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  • 1.
    Budnjo, Almir
    Högskolan i Skövde, Institutionen för biovetenskap.
    Gene expression of MAP2K1 and Cyclin D1 in BDII rat model of Endometrial cancer2016Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
    Abstract [en]

    Endometrial adenocarcinoma (EAC) is the most frequently diagnosed gynecological cancer of the female genital tract in the Western world. Research studies in EC is difficult to conduct on human tumor samples due to the complex nature of tumor arousal and genetic heterogeneousness in the human population. Therefore, inbred animal models can be promising tools to use in EC research due to similar histopathology and pathogenesis as humans. Studies performed on MAP2K1 and CCND1 has shown that their altered expression play a crucial role in carcinogenesis. CCND1 has been demonstrated to have oncogenic properties when overexpressed in human neoplasias.

    The aim of this study is to investigate gene expression levels of MAP2K1 and CCND1 in BDII rat model of endometrial adenocarcinoma cells. Quantitative real-time PCR was used to analyze expression levels of MAP2K1 and CCND1 genes in BDII/Han rat model of endometrial cancer cells using TaqMan approach. The differences in gene expression levels of MAP2K1 and CCND1 between pathologically EAC malignant and nonmalignant cells showed an upregulation of MAP2K1 and CCND1 in EAC malignant cells. The analyzed data presented observable mean differences between MAP2K1 and CCND1 in several endometrial cell lines that were examined.

    Although no statistical significance was reached, an alteration in gene expression levels in malignant and nonmalignant endometrial cells could be observed. Furthermore, this present study shows observable upregulation of MAP2K1 and CCND1 in endometrial carcinoma cells vs. nonmalignant endometrium cells and encourages further investigation of the role of CCND1 and MAP2K genes in endometrial carcinogenesis.

  • 2.
    Ghosheh, Nidal
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Olsson, Björn
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Edsbagge, Josefina
    Takara Bio Europe AB, Gothenburg, Sweden.
    Küppers-Munther, Barbara
    Takara Bio Europe AB, Gothenburg, Sweden.
    Van Giezen, Mariska
    Takara Bio Europe AB, Gothenburg, Sweden.
    Asplund, Annika
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Andersson, Tommy B.
    AstraZeneca R&D, CVMD DMPK, Mölndal, Sweden / Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden.
    Björquist, Petter
    NovaHep AB, Gothenburg, Sweden.
    Carén, Helena
    Sahlgrenska Cancer Center, Department of Pathology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Simonsson, Stina
    Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. AstraZeneca R&D, GMD CVMD GMed, Mölndal, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Highly Synchronized Expression of Lineage-Specific Genes during In Vitro Hepatic Differentiation of Human Pluripotent Stem Cell Lines2016Inngår i: Stem Cells International, ISSN 1687-9678, Vol. 2016, artikkel-id 8648356Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human pluripotent stem cells- (hPSCs-) derived hepatocytes have the potential to replace many hepatic models in drug discovery and provide a cell source for regenerative medicine applications. However, the generation of fully functional hPSC-derived hepatocytes is still a challenge. Towards gaining better understanding of the differentiation and maturation process, we employed a standardized protocol to differentiate six hPSC lines into hepatocytes and investigated the synchronicity of the hPSC lines by applying RT-qPCR to assess the expression of lineage-specific genes (OCT4, NANOG, T, SOX17, CXCR4, CER1, HHEX, TBX3, PROX1, HNF6, AFP, HNF4a, KRT18, ALB, AAT, and CYP3A4) which serve as markers for different stages during liver development. The data was evaluated using correlation and clustering analysis, demonstrating that the expression of these markers is highly synchronized and correlated well across all cell lines. The analysis also revealed a distribution of the markers in groups reflecting the developmental stages of hepatocytes. Functional analysis of the differentiated cells further confirmed their hepatic phenotype. Taken together, these results demonstrate, on the molecular level, the highly synchronized differentiation pattern across multiple hPSC lines. Moreover, this study provides additional understanding for future efforts to improve the functionality of hPSC-derived hepatocytes and thereby increase the value of related models.

