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  • 301.
    Li, Wei
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Lidebjer, Caroline
    Linköpings universitet, Institutionen för medicin och hälsa, Kardiologi. Linköpings universitet, Hälsouniversitetet.
    Yuan, Ximing
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi.
    Szymanowski, Aleksander
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Kardiologi. Östergötlands Läns Landsting, Hjärtcentrum, Kardiologiska kliniken.
    Backteman, Karin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk immunologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk immunologi och transfusionsmedicin.
    Ernerudh, Jan
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk immunologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk immunologi och transfusionsmedicin.
    Leanderson, Per
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Yrkes- och miljömedicin. Östergötlands Läns Landsting, Smärt- och yrkesmedicinskt centrum, Yrkes- och miljömedicinskt centrum.
    Nilsson, Lennart
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Kardiologi.
    Swahn, Eva
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Kardiologi. Östergötlands Läns Landsting, Hjärtcentrum, Kardiologiska kliniken.
    Jonasson, Lena
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Kardiologi. Östergötlands Läns Landsting, Hjärtcentrum, Kardiologiska kliniken.
    NK cell apoptosis in coronary artery disease. Relation to oxidative stress2008Ingår i: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 199, nr 1, s. 65-72Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: Natural killer (NK) cells, key elements in initiation and modulation of immune responses, were recently found to be reduced in coronary artery disease (CAD). To clarify mechanisms behind this reduction, we here investigated NK cell apoptosis in CAD patients. Since oxidative stress has been linked to NK cell apoptosis, we related the findings to oxidative stress in vivo and evaluated the ex vivo susceptibility of NK cells to oxidized lipids. Methods and results: The number of apoptotic NK cells in peripheral blood was significantly increased in CAD patients compared to controls. Purified NK cells from CAD patients also showed a higher rate of spontaneous apoptosis ex vivo. Dose- and time-dependent effects of oxidized LDL and 7β-hydroxycholesterol (7βOH) on apoptosis and ROS production were determined in NK cells from blood donors. Thereafter, purified NK cells from CAD patients and healthy controls were exposed to the oxidized lipids in a paired design. NK cells from patients were more susceptible to apoptosis induced by oxidized LDL, in particular 7βOH, compared to cells from controls. Plasma measurements of LDL protein oxidation and lipid peroxidation did not show any differences between patients and controls. On the other hand, plasma carotenoids were significantly decreased in patients and inversely correlated to NK cell apoptosis rate. Conclusion: The rate of spontaneous NK cell apoptosis was increased in CAD patients. Although NK cells in CAD patients were more sensitive to oxidized lipids ex vivo, indicating a mechanism contributing to the reduced NK cell activity in CAD, the data could not verify an obvious link between NK cell apoptosis and increased oxidative stress in vivo. © 2007 Elsevier Ireland Ltd. All rights reserved.

  • 302.
    Li, Wei
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Xu, Lihua
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi.
    Forssell, C.
    Sullivan, J.L.
    Burnett College of Biomedical Sciences, University of Central Florida, Orlando, FL 32816.
    Yuan, Ximing
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin.
    Overexpression of transferrin receptor and ferritin related to clinical symptoms and destabilization of human carotid plaques2008Ingår i: Experimental biology and medicine (Maywood, N.J.: Print), ISSN 1535-3702, E-ISSN 1535-3699, Vol. 233, nr 7, s. 818-826Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Accumulation of tissue iron has been implicated in development of atherosclerotic lesions mainly because of increased iron-catalyzed oxidative injury. However, it remains unknown whether cellular iron import and storage in human atheroma are related to human atheroma development. We found that transferrin receptor 1 (TfR1), a major iron importer, is highly expressed in foamy macrophages and some smooth muscle cells in intimal lesions of human carotid atheroma, mainly in cytoplasmic accumulation patterns. In 52 human carotid atherosclerotic lesions, TfR1 expression was positively correlated with macrophage infiltration, ectopic lysosomal cathepsin L, and ferritin expression. Highly expressed TfR1 and ferritin in CD68-positive macrophages were significantly associated with development and severity of human carotid plaques, smoking, and patient's symptoms. The findings suggest that pathologic macrophage iron metabolism may contribute to vulnerability of human atheroma, established risk factors, and their clinical symptoms. The cytoplasmic overexpression of TfR1 may be the result of lysosomal dysfunction and ectopic accumulation of lysosomal cathepsin I caused by atheroma-relevant lipids in atherogenesis. Copyright © 2008 by the Society for Experimental Biology and Medicine.

  • 303.
    Liin, Sara
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Karlsson, Urban
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Bentzen, B. H.
    University of Copenhagen, Denmark.
    Schmitt, N.
    University of Copenhagen, Denmark.
    Elinder, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Polyunsaturated fatty acids are potent openers of human M-channels expressed in Xenopus laevis oocytes2016Ingår i: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 218, nr 1, s. 28-37Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim: Polyunsaturated fatty acids have been reported to reduce neuronal excitability, in part by promoting inactivation of voltage-gated sodium and calcium channels. Effects on neuronal potassium channels are less explored and experimental data ambiguous. The aim of this study was to investigate anti-excitable effects of polyunsaturated fatty acids on the neuronal M-channel, important for setting the resting membrane potential in hippocampal and dorsal root ganglion neurones. Methods: Effects of fatty acids and fatty acid analogues on mouse dorsal root ganglion neurones and on the human KV7.2/3 channel expressed in Xenopus laevis oocytes were studied using electrophysiology. Results: Extracellular application of physiologically relevant concentrations of the polyunsaturated fatty acid docosahexaenoic acid hyperpolarized the resting membrane potential (-2.4 mV by 30 mu M) and increased the threshold current to evoke action potentials in dorsal root ganglion neurones. The polyunsaturated fatty acids docosahexaenoic acid, alpha-linolenic acid and eicosapentaenoic acid facilitated opening of the human M-channel, comprised of the heteromeric human KV7.2/3 channel expressed in Xenopus oocytes, by shifting the conductance-vs.-voltage curve towards more negative voltages (by -7.4 to -11.3 mV by 70 mu M). Uncharged docosahexaenoic acid methyl ester and monounsaturated oleic acid did not facilitate opening of the human KV7.2/3 channel. Conclusions: These findings suggest that circulating polyunsaturated fatty acids, with a minimum requirement of multiple double bonds and a charged carboxyl group, dampen excitability by opening neuronal M-channels. Collectively, our data bring light to the molecular targets of polyunsaturated fatty acids and thus a possible mechanism by which polyunsaturated fatty acids reduce neuronal excitability.

  • 304.
    Liin, Sara
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. University of Miami, FL, USA.
    Larsson, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Berro-Soria, Rene
    University of Miami, FL, USA.
    Hjorth Bentzen, Bo
    The Danish Arrhythmia Research Centre, University of Copenhagen, Copenhagen, Denmark; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Larson, H. Peter
    University of Miami, FL, USA.
    Fatty acid analogue N-arachidonoyl taurine restores function of I-Ks channels with diverse long QT mutations2016Ingår i: eLIFE, E-ISSN 2050-084X, Vol. 5, artikel-id e20272Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    About 300 loss-of-function mutations in the I-Ks channel have been identified in patients with Long QT syndrome and cardiac arrhythmia. How specific mutations cause arrhythmia is largely unknown and there are no approved I-Ks channel activators for treatment of these arrhythmias. We find that several Long QT syndrome-associated IKs channel mutations shift channel voltage dependence and accelerate channel closing. Voltage-clamp fluorometry experiments and kinetic modeling suggest that similar mutation-induced alterations in IKs channel currents may be caused by different molecular mechanisms. Finally, we find that the fatty acid analogue N-arachidonoyl taurine restores channel gating of many different mutant channels, even though the mutations are in different domains of the IKs channel and affect the channel by different molecular mechanisms. N-arachidonoyl taurine is therefore an interesting prototype compound that may inspire development of future IKs channel activators to treat Long QT syndrome caused by diverse IKs channel mutations.

