization in muscle cell development and myofibrillogenesis. UNC45B is exclusively expressed in striated muscles and comprises 3 conserved domains: the N-terminal triple tetratricopeptide repeat (TPR) domain, the central domain of armadillo repeats and the C-terminal UNC45/Cro1/She4p (UCS) domain. The C-terminal UCS domain predominantly mediates the chaperone activity of UNC45B and is crucial for myosin binding, and induces a protective response under stressful conditions, stabilizing myosin and preventing aggregation. The central domain binds the myosin motor domain independent of UCS-myosin binding and exhibits inhibitory effects on the myosin motor domain, halting the power stroke and preventing myosin-mediated actin translocations. The TPR domain interacts with another chaperone protein, the heat shock protein 90 (Hsp90), with which UNC-45B forms a stable complex, binding unfolded myosin motor domains and promoting its folding, as well as mediating a protective response to disruptions in myosin homeostasis. A novel missense mutation in an evolutionarily conserved residue of one of the domains of UNC-45B has recently been identified to be associated with hypertrophic cardiomyopathy by whole exome sequencing. To assess the structural effects of this mutation, rat cardiomyocytes were transfected with GFP-labeled wild-type and mutant UNC-45, and immunostaining was performed to produce an illustration of the morphological effects of the mutation in question. Western blot was also performed to validate the presence of UNC-45 proteins in transfected samples. The results generated in this study were deemed inconclusive and no significant conclusions can be made regarding the possible effects of this mutant variant on sarcomeric organization.

  • 29.
    Keane, Simon
    et al.
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    de Weerd, Hendrik Arnold
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Ejeskär, Katarina
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    DLG2 impairs dsDNA break repair and maintains genome integrity in neuroblastoma2022Inngår i: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 112, artikkel-id 103302Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    In primary neuroblastoma, deletions on chromosome 11q are known to result in an increase in the total number of chromosomal breaks. The DNA double-strand break repair pathways mediated by NHEJ are often upregulated in cancer. DLG2, a candidate tumor suppressor gene on chromosome 11q, has previously been implicated in DNA repair.

    Methods

    We evaluated an association between gene expression and neuroblastoma patient outcome, risk categorization, and 11q status using publicly available microarray data from independent neuroblastoma patient datasets. Functional studies were conducted using comet assay and H2AX phosphorylation in neuroblastoma cell lines and in the fruit fly with UVC-induced DNA breaks.

    Results

    We show that the NHEJ genes PARP1 and FEN1 are over expressed in neuroblastoma and restoration of DLG2 impairs their gene and protein expression. When exposed to UVC radiation, cells with DLG2 over expression show less DNA fragmentation and induce apoptosis in a p53 S46 dependent manner. We could also confirm that DLG2 over expression results in CHK1 phosphorylation consistent with previous reports of G2/M maintenance.

    Conclusions

    Taken together, we show that DLG2 over expression increases p53 mediated apoptosis in response to etoposide and UVC mediated genotoxicity and reduced DNA replication machinery.

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  • 30.
    Keane, Simon
    et al.
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Martinsson, Tommy
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Kogner, Per
    Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Ejeskär, Katarina
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    The loss of DLG2 isoform 7/8, but not isoform 2, is critical in advanced staged neuroblastoma2021Inngår i: Cancer Cell International, E-ISSN 1475-2867, Vol. 21, nr 1, artikkel-id 170Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Neuroblastoma is a childhood neural crest tumor showing large clinical and genetic heterogeneity, one form displaying 11q-deletion is very aggressive. It has been shown that 11q-deletion results in decreased expression of DLG2, a gene residing in the deleted region. DLG2 has a number of different isoforms with the main difference is the presence or absence of a L27 domain. The L27 domain containing DLG proteins can form complexes with CASK/MPP and LIN7 protein family members, which will control cell polarity and signaling. Methods: We evaluated the DLG gene family and the LIN7 gene family for their expression in differently INSS staged neuroblastoma from publically available data and primary tumors, we included two distinct DLG1 and DLG2 N-terminal transcript isoforms encoding L27 domains for their expression. Functionality of DLG2 isoforms and of LIN7A were evaluated in the 11q-deleted neuroblastoma cell line SKNAS. Results: In neuroblastoma only two DLG2 isoforms were expressed: isoform 2 and isoform 7/8. Using the array data we could determine that higher expression of DLG members that contain L27 domains correlated to better survival and prognosis. Whilst DLG1 showed a decrease in both isoforms with increased INSS stage, only the full length L27 containing DLG2 transcripts DLG2-isoform 7/8 showed a decrease in expression in high stage neuroblastoma. We could show that the protein encoded by DLG2-isoform 7 could bind to LIN7A, and increased DLG2-isoform 7 gene expression increased the expression of LIN7A, this reduced neuroblastoma cell proliferation and viability, with increased BAX/BCL2 ratio indicating increased apoptosis. Conclusion: We have provided evidence that gene expression of the L27 domain containing DLG2-isoform 7/8 but not L27 domain lacking DLG2-isoform 2 is disrupted in neuroblastoma, in particular in the aggressive subsets of tumors. The presence of the complete L27 domain allows for the binding to LIN7A, which will control cell polarity and signaling, thus affecting cancer cell viability. 

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  • 31.
    Lindholm, Heléne
    et al.
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Ejeskär, Katarina
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Szekeres, Ferenc
    Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering. Högskolan i Skövde, Institutionen för hälsovetenskaper.
    Na+/K+‑ATPase subunit α3 expression is associated with the efficacy of digitoxin treatment in pancreatic cancer cells2022Inngår i: Medicine International, ISSN 2754-3242, Vol. 2, nr 5, artikkel-id 27Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The alpha subunits (ATP1A1-3) of Na+/K+-ATPase binds digitoxin with varying affinity. The expression levels of these subunits dictate the anticancer effects of digitoxin. In the present study, three pancreatic cancer cell lines, AsPC-1, Panc-1 and CFPAC-1, were used to investigate the effects of digitoxin in relation to the expression of the subunits ATP1A1 and ATP1A3. Cell viability and intracellular calcium concentrations was measured in relation to the gene and protein expression of ATP1A1 and ATP1A3. Digitoxin was used to treat the cells at concentrations of 1-100 nM, and the intracellular calcium concentrations increased in a concentration-dependent manner in the Panc-1 and in the CFPAC-1 cells with treatment at 100 nM. In the AsPC-1 cells only the supraphysiological concentration of digitoxin (100 nM) resulted in a decrease in the number of viable cells (unviable cells increased to 22%), whereas it had no effect on intracellular calcium levels. The number of viable Panc-1 and CFPAC-1 cells decreased after digitoxin treatment at 25-100 nM (unviable Panc-1 cells increased to 33-59%; unviable CFPAC-1 cells increased to 22-56%). Digitoxin treatment also affected the transcriptional expression of the ATP1A1 and ATP1A3 subunits. In Panc-1 cells, ATP1A3 gene expression was negatively associated with the digitoxin concentration (25-100 nM). In the AsPC-1 and CFPAC-1 cells, the expression of the ATP1A1 gene increased in the cells treated with the 100 nM digitoxin concentration. The protein expression of ATP1A1 and ATP1A3 was not altered with digitoxin treatment. The basal protein expression of ATP1A1 was high in the AsPC-1 and CFPAC-1 cells, compared to the Panc-1 cells, in contrast to the basal expression of ATP1A3, which was higher in the Panc-1 cells, compared to the other pancreatic cancer cells used. On the whole, the present study demonstrates that the high expression of ATP1A3 renders pancreatic cancer cells more susceptible to digitoxin-induced cell death. The findings suggest that the expression of ATP1A3 may be used as a marker for tumor sensitivity to digitoxin treatment, where a high expression of ATP1A3 is favorable for the anticancer effects of digitoxin.

