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  • 1.
    Abelius, Martina S
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Janefjord, Camilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Ernerudh, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Berg, Göran
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Matthiesen, Leif
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, Kvinnokliniken i Linköping. Helsingborg Hospital, Helsingborg.
    Duchén, Karel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Nilsson, Lennart J
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Allergicentrum US.
    Jenmalm, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    The Placental Immune Milieu is Characterized by a Th2- and Anti-Inflammatory Transcription Profile, Regardless of Maternal Allergy, and Associates with Neonatal Immunity2015Ingår i: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 73, nr 5, s. 445-459Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PROBLEM: How maternal allergy affects the systemic and local immunological environment during pregnancy and the immune development of the offspring is unclear.

    METHOD OF STUDY: Expression of 40 genes was quantified by PCR arrays in placenta, peripheral blood mononuclear cells (PBMC), and cord blood mononuclear cells (CBMC) from 7 allergic and 12 non-allergic women and their offspring.

    RESULTS: Placental gene expression was dominated by a Th2-/anti-inflammatory profile, irrespectively of maternal allergy, as compared to gene expression in PBMC. p35 expression in placenta correlated with fetal Tbx21 (ρ = -0.88, P < 0.001) and IL-5 expression in PBMC with fetal galectin1 (ρ = 0.91, P < 0.001). Increased expression of Th2-associated CCL22 in CBMC preceded allergy development.

    CONCLUSIONS: Gene expression locally and systemically during pregnancy was partly associated with the offspring's gene expression, possibly indicating that the immunological milieu is important for fetal immune development. Maternal allergy was not associated with an enhanced Th2 immunity in placenta or PBMC, while a marked prenatal Th2 skewing, shown as increased CCL22 mRNA expression, might contribute to postnatal allergy development.

  • 2.
    Abrahamsson, Thomas
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Jakobsson, H.E.
    Karolinska Institute, Stockholm, Sweden.
    Andersson, A.F.
    KTH Royal Institute of Technology, Stockholm, Sweden.
    Björksten, B.
    Karolinska Institute, Stockholm, Sweden; Örebro University, Sweden .
    Engstrand, L.
    Karolinska Institute, Stockholm, Sweden; KTH Royal Institute of Technology, Stockholm, Sweden.
    Jenmalm, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Low gut microbiota diversity in early infancy precedes asthma at school age2014Ingår i: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 44, nr 6, s. 842-850Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND:

    Low total diversity of the gut microbiota during the first year of life is associated with allergic diseases in infancy, but little is known how early microbial diversity is related to allergic disease later in school age.

    OBJECTIVE:

    To assess microbial diversity and characterize the dominant bacteria in stool during the first year of life in relation to the prevalence of different allergic diseases in school age, such as asthma, allergic rhinoconjunctivitis (ARC) and eczema.

    METHODS:

    The microbial diversity and composition was analysed with barcoded 16S rDNA 454 pyrosequencing in stool samples at 1 week, 1 month and 12 months of age in 47 infants which were subsequently assessed for allergic disease and skin prick test reactivity at 7 years of age (ClinicalTrials.gov ID NCT01285830).

    RESULTS:

    Children developing asthma (n = 8) had a lower diversity of the total microbiota than non-asthmatic children at 1 week (P = 0.04) and 1 month (P = 0.003) of age, whereas allergic rhinoconjunctivitis (n = 13), eczema (n = 12) and positive skin prick reactivity (n = 14) at 7 years of age did not associate with the gut microbiota diversity. Neither was asthma associated with the microbiota composition later in infancy (at 12 months). Children having IgE-associated eczema in infancy and subsequently developing asthma had lower microbial diversity than those that did not. There were no significant differences, however, in relative abundance of bacterial phyla and genera between children with or without allergic disease.

    CONCLUSION AND CLINICAL RELEVANCE:

    Low total diversity of the gut microbiota during the first month of life was associated with asthma but not ARC in children at 7 years of age. Measures affecting microbial colonization of the infant during the first month of life may impact asthma development in childhood.

  • 3.
    Adolfsson, Per I
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Bloth, Björn
    Department of Clinical Neuroscience, Laboratory of Translational Neuropharmacology, Center of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Futurum Academy for Health and Care, Jönköping County Council, Sweden.
    Svensson, Samuel P S
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Zinc Induces a Bell-shaped Proliferative Dose-response Effect in Cultured Smooth Muscle Cells From Benign Prostatic Hyperplasia.2015Ingår i: Urology, ISSN 0090-4295, E-ISSN 1527-9995, Vol. 85, nr 3, s. 704.e15-704.e19Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: To investigate the effects of zinc (Zn(2+)) concentrations on cultured benign prostatic hyperplasia (BPH) smooth muscle cell (SMC) proliferation.

    METHODS: The effects of Zn(2+) were studied in primary cultures of human BPH SMC, stimulated with either 10-μM lysophosphatidic acid (LPA) or LPA in combination with 100-nM testosterone. Deoxyribonucleic acid replication and protein synthesis using [(3)H]-thymidine and [(35)S]-methionine incorporation were measured. Furthermore, studies were performed to evaluate if Zn(2+) could potentiate the inhibitory effect of phosphodiesterase-5 blockers, on BPH SMC proliferation.

    RESULTS: Zn(2+) generated a bell-shaped concentration response, both regarding deoxyribonucleic acid replication and protein synthesis in cultured BPH SMC. Below a threshold value (approximately 200 μM), a significant mitogenic effect was seen, whereas higher concentrations inhibited SMC proliferation after stimulation with LPA. This effect was even more pronounced after stimulation of LPA in combination with testosterone. Moreover, phosphodiesterase-5 inhibitors, that is, sildenafil blocked LPA-stimulated BPH SMC proliferation. This antiproliferative effect, was significantly potentiated by coincubation with Zn(2+) in an additative manner.

    CONCLUSION: The bell-shaped concentration response of Zn(2+) on cultured BPH SMC proliferation suggests that changes in prostate Zn(2+) concentrations, during aging, diet, or inflammatory conditions, may be of importance in the pathogenesis of BPH.

  • 4.
    Agholme, Lotta
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Hallbeck, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Getting rid of intracellular Aβ- loss of cellular degradation leads to transfer between connected neurons2014Ingår i: Current pharmaceutical design, ISSN 1381-6128, E-ISSN 1873-4286, Vol. 20, nr 15, s. 2458-2468Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The sporadic, late onset form of Alzheimers disease (AD) shares pathological hallmarks with the familial form; however, no clear reason for increased beta-amyloid (A beta) generation has been found in the former. It has long been speculated that the late onset form of AD is caused by reduced degradation and/or clearance of A beta. Indeed, both intracellular degradation systems, the proteasomal and lysosomal systems, have been shown to be defective in AD. Reduced proteasome activity increases levels of intracellular and secreted A beta. Furthermore, accumulation of improperly degraded A beta in the lysosomes causes lysosomal disruption and cell death. We recently showed that oligomeric A beta can be transmitted from one neuron to another, which causes neurotoxicity. In both the donating and receiving cells, A beta accumulates in the endo-lysosomal compartment. It is possible that ineffective degradation of A beta causes its transfer to neighboring neurons, thereby spreading AD pathology. This review summarizes the data underlying the idea of reduced A beta clearance and subsequent A beta spread in AD, and also suggests new therapeutic methods, which are aimed at targeting the degradation systems and synaptic transfer. By enhancing degradation of intracellular accumulated A beta, it can be possible to remove it and avoid A beta-induced neurodegeneration without disturbing the endogenously important pool of secreted A beta. Additionally, drugs targeted to inhibit the spread of intracellular toxic A beta aggregates may also be useful in stopping the progression of pathology, without affecting the level of A beta that normally occurs in the brain.

  • 5.
    Ahlner, Alexandra
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär Bioteknik. Linköpings universitet, Tekniska högskolan.
    Carlsson, Mats
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär Bioteknik. Linköpings universitet, Tekniska högskolan.
    Jonsson, Bengt-Harald
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär Bioteknik. Linköpings universitet, Tekniska högskolan.
    Lundström, Patrik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär Bioteknik. Linköpings universitet, Tekniska högskolan.
    PINT: a software for integration of peak volumes and extraction of relaxation rates2013Ingår i: Journal of Biomolecular NMR, ISSN 0925-2738, E-ISSN 1573-5001, Vol. 56, nr 3, s. 191-202Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We present the software Peak INTegration (PINT), designed to perform integration of peaks in NMR spectra. The program is very simple to run, yet powerful enough to handle complicated spectra. Peaks are integrated by fitting predefined line shapes to experimental data and the fitting can be customized to deal with, for instance, heavily overlapped peaks. The results can be inspected visually, which facilitates systematic optimization of the line shape fitting. Finally, integrated peak volumes can be used to extract parameters such as relaxation rates and information about low populated states. The utility of PINT is demonstrated by applications to the 59 residue SH3 domain of the yeast protein Abp1p and the 289 residue kinase domain of murine EphB2.

  • 6.
    Ali, Zaheer
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Islam, Anik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Sherrell, Peter
    Imperial Coll London, England.
    Le-Moine, Mark
    Linköpings universitet, Institutionen för medicinsk teknik, Avdelningen för medicinsk teknik. Linköpings universitet, Tekniska fakulteten.
    Lolas, Georgios
    Univ Athens, Greece.
    Syrigos, Konstantinos
    Univ Athens, Greece.
    Rafat, Mehrdad
    Linköpings universitet, Institutionen för medicinsk teknik, Avdelningen för medicinsk teknik. Linköpings universitet, Tekniska fakulteten.
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi.
    Adjustable delivery of pro-angiogenic FGF-2 by alginate: collagen microspheres2018Ingår i: BIOLOGY OPEN, ISSN 2046-6390, Vol. 7, nr 3, artikel-id UNSP bio027060Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Therapeutic induction of blood vessel growth (angiogenesis) in ischemic tissues holds great potential for treatment of myocardial infarction and stroke. Achieving sustained angiogenesis and vascular maturation has, however, been highly challenging. Here, we demonstrate that alginate: collagen hydrogels containing therapeutic, pro-angiogenic FGF-2, and formulated as microspheres, is a promising and clinically relevant vehicle for therapeutic angiogenesis. By titrating the amount of readily dissolvable and degradable collagen with more slowly degradable alginate in the hydrogel mixture, the degradation rates of the biomaterial controlling the release kinetics of embedded proangiogenic FGF-2 can be adjusted. Furthermore, we elaborate a microsphere synthesis protocol allowing accurate control over sphere size, also a critical determinant of degradation/release rate. As expected, alginate: collagen microspheres were completely biocompatible and did not cause any adverse reactions when injected in mice. Importantly, the amount of pro-angiogenic FGF-2 released from such microspheres led to robust induction of angiogenesis in zebrafish embryos similar to that achieved by injecting FGF-2-releasing cells. These findings highlight the use of microspheres constructed from alginate: collagen hydrogels as a promising and clinically relevant delivery system for pro-angiogenic therapy.

  • 7.
    Ali, Zaheer
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Mukwaya, Anthonny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Biesemeier, Antje
    Univ Tubingen, Germany.
    Ntzouni, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Ramskold, Daniel
    Karolinska Inst, Sweden.
    Giatrellis, Sarantis
    Karolinska Inst, Sweden.
    Mammadzada, Parviz
    Karolinska Inst, Sweden.
    Cao, Renhai
    Karolinska Inst, Sweden.
    Lennikov, Anton
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Univ Missouri, MO 65211 USA.
    Marass, Michele
    Max Planck Inst Lung and Heart Res, Germany.
    Gerri, Claudia
    Max Planck Inst Lung and Heart Res, Germany.
    Hildesjö, Camilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Taylor, Michael
    Univ Wisconsin, WI 53706 USA.
    Deng, Qiaolin
    Karolinska Inst, Sweden.
    Peebo, Beatrice
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM. Bayer AB, Sweden.
    del Peso, Luis
    Universidad Autónoma de Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM Madrid, Spain.
    Kvanta, Anders
    Karolinska Inst, Sweden.
    Sandberg, Rickard
    Karolinska Inst, Sweden.
    Schraermeyer, Ulrich
    Univ Tubingen, Germany.
    Andre, Helder
    Karolinska Inst, Sweden.
    Steffensen, John F.
    Univ Copenhagen, Denmark.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Cao, Yihai
    Karolinska Inst, Sweden.
    Kele, Julianna
    Karolinska Inst, Sweden.
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi. Univ Autonoma Madrid, Spain; UAM, Spain.
    Intussusceptive Vascular Remodeling Precedes Pathological Neovascularization2019Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 39, nr 7, s. 1402-1418Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective—

    Pathological neovascularization is crucial for progression and morbidity of serious diseases such as cancer, diabetic retinopathy, and age-related macular degeneration. While mechanisms of ongoing pathological neovascularization have been extensively studied, the initiating pathological vascular remodeling (PVR) events, which precede neovascularization remains poorly understood. Here, we identify novel molecular and cellular mechanisms of preneovascular PVR, by using the adult choriocapillaris as a model.

    Approach and Results—

    Using hypoxia or forced overexpression of VEGF (vascular endothelial growth factor) in the subretinal space to induce PVR in zebrafish and rats respectively, and by analyzing choriocapillaris membranes adjacent to choroidal neovascular lesions from age-related macular degeneration patients, we show that the choriocapillaris undergo robust induction of vascular intussusception and permeability at preneovascular stages of PVR. This PVR response included endothelial cell proliferation, formation of endothelial luminal processes, extensive vesiculation and thickening of the endothelium, degradation of collagen fibers, and splitting of existing extravascular columns. RNA-sequencing established a role for endothelial tight junction disruption, cytoskeletal remodeling, vesicle- and cilium biogenesis in this process. Mechanistically, using genetic gain- and loss-of-function zebrafish models and analysis of primary human choriocapillaris endothelial cells, we determined that HIF (hypoxia-induced factor)-1α-VEGF-A-VEGFR2 signaling was important for hypoxia-induced PVR.

    Conclusions—

    Our findings reveal that PVR involving intussusception and splitting of extravascular columns, endothelial proliferation, vesiculation, fenestration, and thickening is induced before neovascularization, suggesting that identifying and targeting these processes may prevent development of advanced neovascular disease in the future.

    Visual Overview—

    An online visual overview is available for this article.

  • 8.
    Alim, Abdul
    et al.
    Uppsala University, Sweden; Karolinska Institute, Sweden; Uppsala University, Sweden.
    Ackermann, Paul W.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Eliasson, Pernilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Blomgran, Parmis
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Kristiansson, Per
    Uppsala University, Sweden.
    Pejler, Gunnar
    Uppsala University, Sweden; Swedish University of Agriculture Science, Sweden.
    Peterson, Magnus
    Uppsala University, Sweden.
    Increased mast cell degranulation and co-localization of mast cells with the NMDA receptor-1 during healing after Achilles tendon rupture2017Ingår i: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 370, nr 3, s. 451-460Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The role of inflammation and the mechanism of tendon healing after rupture has historically been a matter of controversy. The purpose of the present study is to investigate the role of mast cells and their relation to the NMDA receptor-1 (a glutamate receptor) during healing after Achilles tendon rupture. Eight female Sprague Dawley rats had their right Achilles tendon transected. Three weeks after rupture, histological quantification of mast cell numbers and their state of degranulation was assessed by histochemistry. Co-localization of mast cell tryptase (a mast cell marker) and NMDA receptor-1 was determined by immunofluorescence. The intact left Achilles tendon was used as control. An increased number of mast cells and a higher proportion of degranulated mast cells were found in the healing Achilles tendon compared to the intact. In addition, increased co-localization of mast cell tryptase and NMDA receptor-1 was seen in the areas of myotendinous junction, mid-tendon proper and bone tendon junction of the healing versus the intact tendon. These findings introduce a possible role for mast cells in the healing phase after Achilles tendon rupture.

  • 9.
    Amirhosseini, Mehdi
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Aseptic Loosening of Orthopedic Implants: Osteoclastogenesis Regulation and Potential Therapeutics2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Aseptic loosening is the main cause of failure of orthopedic prostheses. With no pharmaceuticals to prevent or mitigate periprosthetic bone degradation, a surgery to replace the loose implant with a new one is the only choice to restore patients’ function. Most studies on mechanisms for aseptic loosening investigate wear debris particle-induced osteolysis. However, pathological loading conditions around unstable implants can also trigger osteoclast differentiation and bone loss.

    In the first study, global gene expression changes induced by mechanical instability of implants, and by titanium particles were compared in a validated rat model for aseptic loosening. Microarray analysis showed that similar signaling pathways and gene expression patterns are involved in particle- and instability-induced periprosthetic osteolysis with an early onset innate immune response as a hallmark of osteolysis induced by mechanical instability.

    Further, effects of potential therapeutics on restriction of excessive osteoclast differentiation were evaluated. Wnt signaling pathway is known to regulate bone remodeling. In the second study, effects of inactivation of glycogen synthase kinase 3 beta (GSK-3β), a negative regulator of canonical Wnt signaling, on instability-induced periprosthetic osteolysis were examined using our rat model for aseptic loosening. Inhibition of GSK-3β led to a decrease in osteoclast numbers in the periprosthetic bone tissue exposed to mechanical instability while osteoblast perimeter showed an increase. This was accompanied by higher bone volume fraction (BV/TV) in animals treated with the GSK-3β inhibitor.

    In the third study, potential beneficial effects of two selective inhibitors of cyclindependent kinase 8/19 (CDK8/19) on bone tissue were evaluated. CDK8/19 is a Mediator complex-associated transcriptional regulator involved in several signaling pathways. CDK8/19 inhibitors, mainly under investigation as treatments for tumors, are reported to enhance osteoblast differentiation and bone formation. We show in this study, for the first time, that inhibition of CDK8/19 led to marked suppression of osteoclast differentiation from bone marrow macrophages in vitro through disruption of the RANK signaling. In mouse primary osteoblasts downregulation of osteopontin mRNA, a negative regulator of mineralization, together with increased alkaline phosphatase activity and calcium deposition indicated that osteoblast mineralization was promoted by CDK8/19 inhibition. Moreover, local administration of a CDK8/19 inhibitor promoted cancellous bone regeneration in a rat model for bone healing.

    These studies contribute to better understanding of mechanisms behind mechanical instability-induced periprosthetic osteolysis and propose potential therapeutics to restrict bone loss with effects on both osteoclasts and osteoblasts.

    Delarbeten
    1. Mechanical instability and titanium particles induce similar transcriptomic changes in a rat model for periprosthetic osteolysis and aseptic loosening
    Öppna denna publikation i ny flik eller fönster >>Mechanical instability and titanium particles induce similar transcriptomic changes in a rat model for periprosthetic osteolysis and aseptic loosening
    2017 (Engelska)Ingår i: Bone Reports, ISSN 2352-1872, Vol. 7, s. 17-25Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Wear debris particles released from prosthetic bearing surfaces and mechanical instability of implants are two main causes of periprosthetic osteolysis. While particle-induced loosening has been studied extensively, mechanisms through which mechanical factors lead to implant loosening have been less investigated. This study compares the transcriptional profiles associated with osteolysis in a rat model for aseptic loosening, induced by either mechanical instability or titanium particles. Rats were exposed to mechanical instability or titanium particles. After 15 min, 3, 48 or 120 h from start of the stimulation, gene expression changes in periprosthetic bone tissue was determined by microarray analysis. Microarray data were analyzed by PANTHER Gene List Analysis tool and Ingenuity Pathway Analysis (IPA). Both types of osteolytic stimulation led to gene regulation in comparison to unstimulated controls after 3, 48 or 120 h. However, when mechanical instability was compared to titanium particles, no gene showed a statistically significant difference (fold change = ± 1.5 and adjusted p-value = 0.05) at any time point. There was a remarkable similarity in numbers and functional classification of regulated genes. Pathway analysis showed several inflammatory pathways activated by both stimuli, including Acute Phase Response signaling, IL-6 signaling and Oncostatin M signaling. Quantitative PCR confirmed the changes in expression of key genes involved in osteolysis observed by global transcriptomics. Inflammatory mediators including interleukin (IL)-6, IL-1ß, chemokine (C-C motif) ligand (CCL)2, prostaglandin-endoperoxide synthase (Ptgs)2 and leukemia inhibitory factor (LIF) showed strong upregulation, as assessed by both microarray and qPCR. By investigating genome-wide expression changes we show that, despite the different nature of mechanical implant instability and titanium particles, osteolysis seems to be induced through similar biological and signaling pathways in this rat model for aseptic loosening. Pathways associated to the innate inflammatory response appear to be a major driver for osteolysis. Our findings implicate early restriction of inflammation to be critical to prevent or mitigate osteolysis and aseptic loosening of orthopedic implants.