  • 305.
    Liin, Sara
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Lund, Per-Eric
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Larsson, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Brask, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Wallner, Björn
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Elinder, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Biaryl sulfonamide motifs up- or down-regulate ion channel activity by activating voltage sensors2018Ingår i: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 150, nr 8, s. 1215-1230Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Voltage-gated ion channels are key molecules for the generation of cellular electrical excitability. Many pharmaceutical drugs target these channels by blocking their ion-conducting pore, but in many cases, channel-opening compounds would be more beneficial. Here, to search for new channel-opening compounds, we screen 18,000 compounds with high-throughput patch-clamp technology and find several potassium-channel openers that share a distinct biaryl-sulfonamide motif. Our data suggest that the negatively charged variants of these compounds bind to the top of the voltage-sensor domain, between transmembrane segments 3 and 4, to open the channel. Although we show here that biaryl-sulfonamide compounds open a potassium channel, they have also been reported to block sodium and calcium channels. However, because they inactivate voltage-gated sodium channels by promoting activation of one voltage sensor, we suggest that, despite different effects on the channel gates, the biaryl-sulfonamide motif is a general ion-channel activator motif. Because these compounds block action potential-generating sodium and calcium channels and open an action potential-dampening potassium channel, they should have a high propensity to reduce excitability. This opens up the possibility to build new excitability-reducing pharmaceutical drugs from the biaryl-sulfonamide scaffold.

  • 306.
    Liin, Sara
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. University of Miami, FL 33136 USA.
    Silverå Ejneby, Malin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Barro-Soria, Rene
    University of Miami, FL 33136 USA.
    Alexander Skarsfeldt, Mark
    University of Copenhagen, Denmark; University of Copenhagen, Denmark.
    Larsson, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. University of Miami, FL 33136 USA.
    Starck Härlin, Frida
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. University of Miami, FL 33136 USA.
    Parkkari, Teija
    University of Eastern Finland, Finland.
    Hjorth Bentzen, Bo
    University of Copenhagen, Denmark; University of Copenhagen, Denmark.
    Schmitt, Nicole
    University of Copenhagen, Denmark; University of Copenhagen, Denmark.
    Peter Larsson, H.
    University of Miami, FL 33136 USA.
    Elinder, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac I-Ks channel2015Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 18, s. 5714-5719Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Polyunsaturated fatty acids (PUFAs) affect cardiac excitability. Kv7.1 and the beta-subunit KCNE1 form the cardiac I-Ks channel that is central for cardiac repolarization. In this study, we explore the prospects of PUFAs as I-Ks channel modulators. We report that PUFAs open Kv7.1 via an electrostatic mechanism. Both the polyunsaturated acyl tail and the negatively charged carboxyl head group are required for PUFAs to open Kv7.1. We further show that KCNE1 coexpression abolishes the PUFA effect on Kv7.1 by promoting PUFA protonation. PUFA analogs with a decreased pK(a) value, to preserve their negative charge at neutral pH, restore the sensitivity to open I-Ks channels. PUFA analogs with a positively charged head group inhibit I-Ks channels. These different PUFA analogs could be developed into drugs to treat cardiac arrhythmias. In support of this possibility, we show that PUFA analogs act antiarrhythmically in embryonic rat cardiomyocytes and in isolated perfused hearts from guinea pig.

  • 307.
    Likus, W.
    et al.
    Medical University of Silesia, Poland.
    Gruszczynska, K.
    Medical University of Silesia, Poland.
    Markowski, J.
    Medical University of Silesia, Poland.
    Machnikowska-Sokolowska, M.
    Medical University of Silesia, Poland.
    Olczak, Z.
    Upper Silesian Childs Health Centre, Poland.
    Bajor, G.
    Medical University of Silesia, Poland.
    Los, Marek Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Pomeranian Medical University, Poland.
    Baron, J.
    Medical University of Silesia, Poland.
    Correlations between selected parameters of nasal cavity in neonates and young infants - computed tomography study2016Ingår i: FOLIA MORPHOLOGICA, ISSN 0015-5659, Vol. 75, nr 3, s. 334-340Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Correlations between selected metric parameters of the nasal cavity and nasopharynx in children without atresia may be useful for anticipating probable dimensions of this region in living subjects, in terms of changes with age. Materials and methods: One hundred and eighty children, age range 0-3 years, were divided into five age groups, and measurements of 18 distances between structures of nasal cavity and nosopharynx were performed on computed tomography scans. Correlation coefficients and relations between parameters have been determined. Results: Our study confirmed the existence of statistically significant correlations between linear dimensions within nasal cavity in children. The analysis demonstrated that for the values of following indexes: nasal septum length/piriform aperture width, and maximum length of the nasal septum/posterior nares width no statistically significant differences have been noted between age groups of children. All correlations have been positive. No statistically significant differences have been noted between the maximum width of the vomer and osseous parameters measured, both in the anterior and posterior part of the nasal cavity, and nasal septum length. Conclusions: The size of posterior nares changed with age in children by a constant value. So far, no such an analysis has been carried out assessing potential correlations between linear dimensions for the entire nasal cavity, nasopharynx, length of the nasal septum in children, as well as proportions of individual linear dimensions of the anatomical structures analysed, in various age groups.

  • 308.
    Likus, Wirginia
    et al.
    Medical University of Silesia, Poland.
    Siemianowicz, Krzysztof
    Medical University of Silesia, Poland.
    Bienk, Konrad
    Aarhus University, Denmark.
    Pakula, Malgorzata
    Aarhus University, Denmark.
    Pathak, Himani
    Indian Institute Science Educ and Research IISER TVM, India.
    Dutta, Chhanda
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi.
    Wang, Qiong
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teknisk biologi. Linköpings universitet, Tekniska fakulteten.
    Shojaei, Shahla
    Isfahan University of Medical Science, Iran.
    Assaraf, Yehuda G.
    Technion Israel Institute Technology, Israel.
    Ghavami, Saeid
    University of Manitoba, Canada; Shiraz University of Medical Science, Iran.
    Cieslar-Pobuda, Artur
    Silesian Technical University, Poland.
    Los, Marek J.
    LinkoCare Life Science AB, S-58330 Linkoping, Sweden; Medical University of Silesia, Poland.
    Could drugs inhibiting the mevalonate pathway also target cancer stem cells?2016Ingår i: Drug resistance updates, ISSN 1368-7646, E-ISSN 1532-2084, Vol. 25, s. 13-25Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Understanding the connection between metabolic pathways and cancer is very important for the development of new therapeutic approaches based on regulatory enzymes in pathways associated with tumorigenesis. The mevalonate cascade and its rate-liming enzyme HMG CoA-reductase has recently drawn the attention of cancer researchers because strong evidences arising mostly from epidemiologic studies, show that it could promote transformation. Hence, these studies pinpoint HMG CoA-reductase as a candidate proto-oncogene. Several recent epidemiological studies, in different populations, have proven that statins are beneficial for the treatment-outcome of various cancers, and may improve common cancer therapy strategies involving alkylating agents, and antimetabolites. Cancer stem cells/cancer initiating cells (CSC) are key to cancer progression and metastasis. Therefore, in the current review we address the different effects of statins on cancer stem cells. The mevalonate cascade is among the most pleiotropic, and highly interconnected signaling pathways. Through G-protein-coupled receptors (GRCP), it integrates extra-, and intracellular signals. The mevalonate pathway is implicated in cell sternness, cell proliferation, and organ size regulation through the Hippo pathway (e.g. Yap/Taz signaling axis). This pathway is a prime preventive target through the administration of statins for the prophylaxis of obesity related cardiovascular diseases. Its prominent role in regulation of cell growth and sternness also invokes its role in cancer development and progression. The mevalonate pathway affects cancer metastasis in several ways by: (i) affecting epithelial-to-mesenchymal transition (EMT), (ii) affecting remodeling of the cytoskeleton as well as cell motility, (iii) affecting cell polarity (non-canonical Wnt/planar pathway), and (iv) modulation of mesenchymal-to-epithelial transition (MET). Herein we provide an overview of the mevalonate signaling network. We then briefly highlight diverse functions of various elements of this mevalonate pathway. We further discuss in detail the role of elements of the mevalonate cascade in sternness, carcinogenesis, cancer progression, metastasis and maintenance of cancer stem cells. (C) 2016 The Authors. Published by Elsevier Ltd.