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  • 32.
    Lladós Armengol, Núria
    Högskolan i Skövde, Institutionen för biovetenskap.
    Effect of doxorubicin exposure in breast cancer on single-cell level by scRNA-seq analysis2021Independent thesis Basic level (degree of Bachelor), 20 poäng / 30 hpOppgave
    Abstract [en]

    Doxorubicin is a highly effective chemotherapeutic agent against a variety of cancers; however, the exact mechanisms responsible for the effects of doxorubicin on cancer are not widely understood and have not been studied on a single-cell level. Single-cell RNA sequencing analysis is a recent technology that enables the assessment of transcriptional similarities and differences within a population of cells. This thesis aims to study the effects of doxorubicin in breast cancer on a single-cell level and see if there are differently affected subpopulations of cells. A single-cell RNA sequencing pipeline was developed in R and used to analyse breast cancer single-cells treated with doxorubicin. Quality control, filtering, cell-clustering, differently expression gene analysis, pathways analysis and cell type identification were performed. The results identified seven different subpopulations that demonstrated a differential expression of genes and expression-level of pathways such as NEIL3-mediated resolution of induced interstrand crosslinks related with the effect of doxorubicin on cancer cells. The analysis also suggests that two subpopulations of cells could consist of specific cell types potentially treatment-resistant. These findings reinforce the relation of doxorubicin effect on cancer with some important genes and pathways, as well as reaffirming the heterogeneity of breast cancer. As a novel contribution, the results show that different subpopulations of cells could be affected differently by doxorubicin exposure, but future studies with more samples should be performed to see if the analysis leads to similar results

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  • 33.
    Lubovac-Pilav, Zelmina
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Borràs, Daniel M.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Ponce, Esmeralda
    Dominican University of California, United States of America.
    Louie, Maggie C.
    Dominican University of California, United States of America / College of Pharmacy, Touro University of California, United States of America .
    Using expression profiling to understand the effects of chronic cadmium exposure on mcf-7 breast cancer cells2013Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 8, nr 12, artikkel-id e84646Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cadmium is a metalloestrogen known to activate the estrogen receptor and promote breast cancer cell growth. Previous studies have implicated cadmium in the development of more malignant tumors; however the molecular mechanisms behind this cadmium-induced malignancy remain elusive. Using clonal cell lines derived from exposing breast cancer cells to cadmium for over 6 months (MCF-7-Cd4, -Cd6, -Cd7, -Cd8 and -Cd12), this study aims to identify gene expression signatures associated with chronic cadmium exposure. Our results demonstrate that prolonged cadmium exposure does not merely result in the deregulation of genes but actually leads to a distinctive expression profile. The genes deregulated in cadmium-exposed cells are involved in multiple biological processes (i.e. cell growth, apoptosis, etc.) and molecular functions (i.e. cadmium/metal ion binding, transcription factor activity, etc.). Hierarchical clustering demonstrates that the five clonal cadmium cell lines share a common gene expression signature of breast cancer associated genes, clearly differentiating control cells from cadmium exposed cells. The results presented in this study offer insights into the cellular and molecular impacts of cadmium on breast cancer and emphasize the importance of studying chronic cadmium exposure as one possible mechanism of promoting breast cancer progression.

  • 34.
    Lööf, Jasmine
    et al.
    Högskolan i Skövde, Institutionen för vård och natur. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Pfeifer, Daniella
    Linköping University.
    Ding, Zhenyu
    Linköping University.
    Sun, Xiao-Feng
    Linköping University.
    Zhang, Hong
    Högskolan i Skövde, Institutionen för vård och natur. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Effects of ΔNp73β on Cisplatin Treatment in Colon Cancer Cells2012Inngår i: Molecular Carcinogenesis, ISSN 0899-1987, E-ISSN 1098-2744, Vol. 51, nr 8, s. 628-635Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    p73 can activate transcription of p53-responsive genes, thereby inhibiting cell growth. An alternative promoter in the TP73 gene gives rise to an N-terminally truncated isoform of p73, DNp73, which lacks the transactivation domain of the full length TAp73 protein. TAp73 is considered pro-apoptotic, and DNp73 anti-apoptotic. In this study, we overexpressed DNp73β in p53 wild type and p53 mutant colon cancer cell lines and further exposed the cells to cancer therapeutic drug cisplatin. The results showed that cisplatin decreased the protein expression levels of DNp73β in a dose-dependent manner, and both TAp73 and p53 were upregulated after cisplatin treatment. Further, clonogenic potential and cell viability were decreased, and apoptotic cells increased, in p53 mutant and in p53 wild type cells. Cellular viability was significantly higher in DNp73β-cells than mock-transfected cells. However, DNp73β overexpression did not affect the cellular susceptibility to cisplatin. In conclusion, the overexpression of DNp73β increases viability in p53 wild type and p53 mutant colon cancer cells, and cisplatin induces the degradation of DNp73β in a dose-dependent manner.