  • 3.
    Godoy, Patricio
    et al.
    IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany / Department of Physiology, Faculty of Biological Sciences, University of Concepción, Chile.
    Schmidt-Heck, Wolfgang
    Leibniz Institute for Natural Product Research and Infection Biology eV-Hans-Knöll Institute, Jena, Germany.
    Natarajan, Karthick
    University of Cologne, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), Cologne, Germany.
    Lucendo-Villarin, Baltasar
    MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
    Szkolnicka, Dagmara
    MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
    Asplund, Annika
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Björquist, Petter
    NovaHep AB, Gothenburg, Sweden.
    Widera, Agata
    IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.
    Stöber, Regina
    IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.
    Campos, Gisela
    IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.
    Hammad, Seddik
    IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.
    Sachinidis, Agapios
    University of Cologne, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), Cologne, Germany.
    Chaudhari, Umesh
    University of Cologne, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), Cologne, Germany.
    Damm, Georg
    Charité University Medicine Berlin, Department of General-, Visceral- and Transplantation Surgery, Berlin, Germany.
    Weiss, Thomas S.
    Center for Liver Cell Research, Department of Pediatrics and Juvenile Medicine, University of Regensburg Hospital, Regensburg, Germany.
    Nüssler, Andreas
    Eberhard Karls University Tübingen, BG Trauma Center, Siegfried Weller Institut, Tübingen, Germany.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Edlund, Karolina
    IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.
    Küppers-Munther, Barbara
    Takara Bio Europe AB (former Cellartis AB), Gothenburg, Sweden.
    Hay, David C.
    MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
    Hengstler, Jan G.
    IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.
    Gene networks and transcription factor motifs defining the differentiation of stem cells into hepatocyte-like cells2015Inngår i: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 63, nr 4, s. 934-942Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND & AIMS: The differentiation of stem cells to hepatocyte-like cells (HLC) offers the perspective of unlimited supply of human hepatocytes. However, the degree of differentiation of HLC remains controversial. To obtain an unbiased characterization, we performed a transcriptomic study with HLC derived from human embryonic and induced stem cells (ESC, hiPSC) from three different laboratories.

    METHODS: Genome-wide gene expression profiles of ESC and HLC were compared to freshly isolated and up to 14days cultivated primary human hepatocytes. Gene networks representing successful and failed hepatocyte differentiation, and the transcription factors involved in their regulation were identified.

    RESULTS: Gene regulatory network analysis demonstrated that HLC represent a mixed cell type with features of liver, intestine, fibroblast and stem cells. The "unwanted" intestinal features were associated with KLF5 and CDX2 transcriptional networks. Cluster analysis identified highly correlated groups of genes associated with mature liver functions (n=1057) and downregulated proliferation associated genes (n=1562) that approach levels of primary hepatocytes. However, three further clusters containing 447, 101, and 505 genes failed to reach levels of hepatocytes. Key TF of two of these clusters include SOX11, FOXQ1, and YBX3. The third unsuccessful cluster, controlled by HNF1, CAR, FXR, and PXR, strongly overlaps with genes repressed in cultivated hepatocytes compared to freshly isolated hepatocytes, suggesting that current in vitro conditions lack stimuli required to maintain gene expression in hepatocytes, which consequently also explains a corresponding deficiency of HLC.

    CONCLUSIONS: The present gene regulatory network approach identifies key transcription factors which require modulation to improve HLC differentiation.

  • 4.
    Gopalan Nair, Rekha
    Högskolan i Skövde, Institutionen för biovetenskap.
    Cloning and functional analysis of an arsB gene responsible for arsenic sequestration in Lysinibacillus sphaericus2016Independent thesis Advanced level (degree of Master (One Year)), 20 poäng / 30 hpOppgave
  • 5.
    Granéli, Cecilia
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Discovery Sciences, IMED Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
    Hicks, Ryan
    Discovery Sciences, IMED Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
    Brolén, Gabriella
    Discovery Sciences, IMED Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Global Medicines Development, CVRM, AstraZeneca Gothenburg, Mölndal, Sweden.
    Diabetic Cardiomyopathy Modelling Using Induced Pluripotent Stem Cell Derived Cardiomyocytes: Recent Advances and Emerging Models2019Inngår i: Stem Cell Reviews, ISSN 1550-8943, E-ISSN 1558-6804, Vol. 15, nr 1, s. 13-22Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The global burden of diabetes has drastically increased over the past decades and in 2017 approximately 4 million deaths were caused by diabetes and cardiovascular complications. Diabetic cardiomyopathy is a common complication of diabetes with early manifestations of diastolic dysfunction and left ventricular hypertrophy with subsequent progression to systolic dysfunction and ultimately heart failure. An in vitro model accurately recapitulating key processes of diabetic cardiomyopathy would provide a useful tool for investigations of underlying disease mechanisms to further our understanding of the disease and thereby potentially advance treatment strategies for patients. With their proliferative capacity and differentiation potential, human induced pluripotent stem cells (iPSCs) represent an appealing cell source for such a model system and cardiomyocytes derived from induced pluripotent stem cells have been used to establish other cardiovascular related disease models. Here we review recently made advances and discuss challenges still to be overcome with regard to diabetic cardiomyopathy models, with a special focus on iPSC-based systems. Recent publications as well as preliminary data presented here demonstrate the feasibility of generating cardiomyocytes with a diabetic phenotype, displaying insulin resistance, impaired calcium handling and hypertrophy. However, capturing the full metabolic- and functional phenotype of the diabetic cardiomyocyte remains to be accomplished. 