  • 309.
    Likus, Wirginia
    et al.
    Medical University of Silesia, Poland.
    Siemianowicz, Krzysztof
    Medical University of Silesia, Poland.
    Markowski, Jaroslaw
    Medical University of Silesia, Poland.
    Wiaderkiewicz, Jan
    Medical University of Silesia, Poland; George Washington University, DC USA.
    Kostrzab-Zdebel, Anna
    Medical University of Silesia, Poland.
    Jura-Szoltys, Edyta
    Medical University of Silesia, Poland.
    Dziubdziela, Wlodzimierz
    Outpatient Clin Treatment Chron Pain, Poland.
    Wiaderkiewicz, Ryszard
    Medical University of Silesia, Poland.
    Los, Marek Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Pomeranian Medical University, Poland.
    Bacterial Infections and Osteoclastogenesis Regulators in Men and Women with Cholesteatoma2016Ingår i: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 64, nr 3, s. 241-247Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    One of the most distinct features of middle ear cholesteatoma is bone destruction. Aetiology of cholesteatoma is thought to be multifactorial. Endotoxins produced by bacteria are thought to initiate the inflammation process in the middle ear leading to cholesteatoma. There are physiological differences in bone metabolism between men and women. The aim of our study was the immunohistochemical evaluation of the contents of two key components of the OPG/RANK/RANKL triad-RANKL and OPG in cholesteatoma, to analyse if there are any differences between the sexes and to evaluate the bacteria species isolated from cholesteatoma just before surgical treatment and to evaluate their plausible influence on the expression of OPG and RANKL in cholesteatoma. Twenty-one adult patients with acquired cholesteatoma who underwent surgery were analysed. There were no statistically significant differences in the expression of both regulators of osteoclastogenesis between the sexes. In 38.1 % patients cholesteatoma was not infected, whereas in 61.9 % patients various bacterial infections or mycosis were found. The most frequently isolated species was Pseudomonas aeruginosa (14.29 % infections) followed by Staphylococcus aureus (9.52 % infections). There were no statistically significant differences in expression of both OPG and RANKL between uninfected and infected cholesteatomas.

  • 310.
    Lindström, Annelie
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Midtbö, Kristine Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Arnesson, Lars-Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Garvin, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Shabo, Ivan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US. Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Fusion between M2-macrophages and cancer cells results in a subpopulation of radioresistant cells with enhanced DNA-repair capacity2017Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 31, s. 51370-51386Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cell fusion is a natural biological process in normal development and tissue regeneration. Fusion between cancer cells and macrophages results in hybrids that acquire genetic and phenotypic characteristics from both maternal cells. There is a growing body of in vitro and in vivo data indicating that this process also occurs in solid tumors and may play a significant role in tumor progression. However, investigations of the response of macrophage: cancer cell hybrids to radiotherapy have been lacking. In this study, macrophage: MCF-7 hybrids were generated by spontaneous in vitro cell fusion. After irradiation, both hybrids and their maternal MCF-7 cells were treated with 0 Gy, 2.5 Gy and 5 Gy.-radiation and examined by clonogenic survival and comet assays at three time points (0 h, 24 h, and 48 h). Compared to maternal MCF-7 cells, the hybrids showed increased survival fraction and plating efficiency (colony formation ability) after radiation. The hybrids developed less DNA-damage, expressed significantly lower residual DNA-damage, and after higher radiation dose showed less heterogeneity in DNA-damage compared to their maternal MCF-7 cells. To our knowledge this is the first study that demonstrates that macrophage: cancer cell fusion generates a subpopulation of radioresistant cells with enhanced DNA-repair capacity. These findings provide new insight into how the cell fusion process may contribute to clonal expansion and tumor heterogeneity. Furthermore, our results provide support for cell fusion as a mechanism behind the development of radioresistance and tumor recurrence.

  • 311.
    Liu, Na
    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. State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an, China.
    Cox, Thomas R.
    Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
    Cui, Weiyingqi
    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.
    Adell, Gunnar
    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, Onkologiska kliniken US.
    Holmlund, Birgitta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Ping, Jie
    Shanghai Center for Bioinformation Technology, Shanghai, China.
    Jarlsfelt, Ingvar
    Department of Pathology, Ryhov Hospital, Jönköping, Sweden.
    Erler, Janine T.
    Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
    Sun, Xiao-Feng
    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, Onkologiska kliniken US.
    Nuclear expression of lysyl oxidase enzyme is an independent prognostic factor in rectal cancer patients.2017Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 36, s. 60015-60024Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Emerging evidence has implicated a pivotal role for lysyl oxidase (LOX) in cancer progression and metastasis. Whilst the majority of work has focused on the extracellular matrix cross-linking role of LOX, the exact function of intracellular LOX localisation remains unclear. In this study, we analysed the LOX expression patterns in the nuclei of rectal cancer patient samples and determined the clinical significance of this expression. Nuclear LOX expression was significantly increased in patient lymph node metastases compared to their primary tumours. High nuclear LOX expression in tumours was correlated with a high rate of distant metastasis and increased recurrence. Multivariable analysis showed that high nuclear LOX expression was also correlated with poor overall survival and disease free survival. Furthermore, we are the first to identify LOX enzyme isoforms (50 kDa and 32 kDa) within the nucleus of colon cancer cell lines by confocal microscopy and Western blot. Our results show a powerful link between nuclear LOX expression in tumours and patient survival, and offer a promising prognostic biomarker for rectal cancer patients.

  • 312.
    Ljunggren, Stefan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Levels, Johannes H M
    Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
    Turkina, Maria V
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Sundberg, Sofie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Bochem, Andrea E
    Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
    Hovingh, Kees
    Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
    Holleboom, Adriaan G
    Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
    Lindahl, Mats
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Kuivenhoven, Jan Albert
    University of Groningen, Groningen, The Netherlands.
    Karlsson, Helen
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Arbets- och miljömedicin.
    ApoA-I mutations, L202P and K131del, in HDL from heterozygotes with low HDL-C2014Ingår i: PROTEOMICS - Clinical Applications, ISSN 1862-8346, E-ISSN 1862-8354, Vol. 8, nr 3-4, s. 241-250Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE: Mutations in apolipoprotein A-I (apoA-I) may affect plasma high-density lipoprotein (HDL) cholesterol levels and the risk for cardiovascular disease but little is known about the presence and effects of circulating apoA-I variants. This study investigates whether the apoA-I mutations, apoA-I(L202P) and apoA-I(K131del) , are present on plasma HDL particles derived from heterozygote carriers and whether this is associated to changes in HDL protein composition.

    EXPERIMENTAL DESIGN: Plasma HDL of heterozygotes for either apoA-I(L202P) or apoA-I(K131del) and family controls was isolated using ultracentrifugation. HDL proteins were separated by 2DE and analyzed by MS.

    RESULTS: ApoA-I peptides containing apoA-I(L202P) or apoA-I(K131del) were identified in HDL from heterozygotes. The apoA-I(L202P) mutant peptide was less abundant than wild-type peptide while the apoA-I(K131del) mutant peptide was more abundant than wild-type peptide in the heterozygotes. Two-dimensional gel electrophoresis analyses indicated that, compared to controls, HDL in apoA-I(L202P) carriers contained less apoE and more zinc-α-2-glycoprotein while HDL from the apoA-I(K131del) heterozygotes contained more alpha-1-antitrypsin and transthyretin.

    CONCLUSIONS AND CLINICAL RELEVANCE: Both apoA-I(L202P) and apoA-I(K131del) were identified in HDL. In heterozygotes, these mutations have markedly differential effects on the concentration of wild-type apoA-I in the circulation, as well as the HDL proteome, both of which might affect the clinical phenotype encountered in the heterozygous carriers.