    Ort, förlag, år, upplaga, sidor
    Elsevier, 2017
    Nyckelord
    Aseptic loosening; Implant; Instability; Microarray; Wear debris
    Nationell ämneskategori
    Cell- och molekylärbiologi Ortopedi
    Identifikatorer
    urn:nbn:se:liu:diva-146297 (URN)10.1016/j.bonr.2017.07.003 (DOI)28795083 (PubMedID)
    Tillgänglig från: 2018-04-07 Skapad: 2018-04-07 Senast uppdaterad: 2019-03-08
    2. GSK-3 beta inhibition suppresses instability-induced osteolysis by a dual action on osteoblast and osteoclast differentiation
    Öppna denna publikation i ny flik eller fönster >>GSK-3 beta inhibition suppresses instability-induced osteolysis by a dual action on osteoblast and osteoclast differentiation
    Visa övriga...
    2018 (Engelska)Ingår i: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 233, nr 3, s. 2398-2408Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Currently, there are no medications available to treat aseptic loosening of orthopedic implants. Using osteoprotegerin fusion protein (OPG-Fc), we previously blocked instability-induced osteoclast differentiation and peri-prosthetic osteolysis. Wnt/beta-catenin signaling, which regulates OPG secretion from osteoblasts, also modulates the bone tissue response to mechanical loading. We hypothesized that activating Wnt/beta-catenin signaling by inhibiting glycogen synthase kinase-3 beta (GSK-3 beta) would reduce instability-induced bone loss through regulation of both osteoblast and osteoclast differentiation. We examined effects of GSK-3 beta inhibition on regulation of RANKL and OPG in a rat model of mechanical instability-induced peri-implant osteolysis. The rats were treated daily with a GSK-3 beta inhibitor, AR28 (20 mg/kg bw), for up to 5 days. Bone tissue and blood serum were assessed by qRT-PCR, immunohistochemistry, and ELISA on days 3 and 5, and by micro-CT on day 5. After 3 days of treatment with AR28, mRNA levels of beta-catenin, Runx2, Osterix, Col1 alpha 1, and ALP were increased leading to higher osteoblast numbers compared to vehicle-treated animals. BMP-2 and Wnt16 mRNA levels were downregulated by mechanical instability and this was rescued by GSK-3 beta inhibition. Osteoclast numbers were decreased significantly after 3 days of GSK-3 beta inhibition, which correlated with enhanced OPG mRNA expression. This was accompanied by decreased serum levels of TRAP5b on days 3 and 5. Treatment with AR28 upregulated osteoblast differentiation, while osteoclastogenesis was blunted, leading to increased bone mass by day 5. These data suggest that GSK-3 beta inactivation suppresses osteolysis through regulating both osteoblast and osteoclast differentiation in a rat model of instability-induced osteolysis.

    Ort, förlag, år, upplaga, sidor
    WILEY, 2018
    Nyckelord
    bone implant; GSK-3 beta; mechanical instability; osteolysis; Wnt signaling
    Nationell ämneskategori
    Farmakologi och toxikologi
    Identifikatorer
    urn:nbn:se:liu:diva-148660 (URN)10.1002/jcp.26111 (DOI)000433519300056 ()28731198 (PubMedID)
    Anmärkning

    Funding Agencies|VINNOVA [2012-04409]; National Institutes of Health [AR056802]; Vetenskapsradet [K2014-7X-22506-01-3]; Swedish Research Council; Swedish Governmental Agency for Innovation Systems

    Tillgänglig från: 2018-06-18 Skapad: 2018-06-18 Senast uppdaterad: 2019-04-08
    3. Cyclin-dependent kinase 8/19 inhibition suppresses osteoclastogenesis by downregulating RANK and promotes osteoblast mineralization and cancellous bone healing.
    Öppna denna publikation i ny flik eller fönster >>Cyclin-dependent kinase 8/19 inhibition suppresses osteoclastogenesis by downregulating RANK and promotes osteoblast mineralization and cancellous bone healing.
    Visa övriga...
    2019 (Engelska)Ingår i: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 234, nr 9, s. 16503-16516Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Cyclin-dependent kinase 8 (CDK8) is a mediator complex-associated transcriptional regulator that acts depending on context and cell type. While primarily under investigation as potential cancer therapeutics, some inhibitors of CDK8-and its paralog CDK19-have been reported to affect the osteoblast lineage and bone formation. This study investigated the effects of two selective CDK8/19 inhibitors on osteoclastogenesis and osteoblasts in vitro, and further evaluated how local treatment with a CDK8/19 inhibitor affects cancellous bone healing in rats. CDK8/19 inhibitors did not alter the proliferation of neither mouse bone marrow-derived macrophages (BMMs) nor primary mouse osteoblasts. Receptor activator of nuclear factor κΒ (NF-κB) ligand (RANKL)-induced osteoclastogenesis from mouse BMMs was suppressed markedly by inhibition of CDK8/19, concomitant with reduced tartrate-resistant acid phosphatase (TRAP) activity and C-terminal telopeptide of type I collagen levels. This was accompanied by downregulation of PU.1, RANK, NF-κB, nuclear factor of activated T-cells 1 (NFATc1), dendritic cell-specific transmembrane protein (DC-STAMP), TRAP, and cathepsin K in RANKL-stimulated BMMs. Downregulating RANK and its downstream signaling in osteoclast precursors enforce CDK8/19 inhibitors as anticatabolic agents to impede excessive osteoclastogenesis. In mouse primary osteoblasts, CDK8/19 inhibition did not affect differentiation but enhanced osteoblast mineralization by promoting alkaline phosphatase activity and downregulating osteopontin, a negative regulator of mineralization. In rat tibiae, a CDK8/19 inhibitor administered locally promoted cancellous bone regeneration. Our data indicate that inhibitors of CDK8/19 have the potential to develop into therapeutics to restrict osteolysis and enhance bone regeneration.

    Nyckelord
    CDK8, RANK, osteoblasts, osteoclasts
    Nationell ämneskategori
    Cell- och molekylärbiologi Läkemedelskemi
    Identifikatorer
    urn:nbn:se:liu:diva-154927 (URN)10.1002/jcp.28321 (DOI)000470174200186 ()30793301 (PubMedID)
    Anmärkning

    Funding agencies: Vetenskapsradet [521-2013-2593, 2016-06097, K2015-99x-10363-23-4, 2016-01822]; Swedish Research Council

    Tillgänglig från: 2019-03-05 Skapad: 2019-03-05 Senast uppdaterad: 2019-07-03
  • 10.
    Amirhosseini, Mehdi
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Andersson, Göran
    Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Mechanical instability and titanium particles induce similar transcriptomic changes in a rat model for periprosthetic osteolysis and aseptic loosening2017Ingår i: Bone Reports, ISSN 2352-1872, Vol. 7, s. 17-25Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Wear debris particles released from prosthetic bearing surfaces and mechanical instability of implants are two main causes of periprosthetic osteolysis. While particle-induced loosening has been studied extensively, mechanisms through which mechanical factors lead to implant loosening have been less investigated. This study compares the transcriptional profiles associated with osteolysis in a rat model for aseptic loosening, induced by either mechanical instability or titanium particles. Rats were exposed to mechanical instability or titanium particles. After 15 min, 3, 48 or 120 h from start of the stimulation, gene expression changes in periprosthetic bone tissue was determined by microarray analysis. Microarray data were analyzed by PANTHER Gene List Analysis tool and Ingenuity Pathway Analysis (IPA). Both types of osteolytic stimulation led to gene regulation in comparison to unstimulated controls after 3, 48 or 120 h. However, when mechanical instability was compared to titanium particles, no gene showed a statistically significant difference (fold change = ± 1.5 and adjusted p-value = 0.05) at any time point. There was a remarkable similarity in numbers and functional classification of regulated genes. Pathway analysis showed several inflammatory pathways activated by both stimuli, including Acute Phase Response signaling, IL-6 signaling and Oncostatin M signaling. Quantitative PCR confirmed the changes in expression of key genes involved in osteolysis observed by global transcriptomics. Inflammatory mediators including interleukin (IL)-6, IL-1ß, chemokine (C-C motif) ligand (CCL)2, prostaglandin-endoperoxide synthase (Ptgs)2 and leukemia inhibitory factor (LIF) showed strong upregulation, as assessed by both microarray and qPCR. By investigating genome-wide expression changes we show that, despite the different nature of mechanical implant instability and titanium particles, osteolysis seems to be induced through similar biological and signaling pathways in this rat model for aseptic loosening. Pathways associated to the innate inflammatory response appear to be a major driver for osteolysis. Our findings implicate early restriction of inflammation to be critical to prevent or mitigate osteolysis and aseptic loosening of orthopedic implants.

  • 11.
    Amirhosseini, Mehdi
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Bernhardsson, Magnus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Lång, Pernilla
    Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
    Andersson, Göran
    Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
    Flygare, Johan
    Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden..
    Fahlgren, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Cyclin-dependent kinase 8/19 inhibition suppresses osteoclastogenesis by downregulating RANK and promotes osteoblast mineralization and cancellous bone healing.2019Ingår i: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 234, nr 9, s. 16503-16516Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cyclin-dependent kinase 8 (CDK8) is a mediator complex-associated transcriptional regulator that acts depending on context and cell type. While primarily under investigation as potential cancer therapeutics, some inhibitors of CDK8-and its paralog CDK19-have been reported to affect the osteoblast lineage and bone formation. This study investigated the effects of two selective CDK8/19 inhibitors on osteoclastogenesis and osteoblasts in vitro, and further evaluated how local treatment with a CDK8/19 inhibitor affects cancellous bone healing in rats. CDK8/19 inhibitors did not alter the proliferation of neither mouse bone marrow-derived macrophages (BMMs) nor primary mouse osteoblasts. Receptor activator of nuclear factor κΒ (NF-κB) ligand (RANKL)-induced osteoclastogenesis from mouse BMMs was suppressed markedly by inhibition of CDK8/19, concomitant with reduced tartrate-resistant acid phosphatase (TRAP) activity and C-terminal telopeptide of type I collagen levels. This was accompanied by downregulation of PU.1, RANK, NF-κB, nuclear factor of activated T-cells 1 (NFATc1), dendritic cell-specific transmembrane protein (DC-STAMP), TRAP, and cathepsin K in RANKL-stimulated BMMs. Downregulating RANK and its downstream signaling in osteoclast precursors enforce CDK8/19 inhibitors as anticatabolic agents to impede excessive osteoclastogenesis. In mouse primary osteoblasts, CDK8/19 inhibition did not affect differentiation but enhanced osteoblast mineralization by promoting alkaline phosphatase activity and downregulating osteopontin, a negative regulator of mineralization. In rat tibiae, a CDK8/19 inhibitor administered locally promoted cancellous bone regeneration. Our data indicate that inhibitors of CDK8/19 have the potential to develop into therapeutics to restrict osteolysis and enhance bone regeneration.

    Publikationen är tillgänglig i fulltext från 2020-02-21 12:44
  • 12.
    Andersson, Henrik
    et al.
    Linköpings universitet, Medicinska fakulteten. Östergötlands Läns Landsting, Sinnescentrum, Anestesi- och intensivvårdskliniken US. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning.
    Björnström-Karlsson, Karin
    Region Östergötland, Sinnescentrum, Anestesi- och intensivvårdskliniken US. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Eintrei, Christina
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Anestesi- och intensivvårdskliniken US.
    Sundqvist, Tommy
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Orexin A Phosphorylates the gamma-Aminobutyric Acid Type A Receptor beta(2) Subunit on a Serine Residue and Changes the Surface Expression of the Receptor in SH-SY5Y Cells Exposed to Propofol2015Ingår i: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 93, nr 11, s. 1748-1755Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Propofol activates the gamma-aminobutyric acid type A receptor (GABA(A)R) and causes a reversible neurite retraction, leaving a thin, thread-like structure behind; it also reverses the transport of vesicles in rat cortical neurons. The awakening peptide orexin A (OA) inhibits this retraction via phospholipase D (PLD) and protein kinase CE (PKCE). The human SH-SY5Y cells express both GABA(A)Rs and orexin 1 and 2 receptors. These cells are used to examine the interaction between OA and the GABAAR. The effects of OA are studied with flow cytometry and immunoblotting. This study shows that OA stimulates phosphorylation on the serine residues of the GABA(A)R beta(2) subunit and that the phosphorylation is caused by the activation of PLD and PKCE. OA administration followed by propofol reduces the cell surface expression of the GABA(A)R, whereas propofol stimulation before OA increases the surface expression. The GABA(A)R beta(2) subunit is important for receptor recirculation, and the effect of OA on propofol-stimulated cells may be due to a disturbed recirculation of the GABA(A)R. (C) 2015 Wiley Periodicals, Inc.

  • 13.
    Andersson, Theresa
    Linköpings universitet, Institutionen för fysik och mätteknik. Linköpings universitet, Tekniska högskolan.
    Molecular recognition of proteins by functionalized folded polypeptide receptors2004Licentiatavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    This thesis describes the design, synthesis and characterization of synthetic receptor molecules for the recognition and binding of proteins with applications in bioseparation and biosensing. A 42-residue polypeptide, designed to fold into a helix-loop-helix motif and dimerize in solution to form a four-helix bundle, was used as the scaffold. In the first part of the thesis it was functionalized by the incorporation of three substituents at the side chains of lysine residues. A library of 343 receptors was created and screened for affinity towards the human IgG fab fragment using SPR technology. The scaffold was reacted in a stepwise and combinatorial procedure with seven active esters in a pH controlled site-selective acylation reaction to form amides at the side chains of three lysine residues. Four receptor candidates were found to have 0.1 mM affinities and were selected for further investigation.

    Both the unfunctionalized scaffold and the four selected receptors were found to bind well also to HCA II and the molecular interactions with this target protein were studied in detail. NMR studies of their interactions with 15N-labeled HCA II revealed that the peptides bound to a hydrophobic patch near the active site cleft, and SPR studies of modified receptor polypeptides led to the conclusion that mainly hydrophobic interactions were involved in binding.

    In the second part of the thesis two scaffolds were functionalized with a benzenesulfonamide ligand linked to the scaffold by a series of aliphatic spacers of varying length. Benzenesulfonamide is a known inhibitor of HCA II with a dissociation constant of 1.5 µM and it was found that the overall affinity of the functionalized peptide was enhanced by increasing the length of the ligand spacer due to cooperativity between the scaffold and the ligand in the binding to HCA II. The receptor with a seven methylene group spacer bound HCA II with a dissociation constant of 4 n M. It was also shown that the sequence of the scaffold polypeptide strongly affected the overall affinity of the peptide conjugate for the target protein.

  • 14.
    Ansell - Schultz, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Reyes, Juan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Samuelsson, My
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Hallbeck, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Reduced retromer function results in the accumulation of amyloid-beta oligomers2018Ingår i: Molecular and Cellular Probes, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 93, s. 18-26Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Alzheimers disease (AD) is a neurodegenerative disorder characterized by a progressive loss of multiple cognitive functions. Accumulation of amyloid beta oligomers (oA beta) play a major role in the neurotoxicity associated with the disease process. One of the early affected brain regions is the hippocampus, wherein a reduction of the vacuolar protein sorting-associated protein 35 (VPS35), the core protein comprising the retromer complex involved in cellular cargo sorting, has been identified. To investigate the role of the retromer function on the accumulation and clearance of oA beta, we reduced retromer function by selectively inhibiting VPS35 gene expression using siRNA in differentiated neuronal SH-SY5Y cells. As cell-to-cell transfer of oA beta to new brain regions is believed to be important for disease progression we investigated the effect of VPS35 reduction both in cells with direct uptake of oA beta and in cells receiving oA beta from donor cells. We demonstrate that reduced retromer function increases oA beta accumulation in both cell systems, both the number of cells containing intracellular oA beta and the amount within them. This effect was shown at different time points and regardless if the AD originated from the extracellular milieu or via a direct neuronal cell-to-cell transfer. Interestingly, not only did reduced VPS35 cause oA beta accumulation, but oA beta treatment alone also lead to a reduction of VPS35 protein content. The accumulated oA beta seems to co-localize with VPS35 and early endosome markers. Together, these findings provide evidence that reduced retromer function decreases the ability for neurons to transport and clear neurotoxic oA beta received through different routes resulting in the accumulation of oA beta. Thus, enhancing retromer function may be a potential therapeutic strategy to slow down the pathophysiology associated with the progression of AD.

  • 15.
    Armstrong, Andrea
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Mattsson, Niklas
    Sahlgrens University Hospital, Sweden University of Calif San Francisco, CA 94143 USA .
    Appelqvist, Hanna
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Janefjord, Camilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Sandin, Linnea
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Agholme, Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Olsson, Bob
    Sahlgrens University Hospital, Sweden .
    Svensson, Samuel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. AlzeCure Fdn.
    Blennow, Kaj
    Sahlgrens University Hospital, Sweden .
    Zetterberg, Henrik
    Sahlgrens University Hospital, Sweden UCL Institute Neurol, England .
    Kågedal, Katarina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Lysosomal Network Proteins as Potential Novel CSF Biomarkers for Alzheimers Disease2014Ingår i: Neuromolecular medicine, ISSN 1535-1084, E-ISSN 1559-1174, Vol. 16, nr 1, s. 150-160Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The success of future intervention strategies for Alzheimers disease (AD) will likely rely on the development of treatments starting early in the disease course, before irreversible brain damage occurs. The pre-symptomatic stage of AD occurs at least one decade before the clinical onset, highlighting the need for validated biomarkers that reflect this early period. Reliable biomarkers for AD are also needed in research and clinics for diagnosis, patient stratification, clinical trials, monitoring of disease progression and the development of new treatments. Changes in the lysosomal network, i.e., the endosomal, lysosomal and autophagy systems, are among the first alterations observed in an AD brain. In this study, we performed a targeted search for lysosomal network proteins in human cerebrospinal fluid (CSF). Thirty-four proteins were investigated, and six of them, early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were significantly increased in the CSF from AD patients compared with neurological controls. These results were confirmed in a validation cohort of CSF samples, and patients with no neurochemical evidence of AD, apart from increased total-tau, were found to have EEA1 levels corresponding to the increased total-tau levels. These findings indicate that increased levels of LAMP-1, LAMP-2, LC3, Rab3 and Rab7 in the CSF might be specific for AD, and increased EEA1 levels may be a sign of general neurodegeneration. These six lysosomal network proteins are potential AD biomarkers and may be used to investigate lysosomal involvement in AD pathogenesis.

  • 16.
    Aslan, Cynthia
    et al.
    Tabriz Univ Med Sci, Iran.
    Maralbashi, Sepideh
    Kermanshah Univ Med Sci, Iran.
    Salari, Farhad
    Kermanshah Univ Med Sci, Iran.
    Kahroba, Houman
    Tabriz Univ Med Sci, Iran.
    Sigaroodi, Faraz
    Tabriz Univ Med Sci, Iran.
    Kazemi, Tohid
    Tabriz Univ Med Sci, Iran.
    Kharaziha, Pedram
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Tumor-derived exosomes: Implication in angiogenesis and antiangiogenesis cancer therapy2019Ingår i: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 234, nr 10, s. 16885-16903Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Tumor cells utilize different strategies to communicate with neighboring tissues for facilitating tumor progression and invasion, one of these strategies has been shown to be the release of exosomes. Exosomes are small nanovesicles secreted by all kind of cells in the body, especially cancer cells, and mediate cell to cell communications. Exosomes play an important role in cancer invasiveness by harboring various cargoes that could accelerate angiogenesis. Here first, we will present an overview of exosomes, their biology, and their function in the body. Then, we will focus on exosomes derived from tumor cells as tumor angiogenesis mediators with a particular emphasis on the underlying mechanisms in various cancer origins. Also, exosomes derived from stem cells and tumor-associated macrophages will be discussed in this regard. Finally, we will discuss the novel therapeutic strategies of exosomes as drug delivery vehicles against angiogenesis.

  • 17.
    Azim, Kasum
    et al.
    Brain Research Institute, University of Zürich/ETHZ, Zürich, Switzerland.
    Fischer, Bruno
    Brain Research Institute, University of Zürich/ETHZ, Zürich, Switzerland.
    Hurtado-Chong, Anahi
    Brain Research Institute, University of Zürich/ETHZ, Zürich, Switzerland.
    Draganova, Kalina
    Institute of Anatomy, University of Zürich, Switzerland.
    Cantù, Claudio
    Institute of Molecular Life Sciences, University of Zürich, Switzerland.
    Zemke, Martina
    Institute of Anatomy, University of Zürich, Switzerland.
    Sommer, Lukas
    Institute of Anatomy, University of Zürich, Switzerland.
    Butt, Arthur
    Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, Portsmouth University, United Kingdom.
    Raineteau, Olivier
    Brain Research Institute, University of Zürich/ETHZ, Zürich, Switzerland / Stem Cell and Brain Research Institute, INSERMU846, Lyon, France, Universite de Lyon,Universite Lyon, France.
    Persistent Wnt/β‐Catenin Signaling Determines Dorsalization of the Postnatal Subventricular Zone and Neural Stem Cell Specification into Oligodendrocytes and Glutamatergic Neurons2014Ingår i: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 32, nr 5, s. 1301-1312Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In the postnatal and adult central nervous system (CNS), the subventricular zone (SVZ) of the forebrain is the main source of neural stem cells (NSCs) that generate olfactory neurons and oligodendrocytes (OLs), the myelinating cells of the CNS. Here, we provide evidence of a primary role for canonical Wnt/β-catenin signaling in regulating NSC fate along neuronal and oligodendroglial lineages in the postnatal SVZ. Our findings demonstrate that glutamatergic neuronal precursors (NPs) and oligodendrocyte precursors (OPs) are derived strictly from the dorsal SVZ (dSVZ) microdomain under the control of Wnt/β-catenin, whereas GABAergic NPs are derived mainly from the lateral SVZ (lSVZ) microdomain independent of Wnt/β-catenin. Transcript analysis of microdissected SVZ microdomains revealed that canonical Wnt/β-catenin signaling was more pronounced in the dSVZ microdomain. This was confirmed using the β-catenin-activated Wnt-reporter mouse and by pharmacological stimulation of Wnt/β-catenin by infusion of the specific glycogen synthase kinase 3β inhibitor, AR-A014418, which profoundly increased the generation of cycling cells. In vivo genetic/pharmacological stimulation or inhibition of Wnt/β-catenin, respectively, increased and decreased the differentiation of dSVZ-NSCs into glutamatergic NPs, and had a converse effect on GABAergic NPs. Activation of Wnt/β-catenin dramatically stimulated the generation of OPs, but its inhibition had no effect, indicating other factors act in concert with Wnt/β-catenin to fine tune oligodendrogliogenesis in the postnatal dSVZ. These results demonstrate a role for Wnt/β-catenin signaling within the dorsal microdomain of the postnatal SVZ, in regulating the genesis of glutamatergic neurons and OLs.