  • 35.
    Mak, W. C.
    et al.
    Integrative Regenerative Medicine Centre, Department of Clinical and Experimental Medicine, Linköping University, Sweden ; Biosensors and Bioelectronics Centre, Department of Physics, Chemistry and Biology, Linköping University, Sweden.
    Olesen, Kim
    Integrative Regenerative Medicine Centre, Department of Clinical and Experimental Medicine, Linköping University, Sweden.
    Sivlér, P.
    Integrative Regenerative Medicine Centre, Department of Clinical and Experimental Medicine, Linköping University, Sweden.
    Lee, C. J.
    Integrative Regenerative Medicine Centre, Department of Clinical and Experimental Medicine, Linköping University, Sweden.
    Moreno-Jimenez, I.
    Integrative Regenerative Medicine Centre, Department of Clinical and Experimental Medicine, Linköping University, Sweden ; Bone & Joint Research Group, Stem Cells & Regeneration Institute of Developmental Sciences, Southampton General Hospital, Southampton, Hampshire SO16 6YD, UK.
    Edin, J.
    Integrative Regenerative Medicine Centre, Department of Clinical and Experimental Medicine, Linköping University, Sweden.
    Courtman, D.
    Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada.
    Skog, M.
    Integrative Regenerative Medicine Centre, Department of Clinical and Experimental Medicine, Linköping University, Sweden.
    Griffith, M.
    Integrative Regenerative Medicine Centre, Department of Clinical and Experimental Medicine, Linköping University, Sweden.
    Controlled Delivery of Human Cells by Temperature Responsive Microcapsules2015Inngår i: Journal of Functional Biomaterials, E-ISSN 2079-4983, Vol. 6, nr 2, s. 439-453Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cell therapy is one of the most promising areas within regenerative medicine. However, its full potential is limited by the rapid loss of introduced therapeutic cells before their full effects can be exploited, due in part to anoikis, and in part to the adverse environments often found within the pathologic tissues that the cells have been grafted into. Encapsulation of individual cells has been proposed as a means of increasing cell viability. In this study, we developed a facile, high throughput method for creating temperature responsive microcapsules comprising agarose, gelatin and fibrinogen for delivery and subsequent controlled release of cells. We verified the hypothesis that composite capsules combining agarose and gelatin, which possess different phase transition temperatures from solid to liquid, facilitated the destabilization of the capsules for cell release. Cell encapsulation and controlled release was demonstrated using human fibroblasts as model cells, as well as a therapeutically relevant cell line—human umbilical vein endothelial cells (HUVECs). While such temperature responsive cell microcapsules promise effective, controlled release of potential therapeutic cells at physiological temperatures, further work will be needed to augment the composition of the microcapsules and optimize the numbers of cells per capsule prior to clinical evaluation.

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  • 36.
    Marzec-Schmidt, Katarzyna
    et al.
    Department of Soil and Environment, Swedish University of Agricultural Sciences (SLU), Skara, Sweden.
    Ghosheh, Nidal
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Takara Bio Europe, Gothenburg, Sweden.
    Stahlschmidt, Sören Richard
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Küppers-Munther, Barbara
    Takara Bio Europe, Gothenburg, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Sweden.
    Ulfenborg, Benjamin
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Artificial intelligence supports automated characterization of differentiated human pluripotent stem cells2023Inngår i: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 41, nr 9, s. 850-861, artikkel-id sxad049Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Revolutionary advances in AI and deep learning in recent years have resulted in an upsurge of papers exploring applications within the biomedical field. Within stem cell research, promising results have been reported from analyses of microscopy images to e.g., distinguish between pluripotent stem cells and differentiated cell types derived from stem cells. In this work, we investigated the possibility of using a deep learning model to predict the differentiation stage of pluripotent stem cells undergoing differentiation towards hepatocytes, based on morphological features of cell cultures. We were able to achieve close to perfect classification of images from early and late time points during differentiation, and this aligned very well with the experimental validation of cell identity and function. Our results suggest that deep learning models can distinguish between different cell morphologies, and provide alternative means of semi-automated functional characterization of stem cell cultures.

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  • 37.
    McGrath, Sarah
    et al.
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Grimstad, Kristoffer
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Thorarinsdottir, Katrin
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Forslind, Kristina
    Lund University, Sweden ; Spenshult Research and Development Centre, Halmstad, Sweden.
    Glinatsi, Daniel
    Skaraborg Hospital, Skövde, Sweden.
    Leu Agelii, Monica
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Aranburu, Alaitz
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Sundell, Timothy
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Jonsson, Charlotte A.
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Camponeschi, Alessandro
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Hultgård Ekwall, Anna-Karin
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Sahlgrenska University Hospital, Gothenburg, Sweden.
    Tilevik, Andreas
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Gjertsson, Inger
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Sahlgrenska University Hospital, Gothenburg, Sweden.
    Mårtensson, Inga -Lill
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Correlation of Professional Antigen-Presenting Tbet+CD11c+ B Cells With Bone Destruction in Untreated Rheumatoid Arthritis2024Inngår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Subsets of CD21−/low memory B cells (MBCs), including double-negative (DN, CD27−IgD−) and Tbet+CD11c+ cells, are expanded in chronic inflammatory diseases. In rheumatoid arthritis (RA), CD21−/low MBCs correlate with joint destruction. However, whether this is due to the Tbet+CD11c+ subset, its function and pathogenic contribution to RA are unknown. This study aims to investigate the association between CD21−/lowTbet+CD11c+ MBCs and joint destruction as well as other clinical parameters and to elucidate their functional properties in patients with untreated RA (uRA). Methods: Clinical observations were combined with flow cytometry (n = 36) and single-cell RNA sequencing (scRNA-seq) and V(D)J sequencing (n = 4) of peripheral blood (PB) MBCs from patients with uRA. The transcriptome of circulating Tbet+CD11c+ MBCs was compared with scRNA-seq data of synovial B cells. In vitro coculture of Tbet+CD11c+ B cells with T cells was used to assess costimulatory capacity. Results: CD21−/lowTbet+CD11c+ MBCs in PB correlated with bone destruction but no other clinical parameters analyzed. The Tbet+CD11c+ MBCs have undergone clonal expansion and express somatically mutated V genes. Gene expression analysis of these cells identified a unique signature of more than 150 up-regulated genes associated with antigen presentation functions, including B cell receptor activation and clathrin-mediated antigen internalization; regulation of actin filaments, endosomes, and lysosomes; antigen processing, loading, presentation, and costimulation; a transcriptome mirrored in their synovial tissue counterparts. In vitro, Tbet+CD11c+ B cells induced retinoic acid receptor–related orphan nuclear receptor γT expression in CD4+ T cells, thereby polarizing to Th17 cells, a T cell subset critical for osteoclastogenesis and associated with bone destruction. Conclusion: This study suggests that Tbet+CD11c+ MBCs contribute to the pathogenesis of RA by promoting bone destruction through antigen presentation, T cell activation, and Th17 polarization. (Figure presented.). 