  • 313.
    Lopes, Viviana R
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Loitto, Vesa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Audinot, Jean‑Nicolas
    Luxembourg Institute of Science and Technology, Luxembourg.
    Bayat, Narges
    Stockholm University, Sweden.
    Gutleb, Arno C.
    Luxembourg Institute of Science and Technology, Luxembourg.
    Cristobal, Susana
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Dose‑dependent autophagic effectof titanium dioxide nanoparticles in humanHaCaT cells at non‑cytotoxic levels2016Ingår i: Journal of Nanobiotechnology, ISSN 1477-3155, E-ISSN 1477-3155, Vol. 14, nr 22, s. 1-13Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Interactions between nanoparticles and cells are now the focus of a fast-growing area of research.Though many nanoparticles interact with cells without any acute toxic responses, metal oxide nanoparticles includingthose composed of titanium dioxide (TiO2-NPs) may disrupt the intracellular process of macroautophagy.Autophagy plays a key role in human health and disease, particularly in cancer and neurodegenerative diseases. Weherein investigated the in vitro biological effects of TiO2-NPs (18 nm) on autophagy in human keratinocytes (HaCaT)cells at non-cytotoxic levels.Results: TiO2-NPs were characterized by transmission electron microscopy (TEM) and dynamic light scatteringtechniques. Cellular uptake, as evaluated by TEM and NanoSIMS revealed that NPs internalization led to the formationof autophagosomes. TiO2-NPs treatment did not reduce cell viability of HaCaT cells nor increased oxidative stress. Cellularautophagy was additionally evaluated by confocal microscopy using eGFP-LC3 keratinocytes, western blottingof autophagy marker LC3I/II, immunodetection of p62 and NBR1 proteins, and gene expression of LC3II, p62, NBR1,beclin1 and ATG5 by RT-qPCR. We also confirmed the formation and accumulation of autophagosomes in NPs treatedcells with LC3-II upregulation. Based on the lack of degradation of p62 and NBR1 proteins, autophagosomes accumulationat a high dose (25.0 μg/ml) is due to blockage while a low dose (0.16 μg/ml) promoted autophagy. Cellularviability was not affected in either case.Conclusions: The uptake of TiO2-NPs led to a dose-dependent increase in autophagic effect under non-cytotoxicconditions. Our results suggest dose-dependent autophagic effect over time as a cellular response to TiO2-NPs. Mostimportantly, these findings suggest that simple toxicity data are not enough to understand the full impact of TiO2-NPsand their effects on cellular pathways or function.

  • 314.
    Lundberg, Peter
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Röntgenkliniken i Linköping. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US.
    Forsgren, Mikael
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US.
    Nasr, Patrik
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Ignatova, Simone
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Leinhard Dahlqvist, Olof
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US.
    Dahlström, Nils
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Röntgenkliniken i Linköping.
    Ekstedt, Mattias
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Kechagias, Stergios
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Kvantifiering av leversteatos: diagnostisk utvärdering av protonmagnetresonansspektroskopi jämfört med histologiska metoder2016Konferensbidrag (Refereegranskat)
    Abstract [sv]

    Bakgrund

    Leversteatos är den vanligaste manifestationen av leversjukdom i västvärlden. Leverbiopsi med semikvantitativ histologisk gradering är referensmetod vid gradering av leversteatos. Med protonmagnetsresonansspektroskopi (1H-MRS), en metod som föreslagits ersätta leverbiopsi för värdering av steatos, kan leverns innehåll av triglycerider mätas icke-invasivt. Triglyceridinnehåll >5,00 % används ofta som ett diagnostiskt kriterium för leversteatos vid undersökning med 1H-MRS. Syftet med studien var att jämföra 1H-MRS med semikvantitativ histologisk steatosgradering och kvantitativ histologisk steatosmätning.

    Metod

    Patienter remitterade för utredning av förhöjda leverenzymer in-kluderades i studien. Samtliga patienter genomgick klinisk undersökning, laboratorieprovtagning samt 1H-MRS direkt följd av leverbiopsi. För konventionell histologisk semikvantitativ gradering av steatos användes kriterierna utarbetade av Brunt och medarbetare. Kvantitativ mätning av fett i biopsierna utfördes genom att med hjälp av stereologisk punkträkning (SPC) mäta andelen av ytan som innehöll fettvakuoler.

    Resultat

    I studien inkluderades 94 patienter, varav 37 hade icke-alkoholor-sakad fettleversjukdom (NAFLD), 49 hade andra leversjukdomar och 8 hade normal leverbiopsi. En stark korrelation noterades mel-lan 1H-MRS och SPC (r=0,92, p<0,0001; к=0.82). Korrelationen mellan 1H-MRS och Brunts kriterier (к=0.26) samt mellan SPC och Brunts kriterier (к=0.38) var betydligt sämre. När patologens gradering (Brunts kriterier) användes som referensmetod för diag-nos av leversteatos så hade alla patienter med triglyceridinnehåll >5,00 % mätt med 1H-MRS steatos (specificitet 100 %). Emellertid hade 22 av 69 patienter med triglyceridinnehåll ≤5,00 % också le-versteatos enligt Brunts kriterier (sensitivitet 53 %). Motsvarande siffror när man använde gränsvärdet 3,02 % var sensitivitet 79 % och specificitet 100 %. Vid ytterligare reduktion av gränsvärdet för triglyceridinnehåll till 2,00 % ökade sensitiviteten till 87 % med upprätthållande av hög specificitet (94 %).

    Slutsats

    1H-MRS och SPC uppvisade en mycket hög korrelation vid kvantifiering av leversteatos. SPC borde därför föredras framför Brunts kriterier när noggrann histologisk kvantifiering av leversteatos är önskvärd. Många patienter kan ha histologisk leversteatos trots triglyceridinnehåll ≤5,00 % mätt med 1H-MRS. Gränsvärdet för diagnostisering av leversteatos med 1H-MRS bör därför reduceras.

  • 315.
    Lundengård, Karin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Cedersund, Gunnar
    Linköpings universitet, Institutionen för medicinsk teknik. Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Elinder, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Engström, Maria
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Mechanistic Modelling Investigates the Neural Basis behind the Hemodynamic Response in fMRI2015Ingår i: 16TH NORDIC-BALTIC CONFERENCE ON BIOMEDICAL ENGINEERING, Springer Science Business Media , 2015, Vol. 48, s. 86-87Konferensbidrag (Refereegranskat)
    Abstract [en]

    This work serves as a basis for a new type of fMRI analysis, which is based on a mechanistic interpretation of the hemodynamic response to synaptic activity. Activation was measured in the visual cortex of 12 healthy controls and ordinary differential equation models were fitted to the time series of the hemodynamic response. This allowed us to reject or refine previously proposed mechanistic hypotheses. This is the first attempt to describe the hemodynamic response quantitatively based on recent neurobiological findings. This mechanistic approach stands in contrast to the standard phenomenological description using the gamma variate function.

  • 316.
    Lundengård, Karin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Cedersund, Gunnar
    Linköpings universitet, Institutionen för medicinsk teknik. Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi.
    Sten, Sebastian
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Leong, Felix
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten.
    Smedberg, Alexander
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten.
    Elinder, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Engström, Maria
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Mechanistic Mathematical Modeling Tests Hypotheses of the Neurovascular Coupling in fMRI2016Ingår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 12, nr 6, artikel-id e1004971Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Functional magnetic resonance imaging (fMRI) measures brain activity by detecting the blood-oxygen-level dependent (BOLD) response to neural activity. The BOLD response depends on the neurovascular coupling, which connects cerebral blood flow, cerebral blood volume, and deoxyhemoglobin level to neuronal activity. The exact mechanisms behind this neurovascular coupling are not yet fully investigated. There are at least three different ways in which these mechanisms are being discussed. Firstly, mathematical models involving the so-called Balloon model describes the relation between oxygen metabolism, cerebral blood volume, and cerebral blood flow. However, the Balloon model does not describe cellular and biochemical mechanisms. Secondly, the metabolic feedback hypothesis, which is based on experimental findings on metabolism associated with brain activation, and thirdly, the neurotransmitter feed-forward hypothesis which describes intracellular pathways leading to vasoactive substance release. Both the metabolic feedback and the neurotransmitter feed-forward hypotheses have been extensively studied, but only experimentally. These two hypotheses have never been implemented as mathematical models. Here we investigate these two hypotheses by mechanistic mathematical modeling using a systems biology approach; these methods have been used in biological research for many years but never been applied to the BOLD response in fMRI. In the current work, model structures describing the metabolic feedback and the neurotransmitter feed-forward hypotheses were applied to measured BOLD responses in the visual cortex of 12 healthy volunteers. Evaluating each hypothesis separately shows that neither hypothesis alone can describe the data in a biologically plausible way. However, by adding metabolism to the neurotransmitter feed-forward model structure, we obtained a new model structure which is able to fit the estimation data and successfully predict new, independent validation data. These results open the door to a new type of fMRI analysis that more accurately reflects the true neuronal activity.