  • 18.
    Babbin, Brian A.
    et al.
    Epithelial Pathobiology Research Unit, the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
    Koch, Stefan
    Epithelial Pathobiology Research Unit, the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
    Bachar, Moshe
    Epithelial Pathobiology Research Unit, the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
    Conti, Mary-Anne
    Laboratory of Molecular Cardiology, the National Heart, Lung, Blood Institute, National Institutes of Health, Bethesda, Maryland.
    Parkos, Charles A.
    Epithelial Pathobiology Research Unit, the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
    Adelstein, Robert S.
    Laboratory of Molecular Cardiology, the National Heart, Lung, Blood Institute, National Institutes of Health, Bethesda, Maryland.
    Nusrat, Asma
    Epithelial Pathobiology Research Unit, the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
    Ivanov, Andrei I.
    Epithelial Pathobiology Research Unit, the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia; Gastroenterology and Hepatology Division, Department of Medicine, The University of Rochester, Rochester New York.
    Non-muscle myosin IIA differentially regulates intestinal epithelial cell restitution and matrix invasion2009Ingår i: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 174, nr 2, s. 436-448Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Epithelial cell motility is critical for self-rejuvenation of normal intestinal mucosa, wound repair, and cancer metastasis. This process is regulated by the reorganization of the F-actin cytoskeleton, which is driven by a myosin II motor. However, the role of myosin II in regulating epithelial cell migration remains poorly understood. This study addressed the role of non-muscle myosin (NM) IIA in two different modes of epithelial cell migration: two-dimensional (2-D) migration that occurs during wound closure and three-dimensional (3-D) migration through a Matrigel matrix that occurs during cancer metastasis. Pharmacological inhibition or siRNA-mediated knockdown of NM IIA in SK-CO15 human colonic epithelial cells resulted in decreased 2-D migration and increased 3-D invasion. The attenuated 2-D migration was associated with increased cell adhesiveness to collagen and laminin and enhanced expression of beta1-integrin and paxillin. On the 2-D surface, NM IIA-deficient SK-CO15 cells failed to assemble focal adhesions and F-actin stress fibers. In contrast, the enhanced invasion of NM IIA-depleted cells was dependent on Raf-ERK1/2 signaling pathway activation, enhanced calpain activity, and increased calpain-2 expression. Our findings suggest that NM IIA promotes 2-D epithelial cell migration but antagonizes 3-D invasion. These observations indicate multiple functions for NM IIA, which, along with the regulation of the F-actin cytoskeleton and cell-matrix adhesions, involve previously unrecognized control of intracellular signaling and protein expression.

  • 19.
    Babbin, Brian A.
    et al.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Laukoetter, Mike G.
    Department of General Surgery, University of Muenster, Muenster, Germany.
    Nava, Porfirio
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Koch, Stefan
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Lee, Winston Y.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Capaldo, Christopher T.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Peatman, Eric
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Severson, Eric A.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Flower, Roderick J.
    The William Harvey Research Institute, Barts and The London School of Medicine, London, United Kingdom.
    Perretti, Mauro
    The William Harvey Research Institute, Barts and The London School of Medicine, London, United Kingdom.
    Parkos, Charles A.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Nusrat, Asma
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Annexin A1 regulates intestinal mucosal injury, inflammation, and repair2008Ingår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, J Immunol, Vol. 181, nr 7, s. 5035-5044Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    During mucosal inflammation, a complex array of proinflammatory and protective mechanisms regulates inflammation and severity of injury. Secretion of anti-inflammatory mediators is a mechanism that is critical in controlling inflammatory responses and promoting epithelial restitution and barrier recovery. AnxA1 is a potent anti-inflammatory protein that has been implicated to play a critical immune regulatory role in models of inflammation. Although AnxA1 has been shown to be secreted in intestinal mucosal tissues during inflammation, its potential role in modulating the injury/inflammatory response is not understood. In this study, we demonstrate that AnxA1-deficient animals exhibit increased susceptibility to dextran sulfate sodium (DSS)-induced colitis with greater clinical morbidity and histopathologic mucosal injury. Furthermore, impaired recovery following withdrawal of DSS administration was observed in AnxA1 (-/-) animals compared with wild-type (WT) control mice that was independent of inflammatory cell infiltration. Since AnxA1 exerts its anti-inflammatory properties through stimulation of ALX/FPRL-1, we explored the role of this receptor-ligand interaction in regulating DSS-induced colitis. Interestingly, treatment with an ALX/FPRL-1 agonist, 15-epi-lipoxin A4 reversed the enhanced sensitivity of AnxA1 (-/-) mice to DSS colitis. In contrast, 15-epi-lipoxin A4 did not significantly improve the severity of disease in WT animals. Additionally, differential expression of ALX/FPLR-1 in control and DSS-treated WT and AnxA1-deficient animals suggested a potential role for AnxA1 in regulating ALX/FPRL-1 expression under pathophysiological conditions. Together, these results support a role of endogenous AnxA1 in the protective and reparative properties of the intestinal mucosal epithelium.

  • 20.
    Bahrampour, Shahrzad
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Genetic mechanisms regulating proliferation and cell specification in the Drosophila embryonic CNS2017Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The central nervous system (CNS) consists of an enormous number of cells, and large cellular variance, integrated into an elaborate network. The CNS is the most complex animal organ, and therefore its establishment must be controlled by many different genetic programs. Considering the high level of complexity in the human CNS, addressing issues related to human neurodevelopment represents a major challenge. Since comparative studies have revealed that neurodevelopmental programs are well conserved through evolution, on both the genetic and functional levels, studies on invertebrate neurodevelopmental programs are often translatable to vertebrates. Indeed, the basis of our current knowledge about vertebrate CNS development has been greatly aided by studies on invertebrates, and in particular on the Drosophila melanogaster (fruit fly) model system.

    This thesis attempted to identify novel genes regulating neural cell specification and proliferation in the CNS, using the Drosophila model system. Moreover, I aimed to address how those genes govern neural progenitor cells (neuroblasts; NBs) to obtain/maintain their stemness identity and proliferation capacity, and how they drive NBs through temporal windows and series of programmed asymmetric division, which gradually reduces their stemness identity in favor of neural differentiation, resulting in appropriate lineage progression. In the first project, we conducted a forward genetic screen in Drosophila embryos, aimed at isolating genes involved in regulation of neural proliferation and specification, at the single cell resolution. By taking advantage of the restricted expression of the neuropeptide FMRFa in the last-born cell of the NB lineage 5-6T, the Ap4 neuron, we could monitor the entire lineage progression. This screen succeeded in identifying 43 novel genes controlling different aspects of CNS development. One of the genes isolated, Ctr9, displayed extra Ap4/FMRFa neurons. Ctr9 encodes a component of the RNA polymerase II complex Paf1, which is involved in a number of transcriptional processes. The Paf1C, including Ctr9, is highly conserved from yeast to human, and in the past couple of years, its importance for transcription has become increasingly appreciated. However, studies in the Drosophila system have been limited. In the screen, we isolated the first mutant of Drosophila Ctr9 and conducted the first detailed phenotypic study on its function in the Drosophila embryonic CNS. Loss of function of Ctr9 leads to extra NB numbers, higher proliferation ratio and lower expression of neuropeptides. Gene expression analysis identified several other genes regulated by Ctr9, which may explain the Ctr9 mutant phenotypes. In summary, we identified Ctr9 as an essential gene for proper CNS development in Drosophila, and this provides a platform for future study on the Drosophila Paf1C. Another interesting gene isolated in the screen was worniou (wor), a member of the Snail family of transcription factors. In contrast to Ctr9, whichdisplayed additional Ap4/FMRFa neurons, wor mutants displayed a loss of these neurons. Previous studies in our group have identified many genes acting to stop NB lineage progression, but how NBs are pushed to proliferate and generate their lineages was not well known. Since wor may constitute a “driver” of proliferation, we decided to study it further. Also, we identified five other transcription factors acting together with Wor as pro-proliferative in both NBs and their daughter cells. These “drivers” are gradually replaced by the previously identified late-acting “stoppers.” Early and late factors regulate each other and the cell cycle, and thereby orchestrate proper neural lineage progression.

    Delarbeten
    1. Novel Genes Involved in Controlling Specification of Drosophila FMRFamide Neuropeptide Cells
    Öppna denna publikation i ny flik eller fönster >>Novel Genes Involved in Controlling Specification of Drosophila FMRFamide Neuropeptide Cells
    Visa övriga...
    2015 (Engelska)Ingår i: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 200, nr 4, s. 1229-1244Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The expression of neuropeptides is often extremely restricted in the nervous system, making them powerful markers for addressing cell specification . In the developing Drosophila ventral nerve cord, only six cells, the Ap4 neurons, of some 10,000 neurons, express the neuropeptide FMRFamide (FMRFa). Each Ap4/FMRFa neuron is the last-born cell generated by an identifiable and well-studied progenitor cell, neuroblast 5-6 (NB5-6T). The restricted expression of FMRFa and the wealth of information regarding its gene regulation and Ap4 neuron specification makes FMRFa a valuable readout for addressing many aspects of neural development, i.e., spatial and temporal patterning cues, cell cycle control, cell specification, axon transport, and retrograde signaling. To this end, we have conducted a forward genetic screen utilizing an Ap4-specific FMRFa-eGFP transgenic reporter as our readout. A total of 9781 EMS-mutated chromosomes were screened for perturbations in FMRFa-eGFP expression, and 611 mutants were identified. Seventy-nine of the strongest mutants were mapped down to the affected gene by deficiency mapping or whole-genome sequencing. We isolated novel alleles for previously known FMRFa regulators, confirming the validity of the screen. In addition, we identified novel essential genes, including several with previously undefined functions in neural development. Our identification of genes affecting most major steps required for successful terminal differentiation of Ap4 neurons provides a comprehensive view of the genetic flow controlling the generation of highly unique neuronal cell types in the developing nervous system.

    Ort, förlag, år, upplaga, sidor
    Genetics Society of America, 2015
    Nyckelord
    Drosophila; CNS development; neural cell fate specification; forward genetic screening; FMRFamide
    Nationell ämneskategori
    Klinisk medicin
    Identifikatorer
    urn:nbn:se:liu:diva-121318 (URN)10.1534/genetics.115.178483 (DOI)000359917000020 ()26092715 (PubMedID)
    Tillgänglig från: 2015-09-16 Skapad: 2015-09-14 Senast uppdaterad: 2019-03-13Bibliografiskt granskad
    2. Ctr9, a Key Component of the Paf1 Complex, Affects Proliferation and Terminal Differentiation in the Developing Drosophila Nervous System
    Öppna denna publikation i ny flik eller fönster >>Ctr9, a Key Component of the Paf1 Complex, Affects Proliferation and Terminal Differentiation in the Developing Drosophila Nervous System
    2016 (Engelska)Ingår i: G3: Genes, Genomes, Genetics, ISSN 2160-1836, E-ISSN 2160-1836, Vol. 6, nr 10, s. 3229-3239Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The Paf1 protein complex (Paf1C) is increasingly recognized as a highly conserved and broadly utilized regulator of a variety of transcriptional processes. These include the promotion of H3K4 and H3K36 trimethylation, H2BK123 ubiquitination, RNA Pol II transcriptional termination, and also RNA-mediated gene silencing. Paf1C contains five canonical protein components, including Paf1 and Ctr9, which are critical for overall complex integrity, as well as Rtf1, Leo1, and Cdc73/Parafibromin(Hrpt2)/Hyrax. In spite of a growing appreciation for the importance of Paf1C from yeast and mammalian studies, there has only been limited work in Drosophila. Here, we provide the first detailed phenotypic study of Ctr9 function in Drosophila. We found that Ctr9 mutants die at late embryogenesis or early larval life, but can be partly rescued by nervous system reexpression of Ctr9. We observed a number of phenotypes in Ctr9 mutants, including increased neuroblast numbers, increased nervous system proliferation, as well as downregulation of many neuropeptide genes. Analysis of cell cycle and regulatory gene expression revealed upregulation of the E2f1 cell cycle factor, as well as changes in Antennapedia and Grainy head expression. We also found reduction of H3K4me3 modification in the embryonic nervous system. Genome-wide transcriptome analysis points to additional downstream genes that may underlie these Ctr9 phenotypes, revealing gene expression changes in Notch pathway target genes, cell cycle genes, and neuropeptide genes. In addition, we find significant effects on the gene expression of metabolic genes. These findings reveal that Ctr9 is an essential gene that is necessary at multiple stages of nervous system development, and provides a starting point for future studies of the Paf1C in Drosophila.

    Ort, förlag, år, upplaga, sidor
    Genetics Society of America, 2016
    Nyckelord
    neuroblast, lineage tree, cell cycle, epigenetics, terminal differentiation, FlyBook
    Nationell ämneskategori
    Genetik
    Identifikatorer
    urn:nbn:se:liu:diva-132856 (URN)10.1534/g3.116.034231 (DOI)000386581200018 ()27520958 (PubMedID)
    Anmärkning

    Funding Agencies|Swedish Research Council [621-2013-5258]; Knut and Alice Wallenberg Foundation [KAW2011.0165]; Swedish Cancer Foundation [120531]; Swedish Royal Academy of Sciences

    Tillgänglig från: 2016-12-06 Skapad: 2016-11-30 Senast uppdaterad: 2017-11-29
    3. Neural Lineage Progression Controlled by a Temporal Proliferation Program.
    Öppna denna publikation i ny flik eller fönster >>Neural Lineage Progression Controlled by a Temporal Proliferation Program.
    Visa övriga...
    2017 (Engelska)Ingår i: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 43, nr 3, s. 332-348Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Great progress has been made in identifying transcriptional programs that establish stem cell identity. In contrast, we have limited insight into how these programs are down-graded in a timely manner to halt proliferation and allow for cellular differentiation. Drosophila embryonic neuroblasts undergo such a temporal progression, initially dividing to bud off daughters that divide once (type I), then switching to generating non-dividing daughters (type 0), and finally exiting the cell cycle. We identify six early transcription factors that drive neuroblast and type I daughter proliferation. Early factors are gradually replaced by three late factors, acting to trigger the type I→0 daughter proliferation switch and eventually to stop neuroblasts. Early and late factors regulate each other and four key cell-cycle genes, providing a logical genetic pathway for these transitions. The identification of this extensive driver-stopper temporal program controlling neuroblast lineage progression may have implications for studies in many other systems.less thanbr /greater than (Copyright © 2017 Elsevier Inc. All rights reserved.)

    Ort, förlag, år, upplaga, sidor
    Cell Press, 2017
    Nationell ämneskategori
    Utvecklingsbiologi
    Identifikatorer
    urn:nbn:se:liu:diva-143117 (URN)10.1016/j.devcel.2017.10.004 (DOI)000414584300011 ()29112852 (PubMedID)
    Anmärkning

    Funding agencies: Swedish Research Council [621-2013-5258]; Knut and Alice Wallenberg Foundation [KAW2011.0165, KAW2012.0101]; Swedish Cancer Foundation [140780, 150633]

    Tillgänglig från: 2017-11-20 Skapad: 2017-11-20 Senast uppdaterad: 2017-11-20Bibliografiskt granskad
  • 21.
    Ballantyne, Kaye N.
    et al.
    Erasmus MC University, Netherlands Victoria Police Forens Serv Department, Australia .
    Ralf, Arwin
    Erasmus MC University, Netherlands .
    Aboukhalid, Rachid
    Mohammed V Agdal University, Morocco .
    Achakzai, Niaz M.
    University of Punjab, Pakistan .
    Anjos, Maria J.
    National Institute Legal Medical and Forens Science IP, Portugal .
    Ayub, Qasim
    Wellcome Trust Sanger Institute, England .
    Balazic, Joze
    University of Ljubljana, Slovenia .
    Ballantyne, Jack
    University of Central Florida, FL 32816 USA University of Central Florida, FL 32816 USA .
    J. Ballard, David
    Kings Coll London, England .
    Berger, Burkhard
    Medical University of Innsbruck, Austria .
    Bobillo, Cecilia
    University of Buenos Aires, Argentina Consejo Nacl Invest Cient and Tecn, Argentina .
    Bouabdellah, Mehdi
    Mohammed V Agdal University, Morocco .
    Burri, Helen
    University of Zurich, Switzerland .
    Capal, Tomas
    Institute Criminalist Prague, Czech Republic .
    Caratti, Stefano
    University of Turin, Italy .
    Cardenas, Jorge
    University of Santiago de Compostela, Spain .
    Cartault, Francois
    Site Centre Hospital Felix Guyon, Reunion .
    F. Carvalho, Elizeu
    University of Estado Rio De Janeiro, Brazil .
    Carvalho, Monica
    National Institute Legal Medical and Forens Science IP, Portugal .
    Cheng, Baowen
    Yunnan Prov Department Public Secur, Peoples R China .
    D. Coble, Michael
    NIST, MD 20899 USA .
    Comas, David
    University of Pompeu Fabra, Spain .
    Corach, Daniel
    University of Buenos Aires, Argentina Consejo Nacl Invest Cient and Tecn, Argentina .
    E. DAmato, Maria
    University of Western Cape, South Africa .
    Davison, Sean
    University of Western Cape, South Africa .
    de Knijff, Peter
    Leiden University, Netherlands .
    Corazon A. De Ungria, Maria
    University of Philippines, Philippines .
    Decorte, Ronny
    Katholieke University of Leuven, Belgium .
    Dobosz, Tadeusz
    Wroclaw Medical University, Poland .
    M. Dupuy, Berit
    Norwegian Institute Public Heatlh, Norway .
    Elmrghni, Samir
    University of Benghazi, Libya .
    Gliwinski, Mateusz
    Medical University of Gdansk, Poland .
    C. Gomes, Sara
    University of Madeira, Portugal .
    Grol, Laurens
    Netherlands Forens Institute, Netherlands .
    Haas, Cordula
    University of Zurich, Switzerland .
    Hanson, Erin
    University of Central Florida, FL 32816 USA .
    Henke, Juergen
    Institute Blutgruppenforsch LGC GmbH, Germany .
    Henke, Lotte
    Institute Blutgruppenforsch LGC GmbH, Germany .
    Herrera-Rodriguez, Fabiola
    Poder Judicial, Costa Rica .
    R. Hill, Carolyn
    NIST, MD 20899 USA .
    Holmlund, Gunilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Honda, Katsuya
    University of Tsukuba, Japan .
    Immel, Uta-Dorothee
    University of Halle Wittenberg, Germany .
    Inokuchi, Shota
    National Research Institute Police Science, Japan .
    A. Jobling, Mark
    University of Leicester, England .
    Kaddura, Mahmoud
    University of Benghazi, Libya .
    S. Kim, Jong
    Supreme Prosecutors Off, South Korea .
    H. Kim, Soon
    National Forens Serv, South Korea .
    Kim, Wook
    Dankook University, South Korea .
    E. King, Turi
    University of Leicester, England .
    Klausriegler, Eva
    Salzburg University, Austria .
    Kling, Daniel
    Norwegian Institute Public Heatlh, Norway .
    Kovacevic, Lejla
    Institute Genet Engn and Biotechnol, Bosnia and Herceg .
    Kovatsi, Leda
    Aristotle University of Thessaloniki, Greece .
    Krajewski, Pawel
    Medical University of Warsaw, Poland .
    Kravchenko, Sergey
    NASU, Ukraine .
    H. D. Larmuseau, Maarten
    Katholieke University of Leuven, Belgium .
    Young Lee, Eun
    Yonsei University, South Korea .
    Lessig, Ruediger
    University of Halle Wittenberg, Germany .
    A. Livshits, Ludmila
    NASU, Ukraine .
    Marjanovic, Damir
    Institute Genet Engn and Biotechnol, Bosnia and Herceg .
    Minarik, Marek
    Genomac Forens Institute, Czech Republic .
    Mizuno, Natsuko
    National Research Institute Police Science, Japan .
    Moreira, Helena
    University of Aveiro, Portugal .
    Morling, Niels
    University of Copenhagen, Denmark .
    Mukherjee, Meeta
    Govt India, India .
    Munier, Patrick
    Site Centre Hospital Felix Guyon, Reunion .
    Nagaraju, Javaregowda
    Centre DNA Fingerprinting and Diagnost, India .
    Neuhuber, Franz
    Salzburg University, Austria .
    Nie, Shengjie
    Kunming Medical University, Peoples R China .
    Nilasitsataporn, Premlaphat
    Royal Thai Police, Thailand .
    Nishi, Takeki
    University of Tsukuba, Japan .
    H. Oh, Hye
    Supreme Prosecutors Off, South Korea .
    Olofsson, Jill
    University of Copenhagen, Denmark .
    Onofri, Valerio
    University of Politecn Marche, Italy .
    U. Palo, Jukka
    University of Helsinki, Finland .
    Pamjav, Horolma
    Minist Public Adm and Justice, Hungary .
    Parson, Walther
    Medical University of Innsbruck, Austria Penn State University, PA 16802 USA .
    Petlach, Michal
    Genomac Forens Institute, Czech Republic .
    Phillips, Christopher
    University of Santiago de Compostela, Spain .
    Ploski, Rafal
    Medical University of Warsaw, Poland .
    P. R. Prasad, Samayamantri
    Centre DNA Fingerprinting and Diagnost, India .
    Primorac, Dragan
    Penn State University, PA 16802 USA University of New Haven, CT USA University of Split, Croatia University of Osijek, Croatia .
    A. Purnomo, Gludhug
    Eijkman Institute Molecular Biol, Indonesia .
    Purps, Josephine
    Charite, Germany .
    Rangel-Villalobos, Hector
    University of Guadalajara CUCienega UdeG, Mexico .
    Rebala, Krzysztof
    Medical University of Gdansk, Poland .
    Rerkamnuaychoke, Budsaba
    Mahidol University, Thailand .
    Rey Gonzalez, Danel
    University of Santiago de Compostela, Spain .
    Robino, Carlo
    University of Turin, Italy .
    Roewer, Lutz
    Charite, Germany .
    Rosa, Alexandra
    University of Madeira, Portugal University of Madeira, Portugal .
    Sajantila, Antti
    University of Helsinki, Finland University of N Texas, TX USA .
    Sala, Andrea
    University of Buenos Aires, Argentina Consejo Nacl Invest Cient and Tecn, Argentina .
    M. Salvador, Jazelyn
    University of Philippines, Philippines .
    Sanz, Paula
    University of Pompeu Fabra, Spain .
    Schmitt, Cornelia
    University of Cologne, Germany .
    K. Sharma, Anil
    Govt India, India .
    A. Silva, Dayse
    University of Estado Rio De Janeiro, Brazil .
    Shin, Kyoung-Jin
    Yonsei University, South Korea .
    Sijen, Titia
    Netherlands Forens Institute, Netherlands .
    Sirker, Miriam
    University of Cologne, Germany .
    Sivakova, Daniela
    Comenius University, Slovakia .
    Skaro, Vedrana
    Genos Ltd, Croatia .
    Solano-Matamoros, Carlos
    University of Costa Rica, Costa Rica .
    Souto, Luis
    University of Aveiro, Portugal .
    Stenzl, Vlastimil
    Institute Criminalist Prague, Czech Republic .
    Sudoyo, Herawati
    Eijkman Institute Molecular Biol, Indonesia .
    Syndercombe-Court, Denise
    Kings Coll London, England .
    Tagliabracci, Adriano
    University of Politecn Marche, Italy .
    Taylor, Duncan
    Forens Science South Australia, Australia Flinders University of S Australia, Australia .
    Tillmar, Andreas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Linkoping, Sweden .
    S. Tsybovsky, Iosif
    State Comm Forens Expertises, Byelarus .
    Tyler-Smith, Chris
    Wellcome Trust Sanger Institute, England .
    J. van der Gaag, Kristiaan
    Leiden University, Netherlands .
    Vanek, Daniel
    Forens DNA Serv, Czech Republic Charles University of Prague, Czech Republic .
    Volgyi, Antonia
    Minist Public Adm and Justice, Hungary .
    Ward, Denise
    Forens Science South Australia, Australia .
    Willemse, Patricia
    Leiden University, Netherlands .
    P. H. Yap, Eric
    DSO National Labs, Singapore .
    Y. Y. Yong, Rita
    DSO National Labs, Singapore .
    Zupanic Pajnic, Irena
    University of Ljubljana, Slovenia .
    Kayser, Manfred
    Erasmus MC University, Netherlands .
    Toward Male Individualization with Rapidly Mutating Y-Chromosomal Short Tandem Repeats2014Ingår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 35, nr 8, s. 1021-1032Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Relevant for various areas of human genetics, Y-chromosomal short tandem repeats (Y-STRs) are commonly used for testing close paternal relationships among individuals and populations, and for male lineage identification. However, even the widely used 17-loci Yfiler set cannot resolve individuals and populations completely. Here, 52 centers generated quality-controlled data of 13 rapidly mutating (RM) Y-STRs in 14,644 related and unrelated males from 111 worldwide populations. Strikingly, greater than99% of the 12,272 unrelated males were completely individualized. Haplotype diversity was extremely high (global: 0.9999985, regional: 0.99836-0.9999988). Haplotype sharing between populations was almost absent except for six (0.05%) of the 12,156 haplotypes. Haplotype sharing within populations was generally rare (0.8% nonunique haplotypes), significantly lower in urban (0.9%) than rural (2.1%) and highest in endogamous groups (14.3%). Analysis of molecular variance revealed 99.98% of variation within populations, 0.018% among populations within groups, and 0.002% among groups. Of the 2,372 newly and 156 previously typed male relative pairs, 29% were differentiated including 27% of the 2,378 father-son pairs. Relative to Yfiler, haplotype diversity was increased in 86% of the populations tested and overall male relative differentiation was raised by 23.5%. Our study demonstrates the value of RMY-STRs in identifying and separating unrelated and related males and provides a reference database.