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  • 38.
    Monzur, Sadia
    et al.
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan.
    Hassan, Ghmkin
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan.
    Afify, Said M.
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan ; Chemistry Department, Division of Biochemistry, Faculty of Science, Menoufia University, Shebin El Kom-Menoufia, Egypt.
    Kumon, Kazuki
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan.
    Mansour, Hager
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan.
    Nawara, Hend M.
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan.
    Sheta, Mona
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan ; Department of Cancer Biology, National Cancer Institute, Cairo University, Egypt.
    Abu Quora, Hagar A.
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan ; Cytology, Histology and Histochemistry, Zoology Department, Faculty of Science, Menoufia University, Shebin El Kom-Menoufia, Egypt.
    Zahra, Maram H.
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan.
    Xu, Yanning
    Tianjin Key Laboratory of Human Development and Reproductive Regulation, Department of Pathology, Tianjin Central Hospital of Gynecology Obstetrics, Nankai University Affiliated Maternity Hospital, Tianjin, China.
    Fu, Xiaoyin
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan ; Department of Pathology, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
    Seno, Akimasa
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan ; R&D Division, The Laboratory of Natural Food & Medicine Co., Ltd, Okayama University Incubator, Japan.
    Wikström, Per
    Glucox Biotech AB, Färentuna, Sweden.
    Szekeres, Ferenc L. M.
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Seno, Masaharu
    Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Japan.
    Diphenyleneiodonium efficiently inhibits the characteristics of a cancer stem cell model derived from induced pluripotent stem cells2022Inngår i: Cell Biochemistry and Function, ISSN 0263-6484, E-ISSN 1099-0844, Vol. 40, nr 3, s. 310-320Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Diphenyleneiodonium (DPI) has long been evaluated as an anticancer drug inhibiting NADPH oxidase, the IC50 in several cancer cell lines was reported 10 µM, which is too high for efficacy. In this study, we employed miPS-Huh7cmP cells, which we previously established as a cancer stem cell (CSC) model from induced pluripotent stem cells, to reevaluate the efficacy of DPI because CSCs are currently one of the main foci of therapeutic strategy to treat cancer, but generally considered resistant to chemotherapy. As a result, the conventional assay for the cell growth inhibition by DPI accounted for an IC50 at 712 nM that was not enough to define the effectiveness as an anticancer drug. Simultaneously, the wound-healing assay revealed an IC50 of approximately 500 nM. Comparatively, the IC50 values shown on sphere formation, colony formation, and tube formation assays were 5.52, 12, and 8.7 nM, respectively. However, these inhibitory effects were not observed by VAS2780, also a reputed NADPH oxidase inhibitor. It is noteworthy that these three assays are evaluating the characteristic of CSCs and are designed in the three-dimensional (3D) culture methods. We concluded that DPI could be a suitable candidate to target mitochondrial respiration in CSCs. We propose that the 3D culture assays are more efficient to screen anti-CSC drug candidates and better mimic tumor microenvironment when compared to the adherent monolayer of 2D culture system used for a conventional assay, such as cell growth inhibition and wound-healing assays. © 2022 John Wiley & Sons Ltd.

  • 39.
    Nordén, Johan
    Högskolan i Skövde, Institutionen för biovetenskap.
    Assessment of methods for microRNA isolation, microRNA amplification, and development of a normalization strategy for sepsis biomarker research2020Independent thesis Advanced level (degree of Master (Two Years)), 20 poäng / 30 hpOppgave
    Abstract [en]

    Sepsis, defined by organ dysfunction caused by an adverse immune response of the host to an infection, comes with considerable cost in human lives and as a substantial burden financially. Significant upgrades have been made over the past two decades when diagnosing and treating sepsis but still with room for improvements. Early detection is a cornerstone in the fight against sepsis, and the focus on strengthening diagnostics is in the forefront of modern research. The implementation of biomarkers may be the path of progression in this objective. This study aimed at establishing procedural foundations when using microRNAs as potential biomarkers. The study conducted looked at: (1) Isolation procedure, of microRNA from human plasma, of three kits: Total RNA Purification Kit (Norgen Biotech), miRNAeasy Serum/Plasma Kit (Qiagen), and miRNeasy Serum/Plasma Advanced Kit (Qiagen). (2) Amplification of miRNA through two Reverse Transcription Quantitative PCR methods: Two-tailed RT-qPCR (TATAA Biocenter), and miRCURY LNA miRNA PCR (Qiagen). (3) Developing a normalization strategy by identifying miRNA reference targets in a geNorm pilot experiment. Qubit analysis revealed that the two isolation kits from Qiagen performed similar, and better that the Norgen kit. The Two-tailed RT-qPCR failed to amplify miRNA samples, whereas the miRCURY LNA miRNA PCR showed consistent amplification across samples with a high call rate. The geNorm analysis concluded that hsa-miR-425-5p and hsa-miR-93-5p was the optimal reference target set. The study demonstrated that the isolation kits from Qiagen coupled with the miRCURY LNA miRNA PCR is a viable option for future miRNA biomarker studies.

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  • 40.
    Olesen, Kim
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden ; Polymer Chemistry, Department of Chemistry – Ångström Laboratory, Uppsala University, Sweden.
    Extracellular factors for preservation and delivery of stromal cells2021Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Modulating the immune response after a myocardial infarction seems like an appropriate strategy for reducing myocardial fibrosis. Mesenchymal Stromal Cells are immunomodulatory and have thus gained interest, but have so far not achieved the desired clinical outcomes. This is believed to due to the loss of their immunomodulatory and proliferative capacity during expansion and poor cell survival and retention upon delivery to the myocardium. The use of extracellular factors such as extracellular matrices, paracrine factors, nutrients as well as manipulation gas composition during culture might be used to overcome some of these shortcomings, which is further explored in this thesis.

    We demonstrated in Study I, that encapsulation of human cells by thermos-responsive microcapsules, which upon exposure to physiological temperature partially decompose and enable release of the cells. The hydrogel combination of agarose, gelatin and fibrinogen provided both thermos-responsive features and attachment points for the cells, preventing cell death. However, additional components can be used to support the encapsulated cells while retaining the thermo-responsiveness. In order to discover such components, we developed an in vitro model to study the cell- and extracellular matrix dynamics making use of the organ’s extracellular matrix and define anatomical regions that are capable of retaining the desired phenotype of the cell. To generate such a syngeneic model, naïve stromal cells were isolated from fetal rat hearts, and cultured on decellularized extracellular matrix sections of adult rat hearts. We found that when culturing cells with pericyte-like characteristics on the matrices, the surface marker expressions of CD146 and PDGFR-β were depending on the matrix composition, and especially of laminin alpha 4. Cells expressing CD146 were mainly located to the atrioventricular junction and to the perivascular niche, while PDGFR-β expression was more widespread. Since CD146 is also a potency marker for Mesenchymal Stromal Cells, these results indicate a matrix dependent niche for naïve stromal cells. These findings were next verified by immunohistochemistry of the native rat heart, where CD146 populations were mainly found in the atrioventricular and perivascular niche.

    In Study III, we explored the preferred metabolism of adult and fetal MSCs. It is known that proliferating stem-, progenitor cells utilize glycolysis, even in presence of oxygen. Therefore, we wanted to explore the metabolic profiles of human fetal (naïve) and MSCs during culture in either hypoxia 3% (close to physiological oxygen tension) or normoxia 20%. Adult MSCs grown in hypoxia retained oxidative phosphorylation and increased glycolytic activity, adapting a progenitor metabolic profile while in normoxia the adult MSCs down-regulated glycolysis and adapted an adult, or differentiated cell metabolic profile. Fetal MSCs demonstrated preserved oxidative phosphorylation and glycolytic activity regardless of oxygen tension, thus exhibiting a stem-, progenitor metabolic profile.