  • 317.
    Lundengård, Karin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Elinder, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Engström, Maria
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    A mechanistic model for blood flow regulation in response to neuronal activity2013Konferensbidrag (Övrigt vetenskapligt)
  • 318.
    Lykiardopoulos, Byron
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten.
    Hagström, Hannes
    Karolinska Institute, Sweden.
    Fredrikson, Mats
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Ignatova, Simone
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Stal, Per
    Karolinska Institute, Sweden.
    Hultcrantz, Rolf
    Karolinska Institute, Sweden.
    Ekstedt, Mattias
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Kechagias, Stergios
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Development of Serum Marker Models to Increase Diagnostic Accuracy of Advanced Fibrosis in Nonalcoholic Fatty Liver Disease: The New LINKI Algorithm Compared with Established Algorithms2016Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 12, artikel-id e0167776Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background and Aim Detection of advanced fibrosis (F3-F4) in nonalcoholic fatty liver disease (NAFLD) is important for ascertaining prognosis. Serum markers have been proposed as alternatives to biopsy. We attempted to develop a novel algorithm for detection of advanced fibrosis based on a more efficient combination of serological markers and to compare this with established algorithms. Methods We included 158 patients with biopsy-proven NAFLD. Of these, 38 had advanced fibrosis. The following fibrosis algorithms were calculated: NAFLD fibrosis score, BARD, NIKEI, NASH-CRN regression score, APRI, FIB-4, Kings score, GUCI, Lok index, Forns score, and ELF. Study population was randomly divided in a training and a validation group. A multiple logistic regression analysis using bootstrapping methods was applied to the training group. Among many variables analyzed age, fasting glucose, hyaluronic acid and AST were included, and a model (LINKI-1) for predicting advanced fibrosis was created. Moreover, these variables were combined with platelet count in a mathematical way exaggerating the opposing effects, and alternative models (LINKI-2) were also created. Models were compared using area under the receiver operator characteristic curves (AUROC). Results Of established algorithms FIB-4 and Kings score had the best diagnostic accuracy with AUROCs 0.84 and 0.83, respectively. Higher accuracy was achieved with the novel LINKI algorithms. AUROCs in the total cohort for LINKI-1 was 0.91 and for LINKI-2 models 0.89. Conclusion The LINKI algorithms for detection of advanced fibrosis in NAFLD showed better accuracy than established algorithms and should be validated in further studies including larger cohorts.

  • 319.
    Ma, Wei
    et al.
    Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) Gatersleben, Corrensstrasse 3, 06466 Stadt Seeland, Germany;.
    Gabriel, Tobias Sebastian
    Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) Gatersleben, Corrensstrasse 3, 06466 Stadt Seeland, Germany;.
    Martis, Mihaela-Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Institute of Bioinformatics and Systems Biology/Munich Information Center for Protein Sequences, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
    Gursinsky, Torsten
    Institute of Biochemistry and Biotechnology, Section Microbial Biotechnology, Faculty of Life Sciences, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, 06120 Halle/Saale, Germany.
    Schubert, Veit
    Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) Gatersleben, Corrensstrasse 3, 06466 Stadt Seeland, Germany;.
    Vrana, Jan
    Institute of Experimental Botany, Center of the Region Hana for Biotechnological and Agricultural Research, Slechtitelu 31, 78371 Olomouc, Czech Republic.
    Dolezel, Jaroslav
    Institute of Experimental Botany, Center of the Region Hana for Biotechnological and Agricultural Research, Slechtitelu 31, 78371 Olomouc, Czech Republic.
    Gundlach, Heidrun
    Institute of Bioinformatics and Systems Biology/Munich Information Center for Protein Sequences, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
    Altschmied, Lothar
    Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) Gatersleben, Corrensstrasse 3, 06466 Stadt Seeland, Germany;.
    Scholz, Uwe
    Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) Gatersleben, Corrensstrasse 3, 06466 Stadt Seeland, Germany;.
    Himmelbach, Axel
    Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) Gatersleben, Corrensstrasse 3, 06466 Stadt Seeland, Germany;.
    Behrens, Sven-Erik
    Institute of Biochemistry and Biotechnology, Section Microbial Biotechnology, Faculty of Life Sciences, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, 06120 Halle/Saale, Germany.
    Banaei-Moghaddam, Ali Mohammad
    Department of Biochemistry, Institute of Biochemistry and Biophysics (IBB), University of Tehran, PO Box 13145-1384 Tehran, Iran.
    Houben, Andreas
    Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) Gatersleben, Corrensstrasse 3, 06466 Stadt Seeland, Germany;.
    Rye B chromosomes encode a functional Argonaute-like proteinwith in vitro slicer activities similar to its A chromosome paralog2017Ingår i: New Phytologist, ISSN 0028-646X, E-ISSN 1469-8137, Vol. 213, nr 2, s. 904-916Artikel i tidskrift (Refereegranskat)
    Abstract [en]
    • B chromosomes (Bs) are supernumerary, dispensable parts of the nuclear genome, whichappear in many different species of eukaryote. So far, Bs have been considered to be geneti-cally inert elements without any functional genes.
    • Our comparative transcriptome analysis and the detection of active RNA polymerase II(RNAPII) in the proximity of B chromatin demonstrate that the Bs of rye (Secale cereale) con-tribute to the transcriptome. In total, 1954 and 1218 B-derived transcripts with an open read-ing frame were expressed in generative and vegetative tissues, respectively. In addition to B-derived transposable element transcripts, a high percentage of short transcripts withoutdetectable similarity to known proteins and gene fragments from A chromosomes (As) werefound, suggesting an ongoing gene erosion process.
    • In vitro analysis of the A- and B-encoded AGO4B protein variants demonstrated that bothpossess RNA slicer activity. These data demonstrate unambiguously the presence of a func-tional AGO4B gene on Bs and that these Bs carry both functional protein coding genes andpseudogene copies.
    • Thus, B-encoded genes may provide an additional level of gene control and complexity incombination with their related A-located genes. Hence, physiological effects, associated withthe presence of Bs, may partly be explained by the activity of B-located (pseudo)genes.
  • 320.
    Ma, Wei
    et al.
    Leibniz Institute Plant Genet and Crop Plant Research IPK, Germany.
    Schubert, Veit
    Leibniz Institute Plant Genet and Crop Plant Research IPK, Germany.
    Martis, Mihaela-Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Helmholtz Centre Munich, Germany.
    Hause, Gerd
    University of Halle Wittenberg, Germany.
    Liu, Zhaojun
    Leibniz Institute Plant Genet and Crop Plant Research IPK, Germany.
    Shen, Yi
    Chinese Academic Science, Peoples R China.
    Conrad, Udo
    Leibniz Institute Plant Genet and Crop Plant Research IPK, Germany.
    Shi, Wenqing
    Chinese Academic Science, Peoples R China.
    Scholz, Uwe
    Leibniz Institute Plant Genet and Crop Plant Research IPK, Germany.
    Taudien, Stefan
    Leibniz Institute Aging Fritz Lipmann Institute eV FLI, Germany.
    Cheng, Zhukuan
    Chinese Academic Science, Peoples R China.
    Houben, Andreas
    Leibniz Institute Plant Genet and Crop Plant Research IPK, Germany.
    The distribution of alpha-kleisin during meiosis in the holocentromeric plant Luzula elegans2016Ingår i: Chromosome Research, ISSN 0967-3849, E-ISSN 1573-6849, Vol. 24, nr 3, s. 393-405Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Holocentric chromosomes occur in a number of independent eukaryotic lineages, and they form holokinetic kinetochores along the entire poleward chromatid surfaces. Due to this alternative chromosome structure, Luzula elegans sister chromatids segregate already in anaphase I followed by the segregation of the homologues in anaphase II. However, not yet known is the localization and dynamics of cohesin and the structure of the synaptonemal complex (SC) during meiosis. We show here that the alpha-kleisin subunit of cohesin localizes at the centromeres of both mitotic and meiotic metaphase chromosomes and that it, thus, may contribute to assemble the centromere in L. elegans. This localization and the formation of a tripartite SC structure indicate that the prophase I behaviour of L. elegans is similar as in monocentric species.