  • 6.
    Holmgren, Gustav
    Sahlgrenska Academy at University of Gothenburg.
    In vitro toxicity testing using human pluripotent stem cell derivatives2016Doktoravhandling, med artikler (Annet vitenskapelig)
  • 7.
    Jonsson, Malin K. B.
    et al.
    Genome Institute of Singapore, Genome, Singapore.
    van Veen, Toon A. B.
    Department of Medical Physiology, Division of Heart & Lungs, UMC Utrecht, Utrecht, Netherlands.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för naturvetenskap. Högskolan i Skövde, Institutionen för biovetenskap.
    Becker, Bruno
    Department of Psychiatry and Neurochemistry, Sahlgrenska University Hospital, Mölndal, Sweden.
    Towards Creating the Perfect In Vitro Cell Model2016Inngår i: Stem Cells International, ISSN 1687-9678, Vol. 2016, artikkel-id 3459730Artikkel i tidsskrift (Fagfellevurdert)
  • 8.
    Kristensson, Lisbeth
    et al.
    AstraZeneca, Mölndal, Sweden.
    Lundin, Anders
    AstraZeneca, Mölndal, Sweden / Karolinska Institutet, Stockholm, Sweden.
    Gustafsson, David
    Emeriti Bio, AZ Bioventure Hub, Mölndal, Sweden.
    Fryklund, Jan
    Emeriti Bio, AZ Bioventure Hub, Mölndal, Sweden.
    Fex, Tomas
    Emeriti Bio, AZ Bioventure Hub, Mölndal, Sweden.
    Delsing, Louise
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. AstraZeneca, Mölndal, Sweden / the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
    Ryberg, Erik
    AstraZeneca, Mölndal, Sweden.
    Plasminogen binding inhibitors demonstrate unwanted activities on GABAA and glycine receptors in human iPSC derived neurons2018Inngår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 681, s. 37-43, artikkel-id S0304-3940(18)30351-3Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Plasminogen binding inhibitors (PBIs) reduce the risk of bleeding in hemorrhagic conditions. However, generic PBIs are also associated with an increased risk of seizures, an adverse effect linked to unwanted activities towards inhibitory neuronal receptors. Development of novel PBIs serve to remove compounds with such properties, but progress is limited by a lack of higher throughput methods with human translatability. Herein we apply human induced pluripotent stem cell (hiPSC) derived neurons in combination with dynamic mass redistribution (DMR) technology to demonstrate robust and reproducible modulation of both GABAA and glycine receptors. These cells respond to GABA (EC50 0.33 ± 0.18 μM), glycine (EC50 11.0 ± 3.7 μM) and additional ligands in line with previous reports from patch clamp technologies. Additionally, we identify and characterize a competitive antagonistic behavior of the prototype inhibitor and drug tranexamic acid (TXA). Finally, we demonstrate proof of concept for effective counter-screening of lead series compounds towards unwanted GABAAreceptor activities. No activity was observed for a previously identified PBI candidate drug, AZD6564, whereas a discontinued analog, AZ13267257, could be characterized as a potent GABAA receptor agonist.