  • 22.
    Barker, A.
    et al.
    Cambridge Institute Public Heatlh, England .
    Lauria, A.
    University of Campus Biomed, Italy .
    Schloot, N.
    University of Dusseldorf, Germany University of Dusseldorf, Germany .
    Hosszufalusi, N.
    Semmelweis University, Hungary .
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Mathieu, C.
    Katholieke University of Leuven, Belgium .
    Mauricio, D.
    Hospital Arnau Vilanova, Spain .
    Nordwall, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Norrköping.
    Van der Schueren, B.
    Katholieke University of Leuven, Belgium .
    Mandrup-Poulsen, T.
    University of Copenhagen, Denmark .
    Scherbaum, W .A.
    University of Dusseldorf, Germany .
    Weets, I.
    Vrije University of Brussel, Belgium Vrije University of Brussel, Belgium Belgian Diabet Registry BDR, Belgium .
    Gorus, F. K.
    Vrije University of Brussel, Belgium Vrije University of Brussel, Belgium Belgian Diabet Registry BDR, Belgium .
    Wareham, N.
    Cambridge Institute Public Heatlh, England .
    Leslie, R. D.
    Queen Mary University of London, England .
    Pozzilli, P.
    University of Campus Biomed, Italy Queen Mary University of London, England .
    Age-dependent decline of beta-cell function in type 1 diabetes after diagnosis: a multi-centre longitudinal study2014Ingår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 16, nr 3, s. 262-267Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AimsC-peptide secretion is currently the only available clinical biomarker to measure residual -cell function in type 1 diabetes. However, the natural history of C-peptide decline after diagnosis can vary considerably dependent upon several variables. We investigated the shape of C-peptide decline over time from type 1 diabetes onset in relation to age at diagnosis, haemoglobin A1c (HbA1c) levels and insulin dose. MethodsWe analysed data from 3929 type 1 diabetes patients recruited from seven European centres representing all age groups at disease onset (childhood, adolescence and adulthood). The influence of the age at onset on -cell function was investigated in a longitudinal analysis at diagnosis and up to 5-years follow-up. ResultsFasting C-peptide (FCP) data at diagnosis were available in 3668 patients stratified according to age at diagnosis in four groups (less than5years, n=344; greater than5yearsless than10years, n=668; greater than10yearsless than18years, n=991; greater than18years, n=1655). FCP levels were positively correlated with age (pless than0.001); the subsequent decline in FCP over time was log-linear with a greater decline rate in younger age groups (pless than0.0001). ConclusionsThis study reveals a positive correlation between age at diagnosis of type 1 diabetes and FCP with a more rapid decline of -cell function in the very young patients. These data can inform the design of clinical trials using C-peptide values as an end-point for the effect of a given treatment.

  • 23.
    Barranco, Isabel
    et al.
    University of Murcia, Murcia, Spain.
    Perez-Patiño, Cristina
    University of Murcia, Murcia, Spain.
    Tvarijonaviciute, Asta
    University of Murcia, Murcia, Spain.
    Parrilla, Inmaculada
    University of Murcia, Murcia, Spain.
    Vicente-Carrillo, Alejandro
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Alvarez-Rodriguez, Manuel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Ceron, Jose J
    University of Murcia, Murcia, Spain.
    Martinez, Emilio A
    University of Murcia, Murcia, Spain.
    Rodriguez-Martinez, Heriberto
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Roca, Jordi
    University of Murcia, Murcia, Spain.
    Active paraoxonase 1 is synthesised throughout the internal boar genital organs.2017Ingår i: Reproduction (Cambridge, England), ISSN 1741-7899, Vol. 154, nr 3, s. 237-243Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The paraoxonase type 1 (PON1) is an enzyme with antioxidant properties recently identified in the seminal plasma (SP) of several species, including the porcine. The aims of the present study were to (1) describe the immunohistochemical localisation of PON1 in the genital organs of fertile boars and (2) evaluate the relationship among PON1 activity and high-density lipoprotein cholesterol (HDL-C) concentration in fluids of the boar genital organs. Immunohistochemical analysis demonstrated that PON1 was present in testis (specifically in Leydig cells, blood vessels, spermatogonia and elongated spermatids), epididymis (specifically in the cytoplasm of the principal epithelial cells, luminal secretion and in the surrounding smooth muscle) and the lining epithelia of the accessory sexual glands (cytoplasmic location in the prostate and membranous in the seminal vesicle and bulbourethral glands). The Western blotting analysis confirmed the presence of PON1 in all boar genital organs, showing in all of them a band of 51 kDa and an extra band of 45 kDa only in seminal vesicles. PON1 showed higher activity levels in epididymal fluid than those in SP of the entire ejaculate or of specific ejaculate portions. A highly positive relationship between PON1 activity and HDL-C concentration was found in all genital fluids. In sum, all boar genital organs contributing to sperm-accompanying fluid/s were able to express PON1, whose activity in these genital fluids is highly dependent on the variable HDL-C concentration present.

  • 24.
    Baumeister, Ulf
    et al.
    Institute of Cell Biology, ZMBE, University of Münster, Münster, Germany.
    Funke, Ruth
    Institute of Cell Biology, ZMBE, University of Münster, Münster, Germany.
    Ebnet, Klaus
    Institute of Cell Biology, ZMBE, University of Münster, Münster, Germany.
    Vorschmitt, Henrik
    Max‐Planck‐Institute of Molecular Biomedicine, Münster, Germany.
    Koch, Stefan
    Max‐Planck‐Institute of Molecular Biomedicine, Münster, Germany.
    Vestweber, Dietmar
    Institute of Cell Biology, ZMBE, University of Münster, Münster, Germany; Max‐Planck‐Institute of Molecular Biomedicine, Münster, Germany.
    Association of Csk to VE-cadherin and inhibition of cell proliferation2005Ingår i: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 24, nr 9, s. 1686-1695Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Vascular endothelial cadherin (VE-cadherin) mediates contact inhibition of cell growth in quiescent endothelial cell layers. Searching for proteins that could be involved in VE-cadherin signaling, we found the cytosolic C-terminal Src kinase (Csk), a negative regulator of Src family kinases. We show that Csk binds via its SH2 domain to the phosphorylated tyrosine 685 of VE-cadherin. VE-cadherin recruits Csk to cell contacts and both proteins can be co-precipitated from cell lysates of transfected cells and endothelial cells. Association of VE-cadherin and Csk in endothelial cells increased with increasing cell density. CHO cells expressing the tyrosine replacement mutant VE-cadherin-Y685F grow to higher cell densities than cells expressing wild-type VE-cadherin. Overexpression of Csk in these cells under an inducible promoter inhibits cell proliferation in the presence and absence of VE-cadherin, but not in the presence of VE-cadherin-Y685F. Reduction of Csk expression by RNA interference enhances endothelial cell proliferation. Our results suggest that the phosphorylated tyrosine residue 685 of VE-cadherin and probably the binding of Csk to this site are involved in inhibition of cell growth triggered by cell density.

  • 25.
    Baumgartner, Johanna
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska fakulteten.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för hematopoes och utvecklingsbiologi.
    Jager, Edwin W. H.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Sensor- och aktuatorsystem. Linköpings universitet, Tekniska fakulteten.
    Switchable presentation of cytokines on electroactive polypyrrole surfaces for hematopoietic stem and progenitor cells2018Ingår i: Journal of Materials Chemistry B, ISSN 2050-750X, Vol. 6, s. 4665-4675Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hematopoietic stem cells are used in transplantations for patients with hematologic malignancies. Scarce sources require efficient strategies of expansion, including polymeric biomaterials mimicking architectures of bone marrow tissue. Tissue microenvironment and mode of cytokine presentation strongly influence cell fate. Although several cytokines with different functions as soluble or membrane-bound mediators have already been identified, their precise roles have not yet been clarified. A need exists for in vitro systems that mimic the in vivo situation to enable such studies. One way is to establish surfaces mimicking physiological presentation using protein-immobilization onto polymer films. However these films merely provide a static presentation of the immobilized proteins. It would be advantageous to also dynamically change protein presentation and functionality to better reflect the in vivo conditions. The electroactive polymer polypyrrole shows excellent biocompatibility and electrochemically alters its surface properties, becoming an interesting choice for such setups. Here, we present an in vitro system for switchable presentation of membrane-bound cytokines. We use interleukin IL-3, known to affect hematopoiesis, and show that when immobilized on polypyrrole films, IL-3 is bioavailable for the bone marrow-derived FDC-P1 progenitor cell line. Moreover, IL-3 presentation can be successfully altered by changing the redox state of the film, in turn influencing FDC-P1 cell viability. This novel in vitro system provides a valuable tool for stimuli-responsive switchable protein presentation allowing the dissection of relevant mediators in stem and progenitor cell behavior.

  • 26.
    Baxtera, Shannon A.
    et al.
    University of Manitoba, Winnipeg, Canada.
    Cheung, David Y.
    University of Manitoba, Winnipeg, Canada.
    Bocangel, Patricia
    University of Manitoba, Winnipeg, Canada.
    Kim, Hae K.
    University of Manitoba, Winnipeg, Canada.
    Herbert, Krista
    University of Manitoba, Winnipeg, Canada.
    Douville, Josette M.
    University of Manitoba, Winnipeg, Canada.
    Jangamreddy, Jaganmohan Reddy
    University of Manitoba, Winnipeg, Canada.
    Zhang, Shunzhen
    University of Manitoba, Winnipeg, Canada.
    Eisensta, David D.
    University of Manitoba, Winnipeg, Canada.
    Wigle, Jeffrey T.
    University of Manitoba, Winnipeg, Canada.
    Regulation of the lymphatic endothelial cell cycle by the PROX1 homeodomain protein2011Ingår i: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1813, nr 1, s. 201-212Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The homeobox transcription factor PROX1 is essential for the development and maintenance of lymphatic vasculature. How PROX1 regulates lymphatic endothelial cell fate remains undefined. PROX1 has been shown to upregulate the expression of Cyclin E, which mediates the G1 to S transition of the cell cycle. Here we demonstrate that PROX1 activates the mouse Cyclin E1 (Ccne1) promoter via two proximal E2F-binding sites. We have determined that the N-terminal region of PROX1 is sufficient to activate a 1-kb Ccne1 promoter, whereas the homeodomain is dispensable for activation. We have identified that the Prospero domain 1 (PD1) is required for the nuclear localization of PROX1. Our comparison of two DNA-binding-deficient constructs of PROX1 showed a cell-type-specific difference between these two proteins in both their localization and function. We demonstrated that siRNA-mediated knockdown of PROX1 in lymphatic endothelial cells decreases progression from G1 to S phase of the cell cycle. We conclude that PROX1 activates the Ccne1 promoter independent of DNA binding, and our results illustrate a novel role for PROX1 in the regulation of lymphatic endothelial cell proliferation.

  • 27.
    Behrens, Kira
    et al.
    Leibniz Institute Expt Virol, Germany; Walter and Eliza Hall Institute Medical Research, Australia.
    Maul, Katrin
    Leibniz Institute Expt Virol, Germany.
    Tekin, Nilguen
    Leibniz Institute Expt Virol, Germany; Leibniz Institute Expt Virol, Germany.
    Kriebitzsch, Neele
    Leibniz Institute Expt Virol, Germany.
    Indenbirken, Daniela
    Leibniz Institute Expt Virol, Germany.
    Prassolov, Vladimir
    Engelhardt Institute Molecular Biol, Russia.
    Mueller, Ursula
    Leibniz Institute Expt Virol, Germany.
    Serve, Hubert
    Goethe University of Frankfurt, Germany.
    Cammenga, Jörg
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Stocking, Carol
    Leibniz Institute Expt Virol, Germany.
    RUNX1 cooperates with FLT3-ITD to induce leukemia2017Ingår i: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 214, nr 3, s. 737-752Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Acute myeloid leukemia (AML) is induced by the cooperative action of deregulated genes that perturb self-renewal, proliferation, and differentiation. Internal tandem duplications (ITDs) in the FLT3 receptor tyrosine kinase are common mutations in AML, confer poor prognosis, and stimulate myeloproliferation. AML patient samples with FLT3-ITD express high levels of RUNX1, a transcription factor with known tumor-suppressor function. In this study, to understand this paradox, we investigated the impact of RUNX1 and FLT3-ITD coexpression. FLT3-ITD directly impacts on RUNX1 activity, whereby up-regulated and phosphorylated RUNX1 cooperates with FLT3-ITD to induce AML. Inactivating RUNX1 in tumors releases the differentiation block and down-regulates genes controlling ribosome biogenesis. We identified Hhex as a direct target of RUNX1 and FLT3-ITD stimulation and confirmed high HHEX expression in FLT3-ITD AMLs. HHEX could replace RUNX1 in cooperating with FLT3-ITD to induce AML. These results establish and elucidate the unanticipated oncogenic function of RUNX1 in AML. We predict that blocking RUNX1 activity will greatly enhance current therapeutic approaches using FLT3 inhibitors.

  • 28.
    Berger, Birgit S.
    et al.
    Division of Molecular Embryology, DKFZ‐ZMBH Alliance, Heidelberg, Germany.
    Acebron, Sergio P.
    Division of Molecular Embryology, DKFZ‐ZMBH Alliance, Heidelberg, Germany.
    Herbst, Jessica
    Division of Molecular Embryology, DKFZ‐ZMBH Alliance, Heidelberg, Germany.
    Koch, Stefan
    Division of Molecular Embryology, DKFZ‐ZMBH Alliance, Heidelberg, Germany.
    Niehrs, Christof
    Division of Molecular Embryology, DKFZ‐ZMBH Alliance, Heidelberg, Germany; Institute of Molecular Biology, Mainz, Germany.
    Parkinson's disease-associated receptor GPR37 is an ER chaperone for LRP62017Ingår i: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 18, nr 5, s. 712-725Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Wnt/beta-catenin signaling plays a key role in embryonic development, stem cell biology, and neurogenesis. However, the mechanisms of Wnt signal transmission, notably how the receptors are regulated, remain incompletely understood. Here we describe that the Parkinson's disease-associated receptor GPR37 functions in the maturation of the N-terminal bulky beta-propellers of the Wnt co-receptor LRP6. GPR37 is required for Wnt/beta-catenin signaling and protects LRP6 from ER-associated degradation via CHIP (carboxyl terminus of Hsc70-interacting protein) and the ATPase VCP GPR37 is highly expressed in neural progenitor cells (NPCs) where it is required for Wnt-dependent neurogenesis. We conclude that GPR37 is crucial for cellular protein quality control during Wnt signaling.

  • 29.
    Bergh, Ann-Charlotte
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Filosofiska fakulteten.
    Importance of microenvironment and antigen in the regulation of growth and survival of CLL cells2016Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Chronic lymphocytic leukemia (CLL) cells rapidly die when put in culture implying that microenvironmental signals delivered by accessory cells confer CLL cells with a growth advantage. Recent findings show that CLL cells are antigen experienced and antigen binding play a critical role in the pathogenesis of the disease. The overall aim of this thesis was to study the influence of the microenvironment and antigen binding in CLL.

    In paper I, we studied the influence of the small redox-regulatory molecule thioredoxin (Trx) on CLL cell survival and proliferation. We found Trx to be highly expressed in CLL lymph nodes (LNs), secreted from stromal cells surrounding proliferating CLL cells in proliferation centers, indicating growth promoting properties. Secreted Trx was also shown to protect CLL cells from apoptosis.

    In paper II, oxidized LDL was added to subset #1 CLL cells. However, in contrast to our hypothesis, we could not observe activation and proliferation of CLL cells. Instead subset #1 CLL cells were unresponsive/anergic through the B cell receptor (BcR). This anergic state could however be overcome by “wash out” of bound antigen or addition of toll-like receptor 9 stimulation in some patients.

    Gene expression profiles differ between groups of CLL patients and in peripheral blood (PB) and LN compartment, due to different microenvironments. However, it is not known whether these differences also apply for DNA methylation. In paper III, we identified various genes that were alternatively methylated between IGHV mutated (M) and unmutated (UM) groups. For example prognostic genes, CLLU1 and LPL, genes involved in B cell signaling, IBTK, as well as numerous TGF-β and NF-κB/TNF pathway genes.

    The intensity and duration of BcR signals are fine-tuned by enhancing or inhibitory coreceptors. SHP-1 inhibits BcR-signals by dephosphorylation. In paper IV, we compared the expression and activity of SHP-1 in CLL cells from LN with matched PB samples. However, in contrast to our hypothesis, SHP-1 activity/phosphorylation status in PB and LN, did not differ significantly.

    This thesis, add another piece to the puzzle, on how the microenvironment and antigens influence CLL pathogenesis. Since great variations among individuals are seen, further studies in different groups of patients are necessary to elucidate the importance of antigen for the development of CLL.