  • 321.
    Machado, Isabel
    et al.
    SOMAprobes, Spain.
    Garrido, Victoria
    CSIC UPNa Gobierno Navarra, Spain.
    Hernandez, Luiza
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. SOMAprobes, Spain.
    Botero, Juliana
    SOMAprobes, Spain.
    Bastida, Nora
    SOMAprobes, Spain.
    San-Roman, Beatriz
    CSIC UPNa Gobierno Navarra, Spain.
    Grillo, Maria-Jesus
    CSIC UPNa Gobierno Navarra, Spain.
    Hernandez, Frank
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär ytfysik och nanovetenskap. Linköpings universitet, Tekniska fakulteten.
    Rapid and specific detection of Salmonella infections using chemically modified nucleic acid probes2019Ingår i: Analytica Chimica Acta, ISSN 0003-2670, E-ISSN 1873-4324, Vol. 1054, s. 157-166Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Salmonella is a leading source of bacterial foodborne illness in humans, causing gastroenteritis outbreaks with bacteraemia occurrences that can lead to clinical complications and death. Eggs, poultry and pig products are considered as the main carriers of the pathogenic Salmonella for humans. To prevent this relevant zoonosis, key changes in food safety regulations were undertaken to improve controls in the food production chain. Despite these measures, large outbreaks of salmonellosis were reported worldwide in the last decade. Thus, new strategies for Salmonella detection are a priority for both, food safety and public health authorities. Such detection systems should provide significant reduction in diagnostic time (hours) compared to the currently available methods (days). Herein, we report on the discovery and characterization of nucleic acid probes for the sensitive and specific detection of live Salmonella within less than 8 h of incubation. We are the first to postulate the nuclease activity derived from Salmonella as biomarker of infection and its utility to develop innovative detection strategies. Our results have shown the screening and identification of two oligonucleotide sequences (substrates) as the most promising probes for detecting Salmonella - Sal-3 and Sal-5. The detection limits for both probes were determined with the reference Salmonella Typhimurium (STM 1) and Salmonella Enteritidis (SE 1) cultures. Sal-3 has reported LOD values around 10(5) CFU mL(-1) for STM 1 and 10(4) CFU mL(-1) for SE 1, while Sal-5 proves to be a slightly better probe, with LODs of 10(4) CFU mL(-1) for STM 1 and 10(4) CFU mL(-1) for SE 1. Both selected probes have shown the capability to recognize 49 out of 51 different Salmonella serotypes tested in vitro and the most frequent serotypes in porcine mesenteric lymph nodes as a standard sample used in fattening-pig salmonellosis baseline studies. Notably, our results showed 100% correlation between nuclease detection and the PCR-InvA or ISO-6579 standard method, underlining the great potential of this innovative nucleic acids technology to be implemented as a rapid method for food safety testing. (C) 2018 Elsevier B.V. All rights reserved.

    Publikationen är tillgänglig i fulltext från 2019-12-21 15:32
  • 322.
    Macwan, Ankit
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten.
    Boknäs, Niklas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Ntzouni, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Ramström, Sofia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi. Orebro Univ, Sweden.
    Gibbins, Jonathan M.
    Univ Reading, England.
    Faxälv, Lars
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Gradient-dependent inhibition of stimulatory signaling from platelet G protein-coupled receptors2019Ingår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 104, nr 7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    As platelet activation is an irreversible and potentially harmful event, platelet stimulatory signaling must be tightly regulated to ensure the filtering-out of inconsequential fluctuations of agonist concentrations in the vascular milieu. Herein, we show that platelet activation via G protein-coupled receptors is gradient-dependent, i.e., determined not only by agonist concentrations per se but also by how rapidly concentrations change over time. We demonstrate that gradient-dependent inhibition is a common feature of all major platelet stimulatory G protein-coupled receptors, while platelet activation via the non-G protein-coupled receptor glycoprotein VI is strictly concentration-dependent. By systematically characterizing the effects of variations in temporal agonist concentration gradients on different aspects of platelet activation, we demonstrate that gradient-dependent inhibition of protease-activated receptors exhibits different kinetics, with platelet activation occurring at lower agonist gradients for protease-activated receptor 4 than for protease-activated receptor 1, but shares a characteristic bimodal effect distribution, as gradient-dependent inhibition increases over a narrow range of gradients, below which aggregation and granule secretion is effectively shut off. In contrast, the effects of gradient-dependent inhibition on platelet activation via adenosine diphosphate and thromboxane receptors increase incrementally over a large range of gradients. Furthermore, depending on the affected activation pathway, gradient-dependent inhibition results in different degrees of refractoriness to subsequent autologous agonist stimulation. Mechanistically, our study identifies an important role for the cyclic adenosine monophosphate-dependent pathway in gradient-dependent inhibition. Together, our findings suggest that gradient-dependent inhibition may represent a new general mechanism for hemostatic regulation in platelets.

  • 323.
    Magnusson, Henrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för fysioterapi. Linköpings universitet, Medicinska fakulteten.
    Guorgis, Ghassan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten.
    Anderson, Chris D
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Falk, Magnus
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Primärvårdscentrum, Vårdcentralen Kärna, Linköping.
    Sustainable effect of individualised sun protection advice on sun protection behaviour: a 10-year follow-up of a randomised controlled study in primary care.2019Ingår i: BJGP open, ISSN 2398-3795, Vol. 3, nr 3, artikel-id bjgpopen19X101653Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: In the light of increasing skin cancer incidences worldwide, preventive measures to promote sun protection in individuals with risky sun habits have continued relevance and importance.

    AIM: To report the long-term effect of individualised sun protection advice given in primary health care (PHC), on sun habits and sun protection behaviour.

    DESIGN & SETTING: In 2005, 309 PHC patients were enrolled in a randomised controlled study performed in a Swedish PHC setting.

    METHOD: At baseline, the study participants completed a Likert scale-based questionnaire, mapping sun habits, propensity to increase sun protection, and attitudes towards sun exposure, followed by randomisation into three intervention groups, all receiving individualised sun protection advice: in Group 1 (n = 116) by means of a letter, and in Group 2 (n = 97) and 3 (n = 96) communicated personally by a GP. In Group 3, participants also underwent a skin ultraviolet-sensitivity phototest, with adjusted sun protection advice based on the result. A repeated questionnaire was administered after 3 and 10 years.

    RESULTS: Statistically significant declines were observed in all groups for sun exposure mean scores over time. When using a cumulative score, according to the Sun Exposure and Protection Index (SEPI), significantly greater decrease in SEPI mean score was observed in Groups 2 and 3 (GP), compared to Group 1 (letter); P<0.01. The addition of a phototest did not enhance the effect of the intervention.

    CONCLUSION: Individualised sun protection advice mediated verbally by the GP can lead to sustained improvement of sun protective behaviour.

  • 324.
    Magnusson, Karin
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Appelqvist, Hanna
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Cieslar-Pobuda, Artur
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Institute of Automatic Control, Silesian University of of TechnologyGliwice, Poland.
    Wigenius, Jens
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biomolekylär och Organisk Elektronik. Linköpings universitet, Tekniska högskolan. Carl Zeiss AB, Sweden.
    Karlsson, Thommie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Application Specialist Confocal Microscopy at Leica MicrosystemsIL, United States.
    Los, Marek Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Department of Pathology, Pomeranian Medical UniversitySzczecin, Poland.
    Kågedal, Bertil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Jonasson, Jon
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Nilsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Differential vital staining of normal fibroblasts and melanoma cells by an anionic conjugated polyelectrolyte2015Ingår i: Cytometry Part A, ISSN 1552-4922, E-ISSN 1552-4930, Vol. 87, nr 3, s. 262-272Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Molecular probes for imaging of live cells are of great interest for studying biological and pathological processes. The anionic luminescent conjugated polythiophene (LCP) polythiophene acetic acid (PTAA), has previously been used for vital staining of cultured fibroblasts as well as transformed cells with results indicating differential staining due to cell phenotype. Herein, we investigated the behavior of PTAA in two normal and five transformed cells lines. PTAA fluorescence in normal cells appeared in a peripheral punctated pattern whereas the probe was more concentrated in a one-sided perinuclear localization in the five transformed cell lines. In fibroblasts, PTAA fluorescence was initially associated with fibronectin and after 24 h partially localized to lysosomes. The uptake and intracellular target in malignant melanoma cells was more ambiguous and the intracellular target of PTAA in melanoma cells is still elusive. PTAA was well tolerated by both fibroblasts and melanoma cells, and microscopic analysis as well as viability assays showed no signs of negative influence on growth. Stained cells maintained their proliferation rate for at least 12 generations. Although the probe itself was nontoxic, photoinduced cellular toxicity was observed in both cell lines upon irradiation directly after staining. However, no cytotoxicity was detected when the cells were irradiated 24 h after staining, indicating that the photoinduced toxicity is dependent on the cellular location of the probe. Overall, these studies certified PTAA as a useful agent for vital staining of cells, and that PTAA can potentially be used to study cancer-related biological and pathological processes.