  • 9.
    Kunze, Angelika
    et al.
    Department of Applied Physics, Chalmers University of Technology, Göteborg, Sweden / Institute of Physical Chemistry, University of Göttingen, Göttingen, Germany.
    Steel, Daniella
    Cellectis AB, Göteborg, Sweden / Abcam, Cambridge, United Kingdom.
    Dahlenborg, Kerstin
    Cellectis AB, Göteborg, Sweden.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Cellectis AB, Göteborg, Sweden / AstraZeneca R&D, Mölndal, Sweden.
    Svedhem, Sofia
    Department of Applied Physics, Chalmers University of Technology, Göteborg, Sweden.
    Non-Invasive Acoustical sensing of Drug-Induced Effects on the Contractile Machinery of Human Cardiomyocyte Clusters2015Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 5, s. 1-10, artikkel-id e0125540Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There is an urgent need for improved models for cardiotoxicity testing. Here we propose acoustic sensing applied to beating human cardiomyocyte clusters for non-invasive, surrogate measuring of the QT interval and other characteristics of the contractile machinery. In experiments with the acoustic method quartz crystal microbalance with dissipation monitoring (QCM-D), the shape of the recorded signals was very similar to the extracellular field potential detected in electrochemical experiments, and the expected changes of the QT interval in response to addition of conventional drugs (E-4031 or nifedipine) were observed. Additionally, changes in the dissipation signal upon addition of cytochalasin D were in good agreement with the known, corresponding shortening of the contraction-relaxation time. These findings suggest that QCM-D has great potential as a tool for cardiotoxicological screening, where effects of compounds on the cardiomyocyte contractile machinery can be detected independently of whether the extracellular field potential is altered or not.

  • 10.
    Küppers-Munther, Barbara
    et al.
    Takara Bio Europe AB, Gothenburg, Sweden.
    Asplund, A.
    Takara Bio Europe AB, Gothenburg, Sweden.
    Ulfenborg, Benjamin
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Abadie, A.
    Takara Bio Europe SAS, Paris, France.
    Novel human iPSC-derived hepatocytes with advanced functionality and long-term 2D cultures of human primary hepatocytes for metabolic disease studies2018Inngår i: Human Gene Therapy, ISSN 1043-0342, E-ISSN 1557-7422, Vol. 29, nr 12, s. A146-A146, artikkel-id P406Artikkel i tidsskrift (Fagfellevurdert)
  • 11.
    Lundin, Anders
    et al.
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden / Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Delsing, Louise
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden / Institute of Neuroscience and Physiology, Department of Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
    Clausen, Maryam
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Ricchiuto, Piero
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Sanchez, José
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Sabirsh, Alan
    Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Ding, Mei
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Zetterberg, Henrik
    Institute of Neuroscience and Physiology, Department of Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden / Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden / Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK / UK Dementia Research Institute at UCL, London, UK.
    Brolén, Gabriella
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Hicks, Ryan
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Herland, Anna
    Department of Micro and Nanosystems KTH Royal Institute of Technology, Stockholm, Sweden / Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Falk, Anna
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Human iPS-Derived Astroglia from a Stable Neural Precursor State Show Improved Functionality Compared with Conventional Astrocytic Models2018Inngår i: Stem Cell Reports, ISSN 2213-6711, Vol. 10, nr 3, s. 1030-1045Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In vivo studies of human brain cellular function face challenging ethical and practical difficulties. Animal models are typically used but display distinct cellular differences. One specific example is astrocytes, recently recognized for contribution to neurological diseases and a link to the genetic risk factor apolipoprotein E (APOE). Current astrocytic in vitro models are questioned for lack of biological characterization. Here, we report human induced pluripotent stem cell (hiPSC)-derived astroglia (NES-Astro) developed under defined conditions through long-term neuroepithelial-like stem (ltNES) cells. We characterized NES-Astro and astrocytic models from primary sources, astrocytoma (CCF-STTG1), and hiPSCs through transcriptomics, proteomics, glutamate uptake, inflammatory competence, calcium signaling response, and APOE secretion. Finally, we assess modulation of astrocyte biology using APOE-annotated compounds, confirming hits of the cholesterol biosynthesis pathway in adult and hiPSC-derived astrocytes. Our data show large diversity among astrocytic models and emphasize a cellular context when studying astrocyte biology.