    Delarbeten
    1. Thioredoxin, produced by stromal cells retrieved from the lymph node microenvironment, rescues chronic lymphocytic leukemia cells from apoptosis in vitro
    Öppna denna publikation i ny flik eller fönster >>Thioredoxin, produced by stromal cells retrieved from the lymph node microenvironment, rescues chronic lymphocytic leukemia cells from apoptosis in vitro
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    2007 (Engelska)Ingår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 92, nr 11, s. 1495-1504Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background and Objectives: The redox-regulatory protein thioredoxin has several functions including transcriptional regulation, and antioxidant, cytokine, and chemokine activities. We have previously shown that extracellular thioredoxin protects B-cell chronic lymphocytic leukemia (CLL) cells from apoptosis in vitro. In this study we were interested to determine whether thioredoxin is produced by cells surrounding the CLL cells in the in vivo microenvironment and whether this cell-derived thioredoxin has any leukemia growth-promoting effect in vitro. Design and Methods: Lymph nodes from CLL patients (n=25) were analyzed for thioredoxin expression by immunohistology. Stromal cells purified from the lymph nodes were analyzed for thioredoxin secretion at the single cell level using an ELIspot assay. The survival effect of the stromal-derived thioredoxin was tested by co-culturing stromal- and CLL cells with and without Fab-fragments of an anti-thioredoxin antibody. Results: The results indicated that the thioredoxin production correlated with the amount of proliferating cells and was mainly localized to the proliferation centers (pseudofollicles) in the CLL lymph nodes. The leukemia cells per se showed minimal thioredoxin levels, in contrast, stromal cells strongly expressed thioredoxin. Purified primary stromal cells, which secreted extracellular thioredoxin, significantly protected the CLL cells from undergoing apoptosis in 72 h co-cultures. Interestingly, this anti-apoptotic effect could be abrogated by addition of Fab-fragments of an anti- thioredoxin antibody. Interpretation and Conclusions: In conclusion, we have shown that stromal cells in the lymph node microenvironment produce thioredoxin and that the thioredoxin production is localized to the proliferation centers of the CLL lymph nodes. In addition, thioredoxin produced by purified stromal cells rescued CLL cells from apoptosis in vitro. ©2007 Ferrata Storti Foundation.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-40728 (URN)10.3324/haematol.11448 (DOI)54003 (Lokalt ID)54003 (Arkivnummer)54003 (OAI)
    Tillgänglig från: 2009-10-10 Skapad: 2009-10-10 Senast uppdaterad: 2017-12-13
    2. Silenced B-cell receptor response to autoantigen in a poor-prognostic subset of chronic lymphocytic leukemia
    Öppna denna publikation i ny flik eller fönster >>Silenced B-cell receptor response to autoantigen in a poor-prognostic subset of chronic lymphocytic leukemia
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    2014 (Engelska)Ingår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, nr 11, s. 1722-1730Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Chronic lymphocytic leukemia B-cells express auto/xeno-antigen-reactive antibodies that bind to self-epitopes and resemble natural IgM antibodies in their repertoire. One of the antigenic structures recognized is oxidation-induced malonedialdehyde present on low-density lipoprotein, apoptotic blebs, and on certain microbes. The poor-prognostic stereotyped subset #1 (Clan I IGHV genes-IGKV1(D)-39) express IgM B-cell receptors that bind oxidized low-density lipoprotein. In this study, we have used for the first time this authentic cognate antigen, since it is more faithful to B-cell physiology than anti-IgM, for analysis of downstream B-cell receptor-signal transduction events. Multivalent oxidized low-density lipoprotein showed specific binding to subset #1 IgM/IgD B-cell receptors, whereas native low-density lipoprotein did not. The antigen-binding induced prompt receptor-clustering, followed by internalization. However, the receptor-signal transduction was silenced, revealing no Ca2+ mobilization or cell-cycle entry, while phosphorylated extracellular-regulated kinase1/2 basal levels were high and could not be elevated further by oxidized low-density lipoprotein. Interestingly, B-cell receptor responsiveness was recovered after 48 hours culture in the absence of antigen in half of the cases. Toll-like receptor 9-ligand was found to breach the B-cell receptor-signaling incompetence in 5 of 12 cases pointing to intra-subset heterogeneity. Altogether, this study supports B-cell receptor-unresponsiveness to cognate self-antigen on its own in poor-prognostic subset #1 chronic lymphocytic leukemia indicating that these cells proliferate by other mechanisms that may override B-cell receptor-silencing brought about in a context of self-tolerance/anergy. These novel findings have implications for the understanding of chronic lymphocytic leukemia pathobiology and therapy.

    Ort, förlag, år, upplaga, sidor
    Ferrata Storti Foundation, 2014
    Nyckelord
    Anergy; B-cell Receptor Signaling; Chronic Lymphocytic Leukemia; Oxidized LDL; Stereotyped subsets
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-109020 (URN)10.3324/haematol.2014.106054 (DOI)000347016300013 ()25085355 (PubMedID)
    Tillgänglig från: 2014-07-28 Skapad: 2014-07-28 Senast uppdaterad: 2017-12-05
    3. 450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments
    Öppna denna publikation i ny flik eller fönster >>450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments
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    2013 (Engelska)Ingår i: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 27, nr 1, s. 150-158Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    In chronic lymphocytic leukemia (CLL), the microenvironment influences gene expression patterns; however, knowledge is limited regarding the extent to which methylation changes with time and exposure to specific microenvironments. Using high-resolution 450K-arrays, we provide the most comprehensive DNA methylation study of CLL to date, analysing paired diagnostic/follow-up samples from IGHV-mutated/untreated and IGHV-unmutated/treated patients (n=36) and patient-matched peripheral blood and lymph node samples (n=20). On an unprecedented scale, we revealed 2239 differentially methylated CpG sites between IGHV-mutated and unmutated patients, with the majority of sites positioned outside annotated CpG islands. Intriguingly, CLL prognostic genes (e.g. CLLU1, LPL, ZAP70, NOTCH1), epigenetic regulator (e.g. HDAC9, HDAC4, DNMT3B), B-cell signaling (e.g. IBTK) and numerous TGF-ß and NF-κB/TNF pathway genes were alternatively methylated between subgroups. Contrary, DNA methylation over time was deemed rather stable with few recurrent changes noted within subgroups. Although a larger number of non-recurrent changes were identified among IGHV-unmutated relative to mutated cases over time, these equated to a low global change. Similarly, few changes were identified between compartment cases. Altogether, we reveal CLL subgroups to display unique methylation profiles and unveil methylation as relatively stable over time and similar within different CLL compartments, implying aberrant methylation as an early leukemogenic event.Leukemia accepted article preview online, 27 August 2012; doi:10.1038/leu.2012.245.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-80705 (URN)10.1038/leu.2012.245 (DOI)000313511400021 ()22922567 (PubMedID)
    Tillgänglig från: 2012-08-29 Skapad: 2012-08-29 Senast uppdaterad: 2017-12-07
    4. B cell receptor signaling suppressor SHP-1 is active in CLL lymph node and peripheral blood
    Öppna denna publikation i ny flik eller fönster >>B cell receptor signaling suppressor SHP-1 is active in CLL lymph node and peripheral blood
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    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Protein tyrosine phosphatase SHP-1 expression and activity is downregulated or lost in several leukemias and lymphomas due to DNA promotor hypermethylation, catalytic site mutation or oxidation, or phosphorylation at inhibitory sites, implying a negative role of SHP-1 in development of leukemias/lymphomas. In chronic lymphocytic leukemia (CLL), B cell receptor (BcR) and microenvironment signal levels are important in the pathogenesis. Considering that SHP-1 is a BcR signaling suppressor, we hypothesized that SHP-1 would be down-regulated and/or inactivated in the proliferative center lymph node (LN) cells. We analyzed PTPN6 (SHP-1) gene expression, SHP-1 protein expression and phosphorylation status in matched CD5+/CD19+ peripheral blood (PB) and LN cells from 6 CLL patients, and in comparison, BcR (anti-IgM) in vitro triggered CLL PB cells from 10 patients. Gene expression of PTPN6 was significantly higher in PB compared to LN CLL cells in 50% of the cases. SHP-1 protein expression level and phosphorylation at SHP-1Y536 and SHP-1S591 were, however, equal in PB and LN samples. SHP-1 phosphorylation at Y536 and S591, in PB CLL cells cultured ex vivo was significantly reduced upon BcR engagement in all patient samples. These results indicate that in vivo BcR signaling in CLL is paralyzed.

    Nyckelord
    B cell, chronic lymphocytic leukemia, SHP-1, suppressor, tyrosine phosphorylation
    Nationell ämneskategori
    Cell- och molekylärbiologi Klinisk medicin
    Identifikatorer
    urn:nbn:se:liu:diva-124575 (URN)
    Tillgänglig från: 2016-02-04 Skapad: 2016-02-04 Senast uppdaterad: 2018-01-10Bibliografiskt granskad
  • 30.
    Bergh, Ann-Charlotte
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    El-Schich, Zahra
    Department of Biomedical Science, Health and Society, Malmö University, Malmö, Sweden.
    Delfani, Payam
    Department of Immunotechnology, Lund Institute of Technology, Lund University, Lund, Sweden.
    Ohlsson, Lars
    Department of Biomedical Science, Health and Society, Malmö University, Malmö, Sweden.
    Rosén, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Gjörloff Wingren, Anette
    Department of Biomedical Science, Health and Society, Malmö University, Malmö, Sweden.
    B cell receptor signaling suppressor SHP-1 is active in CLL lymph node and peripheral bloodManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Protein tyrosine phosphatase SHP-1 expression and activity is downregulated or lost in several leukemias and lymphomas due to DNA promotor hypermethylation, catalytic site mutation or oxidation, or phosphorylation at inhibitory sites, implying a negative role of SHP-1 in development of leukemias/lymphomas. In chronic lymphocytic leukemia (CLL), B cell receptor (BcR) and microenvironment signal levels are important in the pathogenesis. Considering that SHP-1 is a BcR signaling suppressor, we hypothesized that SHP-1 would be down-regulated and/or inactivated in the proliferative center lymph node (LN) cells. We analyzed PTPN6 (SHP-1) gene expression, SHP-1 protein expression and phosphorylation status in matched CD5+/CD19+ peripheral blood (PB) and LN cells from 6 CLL patients, and in comparison, BcR (anti-IgM) in vitro triggered CLL PB cells from 10 patients. Gene expression of PTPN6 was significantly higher in PB compared to LN CLL cells in 50% of the cases. SHP-1 protein expression level and phosphorylation at SHP-1Y536 and SHP-1S591 were, however, equal in PB and LN samples. SHP-1 phosphorylation at Y536 and S591, in PB CLL cells cultured ex vivo was significantly reduced upon BcR engagement in all patient samples. These results indicate that in vivo BcR signaling in CLL is paralyzed.

  • 31.
    Bergström, Ida
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    Lundberg, Anna
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    Jönsson, Simon
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    Ernerudh, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Särndahl, Eva
    Department of Clinical Medicine, School of Health and Medical Sciences, and iRiSC - Inflammatory 18 Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Jonasson, Lena
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Kardiologiska kliniken US.
    Annexin A1 expression in blood mononuclear cells: a potential marker of glucocorticoid activity in patients with coronary artery disease2014Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    An imbalance between pro- and anti-inflammatory actions is believed to drive progression of atherosclerosis. Annexin A1 (AnxA1) is a key player in resolution of inflammation and a mediator of anti-inflammatory effects of glucocorticoids. Here, we investigated whether expression of AnxA1 in peripheral blood mononuclear cells (PBMCs) was altered in patients with coronary artery disease (CAD) and also related findings to glucocorticoid sensitivity ex vivo.

    We included 57 patients 6-12 months after acute coronary syndrome (ACS), 10 patients with ACS, and healthy controls. AnxA1 mRNA was measured in PBMCs and AnxA1 protein was assessed in monocytes and lymphocyte subsets by flow cytometry. In post-ACS patients and controls, glucocorticoid sensitivity was determined by measuring inhibitory effects of dexamethasone on LPS46 induced cytokine secretion.

    AnxA1 mRNA levels in PBMCs were higher in patients compared with controls, although most pronounced in ACS patients. AnxA1 protein was most abundant in the monocyte fraction. ACS patients exhibited the highest levels of cell surface-associated AnxA1 protein while levels in post-ACS patients and controls were similar. Ex vivo assays showed that PBMCs from post-ACS patients were more prone to release IL-6. Glucocorticoid sensitivity correlated with cell surface-associated AnxA1 protein in peripheral monocytes. Dexamethasone also induced upregulation of AnxA1 mRNA.

    AnxA1 expression in PBMCs is closely associated with glucocorticoid actions and cell surface associated AnxA1 appears to be a marker of glucocorticoid sensitivity. Although still speculative, a “normal” expression of cell surface-associated AnxA1 in post-ACS patients may suggest that glucocorticoid actions in vivo are insufficient to provide adequate anti-inflammatory effects in these patients.

  • 32.
    Bergström, Ida
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    Lundberg, Anna
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    Reutelingsperger, Chris
    Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands.
    Ernerudh, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Särndahl, Eva
    Department of Clinical Medicine, School of Health and Medical Sciences, and iRiSC - Inflammatory 18 Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Jonasson, Lena
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Kardiologiska kliniken US.
    Higher expression of annexin A1 in 1 CD56+ than in CD56-T cells: Potential implications for coronary artery disease2014Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Background: Increased proportions of circulating proinflammatory CD56+ T cells have been reported in patients with coronary artery disease (CAD). Yet, little is known about regulation of these cells. In the present study, we investigated the expression and potential role of the glucocorticoid-mediated protein annexin A1 (AnxA1) in CD56+ and CD56-T cell subsets, with focus on CAD.

    Methods and Results: We included totally 52 healthy individuals, 28 patients with acute coronary syndrome (ACS) and 57 patients with a history of ACS. AnxA1 mRNA expression was assessed in peripheral blood mononuclear cells. AnxA1 protein expression (total and cell surface-associated) was measured by whole blood flow cytometry in circulating CD56+ and CD56- T cell subsets. Furthermore, inhibitory effects of dexamethasone and/or recombinant AnxA1 on cytokine secretion by CD56+ and CD56- T cells were explored in vitro. We found that CD56+ T cells (the majority CD8+), expressed higher levels of AnxA1 mRNA and protein than did CD56- T cells. When comparing CAD patients with healthy controls, significantly higher levels of cell surface-associated AnxA1 expression were seen in patients, most pronounced in ACS patients. In vitro, dexamethasone reduced cytokine secretion by CD56+ T cells, whereas AnxA1 alone had no effect, and AnxA1 combined with dexamethasone abolished the dexamethasone-induced suppressive effects.

    Conclusion: AnxA1 was expressed more abundantly in proinflammatory CD56+ T cells. Patients with ACS exhibited increased levels of cell surface-associated AnxA1, thus indicating increased activation of the AnxA1 pathway. Our data further suggested that AnxA1 might counteract glucocorticoid mediated anti-inflammatory effects in T cells.

  • 33.
    Bialowas, Sonja
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Hagbom, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Karlsson, Thommie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Nordgren, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Sharma, Sumit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Magnusson, Karl-­Eric
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Svensson, Lennart
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Intracellularly expressed rotavirus NSP4 stimulates release of serotonin (5-HT) from human enterochromaffin cellsManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Rotavirus (RV) is associated with diarrhoea and vomiting, but the mechanisms behind these symptoms remain unresolved. While RV have been shown to infect and stimulate secretion of serotonin (5-hydroxytryptamine; 5-HT) from human enterochromaffin (EC) cells and to infect EC cells in the small intestine of mice, it remains to identify which intracellularly expressed viral protein (VP) being responsible for this novel property.

    To address this issue, human EC cells were transfected with small interfering RNA (siRNA) targeting the structural (VP4, VP6 and VP7) and the non-structural protein 4 (NSP4) followed by infection with Rhesus rotavirus (RRV). siRNA specific to NSP4 (siRNANSP4) significantly attenuated secretion of 5-HT compared to siRNAVP4, siRNAVP6 , siRNAVP7 and non-targeting (Nt) siRNAnt. Intracellular calcium clamping with BABTA/AM showed that intracellularly expressed NSP4-stimulated secretion of 5-HT from EC cells was calcium-dependent. Furthermore RV down-regulated the 5-HT transporter (SERT) mRNA in ileum but not tryptophan hydroxylase 1 (TPH1) mRNA the rate-limiting enzyme for 5-HT synthesis. The unaffected expression of TPH1 mRNA in the intestinal segments suggests that release of 5- HT primarily originates from pre-made 5-HT rather than from newly synthesised 5-HT mRNA. Moreover, down-regulation of SERT mRNA in ileum presumably resulted in reduced re- uptake of 5-HT by SERT to EC cells and thus increased extracellular 5-HT in the small intestine. Moreover, 7/7 infant mice responded following intraperitoneal administration of 5-HT with rapid (<30 min) diarrhoea in dose-dependent manner. In the light of these results and the fact that both 5-HT and NSP4 can induce diarrhoea in mice, a disease mechanism to RV diarrhoea is proposed.

  • 34.
    Bialowas, Sonja
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Hagbom, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Nordgren, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Karlsson, Thommie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Sharma, Sumit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Magnusson, Karl-Eric
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Svensson, Lennart
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Rotavirus and Serotonin Cross-Talk in Diarrhoea2016Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 7, s. e0159660-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Rotavirus (RV) has been shown to infect and stimulate secretion of serotonin from human enterochromaffin (EC) cells and to infect EC cells in the small intestine of mice. It remains to identify which intracellularly expressed viral protein(s) is responsible for this novel property and to further establish the clinical role of serotonin in RV infection. First, we found that siRNA specifically silencing NSP4 (siRNA(NSP4)) significantly attenuated secretion of serotonin from Rhesus rotavirus (RRV) infected EC tumor cells compared to siRNA(VP4), siRNA(VP6) and siRNA(VP7). Second, intracellular calcium mobilization and diarrhoeal capacity from virulent and avirulent porcine viruses correlated with the capacity to release serotonin from EC tumor cells. Third, following administration of serotonin, all (10/10) infants, but no (0/8) adult mice, responded with diarrhoea. Finally, blocking of serotonin receptors using Ondansetron significantly attenuated murine RV (strain EDIM) diarrhoea in infant mice (2.9 vs 4.5 days). Ondansetron-treated mice (n = 11) had significantly (p amp;lt; 0.05) less diarrhoea, lower diarrhoea severity score and lower total diarrhoea output as compared to mock-treated mice (n = 9). Similarly, Ondansetron-treated mice had better weight gain than mock-treated animals (p amp;lt; 0.05). A most surprising finding was that the serotonin receptor antagonist significantly (p amp;lt; 0.05) also attenuated total viral shedding. In summary, we show that intracellularly expressed NSP4 stimulates release of serotonin from human EC tumor cells and that serotonin participates in RV diarrhoea, which can be attenuated by Ondansetron.

  • 35.
    Bivik Eding, Cecilia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Enerbäck, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Involved and Uninvolved Psoriatic Keratinocytes Display a Resistance to Apoptosis that may Contribute to Epidermal Thickness2017Ingår i: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 97, nr 7, s. 788-796Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Psoriasis is a common autoimmune skin disease. The aim of this study was to investigate whether the apoptotic process is disturbed in psoriatic keratinocytes. In vitro culture of keratinocytes derived from both involved and uninvolved psoriatic skin, revealed higher viability and resistance to apoptosis following exposure to ultraviolet B, compared with cells from healthy controls. The position of apoptotic dysregulation was found to be upstream of cytochrome c release in the mitochondrial apoptotic pathway. Microarray transcriptome analysis revealed that 87 genes were differentially expressed in both involved and uninvolved psoriatic keratinocytes compared with controls. Among these, a general upregulation of anti-apoptotic genes and downregulation of pro-apoptotic genes were identified. This distinct apoptosis-resistant phenotype, unrelated to the inflammatory component of the disease, implies that intrinsic abnormalities in keratinocytes may contribute to the pathogenesis of psoriasis.

  • 36.
    Bivik Stadler, Caroline
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Genetic pathways controlling CNS development: The role of Notch signaling in regulating daughter cell proliferation in Drosophila2016Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The human central nervous system (CNS) displays the greatest cellular diversity of any organ system, consisting of billions of neurons, of numerous cell sub-types, interconnected in a vast network. Given this enormous complexity, decoding the genetic programs controlling the multistep process of CNS development remains a major challenge. While great progress has been made with respect to understanding sub-type specification, considerably less is known regarding how the generation of the precise number of each sub-type is controlled.

    The aim of this thesis was to gain deeper knowledge into the regulatory programs controlling cell specification and proliferation. To address these questions I have studied the Drosophila embryonic CNS as a model system, to thereby be able to investigate the genetic mechanisms at high resolution. Despite the different size and morphology between the Drosophila and the mammalian CNS, the lineages of their progenitors share similarity. Importantly for this thesis, both species progenitors show elaborate variations in their proliferation modes, either giving rise to daughters that can directly differentiate into neurons or glia (type 0), divide once (type I), or multiple times (type II).

    The studies launched off with a comprehensive chemical forward genetic screen, for the very last born cell in the well-studied lineage of progenitor NB5-6T: the Ap4 neuron, which expresses the neuropeptide FMRFa. NB5-6T is a powerful model to use, because it undergoes a programmed type I>0 daughter cell proliferation switch. An FMRF-eGFP transgenic reporter was utilized as readout for successful terminal differentiation of Ap4/FMRFa and thereby proper lineage progression of the ∼20 cells generated. The strongest mutants were mapped to genes with both known and novel essential functions e.g., spatial and temporal patterning, cell cycle control, cell specification and chromatin modification. Subsequently, we focused on some of the genes that showed a loss of function phenotype with an excess of lineage cells. We found that Notch is critical for the type I>0 daughter cell proliferation switch in the NB5-6T lineage and globally as well. When addressing the broader relevance of these findings, and to further decipher the Notch pathway, we discovered that selective groups of E(spl) genes is controlling the switch in a close interplay with four key cell cycle factors: Cyclin E, String, E2F and Dacapo, in most if not all embryonic progenitors. The Notch mediation of the switch is likely to be by direct transcriptional regulation. Furthermore, another gene identified in the screen, sequoia, was investigated. The analysis revealed that sequoia is also controlling the daughter cell switch in the CNS, and this partly through context dependent interactions with the Notch pathway.

    Taken together, the findings presented in this thesis demonstrate that daughter cell proliferation switches in Drosophila neural lineages are genetically programmed, and that Notch contributes to the triggering of these events. Given that early embryonic processes is frequently shown to be evolutionary conserved, you can speculate that changeable daughter proliferation programs could be applied to mammals, and contribute to a broader understanding of proliferation processes in humans as well.