  • 325.
    Magnusson, Karin
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Appelqvist, Hanna
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Cieślar-Pobuda, Artur
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Bäck, Marcus
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Kågedal, Bertil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Jonasson, Jon
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Los, Marek J.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Nilsson, Peter R.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    An imidazole functionalized pentameric thiophene displays different staining patterns in normal and malignant cells2015Ingår i: Frontiers in Chemistry, E-ISSN 2296-2646, Vol. 3, artikel-id 58Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Molecular tools for fluorescent imaging of cells and their components are vital for understanding the function and activity of cells. Here, we report an imidazole functionalized pentameric oligothiophene, p-HTIm, that can be utilized for fluorescent imaging of cells. p-HTIm fluorescence in normal cells appeared in a peripheral punctate pattern partially co-localized with lysosomes, whereas a one-sided perinuclear Golgi associated localization of the dye was observed in malignant cells. The uptake of p-HTIm was temperature dependent and the intracellular target was reached within 1 h after staining. The ability of p-HTIm to stain cells was reduced when the imidazole side chain was chemically altered, verifying that specific imidazole side-chain functionalities are necessary for achieving the observed cellular staining. Our findings confirm that properly functionalized oligothiophenes can be utilized as fluorescent tools for vital staining of cells and that the selectivity towards distinct intracellular targets are highly dependent on the side-chain functionalities along the conjugated thiophene backbone.

  • 326.
    Magnusson, Rasmus
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Gustafsson, Mika
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Cedersund, Gunnar
    Linköpings universitet, Institutionen för medicinsk teknik, Avdelningen för medicinsk teknik. Linköpings universitet, Tekniska fakulteten.
    Strålfors, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Nyman, Elin
    Linköpings universitet, Institutionen för medicinsk teknik, Avdelningen för medicinsk teknik. Linköpings universitet, Tekniska fakulteten. CVMD iMedical DMPK AstraZeneca RandD, Sweden.
    Cross-talks via mTORC2 can explain enhanced activation in response to insulin in diabetic patients2017Ingår i: Bioscience Reports, ISSN 0144-8463, E-ISSN 1573-4935, Vol. 37, artikel-id BSR20160514Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The molecular mechanisms of insulin resistance in Type 2 diabetes have been extensively studied in primary human adipocytes, and mathematical modelling has clarified the central role of attenuation of mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activity in the diabetic state. Attenuation of mTORC1 in diabetes quells insulin-signalling network-wide, except for the mTOR in complex 2 (mTORC2)-catalysed phosphorylation of protein kinase B (PKB) at Ser(473) (PKB-S473P), which is increased. This unique increase could potentially be explained by feedback and interbranch cross-talk signals. To examine if such mechanisms operate in adipocytes, we herein analysed data from an unbiased phosphoproteomic screen in 3T3-L1 adipocytes. Using a mathematical modelling approach, we showed that a negative signal from mTORC1-p70 S6 kinase (S6K) to rictor-mTORC2 in combination with a positive signal from PKB to SIN1-mTORC2 are compatible with the experimental data. This combined cross-branch signalling predicted an increased PKB-S473P in response to attenuation of mTORC1 - a distinguishing feature of the insulin resistant state in human adipocytes. This aspect of insulin signalling was then verified for our comprehensive model of insulin signalling in human adipocytes. Introduction of the cross-branch signals was compatible with all data for insulin signalling in human adipocytes, and the resulting model can explain all data network-wide, including the increased PKB-S473P in the diabetic state. Our approach was to first identify potential mechanisms in data from a phosphoproteomic screen in a cell line, and then verify such mechanisms in primary human cells, which demonstrates how an unbiased approach can support a direct knowledge-based study.

  • 327.
    Mak, Wing Cheung
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska fakulteten.
    Cheung, K.Y.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Orban, Jenny
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska fakulteten.
    Lee, C-J
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska fakulteten.
    Turner, Anthony
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska fakulteten.
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Theranostic Contact Lens for Modulation and Detection of Viral Infection2017Ingår i: 26th Anniversary World Congress on Biosensors (Biosensors), Elsevier, 2017Konferensbidrag (Övrigt vetenskapligt)
  • 328.
    Mak, Wing Cheung
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Sensor- och aktuatorsystem. Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Magne, B.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Cheung, Kitt
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Atanasova, Diana
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. University of Montreal, Canada.
    Thermo-rheological responsive microcapsules for time-dependent controlled release of human mesenchymal stromal cells2017Ingår i: Biomaterials Science, ISSN 2047-4830, E-ISSN 2047-4849, Vol. 5, nr 11, s. 2241-2250Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Human mesenchymal stromal cells (hMSCs) are adult-source cells that have been extensively evaluated for cell-based therapies. hMSCs delivered by intravascular injection have been reported to accumulate at the sites of injury to promote tissue repair and can also be employed as vectors for the delivery of therapeutic genes. However, the full potential of hMSCs remains limited as the cells are lost after injection due to anoikis and the adverse pathologic environment. Encapsulation of cells has been proposed as a means of increasing cell viability. However, controlling the release of therapeutic cells over time to target tissue still remains a challenge today. Here, we report the design and development of thermo-rheological responsive hydrogels that allow for precise, time dependent controlled-release of hMSCs. The encapsulated hMSCs retained good viability from 76% to 87% dependent upon the hydrogel compositions. We demonstrated the design of different blended hydrogel composites with modulated strength (S parameter) and looseness of hydrogel networks (N parameter) to control the release of hMSCs from thermoresponsive hydrogel capsules. We further showed the feasibility for controlled-release of encapsulated hMSCs within 3D matrix scaffolds. We reported for the first time by a systematic analysis that there is a direct correlation between the thermo-rheological properties associated with the degradation of the hydrogel composite and the cell release kinetics. This work therefore provides new insights into the further development of smart carrier systems for stem cell therapy.

  • 329.
    Mak, Wing Cheung
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Olesen, Kim
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Sivlér, Petter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Lee, Chyan-Jang
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Moreno- Jimenzen, Inés
    Southampton General Hospital, Southampton, Hampshire SO16 6YD, UK .
    Edin, Joel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Courtman, David
    Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada.
    Skog, Mårten
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Controlled delivery of human cells by temperature responsive microcapsules2015Ingår i: Journal of Functional Biomaterials, ISSN 2079-4983, E-ISSN 2079-4983, Vol. 6, nr 2, s. 439-453Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 330.
    Mak, Wing Cheung
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Sensor- och aktuatorsystem. Linköpings universitet, Tekniska fakulteten.
    Olesen, Kim
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Sivlér, Petter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Lee, Chyan-Jang
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Moreno-Jimenez, Ines
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Bone & Joint Research Group, Stem Cells & Regeneration Institute of Developmental Sciences, Southampton General Hospital, UK.
    Edin, Joel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Courtman, D.
    Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada.
    Skog, Mårten
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Correction: W.C. Mak, et al. Controlled Delivery of Human Cells by Temperature Responsive Microcapsules. J. Funct. Biomater. 2015, 6, 439-4532018Ingår i: Journal of Functional Biomaterials, ISSN 2079-4983, E-ISSN 2079-4983, Vol. 9, nr 2, artikel-id 26Artikel i tidskrift (Övrigt vetenskapligt)
  • 331.
    Malmström, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Studies for Better Treatment of Patients with Glioma2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    In Sweden annually over 500 people will be diagnosed with the malignant brain tumor glioma. They are graded from I-IV. The majority are glioblastoma (grade IV) (GBM), these being the most aggressive type. Median survival for those treated with standard of care is expected to be around 15 months. This tumor will mainly affect those 60 years or older.

    The studies in this thesis focus on treatment of patients with malignant gliomas grade III and IV. The aim of the studies is to improve the care of glioma patients. Papers I and II explored different therapeutic options in randomized trials, to facilitate individualized treatment recommendations. Findings from studies I and II, together with additional trials, demonstrated the importance of analyzing the tumor marker O6-methylguanine DNA methyltransferase (MGMT) methylation status for survival of GBM patients treated with Temozolomide (TMZ). The third paper investigated how the analysis of this marker is implemented internationally.