  • 12.
    Nguyen, Duong T.
    et al.
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    O'Hara, Matthew
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Granéli, Cecilia
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Hicks, Ryan
    Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Miliotis, Tasso
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Nyström, Ann-Christin
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Hansson, Sara
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Davidsson, Pia
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Gan, Li-Ming
    Early Clinical and Development, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Magnone, Maria Chiara
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Althage, Magnus
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Heydarkhan-Hagvall, Sepideh
    Cardiovascular, Renal and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Humanizing Miniature Hearts through 4-Flow Cannulation Perfusion Decellularization and Recellularization2018Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikkel-id 7458Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Despite improvements in pre-clinical drug testing models, predictability of clinical outcomes continues to be inadequate and costly due to poor evidence of drug metabolism. Humanized miniature organs integrating decellularized rodent organs with tissue specific cells are translational models that can provide further physiological understanding and evidence. Here, we evaluated 4-Flow cannulated rat hearts as the fundamental humanized organ model for cardiovascular drug validation. Results show clearance of cellular components in all chambers in 4-Flow hearts with efficient perfusion into both coronary arteries and cardiac veins. Furthermore, material characterization depicts preserved organization and content of important matrix proteins such as collagens, laminin, and elastin. With access to the complete vascular network, different human cell types were delivered to show spatial distribution and integration into the matrix under perfusion for up to three weeks. The feature of 4-Flow cannulation is the preservation of whole heart conformity enabling ventricular pacing via the pulmonary vein as demonstrated by noninvasive monitoring with fluid pressure and ultrasound imaging. Consequently, 4-Flow hearts surmounting organ mimicry challenges with intact complexity in vasculature and mechanical compliance of the whole organ providing an ideal platform for improving pre-clinical drug validation in addition to understanding cardiovascular diseases.

  • 13.
    Olofsson, Peder S.
    et al.
    Center for Bioelectronic Medicine, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden / Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Steinberg, Benjamin E.
    Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA / The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada.
    Sobbi, Roozbeh
    Division of Cardiology, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.
    Cox, Maureen A.
    The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada.
    Ahmed, Mohamed N.
    Center for Heart and Lung Research, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Oswald, Michaela
    Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Szekeres, Ferenc
    Högskolan i Skövde, Institutionen för hälsa och lärande. Högskolan i Skövde, Forskningsspecialiseringen Hälsa och Lärande. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Hanes, William M.
    Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Introini, Andrea
    Department of Medicine, Solna, Unit of Infectious Diseases, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Liu, Shu Fang
    Center for Heart and Lung Research, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Holodick, Nichol E.
    Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Rothstein, Thomas L.
    Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Lövdahl, Cecilia
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Chavan, Sangeeta S.
    Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Yang, Huan
    Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Pavlov, Valentin A.
    Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Broliden, Kristina
    Department of Medicine, Solna, Unit of Infectious Diseases, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Andersson, Ulf
    Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Diamond, Betty
    The Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Miller, Edmund J.
    Center for Heart and Lung Research, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Arner, Anders
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Gregersen, Peter K.
    Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Backx, Peter H.
    Division of Cardiology, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada / Department of Biology, York University, Toronto, Ontario, Canada.
    Mak, Tak W.
    The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada.
    Tracey, Kevin J.
    Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Blood pressure regulation by CD4lymphocytes expressing choline acetyltransferase2016Inngår i: Nature Biotechnology, ISSN 1087-0156, E-ISSN 1546-1696, Vol. 34, nr 10, s. 1066-1071Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Blood pressure regulation is known to be maintained by a neuro-endocrine circuit, but whether immune cells contribute to blood pressure homeostasis has not been determined. We previously showed that CD4(+) T lymphocytes that express choline acetyltransferase (ChAT), which catalyzes the synthesis of the vasorelaxant acetylcholine, relay neural signals(1). Here we show that these CD4(+)CD44(hi)CD62L(Io) T helper cells by gene expression are a distinct T-cell population defined by ChAT (CD4 T-ChAT). Mice lacking ChAT expression in CD4(+) cells have elevated arterial blood pressure, compared to littermate controls. Jurkat T cells overexpressing ChAT (JT(ChAT)) decreased blood pressure when infused into mice. Co-incubation of JT(ChAT) and endothelial cells increased endothelial cell levels of phosphorylated endothelial nitric oxide synthase, and of nitrates and nitrites in conditioned media, indicating increased release of the potent vasorelaxant nitric oxide. The isolation and characterization of CD4 T-ChAT cells will enable analysis of the role of these cells in hypotension and hypertension, and may suggest novel therapeutic strategies by targeting cell-mediated vasorelaxation.