    The findings from these studies might help in designing future culture protocols and delivery systems for cell therapies.

  • 41.
    Olesen, Kim
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Moruzzi, Noah
    The Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Bulatovic, Ivana
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Folmes, Clifford
    Departments of Cardiovascular Medicine, And Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, AZ, USA.
    Jeon, Ryounghoon
    Departments of Cardiovascular Medicine, And Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, AZ, USA.
    Felldin, Ulrika
    Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Terzic, Andre
    Departments of Cardiovascular Medicine, And Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, AZ, USA.
    Simonson, Oscar E.
    Department of Surgical Sciences, Uppsala University, Sweden ; Department of Cardiothoracic Surgery and Anesthesiology, Uppsala University Hospital, Sweden.
    Le Blanc, Katarina
    Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Österholm, Cecilia
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Berggren, Per-Olof
    The Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Schiffer, Thomas
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Rodin, Sergey
    Department of Surgical Sciences, Uppsala University, Sweden ; Department of Cardiothoracic Surgery and Anesthesiology, Uppsala University Hospital, Sweden ; Endocrinology Research Centre, Moscow, Russia.
    Tilevik, Andreas
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Grinnemo, Karl-Henrik
    Department of Surgical Sciences, Uppsala University, Sweden ; Department of Cardiothoracic Surgery and Anesthesiology, Uppsala University Hospital, Sweden.
    Diversity of respiratory parameters and metabolic adaptation to low oxygen tension in mesenchymal stromal cells2022Inngår i: Metabolism Open, E-ISSN 2589-9368, Vol. 13, nr March, artikkel-id 100167Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective

    Cell metabolism has been shown to play an active role in regulation of stemness and fate decision. In order to identify favorable culture conditions for mesenchymal stromal cells (MSCs) prior to transplantation, this study aimed to characterize the metabolic function of MSCs from different developmental stages in response to different oxygen tension during expansion.

    Materials and methods

    We cultured human fetal cardiac MSCs and human adult bone-marrow MSCs for a week under hypoxia (3% O2) and normoxia (20% O2). We performed mitochondrial characterization and assessed oxygen consumption- and extracellular acidification-rates (OCR and ECAR) in addition to oxygen-sensitive respiration and mitochondrial complex activities, using both the Seahorse and Oroboros systems.

    Results

    Adult and fetal MSCs displayed similar basal respiration and mitochondrial amount, however fetal MSCs had lower spare respiratory capacity and apparent coupling efficiency. Fetal MSCs expanded in either hypoxia or normoxia demonstrated similar acidification rates, while adult MSCs downregulated their aerobic glycolysis in normoxia. Acute decrease in oxygen tension caused a higher respiratory inhibition in adult compared to fetal MSCs. In both sources of MSCs, minor changes in complex activities in normoxic and hypoxic cultures were found.

    Conclusions

    In contrast to adult MSCs, fetal MSCs displayed similar respiration and aerobic glycolysis at different O2 culture concentrations during expansion. Adult MSCs adjusted their respiration to glycolytic activities, depending on the culture conditions thus displaying a more mature metabolic function. These findings are relevant for establishing optimal in vitro culturing conditions, with the aim to maximize engraftment and therapeutic outcome.

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  • 42.
    Olesen, Kim
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden ; Polymer Chemistry, Department of Chemistry – Ångström Laboratory, Uppsala University, Sweden.
    Rodin, Sergey
    Department of Surgical Sciences, Division of Cardiothoracic Surgery and Anaesthesiology, Uppsala University, Akademiska University Hospital, Uppsala, Sweden.
    Mak, Wing Cheung
    Biosensors and Bioelectronics Centre, Department of Physics, Chemistry and Biology (IFM), Linköping University, Sweden.
    Felldin, Ulrika
    Department of Surgical Sciences, Division of Cardiothoracic Surgery and Anaesthesiology, Uppsala University, Akademiska University Hospital, Uppsala, Sweden.
    Österholm, Cecilia
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Tilevik, Andreas
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Grinnemo, Karl-Henrik
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden ; Department of Surgical Sciences, Division of Cardiothoracic Surgery and Anaesthesiology, Uppsala University, Akademiska University Hospital, Uppsala, Sweden.
    Spatiotemporal extracellular matrix modeling for in situ cell niche studies2021Inngår i: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 39, nr 12, s. 1751-1765Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Extracellular matrix (ECM) components govern a range of cell functions such as migration, proliferation, maintenance of stemness and differentiation. Cell niches that harbor stem-/progenitor cells, with matching ECM, have been shown in a range of organs, although their presence in the heart is still under debate. Determining niches depends on a range of in vitro and in vivo models and techniques, where animal models are powerful tools for studying cell-ECM dynamics, however, they are costly and time-consuming to use. In vitro models based on recombinant ECM proteins lack the complexity of the in vivo ECM. To address these issues, we present the Spatiotemporal Extracellular Matrix Model (StEMM) for studies of cell-ECM dynamics, such as cell niches. This model combines gentle decellularization and sectioning of cardiac tissue, allowing retention of a complex ECM, with recellularization and subsequent image processing using image stitching, segmentation, automatic binning and generation of cluster maps. We have thereby developed an in situ representation of the cardiac ECM that is useful for assessment of repopulation dynamics and to study the effect of local ECM composition on phenotype preservation of reseeded mesenchymal progenitor cells. This model provides a platform for studies of organ-specific cell-ECM dynamics and identification of potential cell niches. © AlphaMed Press 2021 SIGNIFICANCE STATEMENT: Stem cells reside in adult organs within specific microenvironments called cell niches. The heart is a complex organ and so far, the presence and localization of stem-/progenitor cell niches are subject to constant debate. To address these issues, the authors have developed the Spatiotemporal Extracellular Matrix Model (StEMM), which combines a modified protocol for decellularization, with cryo-sectioning, recellularization, and subsequent image processing including automatic binning and generation of cluster maps. StEMM was developed within a cardiac context and validated using syngeneic mesenchymal progenitor cells. However, this model is not restricted with regard to species or organs.