     

    Delarbeten
    1. Novel Genes Involved in Controlling Specification of Drosophila FMRFamide Neuropeptide Cells
    Öppna denna publikation i ny flik eller fönster >>Novel Genes Involved in Controlling Specification of Drosophila FMRFamide Neuropeptide Cells
    Visa övriga...
    2015 (Engelska)Ingår i: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 200, nr 4, s. 1229-1244Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The expression of neuropeptides is often extremely restricted in the nervous system, making them powerful markers for addressing cell specification . In the developing Drosophila ventral nerve cord, only six cells, the Ap4 neurons, of some 10,000 neurons, express the neuropeptide FMRFamide (FMRFa). Each Ap4/FMRFa neuron is the last-born cell generated by an identifiable and well-studied progenitor cell, neuroblast 5-6 (NB5-6T). The restricted expression of FMRFa and the wealth of information regarding its gene regulation and Ap4 neuron specification makes FMRFa a valuable readout for addressing many aspects of neural development, i.e., spatial and temporal patterning cues, cell cycle control, cell specification, axon transport, and retrograde signaling. To this end, we have conducted a forward genetic screen utilizing an Ap4-specific FMRFa-eGFP transgenic reporter as our readout. A total of 9781 EMS-mutated chromosomes were screened for perturbations in FMRFa-eGFP expression, and 611 mutants were identified. Seventy-nine of the strongest mutants were mapped down to the affected gene by deficiency mapping or whole-genome sequencing. We isolated novel alleles for previously known FMRFa regulators, confirming the validity of the screen. In addition, we identified novel essential genes, including several with previously undefined functions in neural development. Our identification of genes affecting most major steps required for successful terminal differentiation of Ap4 neurons provides a comprehensive view of the genetic flow controlling the generation of highly unique neuronal cell types in the developing nervous system.

    Ort, förlag, år, upplaga, sidor
    Genetics Society of America, 2015
    Nyckelord
    Drosophila; CNS development; neural cell fate specification; forward genetic screening; FMRFamide
    Nationell ämneskategori
    Klinisk medicin
    Identifikatorer
    urn:nbn:se:liu:diva-121318 (URN)10.1534/genetics.115.178483 (DOI)000359917000020 ()26092715 (PubMedID)
    Tillgänglig från: 2015-09-16 Skapad: 2015-09-14 Senast uppdaterad: 2019-03-13Bibliografiskt granskad
    2. Control of neuronal cell fate and number by integration of distinct daughter cell proliferation modes with temporal progression
    Öppna denna publikation i ny flik eller fönster >>Control of neuronal cell fate and number by integration of distinct daughter cell proliferation modes with temporal progression
    Visa övriga...
    2012 (Engelska)Ingår i: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 139, nr 4, s. 678-689Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    During neural lineage progression, differences in daughter cell proliferation can generate different lineage topologies. This is apparent in the Drosophila neuroblast 5-6 lineage (NB5-6T), which undergoes a daughter cell proliferation switch from generating daughter cells that divide once to generating neurons directly. Simultaneously, neural lineages, e.g. NB5-6T, undergo temporal changes in competence, as evidenced by the generation of different neural subtypes at distinct time points. When daughter proliferation is altered against a backdrop of temporal competence changes, it may create an integrative mechanism for simultaneously controlling cell fate and number. Here, we identify two independent pathways, Prospero and Notch, which act in concert to control the different daughter cell proliferation modes in NB5-6T. Altering daughter cell proliferation and temporal progression, individually and simultaneously, results in predictable changes in cell fate and number. This demonstrates that different daughter cell proliferation modes can be integrated with temporal competence changes, and suggests a novel mechanism for coordinately controlling neuronal subtype numbers.

    Ort, förlag, år, upplaga, sidor
    Company of Biologists, 2012
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-74790 (URN)10.1242/dev.074500 (DOI)000300259800005 ()
    Anmärkning

    funding agencies|Swedish Research Council||Knut and Alice Wallenberg foundation||Swedish Cancer Foundation||

    Tillgänglig från: 2012-02-08 Skapad: 2012-02-08 Senast uppdaterad: 2019-03-13
    3. Control of Neural Daughter Cell Proliferation by Multi-level Notch/Su(H)/E(spl)-HLH Signaling
    Öppna denna publikation i ny flik eller fönster >>Control of Neural Daughter Cell Proliferation by Multi-level Notch/Su(H)/E(spl)-HLH Signaling
    Visa övriga...
    2016 (Engelska)Ingår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, nr 4, artikel-id e1005984Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The Notch pathway controls proliferation during development and in adulthood, and is frequently affected in many disorders. However, the genetic sensitivity and multi-layered transcriptional properties of the Notch pathway has made its molecular decoding challenging. Here, we address the complexity of Notch signaling with respect to proliferation, using the developing Drosophila CNS as model. We find that a Notch/Su(H)/E(spl)-HLH cascade specifically controls daughter, but not progenitor proliferation. Additionally, we find that different E(spl)-HLH genes are required in different neuroblast lineages. The Notch/Su(H)/E(spl)-HLH cascade alters daughter proliferation by regulating four key cell cycle factors: Cyclin E, String/Cdc25, E2f and Dacapo (mammalian p21(CIP1)/p27(KIP1)/p57(Kip2)). ChIP and DamID analysis of Su(H) and E(spl)-HLH indicates direct transcriptional regulation of the cell cycle genes, and of the Notch pathway itself. These results point to a multi-level signaling model and may help shed light on the dichotomous proliferative role of Notch signaling in many other systems.

    Ort, förlag, år, upplaga, sidor
    PUBLIC LIBRARY SCIENCE, 2016
    Nationell ämneskategori
    Klinisk medicin
    Identifikatorer
    urn:nbn:se:liu:diva-128759 (URN)10.1371/journal.pgen.1005984 (DOI)000375231900032 ()27070787 (PubMedID)
    Anmärkning

    Funding Agencies|Knut and Alice Wallenberg Foundation [KAW2012.0101]; Swedish Research Council [621-2010-5214]; Swedish Cancer Foundation [120531]

    Tillgänglig från: 2016-05-31 Skapad: 2016-05-30 Senast uppdaterad: 2019-03-13
    4. sequoia controls the type I>0 daughter proliferation switch in the developing Drosophila nervous system
    Öppna denna publikation i ny flik eller fönster >>sequoia controls the type I>0 daughter proliferation switch in the developing Drosophila nervous system
    2016 (Engelska)Ingår i: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 143, nr 20, s. 3774-3784Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Neural progenitors typically divide asymmetrically to renew themselves, while producing daughters with more limited potential. In the Drosophila embryonic ventral nerve cord, neuroblasts initially produce daughters that divide once to generate two neurons/glia (type I proliferation mode). Subsequently, many neuroblasts switch to generating daughters that differentiate directly (type 0). This programmed type I&gt;0 switch is controlled by Notch signaling, triggered at a distinct point of lineage progression in each neuroblast. However, how Notch signaling onset is gated was unclear. We recently identified Sequoia (Seq), a C2H2 zinc-finger transcription factor with homology to Drosophila Tramtrack (Ttk) and the positive regulatory domain (PRDM) family, as important for lineage progression. Here, we find that seq mutants fail to execute the type I&gt;0 daughter proliferation switch and also display increased neuroblast proliferation. Genetic interaction studies reveal that seq interacts with the Notch pathway, and seq furthermore affects expression of a Notch pathway reporter. These findings suggest that seq may act as a context-dependent regulator of Notch signaling, and underscore the growing connection between Seq, Ttk, the PRDM family and Notch signaling.

    Ort, förlag, år, upplaga, sidor
    The Company of Biologists Ltd, 2016
    Nyckelord
    Lineage tree, Cell cycle, Asymmetric division, Combinatorial control, Notch
    Nationell ämneskategori
    Cell- och molekylärbiologi Biokemi och molekylärbiologi Cellbiologi Medicinsk bioteknologi
    Identifikatorer
    urn:nbn:se:liu:diva-132739 (URN)10.1242/dev.139998 (DOI)000393452500013 ()27578794 (PubMedID)
    Anmärkning

    Funding agencies: Swedish Research Council (Vetenskapsradet); Knut and Alice Wallenberg Foundation (Knut och Alice Wallenbergs Stiftelse); Swedish Cancer Foundation (Cancerfonden)

    Tillgänglig från: 2016-11-22 Skapad: 2016-11-22 Senast uppdaterad: 2019-03-13Bibliografiskt granskad
  • 37.
    Blockhuys, Stephanie
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Chalmers, Sweden.
    Liu, Na
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Rani Agarwal, Nisha
    Chalmers, Sweden.
    Enejder, Annika
    Chalmers, Sweden.
    Loitto, Vesa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    X-radiation enhances the collagen type I strap formation and migration potentials of colon cancer cells2016Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 44, s. 71390-71399Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Rectal cancer treatment still fails with local and distant relapses of the disease. It is hypothesized that radiotherapy could stimulate cancer cell dissemination and metastasis. In this study, we evaluated the effect of X-radiation on collagen type I strap formation potential, i.e. matrix remodeling associated with mesenchymal cell migration, and behaviors of SW480, SW620, HCT116 p53(+/+) and HCT116 p53(-/-) colon cancer cells. We determined a radiation-induced increase in collagen type I strap formation and migration potentials of SW480 and HCT116 p53(+/+). Further studies with HCT116 p53(+/+), indicated that after X-radiation strap forming cells have an increased motility. More, we detected a decrease in adhesion potential and mature integrin beta 1 expression, but no change in non-muscle myosin II expression for HCT116 p53(+/+) after X-radiation. Integrin beta 1 neutralization resulted in a decreased cell adhesion and collagen type I strap formation in both sham and X-radiated conditions. Our study indicates collagen type I strap formation as a potential mechanism of colon cancer cells with increased migration potential after X-radiation, and suggests that other molecules than integrin beta 1 and non-muscle myosin II are responsible for the radiation-induced collagen type I strap formation potential of colon cancer cells. This work encourages further molecular investigation of radiation-induced migration to improve rectal cancer treatment outcome.

  • 38.
    Blomgran, Parmis
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Blomgran, Robert
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Ernerudh, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    A possible link between loading, inflammation and healing: Immune cell populations during tendon healing in the rat2016Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, nr 29824Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Loading influences tendon healing, and so does inflammation. We hypothesized that the two are connected. 48 rats underwent Achilles tendon transection. Half of the rats received Botox injections into calf muscles to reduce mechanical loading. Cells from the regenerating tissue were analyzed by flow cytometry. In the loaded group, the regenerating tissue contained 83% leukocytes (CD45(+)) day 1, and 23% day 10. The M1/M2 macrophage ratio (CCR7/CD206) peaked at day 3, while T helper (CD3(+)CD4(+)) and T-reg cells (CD25(+) Foxp3(+)) increased over time. With Botox, markers associated with down-regulation of inflammation were more common day 5 (CD163, CD206, CD25, Foxp3), and M1 or M2 macrophages and T-reg cells were virtually absent day 10, while still present with full loading. The primary variable, CCR7/CD206 ratio day 5, was higher with full loading (p = 0.001) and the T-reg cell fraction was lower (p amp;lt; 0.001). Free cage activity loading is known to increase size and strength of the tendon in this model compared to Botox. Loading now appeared to delay the switch to an M2 type of inflammation with more T-reg cells. It seems a prolonged M1 phase due to loading might make the tendon regenerate bigger.

  • 39.
    Boij, Roland
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Aspects of inflammation, angiogenesis and coagulation in preeclampsia2016Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Preeclampsia is a major challenge to obstetricians, due to its impact on maternal and fetal morbidity and mortality and the lack of preventive and treatment strategies. The overall aim of this thesis is to increase the knowledge of the pathogenesis of preeclampsia including the role of inflammation, angiogenesis and coagulation, both locally at the fetomaternal interface and in the maternal circulation. Uncompensated maternal endothelial inflammatory responses to factors from stressed trophoblasts seem to be a major contributor to the syndrome, together with an imbalance in angiogenesis and an activated coagulation system. An increasing amount of data indicates an involvement of the immune system with defect tolerance to the conceptus as an integral part of the pathogenesis, at least in early-onset preeclampsia (EOP).

    We showed that a single administration of human preeclampsia serum in pregnant IL-10−/− mice induced the full spectrum of preeclampsia-like symptoms including hypoxic injury in uteroplacental tissues and endotheliosis in maternal kidneys. Importantly, preeclampsia serum, as early as 12 to 14 weeks of gestation, disrupted cross talk between trophoblasts and endothelial cells in an in vitro model of endovascular activity (Tube formation test). These results indicate that preeclamptic sera can be used to better understand the pathophysiology and to predict the disorder. Preeclampsia has been associated with increased inflammation, aberrant angiogenesis and activated coagulation, but their correlation and relative contribution are unknown. We found that markers for all these mechanisms were independently associated with preeclampsia. Cytokines, chemokines, and complement factors seem all to be part of a Th1-associated inflammatory reaction in preeclampsia, more pronounced in EOP than in late-onset preeclampsia (LOP), in line with a more homogeneous pathogenesis in EOP as based on placental pathology. In women with intrauterine growth restriction (IUGR), with an anticipated pathologic placentation, only differences in levels for sFlt-1 and PlGF were found in comparison with mothers without IUGR. Thus, sFlt-1 and PlGF seem to be indicators of placental pathology, while other biomarkers might also reflect maternal endothelial pathology. Chemokines, in contrast to cytokines, may prove to be useful markers in preeclampsia.

    A deficiency in regulatory T (Treg) cells causing reduced immune regulatory capacity has been proposed in preeclampsia. Utilizing recent advances in flow cytometry phenotyping, we found no major alterations in circulating Treg numbers in preeclamptic women compared with normal pregnant and non-pregnant women. However, preeclampsia was associated with increased fractions of CTLA-4+ and CCR4+ cells within Treg subpopulations, which is in line with a migratory defect of Treg cells, and potentially associated with a reduced number of suppressive Treg cells at the fetomaternal interface. As we found that corticosteroid treatment affected the results, it should be accounted for in studies of EOP. Chemokines are supposed to be part of the immune adaptation in pregnancy. We found a decreased expression of CCL18  (Th2/Tregassociated), in trophoblasts from preeclamptic compared to normal pregnant women, indicating a local regulatory defect in preeclampsia, in line with our finding of a possible migratory defect of circulating Treg cells. Due to increased expression of CCL20 (Th17) and CCL22 (Th2) in first trimester placenta and increased circulating levels of CXCL10 (Th1) and CCL20 (Th17) in third trimester preeclamptic women, we suggest that CCL20 and CCL22 may be important for implantation and early placentation while in third trimester of a preeclamptic pregnancy CXCL10 and CCL20 mainly mirror maternal increased endothelial inflammation and aberrant angiogenesis. In summary, we found that preeclampsia is associated with increased inflammation, aberrant angiogenesis and activated coagulation, caused by placental factors in maternal peripheral circulation, more pronounced in the early-onset form of preeclampsia. It also appears that there is a defective modulation of the immune system in preeclamptic pregnancies. The results provide a better understanding of the pathogenesis of preeclampsia and have given suggestions to predictive markers for preeclampsia in the future.

    Delarbeten
    1. Sera from Preeclampsia Patients Elicit Symptoms of Human Disease in Mice and Provide a Basis for an in Vitro Predictive Assay
    Öppna denna publikation i ny flik eller fönster >>Sera from Preeclampsia Patients Elicit Symptoms of Human Disease in Mice and Provide a Basis for an in Vitro Predictive Assay
    Visa övriga...
    2010 (Engelska)Ingår i: AMERICAN JOURNAL OF PATHOLOGY, ISSN 0002-9440, Vol. 177, nr 5, s. 2387-2398Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Early diagnosis and treatment of preeclampsia would significantly reduce maternal and fetal morbidity and mortality. However, its etiology and prediction have remained elusive. Based on the hypothesis that sera from patients with preeclampsia could function as a "blueprint" of causative factors, we describe a serum-based pregnancy-specific mouse model that closely mirrors the human condition as well as an in vitro predictive assay. We show that a single administration of human preeclampsia serum in pregnant IL-10(-/-) mice induced the full spectrum of preeclampsia-like symptoms, caused hypoxic injury in uteroplacental tissues, and elevated soluble fins-like tyrosine kinase 1 and soluble endoglin, markers thought to be related to the disease. The same serum sample(s) induced a partial preeclampsia phenotype in wild-type mice. Importantly, preeclampsia serum disrupted cross talk between trophoblasts and endothelial cells in an in vitro model of endovascular activity. Disruption of endovascular activity could be documented in serum samples as early as 12 to 14 weeks of gestation from patients who subsequently developed preeclampsia. These results indicate that preeclampsia patient sera can be used to understand the pregnancy-specific disease pathology in mice and can predict the disorder.

    Ort, förlag, år, upplaga, sidor
    American Society for Investigative Pathology (ASIP), 2010
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-62755 (URN)10.2353/ajpath.2010.100475 (DOI)000284182900026 ()
    Tillgänglig från: 2010-12-03 Skapad: 2010-12-03 Senast uppdaterad: 2016-11-11
    2. Biomarkers of Coagulation, Inflammation, and Angiogenesis are Independently Associated with Preeclampsia
    Öppna denna publikation i ny flik eller fönster >>Biomarkers of Coagulation, Inflammation, and Angiogenesis are Independently Associated with Preeclampsia
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    2012 (Engelska)Ingår i: AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, ISSN 1046-7408, Vol. 68, nr 3, s. 258-270Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Problem Although preeclampsia has been associated with inflammation, coagulation, and angiogenesis, their correlation and relative contribution are unknown. Method of Study About 114 women with preeclampsia, 31 with early onset (EOP) and 83 with late onset preeclampsia (LOP), and 100 normal pregnant controls were included. A broad panel of 32 biomarkers reflecting coagulation, inflammation, and angiogenesis was analyzed. Results Preeclampsia was associated with decreased antithrombin, IL-4 and placental growth factor levels and with increased C3a, pentraxin-3, and sFlt-1 levels, with more marked differences in the EOP group. The Th1-associated chemokines CXCL10 and CXCL11 were significantly higher in the preeclampsia and EOP group than in controls, respectively. No correlations between the biomarkers were found in preeclampsia. Multivariate logistic regression tests confirmed the results. Conclusions Cytokines, chemokines and complement activation seem to be part of a Th1-like inflammatory reaction in preeclampsia, most pronounced in EOP, where chemokines may be more useful than cytokines as biomarkers. Biomarkers were not correlated suggesting partly independent or in time separated mechanisms.

    Ort, förlag, år, upplaga, sidor
    John Wiley and Sons, 2012
    Nyckelord
    preeclampsia, coagulation, inflammation, angiogenesis, chemokines, cytokines and early onset preeclampsia
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-81815 (URN)10.1111/j.1600-0897.2012.01158.x (DOI)000307440300012 ()
    Anmärkning

    Funding Agencies|FORSS (Medical Research Council of Southeast Sweden)||Futurum (the Research department of County of Jonkoping)||Swedish Research Council|2007-15809-48800-58|Linneaus University (Sweden)||

    Tillgänglig från: 2012-09-26 Skapad: 2012-09-24 Senast uppdaterad: 2016-11-11
    3. Regulatory T-cell Subpopulations in Severe or Early-onset Preeclampsia
    Öppna denna publikation i ny flik eller fönster >>Regulatory T-cell Subpopulations in Severe or Early-onset Preeclampsia
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    2015 (Engelska)Ingår i: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 74, nr 4, s. 368-378Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Problem A deficiency in regulatory T (Treg) cells causing reduced immune regulatory capacity has been proposed in preeclampsia. Objective Utilizing recent advances in flow cytometry phenotyping, we aimed to assess whether a deficiency of Treg subpopulations occurs in preeclampsia. Method of study Six-color flow cytometry was used for Treg phenotyping in 18 preeclamptic women (one early-onset, one severe and 16 both), 20 women with normal pregnancy, and 20 non-pregnant controls. Results No differences were found in major Treg populations including CD127(low)CD25(+)/CD127(ow)FOXP3(+), resting (FOXP3(dim)CD45RA(+)), and activated (FOXP3(bright)CD45RA(-)) Treg cells, whereas preeclamptic women showed increased CTLA-4(+) and CCR4(+) proportions within resting/activated Treg populations. Corticosteroid treatment prior to blood sampling (n = 10) affected the distribution of Treg populations. Conclusions Although we found no major alterations in circulating Treg frequencies, differences in CTLA-4(+) and CCR4(+) frequencies suggest a migratory defect of Treg cells in preeclampsia. Corticosteroid treatment should be taken into account when evaluating Treg cells.