  • 14.
    Sartipy, Peter
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Cellectis AB, Göteborg, Sweden.
    Björquist, Petter
    Cellectis AB, Göteborg, Sweden / NovaHep AB, Göteborg, Sweden.
    Employment of the Triple Helix concept for development of regenerative medicine applications based on human pluripotent stem cells2014Inngår i: Clinical and translational medicine, ISSN 2001-1326, Vol. 3, s. 1-7, artikkel-id 9Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Using human pluripotent stem cells as a source to generate differentiated progenies for regenerative medicine applications has attracted substantial interest during recent years. Having the capability to produce large quantities of human cells that can replace damaged tissue due to disease or injury opens novel avenues for relieving symptoms and also potentially offers cures for many severe human diseases. Although tremendous advancements have been made, there is still much research and development left before human pluripotent stem cell derived products can be made available for cell therapy applications. In order to speed up the development processes, we argue strongly in favor of cross-disciplinary collaborative efforts which have many advantages, especially in a relatively new field such as regenerative medicine based on human pluripotent stem cells. In this review, we aim to illustrate how some of the hurdles for bringing human pluripotent stem cell derivatives from bench-to-bed can be effectively addressed through the establishment of collaborative programs involving academic institutions, biotech industries, and pharmaceutical companies. By taking advantage of the strengths from each organization, innovation and productivity can be maximized from a resource perspective and thus, the chances of successfully bringing novel regenerative medicine treatment options to patients increase.

  • 15.
    Saxenborn, Patricia
    Högskolan i Skövde, Institutionen för hälsa och lärande.
    Investigating the Effect of 1,25-Dihydroxyvitamin D3 and Retinoic acid on Viability, Differentiation and Migration in NB69 and T47D cells.2016Independent thesis Basic level (degree of Bachelor), 20 poäng / 30 hpOppgave
    Abstract [en]

    Cancer is a well-known disease that many people encounter in their lifetime. There is constantly research being performed on cancer to find treatments for those types where none has been found, or even find better or more efficient treatments for those cancer types where there already is treatment available. Two types of cancer that have been studied in this thesis are neuroblastoma, which is a form of cancer that affects children and infants, and breast cancer. The 13-cis retinoic acid is presently used as treatment for neuroblastoma post-surgery and post-chemo therapy, but the treatment is quite invasive. It has been shown that 1,25-dihydroxyvitamin D3 is a good candidate for cancer treatment, and the aim of this study was to investigate whether a combination of 1,25-dihydroxyvitamin D3 and two forms of retinoic acid, all-trans and 13-cis, could cause synergistic effects on cell viability, invasion, and differentiation of the cells. The two vitamins were combined at different concentrations and ratios to make the different treatments. A proliferation assay with absorbance measurement was performed to determine cell viability, and a migration assay was performed to observe the migratory properties of the cells after treatment. The results concluded that the combined treatments had greater effect than the single treatments on cell viability in both neuroblastoma and breast cancer cells. The results showed that single treatment of 13-cis retinoic acid and combined treatments had the highest effect on invasion and differentiation on neuroblastoma cells.

  • 16.
    Synnergren, Jane
    et al.
    Högskolan i Skövde, Institutionen för vård och natur. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Améen, Caroline
    Cellartis, Gothenburg, Sweden.
    Lindahl, Anders
    Dept of Clinical Chemistry/Transfusion Medicine, Sahlgrenska University Hospital, Sweden.
    Olsson, Björn
    Högskolan i Skövde, Institutionen för vård och natur. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Sartipy, Peter
    Cellartis, Gothenburg, Sweden .
    Expression of microRNAs and their target mRNAs in human stem cell-derived cardiomyocyte clusters and in heart tissue2011Inngår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 43, nr 10, s. 581-594Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Recent studies have shown that microRNAs (miRNAs) act as posttranscriptional regulators and that they play important roles during heart development and in cardiac function. Thus, they may provide new means of altering stem cell fate and differentiation processes. However, information about the correlation between global miRNA and mRNA expression in cardiomyocyte clusters (CMCs) derived from human embryonic stem cells (hESC) and in fetal and adult heart tissue is lacking. In the present study the global miRNA and mRNA expression in hESC-derived CMCs and in fetal and adult heart tissue was investigated in parallel using microarrays. Target genes for the differentially expressed miRNAs were predicted using computational methods, and the concordance in miRNA expression and mRNA levels of potential target genes was determined across the experimental samples. The biology of the predicted target genes was further explored regarding their molecular functions and involvement in known regulatory pathways. A clear correlation between the global miRNA expression and corresponding target mRNA expression was observed. Using three different sources of cardiac tissue-like samples, we defined the similarities between in vitro hESC-derived CMCs and their in vivo counterparts. The results are in line with previously reported observations that miRNAs repress mRNA expression and additionally identify a number of novel miRNAs with potential important roles in human cardiac tissue. The concordant miRNA expression pattern observed among all the cardiac tissue-like samples analyzed here provide a starting point for future ambitious studies aiming towards assessment of the functional roles of specific miRNAs during cardiomyocyte differentiation.

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