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  • 43.
    Roje, Blanka
    et al.
    Laboratory for Cancer Research, University of Split School of Medicine, Croatia.
    Elek, Anamaria
    Bioinformatics Group, Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, Croatia.
    Palada, Vinko
    Department of Physiology and Pharmacology, Karolinska Institute, Solna, Sweden.
    Bom, Joana
    Instituto Gulbenkian de Ciência, Oeiras, Portugal.
    Iljazović, Aida
    Helmholtz Institute for Infection Research, Braunschweig, Germany.
    Šimić, Ana
    Laboratory for Cancer Research, University of Split School of Medicine, Croatia.
    Sušak, Lana
    Laboratory for Cancer Research, University of Split School of Medicine, Croatia.
    Vilović, Katarina
    Department of Pathology, University Hospital Split, Croatia.
    Strowig, Till
    Helmholtz Institute for Infection Research, Braunschweig, Germany.
    Vlahoviček, Kristian
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Bioinformatics Group, Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, Croatia.
    Terzić, Janos
    Laboratory for Cancer Research, University of Split School of Medicine, Croatia.
    Microbiota alters urinary bladder weight and gene expression2020Inngår i: Microorganisms, E-ISSN 2076-2607, Vol. 8, nr 3, artikkel-id 421Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We studied the effect of microbiota on the transcriptome and weight of the urinary bladder by comparing germ-free (GF) and specific pathogen-free (SPF) housed mice. In total, 97 genes were differently expressed (fold change > ±2; false discovery rate (FDR) p-value < 0.01) between the groups, including genes regulating circadian rhythm (Per1, Per2 and Per3), extracellular matrix (Spo1, Spon2), and neuromuscular synaptic transmission (Slc18a3, Slc5a7, Chrnb4, Chrna3, Snap25). The highest increase in expression was observed for immunoglobulin genes (Igkv1-122, Igkv4-68) of unknown function, but surprisingly the absence of microbiota did not change the expression of the genes responsible for recognizing microbes and their products. We found that urinary bladder weight was approximately 25% lighter in GF mice (p = 0.09 for males, p = 0.005 for females) and in mice treated with broad spectrum of antibiotics (p = 0.0002). In conclusion, our data indicate that microbiota is an important determinant of urinary bladder physiology controlling its gene expression and size.

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  • 44.
    Rosenhahn, Erik
    et al.
    Institute of Human Genetics, University of Leipzig Medical Center, Germany.
    O'Brien, Thomas J.
    MRC London Institute of Medical Sciences, United Kingdom.
    Zaki, Maha S.
    Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
    Sorge, Ina
    Department of Pediatric Radiology, University Hospital Leipzig, Germany.
    Wieczorek, Dagmar
    Institute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Germany.
    Rostasy, Kevin
    Department of Pediatric Neurology, Children's and Adolescents’ Hospital Datteln, Witten/Herdecke University, Germany.
    Vitobello, Antonio
    UF6254 Innovation en Diagnostic Genomique des Maladies Rares, CHU Dijon Bourgogne, FHU translad, Génétique des Anomalies du Développement, INSERM UMR 1231, Université de Bourgogne-Franche Comté, Dijon, France.
    Nambot, Sophie
    Centre de Génétique et Centre de référence des Maladies rare, Anomalies du Développement et Syndromes Malformatifs, Hôpital d'Enfants, Centre Hospitalier Universitaire de Dijon, France.
    Alkuraya, Fowsan S.
    Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia ; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
    Hashem, Mais O.
    Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
    Alhashem, Amal
    Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia ; Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
    Tabarki, Brahim
    Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
    Alamri, Abdullah S.
    Department of Pediatrics, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia.
    Al Safar, Ayat H.
    Department of Pediatrics, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia.
    Bubshait, Dalal K.
    Department of Pediatrics, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia.
    Alahmady, Nada F.
    Biology Department, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia.
    Gleeson, Joseph G.
    Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA ; Rady Children’s Institute for Genomic Medicine, San Diego, La Jolla, CA, USA.
    Abdel-Hamid, Mohamed S.
    Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
    Lesko, Nicole
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden ; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
    Ygberg, Sofia
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden ; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden ; Neuropediatric Unit, Department of Women’s and Children’s Health, Karolinska University Hospital, Stockholm, Sweden.
    Correia, Sandrina P.
    Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden ; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Wredenberg, Anna
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden ; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
    Alavi, Shahryar
    Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Iran ; Palindrome, Isfahan, Iran.
    Seyedhassani, Seyed M.
    Dr. Seyedhassani Medical Genetic Center, Yazd, Iran.
    Ebrahimi Nasab, Mahya
    Dr. Seyedhassani Medical Genetic Center, Yazd, Iran.
    Hussien, Haytham
    Alexandria University Children’s Hospital, Faculty of Medicine, Alexandria University, Egypt.
    Omar, Tarek E. I.
    Alexandria University Children’s Hospital, Faculty of Medicine, Alexandria University, Egypt.
    Harzallah, Ines
    Clinical, Chromosomal and Molecular Genetics Department, University Hospital Center, Saint-Étienne, France.
    Touraine, Renaud
    Clinical, Chromosomal and Molecular Genetics Department, University Hospital Center, Saint-Étienne, France.
    Tajsharghi, Homa
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Morsy, Heba
    UCL Queen Square Institute of Neurology, University College London, UK.
    Houlden, Henry
    UCL Queen Square Institute of Neurology, University College London, UK.
    Shahrooei, Mohammad
    Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran ; Department of Microbiology and Immunology, Clinical and Diagnostic Immunology, KU Leuven, Belgium.
    Ghavideldarestani, Maryam
    Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran.
    Abdel-Salam, Ghada M. H.
    Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
    Torella, Annalaura
    Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy ; Telethon Institute of Genetics and Medicine, Naples, Italy.
    Zanobio, Mariateresa
    Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy.
    Terrone, Gaetano
    Child Neurology Unit, Department of Translational Medical Science, University of Naples Federico II, Naples, Italy.
    Brunetti-Pierri, Nicola
    Telethon Institute of Genetics and Medicine, Naples, Italy ; Department of Translational Medicine, Section of Pediatrics, University of Naples Federico II, Italy.
    Omrani, Abdolmajid
    Division of Clinical Studies, The Persian Gulf Nuclear Medicine Research Center, Bushehr University of Medical Sciences, Iran.
    Hentschel, Julia
    Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
    Lemke, Johannes R.
    Institute of Human Genetics, University of Leipzig Medical Center, Germany ; Center for Rare Diseases, University of Leipzig Medical Center, Germany.
    Sticht, Heinrich
    Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
    Abou Jamra, Rami
    Institute of Human Genetics, University of Leipzig Medical Center, Germany.
    Brown, Andre E. X.
    MRC London Institute of Medical Sciences, UK ; Faculty of Medicine, Institute of Clinical Sciences, Imperial College London, UK ; .
    Maroofian, Reza
    UCL Queen Square Institute of Neurology, University College London, UK.
    Platzer, Konrad
    Institute of Human Genetics, University of Leipzig Medical Center, Germany.
    Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications2022Inngår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 109, nr 8, s. 1421-1435Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PPFIBP1 encodes for the liprin-β1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications. 