    Ort, förlag, år, upplaga, sidor
    WILEY-BLACKWELL, 2015
    Nyckelord
    Early-onset preeclampsia; preeclampsia; pregnancy; regulatory T cells
    Nationell ämneskategori
    Reproduktionsmedicin och gynekologi
    Identifikatorer
    urn:nbn:se:liu:diva-122528 (URN)10.1111/aji.12410 (DOI)000362664200009 ()26118401 (PubMedID)
    Anmärkning

    Funding Agencies|FORSS (Medical Research Council of Southeast Sweden); Futurum, academy for Health and Care Jonkoping County Council, Sweden

    Tillgänglig från: 2015-11-09 Skapad: 2015-11-06 Senast uppdaterad: 2017-12-01
  • 40.
    Bojmar, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Metastatic Mechanisms in Malignant Tumors2015Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The ultimate cause of cancer related deaths is metastasis. This thesis is about three of the main human cancers; breast, colorectal and pancreatic cancer, that together account for more than 25% of the cancer-related deaths worldwide. The focus of the thesis is the spread of cancer, metastasis, and the aim was to investigate mechanisms that can be of importance for this process. We analyzed patient samples to validate the role of epithelialto-mesenchymal transition in vivo and found regulations of many related factors. However, these changes tend to fluctuate along the metastatic process, something which makes targeting complicated. We, moreover, focused on the influence of the tumor microenvironment for metastatic spread. In pancreatic cancer, the stroma constitutes the main part of many tumors. We analyzed the crosstalk between tumor and stromal cell and focused on the mediating inflammatory factor interleukin-1 (IL-1) and regulation of microRNAs. The results showed that the most commonly mutated factor in pancreatic cancer, KRAS, associates with the expression of IL-1 and subsequent activation of stromal cells. Blocking KRAS signaling together with IL-1 blockage give a more pronounced effect on in vitro proliferation and migration of cancer cells and suggests the use of a combination therapy. The cancer-associated activation of the stroma was found to be related to changes in microRNA expression. microRNA was analyzed separately in epithelial cells and stromal cells after microdissection of matched samples of primary and secondary tumors of breast and colorectal cancers. miR-214 and miR-199a were upregulated in stroma associated with progressive tumors and in pancreatic cancer stroma we could show that their expression alters the activation of stromal cells and thereby the growth and migratory ability of associated pancreatic tumor cells. In  breast and colorectal cancers we found several common microRNAs to be up- or downregulated in line with progression. We could show that one of these candidates, miR-18a, had a prognostic value in metastatic breast cancer. To further develop these studies we analyzed this microRNA in circulating microvesicles, i.e. exosomes, and investigated their role in the preparation of a pre-metastatic niche. MicroRNAs are stable biomarkers in the circulation, especially protected in exosomes, which can moreover specifically deliver their message to recipient cells. These studies facilitate the understanding of metastatic behavior and suggest new targets to stop cancer metastasis.

    Delarbeten
    1. The Role of MicroRNA-200 in Progression of Human Colorectal and Breast Cancer
    Öppna denna publikation i ny flik eller fönster >>The Role of MicroRNA-200 in Progression of Human Colorectal and Breast Cancer
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    2013 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 12, s. 84815-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The role of the epithelial-mesenchymal transition (EMT) in cancer has been studied extensively in vitro, but involvement of the EMT in tumorigenesis in vivo is largely unknown. We investigated the potential of microRNAs as clinical markers and analyzed participation of the EMT-associated microRNA-200 ZEB E-cadherin pathway in cancer progression. Expression of the microRNA-200 family was quantified by real-time RT-PCR analysis of fresh-frozen and microdissected formalin-fixed paraffin-embedded primary colorectal tumors, normal colon mucosa, and matched liver metastases. MicroRNA expression was validated by in situ hybridization and after in vitro culture of the malignant cells. To assess EMT as a predictive marker, factors considered relevant in colorectal cancer were investigated in 98 primary breast tumors from a treatment-randomized study. Associations between the studied EMTmarkers were found in primary breast tumors and in colorectal liver metastases. MicroRNA-200 expression in epithelial cells was lower in malignant mucosa than in normal mucosa, and was also decreased in metastatic compared to non-metastatic colorectal cancer. Low microRNA-200 expression in colorectal liver metastases was associated with bad prognosis. In breast cancer, low levels of microRNA-200 were related to reduced survival and high expression of microRNA-200 was predictive of benefit from radiotheraphy. MicroRNA-200 was associated with ER positive status, and inversely correlated to HER2 and overactivation of the PI3K/AKT pathway, that was associated with high ZEB1 mRNA expression. Our findings suggest that the stability of microRNAs makes them suitable as clinical markers and that the EMT-related microRNA-200 - ZEB - E-cadherin signaling pathway is connected to established clinical characteristics and can give useful prognostic and treatment-predictive information in progressive breast and colorectal cancers.

    Ort, förlag, år, upplaga, sidor
    Public Library of Science, 2013
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-103717 (URN)10.1371/journal.pone.0084815 (DOI)000328745100188 ()
    Tillgänglig från: 2014-01-24 Skapad: 2014-01-24 Senast uppdaterad: 2019-02-11
    2. IL-1α Expression in Pancreatic Ductal Adenocarcinoma Affects the Tumor Cell Migration and Is Regulated by the p38MAPK Signaling Pathway
    Öppna denna publikation i ny flik eller fönster >>IL-1α Expression in Pancreatic Ductal Adenocarcinoma Affects the Tumor Cell Migration and Is Regulated by the p38MAPK Signaling Pathway
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    2013 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 8Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The interplay between the tumor cells and the surrounding stroma creates inflammation, which promotes tumor growth and spread. The inflammation is a hallmark for pancreatic adenocarcinoma (PDAC) and is to high extent driven by IL-1α. IL-1α is expressed and secreted by the tumor cells and exerting its effect on the stroma, i.e. cancer associated fibroblasts (CAF), which in turn produce massive amount of inflammatory and immune regulatory factors. IL-1 induces activation of transcription factors such as nuclear factor-κβ (NF-κβ), but also activator protein 1 (AP-1) via the small G-protein Ras. Dysregulation of Ras pathways are common in cancer as this oncogene is the most frequently mutated in many cancers. In contrast, the signaling events leading up to the expression of IL-1α by tumor cells are not well elucidated. Our aim was to examine the signaling cascade involved in the induction of IL-1α expression in PDAC. We found p38MAPK, activated by the K-Ras signaling pathway, to be involved in the expression of IL-1α by PDAC as blocking this pathway decreased both the gene and protein expression of IL-1α. Blockage of the P38MAPK signaling in PDAC also dampened the ability of the tumor cell to induce inflammation in CAFs. In addition, the IL-1α autocrine signaling regulated the migratory capacity of PDAC cells. Taken together, the blockage of signaling pathways leading to IL-1α expression and/or neutralization of IL-1α in the PDAC microenvironment should be taken into consideration as possible treatment or complement to existing treatment of this cancer.

    Ort, förlag, år, upplaga, sidor
    Public Library of Science, 2013
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-97445 (URN)10.1371/journal.pone.0070874 (DOI)000323097300061 ()
    Anmärkning

    Funding Agencies|Swedish Research Council|AI52731|VINNMER (Vinnova)||Medical Research Council of Southeast Sweden||Swedish Society of Medicine||

    Tillgänglig från: 2013-09-12 Skapad: 2013-09-12 Senast uppdaterad: 2017-12-06
    3. MicroRNA-199a and -214 as potential therapeutic targets in pancreatic stellate cells in pancreatic tumor
    Öppna denna publikation i ny flik eller fönster >>MicroRNA-199a and -214 as potential therapeutic targets in pancreatic stellate cells in pancreatic tumor
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    2016 (Engelska)Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 13, s. 16396-16408Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Pancreatic stellate cells (PSCs) are the key precursor cells for cancer-associated fibroblasts (CAFs) in pancreatic tumor stroma. Although depletion of tumor stroma is debatable, attenuation of PSC activity is still an interesting strategy to treat pancreatic cancer. In this study, we explored miRNA as therapeutic targets in tumor stroma and found miR-199a-3p and miR-214-3p induced in patient-derived pancreatic CAFs as well as in TGF-β-activated human PSCs (hPSCs). Inhibition of miR-199a or miR-214 using their hairpin inhibitors in hPSCs significantly inhibited their TGFβ-induced differentiation (gene and protein levels of α-SMA, Collagen, PDGFβR), migration and proliferation. Furthermore, heterospheroids of Panc-1 and hPSCs were prepared, which attained smaller size when hPSCs were transfected with anti-miR-199a or -214 than those transfected with control anti-miR. The conditioned medium obtained from TGFβ-activated hPSCs induced tumor cell proliferation and endothelial cell tube formation, but these effects were abrogated when hPSCs were transfected with anti-miR-199a or miR-214. Moreover, IPA analyses revealed signaling pathways related to miR-199a (TP53, mTOR, Smad1) and miR-214 (PTEN, Bax, ING4). Taken together, this study reveals miR-199a-3p and miR-214-3p as major regulators of PSC activation and PSC-induced pro-tumoral effects, representing them as key therapeutic targets in PSCs in pancreatic cancer.

    Ort, förlag, år, upplaga, sidor
    Impact press, 2016
    Nationell ämneskategori
    Cancer och onkologi Cell- och molekylärbiologi Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
    Identifikatorer
    urn:nbn:se:liu:diva-122828 (URN)10.18632/oncotarget.7651 (DOI)000375692900085 ()
    Anmärkning

    Funding agencies: Swedish Research Council, Stockholm, Sweden [K7/60501283]

    Vid tiden för disputationen förelåg publikationen endast som manuskript

    Tillgänglig från: 2015-11-26 Skapad: 2015-11-26 Senast uppdaterad: 2018-01-10
    4. miR-18a is regulated between progressive compartments of cancers, and incorporated in exosomes with the potential of creating premetastatic niches and predict cancer outcome
    Öppna denna publikation i ny flik eller fönster >>miR-18a is regulated between progressive compartments of cancers, and incorporated in exosomes with the potential of creating premetastatic niches and predict cancer outcome
    Visa övriga...
    2015 (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The ultimate cause of death for many cancer patients is the spread of the cancer via metastasis. Even so, there are still a lack of knowledge regarding the metastasis process. This study was performed to investigate the role of metastamirs in exosomes and their metastatic patterns. We used the well-established isogeneic murine cancer model of low metastatic 67NR cells, mimicking luminal/basal breast tumors, and highly metastatic 4T1 cells with characteristics of basal breast  tumors. We studied the exosomal properties and pre-metastatic effects in this metastasis model and compared human materials and exosomes of several other tumor types. Our data clearly demonstrated that exosomes from the highly metastatic cells home to the metastatic organs of their parental cells whereas exosomes from cells with low metastatic potential mostly located to lymph nodes. The exosome protein cargos also resembled their parental cells and potentially affects their target organs, and cells, differently. Furthermore, the exosomes from the highly metastatic cells had a more pronounced effect on tumor growth and pre-metastatic changes than the low metastatic exosomes. The microRNA-18a, a predictor of metastasis, was present to a higher extent in metastatic exosomes as compared to low metastatic exosomes, and altered the tumor progressive properties. Our findings support the role of exomirs as important players in the metastatic process, the value as biomarkers and potential therapeutic targets.

    Nationell ämneskategori
    Cancer och onkologi Cell- och molekylärbiologi Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
    Identifikatorer
    urn:nbn:se:liu:diva-122829 (URN)
    Tillgänglig från: 2015-11-26 Skapad: 2015-11-26 Senast uppdaterad: 2018-01-10Bibliografiskt granskad
  • 41.
    Bojmar, Linda
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Zhang, Haiying
    Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medical College, New York, USA.
    Costa da Silva, Bruno
    Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medical College, New York, USA.
    Karlsson, Elin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Olsson, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Vincent, Theresa
    Departments of Physiology and Biophysics and Cell and Developmental Biology, Weill Cornell Medical College, New York, USA / Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Lyden, David
    Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medical College, New York, USA.
    Sandström, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    miR-18a is regulated between progressive compartments of cancers, and incorporated in exosomes with the potential of creating premetastatic niches and predict cancer outcome2015Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The ultimate cause of death for many cancer patients is the spread of the cancer via metastasis. Even so, there are still a lack of knowledge regarding the metastasis process. This study was performed to investigate the role of metastamirs in exosomes and their metastatic patterns. We used the well-established isogeneic murine cancer model of low metastatic 67NR cells, mimicking luminal/basal breast tumors, and highly metastatic 4T1 cells with characteristics of basal breast  tumors. We studied the exosomal properties and pre-metastatic effects in this metastasis model and compared human materials and exosomes of several other tumor types. Our data clearly demonstrated that exosomes from the highly metastatic cells home to the metastatic organs of their parental cells whereas exosomes from cells with low metastatic potential mostly located to lymph nodes. The exosome protein cargos also resembled their parental cells and potentially affects their target organs, and cells, differently. Furthermore, the exosomes from the highly metastatic cells had a more pronounced effect on tumor growth and pre-metastatic changes than the low metastatic exosomes. The microRNA-18a, a predictor of metastasis, was present to a higher extent in metastatic exosomes as compared to low metastatic exosomes, and altered the tumor progressive properties. Our findings support the role of exomirs as important players in the metastatic process, the value as biomarkers and potential therapeutic targets.

  • 42.
    Boman, Andrea
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Lysosomal network proteins as biomarkers and therapeutic targets in neurodegenerative disease2015Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The pre-symptomatic stage of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) occurs several decades before the clinical onset. Changes in the lysosomal network, i.e. the autophagosomal, endosomal and lysosomal vesicular system, are among the first alterations observed. There are currently no treatments to slow or cure neurodegenerative diseases, and there is a great need for discovery of treatment targets in cellular pathways where pathology pre-dates the neuronal death. It is also crucial to be able to diagnose neurodegenerative diseases earlier, both to enable early intervention treatment and aid in selecting clinical trial populations before the patient has widespread pathology.

    This thesis aims at investigating the potential of lysosomal network proteins as biomarkers and therapeutic targets in neurodegenerative disease.

    A targeted search for lysosomal network proteins was performed in cerebrospinal fluid (CSF) from AD patients, and seven proteins: early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), lysozyme, microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were elevated. The levels of EEA1, LAMP-1, LAMP-2, LC3, lysozyme and Rab3 were also measured in CSF from parkinsonian syndrome patients: PD, clinically diagnosed 4-repeat tauopathy, pathologically confirmed corticobasal degeneration (CBD) and pathologically confirmed progressive supranuclear palsy (PSP) patients. LAMP-1 and LAMP-2 were decreased in PD. LC3 and lysozyme levels were increased in 4-repeat tauopathy patients. EEA1 was decreased and lysozyme increased in PSP, and LAMP-1, LAMP-2, LC3 and lysozyme were increased in CBD. The lysosomal network proteins had different CSF protein profiles in all the parkinsonian syndromes, as well as in AD. It should be emphasized that only a select few of the lysosomal network proteins were observed to be changed, rather than a general change in lysosomal network proteins, which implicates the involvement of these seven proteins in specific pathological processes. The most interesting candidates, LAMP-2 and lysozyme, were selected for further study for their involvement in the pathology of AD.

    Lysozyme was found to co-localise with Aβ plaques in AD patients and overexpression prolonged survival and improved the activity in a Drosophila model of AD. Lysozyme was found to alter the aggregation pathway of Aβ1-42, to counteract the formation of toxic Aβ species and to protect from Aβ1-42 induced cell toxicity. Aβ1-42 in turn was found to increase the expression of lysozyme in both neuronal and glial cells. These data suggest that lysozyme levels rise in AD as a compensatory response which is protective against Aβ associated toxicity.

    LAMP-2 mRNA and protein were found increased in brain areas relevant for AD pathology and various cellular models showed complex involvement of LAMP-2 in Aβ related pathology, with extensive crosstalk between LAMP-2 and Aβ. Exposure to oligomeric Aβ1-42 caused an upregulation of LAMP-2 and in turn, overexpression of LAMP-2 caused a reduction in secreted levels of Aβ1-42, as well as changing the generation pattern of Aβ and affecting clearance and secretion of Aβ1-42. These data indicate that the increased levels of LAMP-2 in AD could be an attempt to regulate Aβ generation and secretion.

    In summary, this thesis reports that utilising lysosomal network proteins as biomarkers and novel therapeutic targets for neurodegenerative diseases holds great promise.

    Delarbeten
    1. Lysosomal Network Proteins as Potential Novel CSF Biomarkers for Alzheimers Disease
    Öppna denna publikation i ny flik eller fönster >>Lysosomal Network Proteins as Potential Novel CSF Biomarkers for Alzheimers Disease
    Visa övriga...
    2014 (Engelska)Ingår i: Neuromolecular medicine, ISSN 1535-1084, E-ISSN 1559-1174, Vol. 16, nr 1, s. 150-160Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The success of future intervention strategies for Alzheimers disease (AD) will likely rely on the development of treatments starting early in the disease course, before irreversible brain damage occurs. The pre-symptomatic stage of AD occurs at least one decade before the clinical onset, highlighting the need for validated biomarkers that reflect this early period. Reliable biomarkers for AD are also needed in research and clinics for diagnosis, patient stratification, clinical trials, monitoring of disease progression and the development of new treatments. Changes in the lysosomal network, i.e., the endosomal, lysosomal and autophagy systems, are among the first alterations observed in an AD brain. In this study, we performed a targeted search for lysosomal network proteins in human cerebrospinal fluid (CSF). Thirty-four proteins were investigated, and six of them, early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were significantly increased in the CSF from AD patients compared with neurological controls. These results were confirmed in a validation cohort of CSF samples, and patients with no neurochemical evidence of AD, apart from increased total-tau, were found to have EEA1 levels corresponding to the increased total-tau levels. These findings indicate that increased levels of LAMP-1, LAMP-2, LC3, Rab3 and Rab7 in the CSF might be specific for AD, and increased EEA1 levels may be a sign of general neurodegeneration. These six lysosomal network proteins are potential AD biomarkers and may be used to investigate lysosomal involvement in AD pathogenesis.

    Ort, förlag, år, upplaga, sidor
    Humana Press, 2014
    Nyckelord
    PICALM; DRAM; TFEB; Cathepsins; Proteasome; hsc70
    Nationell ämneskategori
    Cell- och molekylärbiologi
    Identifikatorer
    urn:nbn:se:liu:diva-105235 (URN)10.1007/s12017-013-8269-3 (DOI)000331101900015 ()
    Tillgänglig från: 2014-03-14 Skapad: 2014-03-14 Senast uppdaterad: 2018-01-11
    2. Protective properties of lysozyme on β-amyloid pathology: implications for Alzheimer disease
    Öppna denna publikation i ny flik eller fönster >>Protective properties of lysozyme on β-amyloid pathology: implications for Alzheimer disease
    Visa övriga...
    2015 (Engelska)Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 83, s. 122-133Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The hallmarks of Alzheimer disease are amyloid-β plaques and neurofibrillary tangles accompanied by signs of neuroinflammation. Lysozyme is a major player in the innate immune system and has recently been shown to prevent the aggregation of amyloid-β1-40 in vitro. In this study we found that patients with Alzheimer disease have increased lysozyme levels in the cerebrospinal fluid and lysozyme co-localized with amyloid-β in plaques. In Drosophila neuronal co-expression of lysozyme and amyloid-β1-42 reduced the formation of soluble and insoluble amyloid-β species, prolonged survival and improved the activity of amyloid-β1-42 transgenic flies. This suggests that lysozyme levels rise in Alzheimer disease as a compensatory response to amyloid-β increases and aggregation. In support of this, in vitro aggregation assays revealed that lysozyme associates with amyloid-β1-42 and alters its aggregation pathway to counteract the formation of toxic amyloid-β species. Overall, these studies establish a protective role for lysozyme against amyloid-β associated toxicities and identify increased lysozyme in patients with Alzheimer disease. Therefore, lysozyme has potential as a new biomarker as well as a therapeutic target for Alzheimer disease.

    Ort, förlag, år, upplaga, sidor
    Elsevier, 2015
    Nyckelord
    Lysozyme, Biomarker, Alzheimer disease, Drosophila, Aβ aggregation
    Nationell ämneskategori
    Cell- och molekylärbiologi Kemi
    Identifikatorer
    urn:nbn:se:liu:diva-122341 (URN)10.1016/j.nbd.2015.08.024 (DOI)000366230000012 ()26334479 (PubMedID)
    Tillgänglig från: 2015-10-29 Skapad: 2015-10-29 Senast uppdaterad: 2018-01-10Bibliografiskt granskad
    3. Distinct lysosomal network protein profiles in parkinsonian syndrome cerebrospinal fluid
    Öppna denna publikation i ny flik eller fönster >>Distinct lysosomal network protein profiles in parkinsonian syndrome cerebrospinal fluid
    Visa övriga...
    2016 (Engelska)Ingår i: Journal of Parkinson's Disease, ISSN 1877-7171, E-ISSN 1877-718X, Vol. 6, nr 2, s. 307-315Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Introduction: Clinical diagnosis of parkinsonian syndromes like Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy is hampered by overlapping symptomatology and lack of biomarkers for diagnosis, and definitive diagnosis is only possible post-mortem. Since impaired protein degradation plays an important role in many neurodegenerative disorders, we hypothesized that levels and profiles of lysosomal network proteins in cerebrospinal fluid could be changed in these parkinsonian syndromes.

    Methods: Cerebrospinal fluid samples were collected from Parkinson’s disease patients (n=18), clinically diagnosed 4-repeat tauopathy patients, corticobasal syndrome (n=6) and progressive supranuclear palsy (n=5), pathologically diagnosed progressive supranuclear palsy (n=8) and corticobasal degeneration patients (n=7). Each patient set was compared to its appropriate control group consisting of the same number of age and gender matched individuals. Lysosomal network protein levels were detected via Western blotting.

    Results: Lysosomal network proteins have markedly different cerebrospinal fluid protein levels and profiles in Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy. Lysosomal-associated membrane proteins 1 and 2 were significantly decreased in Parkinson´s disease; early endosomal antigen 1 was decreased and lysozyme increased in progressive supranuclear palsy; and lysosomal-associated membrane proteins 1 and 2, microtubule-associated protein 1 light chain 3 and lysozyme were increased in corticobasal degeneration.

    Conclusions: Lysosomal network proteins hold promise of being interesting novel candidates for biomarker studies and for elucidating disease mechanisms of Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy, but further validation studies will be needed to assess the specificity and the predictive value of these proteins in CSF.

    Ort, förlag, år, upplaga, sidor
    IOS Press, 2016
    Nationell ämneskategori
    Cell- och molekylärbiologi Kemi
    Identifikatorer
    urn:nbn:se:liu:diva-122342 (URN)10.3233/JPD-150759 (DOI)000378352200004 ()
    Anmärkning

    Funding agencies:This work was supported by the Swedish Alzheimer foundation, the Swedish Dementia foundation, Linkoping University Neurobiology Center, Karin & Sten CBD Solutions AB, AZ-KI TSC, ALF, US National Institutes of Health R01AG038791 and U54NS092089, the Tau Consortium, the Hellman Family Foundation.