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  • 45.
    Samuelson, Emma
    et al.
    Department of Medical and Clinical Genetics, Institute of Biomedicine, University of Gothenburg, Sahlgrenska Academy, Sweden ; Department of Cell and Molecular Biology, Genetics, Lundberg Laboratory, University of Gothenburg, Sweden.
    Hedberg, Carola
    Department of Medical and Clinical Genetics, Institute of Biomedicine, University of Gothenburg, Sahlgrenska Academy, Sweden ; Department of Cell and Molecular Biology, Genetics, Lundberg Laboratory, University of Gothenburg, Sweden.
    Nilsson, Staffan
    Department of Mathematical Statistics, Chalmers University of Technology, Gothenburg, Sweden.
    Behboudi, Afrouz
    Department of Medical and Clinical Genetics, Institute of Biomedicine, University of Gothenburg, Sahlgrenska Academy, Sweden.
    Molecular classification of spontaneous endometrial adenocarcinomas in BDII rats2009Inngår i: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 16, nr 1, s. 99-111Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Female rats of the BDII/Han inbred strain are prone to spontaneously develop endometrial carcinomas (EC) that in cell biology and pathogenesis are very similar to those of human. Human EC are classified into two major groups: Type I displays endometroid histology, is hormone-dependent, and characterized by frequent microsatellite instability and PTEN, K-RAS, and CTNNB1 (β-Catenin) mutations; Type II shows non-endometrioid histology, is hormone-unrelated, displays recurrent TP53 mutation, CDKN2A (P16) inactivation, over-expression of ERBB2 (Her2/neu), and reduced CDH1 (Cadherin 1 or E-Cadherin) expression. However, many human EC have overlapping clinical, morphologic, immunohistochemical, and molecular features of types I and II. The EC developed in BDII rats can be related to type I tumors, since they are hormone-related and histologically from endometrioid type. Here, we combined gene sequencing (Pten, Ifr1, and Ctnnb1) and real-time gene expression analysis (Pten, Cdh1, P16, Erbb2, Ctnnb1, Tp53, and Irf1) to further characterize molecular alterations in this tumor model with respect to different subtypes of EC in humans. No mutation in Pten and Ctnnb1 was detected, whereas three tumors displayed sequence aberrations of the Irf1 gene. Significant down regulation of Pten, Cdh1, p16, Erbb2, and Ctnnb1 gene products was found in the tumors. In conclusion, our data suggest that molecular features of spontaneous EC in BDII rats can be related to higher-grade human type I tumors and thus, this model represents an excellent experimental tool for research on this malignancy in human.

  • 46.
    Samuelson, Emma
    et al.
    Genetics, Cell and Molecular Biology, University of Gothenburg, Sweden ; Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Nilsson, Johanna
    Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Walentinsson, Anna
    Genetics, Cell and Molecular Biology, University of Gothenburg, Sweden.
    Szpirer, Claude
    IBMM, Université Libre de Bruxelles, Gosselies, Belgium.
    Behboudi, Afrouz
    Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Absence of Ras mutations in rat DMBA-induced mammary tumors2009Inngår i: Molecular Carcinogenesis, ISSN 0899-1987, E-ISSN 1098-2744, Vol. 48, nr 2, s. 150-155Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Animal cancer models reduce genetic background heterogeneity and thus, may facilitate identification and analysis of specific genetic aberrations in tumor cells. Rat and human mammary glands have high similarity in physiology and show comparable hormone responsiveness. Thus, spontaneous and carcinogen (e.g., NMU and DMBA)-induced rat mammary models are valuable tools for genetic studies of breast cancer. In NMU-induced rat mammary tumors, activating mutations in Hras codon 12 have frequently been reported and are supposed to contribute to the mammary carcinogenic process. Involvement of Ras mutations in DMBA-induced tumors is less clear. In the present study we investigated the mutation status of the three Ras genes, Hras, Kras, and Nras, in DMBA-induced rat mammary tumors. We examined codons 12, 13, and 61 of all three genes for mutations in 71 tumors using direct sequencing method that in experimental conditions is sensitive enough to detect single nucleotide mutations even when present in only 25% of the test sample. No activating Ras gene mutation was found. Thus, in contrast to NMU-induced rat mammary tumor, tumorigenesis in DMBA-induced rat mammary tumors seems to be independent on activating mutations in the Ras genes. Our finding suggests that the genetic pathways selected in mammary tumor development are influenced by and perhaps dependent on the identity of the inducing agent, again emphasizing the importance of tumor etiology on the genetic changes in the tumor cells. © 2008 Wiley-Liss, Inc.

  • 47.
    Sandstedt, Mikael
    et al.
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Vukusic, Kristina
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Johansson, Markus
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Jonsson, Marianne
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Magnusson, Rasmus
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Hultén, Lillemor Mattsson
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Dellgren, Göran
    Molecular and Clinical Medicine, Cardiothoracic Surgery, University of Gothenburg, Sweden.
    Jeppsson, Anders
    Molecular and Clinical Medicine, Cardiothoracic Surgery, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Lindahl, Anders
    Sahlgrenska University Hospital, Göteborg, University of Gothenburg, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Sandstedt, Joakim
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Regional transcriptomic profiling reveals immune system enrichment in nonfailing atria as well as all chambers of the failing human heart2023Inngår i: American Journal of Physiology. Heart and Circulatory Physiology, ISSN 0363-6135, E-ISSN 1522-1539, Vol. 325, nr 6, s. H1430-H1445Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The different chambers of the human heart demonstrate regional physiological traits and may be differentially affected during pathologic remodeling, resulting in heart failure. Few previous studies have, however, characterized the different chambers at a transcriptomic level. We therefore conducted whole-tissue RNA sequencing and gene set enrichment analysis of biopsies collected from the four chambers of adult failing (n = 8) and nonfailing (n = 11) human hearts. Atria and ventricles demonstrated distinct transcriptional patterns. Compared to nonfailing ventricles, the transcriptional pattern of nonfailing atria was enriched for a large number of gene sets associated with cardiogenesis, the immune system and bone morphogenetic protein (BMP), transforming growth factor beta (TGF beta), MAPK/JNK and Wnt signaling. Differences between failing and nonfailing hearts were also determined. The transcriptional pattern of failing atria was distinct compared to that of nonfailing atria and enriched for gene sets associated with the innate and adaptive immune system, TGF beta/SMAD signaling, and changes in endothelial, smooth muscle cell and cardiomyocyte physiology. Failing ventricles were also enriched for gene sets associated with the immune system. Based on the transcriptomic patterns, upstream regulators associated with heart failure were identified. These included many immune response factors predicted to be similarly activated for all chambers of failing hearts. In summary, the heart chambers demonstrate distinct transcriptional patterns that differ between failing and nonfailing hearts. Immune system signaling may be a hallmark of all four heart chambers in failing hearts, and could constitute a novel therapeutic target.

  • 48.
    Sandstedt, Mikael
    et al.
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Clinical Chemistry, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Vukusic, Kristina
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Clinical Chemistry, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Ulfenborg, Benjamin
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Jonsson, Marianne
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Clinical Chemistry, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Mattsson Hultén, Lillemor
    Department of Clinical Chemistry, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden ; Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Universityof Gothenburg, Sweden.
    Dellgren, Göran
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Universityof Gothenburg, Sweden ; Department of Cardiothoracic Surgery, Region Västra Götaland, Sahlgrenska University Hospital, University of Gothenburg, Sweden.
    Jeppsson, Anders
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Universityof Gothenburg, Sweden ; Department of Cardiothoracic Surgery, Region Västra Götaland, Sahlgrenska University Hospital, University of Gothenburg, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Sandstedt, Joakim
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Clinical Chemistry, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Human intracardiac SSEA4+CD34 cells show features of cycling, immature cardiomyocytes and are distinct from Side Population and C-kit+CD45- cells2022Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 17, nr 6, artikkel-id e0269985Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cardiomyocyte proliferation has emerged as the main source of new cardiomyocytes in the adult. Progenitor cell populations may on the other hand contribute to the renewal of other cell types, including endothelial and smooth muscle cells. The phenotypes of immature cell populations in the adult human heart have not been extensively explored. We therefore investigated whether SSEA4+CD34- cells might constitute immature cycling cardiomyocytes in the adult failing and non-failing human heart. The phenotypes of Side Population (SP) and C-kit+CD45- progenitor cells were also analyzed. Biopsies from the four heart chambers were obtained from patients with end-stage heart failure as well as organ donors without chronic heart failure. Freshly dissociated cells underwent flow cytometric analysis and sorting. SSEA4+CD34- cells expressed high levels of cardiomyocyte, stem cell and proliferation markers. This pattern resembles that of cycling, immature, cardiomyocytes, which may be important in endogenous cardiac regeneration. SSEA4+CD34- cells isolated from failing hearts tended to express lower levels of cardiomyocyte markers as well as higher levels of stem cell markers. C-kit+CD45- and SP CD45- cells expressed high levels of endothelial and stem cell markers-corresponding to endothelial progenitor cells involved in endothelial renewal.

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  • 49.
    Shunnar, Batoul
    Högskolan i Skövde, Institutionen för biovetenskap.
    Different concentrations of GSK3 inhibitor fail to suppress interleukin-6 in stimulated THP-1 macrophage2022Independent thesis Basic level (degree of Bachelor), 20 poäng / 30 hpOppgave
    Abstract [en]

    Inflammation is a defensive process that allows immune cells to be mobilized to help with infection removal and tissue regeneration. Inflammasomes are multiprotein oligomers in the cytoplasm and components of the innate immune system that have a role in inflammation. Glycogen synthase kinase 3 (GSK3) is a critical molecule involved in a wide range of inflammatory reactions. It has been reported to suppress the production of pro-inflammatory mediators in response to LPS when it is inhibited. The aim of this project was to study the effect of GSK3 inhibition in a concentration-dependent manner on the production of IL-6 as well as ASC-speck formation in THP1 ASC GFP cells stimulated with LPS and activated using nigericin. Using the cell culture supernatant ELISA was performed to quantify the IL-6 protein secreted by THP-1 macrophages. Using reverse-transcribed cDNA, qPCR was performed to measure the IL-6 gene expression. Finally, live-cell imaging was done to visualize the ASC-speck formation. It was found that upon stimulation of THP-1 cells a remarkable increase in the production of IL-6 was observed, however, the inhibitor did not suppress the production of IL-6 as hypothesized. This could be primarily due to the presence of another NF-κB pathway which is not mediated by GSK3 and therefore could not be inhibited using the GKS3 inhibitor. Future studies could decrease the LPS concentration to see if the uninhibited pathway can be observed at lower stimulation. Another probable solution could be lowering the FBS percentage to avoid potential inhibition.

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  • 50.
    Simsa, Robin
    et al.
    VERIGRAFT AB, Gothenburg, Sweden / Department of Molecular and Clinical Medicine, Wallenberg Laboratory, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden / Department of Biomedical Engineering, Tufts University, Medford, MA, United States of America.
    Rothenbücher, Theresa
    Department of Molecular Biology, Center of Molecular Biology “Severo Ochoa” (UAM-CSIC), Universidad Autonoma de Madrid, Spain.
    Gürbüz, Hakan
    Department of Biotechnology and Biomedicine, Technical University of Denmark, Kgs. Lyngby, Denmark / FELIXROBOTICS BV, Utrecht, Netherlands.
    Ghosheh, Nidal
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Emneus, Jenny
    Department of Biotechnology and Biomedicine, Technical University of Denmark, Kgs. Lyngby, Denmark.
    Jenndahl, Lachmi
    VERIGRAFT AB, Gothenburg, Sweden.
    Kaplan, David L.
    Department of Biomedical Engineering, Tufts University, Medford, MA, United States.
    Bergh, Niklas
    Department of Molecular and Clinical Medicine, Wallenberg Laboratory, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Serrano, Alberto Martinez
    Department of Molecular Biology, Center of Molecular Biology “Severo Ochoa” (UAM-CSIC), Universidad Autonoma de Madrid, Spain.
    Fogelstrand, Per
    Department of Molecular and Clinical Medicine, Wallenberg Laboratory, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Brain organoid formation on decellularized porcine brain ECM hydrogels2021Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 16, nr 1, artikkel-id e0245685Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human brain tissue models such as cerebral organoids are essential tools for developmental and biomedical research. Current methods to generate cerebral organoids often utilize Matrigel as an external scaffold to provide structure and biologically relevant signals. Matrigel however is a nonspecific hydrogel of mouse tumor origin and does not represent the complexity of the brain protein environment. In this study, we investigated the application of a decellularized adult porcine brain extracellular matrix (B-ECM) which could be processed into a hydrogel (B-ECM hydrogel) to be used as a scaffold for human embryonic stem cell (hESC)-derived brain organoids. We decellularized pig brains with a novel detergent- and enzyme-based method and analyzed the biomaterial properties, including protein composition and content, DNA content, mechanical characteristics, surface structure, and antigen presence. Then, we compared the growth of human brain organoid models with the B-ECM hydrogel or Matrigel controls in vitro. We found that the native brain source material was successfully decellularized with little remaining DNA content, while Mass Spectrometry (MS) showed the loss of several brain-specific proteins, while mainly different collagen types remained in the B-ECM. Rheological results revealed stable hydrogel formation, starting from B-ECM hydrogel concentrations of 5 mg/mL. hESCs cultured in B-ECM hydrogels showed gene expression and differentiation outcomes similar to those grown in Matrigel. These results indicate that B-ECM hydrogels can be used as an alternative scaffold for human cerebral organoid formation, and may be further optimized for improved organoid growth by further improving protein retention other than collagen after decellularization.

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