    Vid tiden för disputationen förelåg publikationen endast som manuskript

    Tillgänglig från: 2015-10-29 Skapad: 2015-10-29 Senast uppdaterad: 2018-01-10Bibliografiskt granskad
    4. The role of LAMP-2 in AβPP processing and Aβ degradation; implications for Alzheimer’s Disease
    Öppna denna publikation i ny flik eller fönster >>The role of LAMP-2 in AβPP processing and Aβ degradation; implications for Alzheimer’s Disease
    Visa övriga...
    2015 (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Dysfunction in the lysosomal network, i.e., the endosomal, lysosomal and autophagy systems, are implicated in the pathways in Alzheimer’s disease brain pathology. This dysfunction is mirrored in the cerebrospinal fluid where a specific subset of lysosomal network proteins are found at elevated levels, lysosomal associated membrane protein-2 (LAMP-2) being one of the identified lysosomal proteins. Here we report that hippocampus and frontal cortex in Alzheimer’s disease cases have increased mRNA and protein expression of LAMP-2, and thus these brain areas are likely involved in the increased LAMP-2 levels seen in cerebrospinal fluid from Alzheimer’s disease patients. The increased LAMP-2 levels correlated with increased levels of β-amyloid1-42 (Aβ1-42). Oligomeric Aβ1-42 caused an upregulation of intracellular LAMP-2 in neuroblastoma cells, but did not trigger the release of LAMP-2 to the extracellular milieu, indicating that other cell types or mechanisms are responsible for the LAMP-2 release seen in cerebrospinal fluid. Overexpression of LAMP-2 in neuroblastoma cells caused a trend of reduction of secreted Aβ1-42 and changed the processing pattern of the Aβ precursor protein. These results indicate that Aβ1-42 mediated increase of LAMP-2 expression can act as a regulator of Aβ generation and secretion. LAMP-2 overexpression did not change the cellular uptake of extracellularly added Aβ1-42, but caused a delayed clearance of Aβ1-42. Whether the prolonged intracellular localization of Aβ1-42 in LAMP-2 overexpressing cells can change the transmission or degradation of Aβ remains to be investigated.

    Nyckelord
    AβPP processing, Alzheimer’s disease, β-amyloid, autophagy, LAMP-2, lysosome
    Nationell ämneskategori
    Cell- och molekylärbiologi Kemi
    Identifikatorer
    urn:nbn:se:liu:diva-122345 (URN)
    Tillgänglig från: 2015-10-29 Skapad: 2015-10-29 Senast uppdaterad: 2018-01-10Bibliografiskt granskad
  • 43.
    Boman, Andrea
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Janefjord, Camilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. CBD Solutions, Stockholm, Sweden.
    Halliday, Glenda
    Neuroscience Research Australia and University of New South Wales, Sydney, Australia.
    Zetterberg, Henrik
    Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden / UCL Institute of Neurology, Queen Square, London, United Kingdom.
    Blennow, Kaj
    Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden.
    Garner, Brett
    Illawarra Health and Medical Research Institute, Wollongong, Australia / School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia.
    Miller, Bruce
    Memory and Aging Center, University of California, San Francisco, United States.
    Saftig, Paul
    Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
    Kågedal, Katarina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    The role of LAMP-2 in AβPP processing and Aβ degradation; implications for Alzheimer’s Disease2015Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Dysfunction in the lysosomal network, i.e., the endosomal, lysosomal and autophagy systems, are implicated in the pathways in Alzheimer’s disease brain pathology. This dysfunction is mirrored in the cerebrospinal fluid where a specific subset of lysosomal network proteins are found at elevated levels, lysosomal associated membrane protein-2 (LAMP-2) being one of the identified lysosomal proteins. Here we report that hippocampus and frontal cortex in Alzheimer’s disease cases have increased mRNA and protein expression of LAMP-2, and thus these brain areas are likely involved in the increased LAMP-2 levels seen in cerebrospinal fluid from Alzheimer’s disease patients. The increased LAMP-2 levels correlated with increased levels of β-amyloid1-42 (Aβ1-42). Oligomeric Aβ1-42 caused an upregulation of intracellular LAMP-2 in neuroblastoma cells, but did not trigger the release of LAMP-2 to the extracellular milieu, indicating that other cell types or mechanisms are responsible for the LAMP-2 release seen in cerebrospinal fluid. Overexpression of LAMP-2 in neuroblastoma cells caused a trend of reduction of secreted Aβ1-42 and changed the processing pattern of the Aβ precursor protein. These results indicate that Aβ1-42 mediated increase of LAMP-2 expression can act as a regulator of Aβ generation and secretion. LAMP-2 overexpression did not change the cellular uptake of extracellularly added Aβ1-42, but caused a delayed clearance of Aβ1-42. Whether the prolonged intracellular localization of Aβ1-42 in LAMP-2 overexpressing cells can change the transmission or degradation of Aβ remains to be investigated.

  • 44.
    Boman, Andrea
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Svensson, Samuel
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. CBD Solutions, Stockholm, Sweden.
    Boxer, Adam
    Memory and Aging Center, University of California, San Francisco, United States.
    Rojas, Julio C.
    Memory and Aging Center, University of California, San Francisco, United States.
    Seeley, William W.
    Memory and Aging Center, University of California, San Francisco, United States.
    Karydas, Anna
    Memory and Aging Center, University of California, San Francisco, United States.
    Miller, Bruce
    Memory and Aging Center, University of California, San Francisco, United States.
    Kågedal, Katarina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Svenningsson, Per
    Translational Neuropharmacology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    Distinct lysosomal network protein profiles in parkinsonian syndrome cerebrospinal fluid2016Ingår i: Journal of Parkinson's Disease, ISSN 1877-7171, E-ISSN 1877-718X, Vol. 6, nr 2, s. 307-315Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: Clinical diagnosis of parkinsonian syndromes like Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy is hampered by overlapping symptomatology and lack of biomarkers for diagnosis, and definitive diagnosis is only possible post-mortem. Since impaired protein degradation plays an important role in many neurodegenerative disorders, we hypothesized that levels and profiles of lysosomal network proteins in cerebrospinal fluid could be changed in these parkinsonian syndromes.

    Methods: Cerebrospinal fluid samples were collected from Parkinson’s disease patients (n=18), clinically diagnosed 4-repeat tauopathy patients, corticobasal syndrome (n=6) and progressive supranuclear palsy (n=5), pathologically diagnosed progressive supranuclear palsy (n=8) and corticobasal degeneration patients (n=7). Each patient set was compared to its appropriate control group consisting of the same number of age and gender matched individuals. Lysosomal network protein levels were detected via Western blotting.

    Results: Lysosomal network proteins have markedly different cerebrospinal fluid protein levels and profiles in Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy. Lysosomal-associated membrane proteins 1 and 2 were significantly decreased in Parkinson´s disease; early endosomal antigen 1 was decreased and lysozyme increased in progressive supranuclear palsy; and lysosomal-associated membrane proteins 1 and 2, microtubule-associated protein 1 light chain 3 and lysozyme were increased in corticobasal degeneration.

    Conclusions: Lysosomal network proteins hold promise of being interesting novel candidates for biomarker studies and for elucidating disease mechanisms of Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy, but further validation studies will be needed to assess the specificity and the predictive value of these proteins in CSF.

  • 45.
    Borgström, Annelie
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Analysis of tumour infiltrating leukocytes in colon cancer carcinoma in a syngeneic rat model2010Självständigt arbete på avancerad nivå (magisterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Tumour immunity is a balance between immune mediators that promote tumor progression versus mediators that promote tumor rejection. Infiltrating lymphocytes in human colorectal cancer tissues are independent prognostic factors for a better survival and a high number of cytotoxic CD8+ T-cells have been associated with a better prognosis in terms of a longer and disease free survival for the patient. In our syngeneic rat model we induce colon carcinoma subperitoneally by injecting a colon cancer cell line BN7005, a cell line expressing the epitope (Lewis Y) for the BR96 antibody. Tumours are dissected out and treated with different fixatives and then either frozen, snap-frozen or embedded in paraffin followed by sectioning. Immunohistochemistry using monoclonal antibodies against the tumour infiltrating leukocytes was performed on the tissue.

    The results were seen as an infiltration of different leukocytes in the tumours.

     

  • 46.
    Braian, Clara
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Svensson, Mattias
    Karolinska Institute, Sweden.
    Brighenti, Susanna
    Karolinska Institute, Sweden.
    Lerm, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Parasa, Venkata R.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    A 3D Human Lung Tissue Model for Functional Studies on Mycobacterium tuberculosis Infection2015Ingår i: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, nr 104, s. 1-9, artikel-id e53084Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Tuberculosis (TB) still holds a major threat to the health of people worldwide, and there is a need for cost-efficient but reliable models to help us understand the disease mechanisms and advance the discoveries of new treatment options. In vitro cell cultures of monolayers or co-cultures lack the three-dimensional (3D) environment and tissue responses. Herein, we describe an innovative in vitro model of a human lung tissue, which holds promise to be an effective tool for studying the complex events that occur during infection with Mycobacterium tuberculosis (M. tuberculosis). The 3D tissue model consists of tissue-specific epithelial cells and fibroblasts, which are cultured in a matrix of collagen on top of a porous membrane. Upon air exposure, the epithelial cells stratify and secrete mucus at the apical side. By introducing human primary macrophages infected with M. tuberculosis to the tissue model, we have shown that immune cells migrate into the infected-tissue and form early stages of TB granuloma. These structures recapitulate the distinct feature of human TB, the granuloma, which is fundamentally different or not commonly observed in widely used experimental animal models. This organotypic culture method enables the 3D visualization and robust quantitative analysis that provides pivotal information on spatial and temporal features of host cell-pathogen interactions. Taken together, the lung tissue model provides a physiologically relevant tissue micro-environment for studies on TB. Thus, the lung tissue model has potential implications for both basic mechanistic and applied studies. Importantly, the model allows addition or manipulation of individual cell types, which thereby widens its use for modelling a variety of infectious diseases that affect the lungs.

  • 47.
    Bratengeier, Cornelia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Mechanisms of mechanically induced Osteoclastogenesis: in a novel in vitro model for bone implant loosening2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Total joint arthroplasty is the primary intervention in the treatment of end-stage osteoarthritis. Despite the high success rate, in some patients, the replacement will fail during their lifetime requiring a revision of the implant. These revisions are strenuous for the patient and costly for health care. Joint replacement at a younger age, in combination with a more active lifestyle, increases the need for an early revision of the joint prosthesis. The main reason for revision surgeries is aseptic loosening, a condition where the prosthesis is loosening due to bone degradation at the peri-prosthetic interface in the absence of infections. The most well-established pathological mechanism for aseptic loosening is related to wear particles, generated from different parts of the prosthesis that will trigger bone degradation and bone loss. In addition, early micromotions of the prosthesis and resulting local pressurized fluid flow in the peri-prosthetic interface (supraphysiological loading) have also been identified as a cause for aseptic loosening. However, it remains unknown what cells are the primary responders to supraphysiological loading, and what underlying physical, cellular and molecular mechanism that triggers osteoclast differentiation and osteolysis.

    In this thesis, we intended to shed light on three currently unknown aspects of mechanical loading-induced peri-prosthetic osteolysis, leading to aseptic loosening of orthopedic prostheses: (1)Which cells are the primary responder to supraphysiological loading? (2)What characteristics of the mechanical stimulus induce an osteo-protective or osteo-destructive response? (3)Which cellular mechano-sensing mechanisms are involved in an osteo-destructive response?

    We successfully implemented supraphysiological mechanical loading, mimicking the periprosthetic pressurized fluid flow around a loosening implant, in an in vitro model for bone implant loosening. Using this model, we uncovered the involvement of mesenchymal stem cells and myeloid progenitor cells (monocytes) in mechanical loading-induced peri-prosthetic osteolysis. Applying supraphysiological loading on cells from patients undergoing primary hip arthroplasty, successfully validated the in vitro model for the use of cells of human origin. We further identified in murine myeloid progenitor cells that a combination of high loading amplitude (3.0±0.2Pa), prolonged active loading duration per cycle (duty cycle 22%-50%), and rapid alterations in minimum/maximum values of the loading profile (square wave) is necessary to induce an osteo-destructive response. Further, the loading-induced ATP release and subsequent activation of the P2X7 receptor was essential for the release of soluble factors modulating osteoclastogenesis.

    In conclusion, we expect that the proposed new in vitro model is a helpful tool to further advance the knowledge in aseptic loosening, by uncovering the mechanoresponsive cellular mechanism to supraphysiological mechanical loading. The identification of the respondent cells in mechanical loading-induced prosthetic loosening gives the opportunity to deliver targeted treatment strategies. Furthermore, identifying the physical parameters that define the shift towards an osteo-destructive response emphasizes the importance of the prosthetic design and surgical technique to reduce mechanical loading-induced bone degradation around a prosthesis.

    Delarbeten
    1. Supraphysiological loading induces osteocyte-mediated osteoclastogenesis in a novel in vitro model for bone implant loosening
    Öppna denna publikation i ny flik eller fönster >>Supraphysiological loading induces osteocyte-mediated osteoclastogenesis in a novel in vitro model for bone implant loosening
    Visa övriga...
    2018 (Engelska)Ingår i: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 36, nr 5, s. 1425-1434Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    We aimed to develop an in vitro model for bone implant loosening, allowing analysis of biophysical and biological parameters contributing to mechanical instability-induced osteoclast differentiation and peri-implant bone loss. MLO-Y4-osteocytes were mechanically stimulated for 1h by fluid shear stress using regimes simulating: (i) supraphysiological loading in the peri-prosthetic interface (2.9 +/- 2.9Pa, 1Hz, square wave); (ii) physiologic loading in the cortical bone (0.7 +/- 0.7Pa, 5Hz, sinusoidal wave); and (iii) stress shielding. Cellular morphological parameters, membrane-bound RANKL expression, gene expression influencing osteoclast differentiation, nitric oxide release and caspase 3/7-activity were determined. Either Mouse bone marrow cells were cultured on top of loaded osteocytes or osteocyte-conditioned medium was added to bone marrow cells. Osteoclast differentiation was assessed after 6 days. We found that osteocytes subjected to supraphysiological loading showed similar morphology and caspase 3/7-activity compared to simulated physiological loading or stress shielding. Supraphysiological stimulation of osteocytes enhanced osteoclast differentiation by 1.9-fold compared to physiological loading when cell-to-cell contact was permitted. In addition, it enhanced the number of osteoclasts using conditioned medium by 1.7-fold, membrane-bound RANKL by 3.3-fold, and nitric oxide production by 3.2-fold. The stimulatory effect of supraphysiological loading on membrane-bound RANKL and nitric oxide production was higher than that achieved by stress shielding. In conclusion, the in vitro model developed recapitulated the catabolic biological situation in the peri-prosthetic interface during instability that is associated with osteoclast differentiation and enhanced RANKL expression. The model thus provides a platform for pre-clinical testing of pharmacological interventions with potential to stop instability-induced bone implant loosening. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1425-1434, 2018.

    Ort, förlag, år, upplaga, sidor
    WILEY, 2018
    Nyckelord
    osteocyte; osteoclast; implant; osteolysis; RANKL
    Nationell ämneskategori
    Cell- och molekylärbiologi
    Identifikatorer
    urn:nbn:se:liu:diva-150301 (URN)10.1002/jor.23780 (DOI)000434360700015 ()29068483 (PubMedID)
    Anmärkning

    Funding Agencies|Swedish Research Council [521-2013-2593, 2016-01822, 2016-06097]; Swedish Governmental Agency for Innovation Systems [2012-04409]

    Tillgänglig från: 2018-08-16 Skapad: 2018-08-16 Senast uppdaterad: 2019-08-21
    2. Mechanical loading releases osteoclastogenesis-modulating factors through stimulation of the P2X7 receptor in hematopoietic progenitor cells
    Öppna denna publikation i ny flik eller fönster >>Mechanical loading releases osteoclastogenesis-modulating factors through stimulation of the P2X7 receptor in hematopoietic progenitor cells
    2019 (Engelska)Ingår i: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 234, nr 8, s. 13057-13067Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Mechanical instability of bone implants stimulate osteoclast differentiation and peri-implant bone loss, leading to prosthetic loosening. It is unclear which cells at the periprosthetic interface transduce mechanical signals into a biochemical response, and subsequently facilitate bone loss. We hypothesized that mechanical overloading of hematopoietic bone marrow progenitor cells, which are located near to the inserted bone implants, stimulates the release of osteoclast-inducing soluble factors. Using a novel in vitro model to apply mechanical overloading, we found that hematopoietic progenitor cells released adenosine triphosphate (ATP) after only 2min of mechanical loading. The released ATP interacts with its specific receptor P2X7 to stimulate the release of unknown soluble factors that inhibit (physiological loading) or promote (supraphysiological loading) the differentiation of multinucleated osteoclasts derived from bone marrow cultures. Inhibition of ATP-receptor P2X7 by Brilliant Blue G completely abolished the overloading-induced stimulation of osteoclast formation. Likewise, stimulation of P2X7 receptor on hematopoietic cells by BzATP enhanced the release of osteoclastogenesis-stimulating signaling molecules to a similar extent as supraphysiological loading. Supraphysiological loading affected neither gene expression of inflammatory markers involved in aseptic implant loosening (e.g., interleukin-1 (IL-1), IL-6, tumor necrosis factor-, and PTGES2) nor expression of the osteoclast modulators receptor activator of nuclear factor -B ligandand osteoprotegerin. Our findings suggest that murine hematopoietic progenitor cells are a potential key player in local mechanical loading-induced bone implant loosening via the ATP/P2X7-axis. Our approach identifies potential therapeutic targets to prevent prosthetic loosening.

    Ort, förlag, år, upplaga, sidor
    WILEY, 2019
    Nyckelord
    fluid flow; implant loosening; mechanoresponsive hematopoietic progenitor cells; osteolysis; purinergic signaling
    Nationell ämneskategori
    Cell- och molekylärbiologi
    Identifikatorer
    urn:nbn:se:liu:diva-158040 (URN)10.1002/jcp.27976 (DOI)000467240800083 ()30536959 (PubMedID)
    Anmärkning

    Funding Agencies|Swedish Research Council [2016-01822, 2016-06097, 521-2013-2593]; Swedish Governmental Agency for Innovation Systems [2012-04409]

    Tillgänglig från: 2019-06-25 Skapad: 2019-06-25 Senast uppdaterad: 2019-08-21
  • 48.
    Bratengeier, Cornelia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Bakker, Astrid D.
    Univ Amsterdam, Netherlands; Vrije Univ Amsterdam, Netherlands.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Mechanical loading releases osteoclastogenesis-modulating factors through stimulation of the P2X7 receptor in hematopoietic progenitor cells2019Ingår i: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 234, nr 8, s. 13057-13067Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mechanical instability of bone implants stimulate osteoclast differentiation and peri-implant bone loss, leading to prosthetic loosening. It is unclear which cells at the periprosthetic interface transduce mechanical signals into a biochemical response, and subsequently facilitate bone loss. We hypothesized that mechanical overloading of hematopoietic bone marrow progenitor cells, which are located near to the inserted bone implants, stimulates the release of osteoclast-inducing soluble factors. Using a novel in vitro model to apply mechanical overloading, we found that hematopoietic progenitor cells released adenosine triphosphate (ATP) after only 2min of mechanical loading. The released ATP interacts with its specific receptor P2X7 to stimulate the release of unknown soluble factors that inhibit (physiological loading) or promote (supraphysiological loading) the differentiation of multinucleated osteoclasts derived from bone marrow cultures. Inhibition of ATP-receptor P2X7 by Brilliant Blue G completely abolished the overloading-induced stimulation of osteoclast formation. Likewise, stimulation of P2X7 receptor on hematopoietic cells by BzATP enhanced the release of osteoclastogenesis-stimulating signaling molecules to a similar extent as supraphysiological loading. Supraphysiological loading affected neither gene expression of inflammatory markers involved in aseptic implant loosening (e.g., interleukin-1 (IL-1), IL-6, tumor necrosis factor-, and PTGES2) nor expression of the osteoclast modulators receptor activator of nuclear factor -B ligandand osteoprotegerin. Our findings suggest that murine hematopoietic progenitor cells are a potential key player in local mechanical loading-induced bone implant loosening via the ATP/P2X7-axis. Our approach identifies potential therapeutic targets to prevent prosthetic loosening.

  • 49.
    Bruno, Valentina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Tor Vergata Univ Hosp, Italy.
    Svensson Arvelund, Judit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Rubér, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Berg, Göran
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Piccione, Emilio
    Tor Vergata Univ Hosp, Italy.
    Jenmalm, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Ernerudh, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Effects of low molecular weight heparin on the polarization and cytokine profile of macrophages and T helper cells in vitro2018Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikel-id 4166Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Low molecular weight heparin (LMWH) is widely used in recurrent miscarriage treatment. The anticoagulant effects are established, while immunological effects are not fully known. Our aim was to assess LMWH effects on activation and polarization of central regulatory immune cells from healthy women, and on placenta tissues from women undergoing elective abortions. Isolated blood monocytes and T helper (Th) cells under different activation and polarizing conditions were cultured with or without LMWH. Flow cytometry showed that LMWH exposure induced increased expression of HLA-DR and CD206 in macrophages. This phenotype was associated with increased secretion of Th17-associated CCL20, and decreased secretion of CCL2 (M2-associated) and CCL22 (Th2), as measured by multiplex bead array. In accordance, LMWH exposure to Th cells reduced the proportion of CD25highFoxp3+ regulatory T-cells, intensified IFN-gamma secretion and showed a tendency to increase the lymphoblast proportions. Collectively, a mainly pro-inflammatory effect was noted on two essential tolerance-promoting cells. Although the