    The first study (paper I, Nordic trial) investigated treatment options for patients 60 years or older with GBM. The trial compared standard radiotherapy (SRT) over 6 weeks versus hypofractionated radiotherapy (HRT) over 2 weeks versus single agent TMZ administered in up to six 4 weekly cycles. In all, 342 patients were included in the trial. This study demonstrated that those randomized to TMZ had superior survival as compared to SRT. In addition, quality of life (QoL) data also suggested a better QoL for TMZ treatment than for radiotherapy. The benefit of TMZ treatment seemed to be limited to those with the tumor molecular marker MGMT methylated (inactivated).

    The second trial (paper II, Neoadjuvant trial) studied whether integrating TMZ treatment with SRT for patients younger than 60 years with GBM (grade IV) and astrocytoma grade III would confer a survival benefit, if administered postoperatively, before the start of SRT (neoadjuvant). TMZ was provided for 2-3 four weekly cycles followed by SRT to patients randomized to neoadjuvant treatment and was compared to postoperative SRT alone. Although this trial could not illustrate any advantage of delaying the start of SRT while administering TMZ for the study cohort in general, for those included as astrocytoma grade III the median survival was found to be superior by 5 years when randomized to neoadjuvant TMZ. This trial also confirmed the importance of MGMT promoter methylation for the efficacy of TMZ.

    The third study (paper III) investigated international practices for analyzing tumor MGMT promoter methylation status. MGMT analysis can be conducted by various laboratory methods, which in some cases can provide opposing results regarding the MGMT methylation status of the patient´s tumor. This can lead to incorrect treatment recommendations. To establish which methods and cut-offs that are regularly used to determine tumor MGMT status in the clinic, an international survey was provided to those working in the field. We also inquired about opinions regarding an international consensus on how MGMT should be tested. The 152 respondents reported several methodologies and different cut-off levels also for the same method. A majority of respondents warrant international guidelines.

    In conclusion, the results of the 2 randomized trials contribute to individualized treatment recommendations for patients affected by GBM or astrocytoma grade III. The results of the survey regarding analyses of MGMT clarify the current problematic situation. The request of the respondents regarding international guidelines might contribute to their future development, so that personalized treatment recommendations can be improved.

    Delarbeten
    1. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial
    Öppna denna publikation i ny flik eller fönster >>Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial
    Visa övriga...
    2012 (Engelska)Ingår i: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 13, nr 9, s. 916-926Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background Most patients with glioblastoma are older than 60 years, but treatment guidelines are based on trials in patients aged only up to 70 years. We did a randomised trial to assess the optimum palliative treatment in patients aged 60 years and older with glioblastoma. less thanbrgreater than less thanbrgreater thanMethods Patients with newly diagnosed glioblastoma were recruited from Austria, Denmark, France, Norway, Sweden, Switzerland, and Turkey. They were assigned by a computer-generated randomisation schedule, stratified by centre, to receive temozolomide (200 mg/m(2) on days 1-5 of every 28 days for up to six cycles), hypofractionated radiotherapy (34.0 Gy administered in 3.4 Gy fractions over 2 weeks), or standard radiotherapy (60.0 Gy administered in 2.0 Gy fractions over 6 weeks). Patients and study staff were aware of treatment assignment. The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered, number ISRCTN81470623. less thanbrgreater than less thanbrgreater thanFindings 342 patients were enrolled, of whom 291 were randomised across three treatment groups (temozolomide n=93, hypofractionated radiotherapy n=98, standard radiotherapy n=100) and 51 of whom were randomised across only two groups (temozolomide n=26, hypofractionated radiotherapy n=25). In the three-group randomisation, in comparison with standard radiotherapy, median overall survival was significantly longer with temozolomide (8.3 months [95% CI 7.1-9.5; n=93] vs 6.0 months [95% CI 5.1-6.8; n=100], hazard ratio [HR] 0.70; 95% CI 0.52-0.93, p=0.01), but not with hypofractionated radiotherapy (7.5 months [6.5-8.6; n=98], HR 0.85 [0.64-1.12], p=0.24). For all patients who received temozolomide or hypofractionated radiotherapy (n=242) overall survival was similar (8.4 months [7.3-9.4; n=119] vs 7.4 months [6.4-8.4; n=123]; HR 0.82, 95% CI 0.63-1.06; p=0.12). For age older than 70 years, survival was better with temozolomide and with hypofractionated radiotherapy than with standard radiotherapy (HR for temozolomide vs standard radiotherapy 0.35 [0.21-0.56], pandlt;0.0001; HR for hypofractionated vs standard radiotherapy 0.59 [95% CI 0.37-0.93], p=0.02). Patients treated with temozolomide who had tumour MGMT promoter methylation had significantly longer survival than those without MGMT promoter methylation (9.7 months [95% CI 8.0-11.4] vs 6.8 months [5.9-7.7]; HR 0.56 [95% CI 0.34-0.93], p=0.02), but no difference was noted between those with methylated and unmethylated MGMT promoter treated with radiotherapy (HR 0.97 [95% CI 0.69-1.38]; p=0.81). As expected, the most common grade 3-4 adverse events in the temozolomide group were neutropenia (n=12) and thrombocytopenia (n=18). Grade 3-5 infections in all randomisation groups were reported in 18 patients. Two patients had fatal infections (one in the temozolomide group and one in the standard radiotherapy group) and one in the temozolomide group with grade 2 thrombocytopenia died from complications after surgery for a gastrointestinal bleed. less thanbrgreater than less thanbrgreater thanInterpretation Standard radiotherapy was associated with poor outcomes, especially in patients older than 70 years. Both temozolomide and hypofractionated radiotherapy should be considered as standard treatment options in elderly patients with glioblastoma. MGMT promoter methylation status might be a useful predictive marker for benefit from temozolomide.

    Ort, förlag, år, upplaga, sidor
    Elsevier, 2012
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-84333 (URN)10.1016/S1470-2045(12)70265-6 (DOI)000308425600019 ()
    Anmärkning

    Funding Agencies|Merck||Lions Cancer Research Foundation||University of Umea||Swedish Cancer Society||Schering-Plough||University of Umea, Sweden||Cancer Fonden, Sweden||

    Tillgänglig från: 2012-10-05 Skapad: 2012-10-05 Senast uppdaterad: 2019-11-06
    2. Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial
    Öppna denna publikation i ny flik eller fönster >>Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial
    Visa övriga...
    2017 (Engelska)Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, nr 12, s. 1776-1785Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Introduction: A pilot study of temozolomide (TMZ) given before radiotherapy (RT) for anaplastic astrocytoma (AA) and glioblastoma (GBM) resulted in prolonged survival compared to historical controls receiving RT alone. We therefore investigated neoadjuvant TMZ (NeoTMZ) in a randomized trial. During enrollment, concomitant and adjuvant radio-chemotherapy with TMZ became standard treatment. The trial was amended to include concurrent TMZ.Patients and methods: Patients, after surgery for GBM or AA, age 60 years and performance status (PS) 0-2, were randomized to either 2-3 cycles of TMZ, 200mg/m(2) days 1-5 every 28 days, followed by RT 60Gy in 30 fractions or RT only. Patients without progressive disease after two TMZ cycles, received the third cycle. From March 2005, TMZ 75mg/m(2) was administered daily concomitant with RT. TMZ was recommended first-line treatment at progression. Primary endpoint was overall survival and secondary safety.Results: The study closed prematurely after enrolling 144 patients, 103 with GBM and 41 with AA. Median age was 53 years (range 24-60) and 89 (62%) were male. PS was 0-1 for 133 (92%) patients, 53 (37%) had complete surgical resection and 18 (12%) biopsy. Ninety-two (64%) received TMZ concomitant with RT. Seventy-two (50%) were randomized to neoadjuvant treatment. For the overall study population survival was 20.3 months for RT and 17.7 months for NeoTMZ (p=.76), this not reaching the primary objective. For the preplanned subgroup analysis, we found that NeoTMZ AA patients had a median survival of 95.1 months compared to 35.2 months for RT (p=.022). For patients with GBM, no difference in survival was observed (p=.10). MGMT and IDH status affected outcome.Conclusions: No advantage of NeoTMZ was noted for the overall study population or subgroup of GBM, while NeoTMZ resulted in 5 years longer median survival for patients diagnosed as AA.

    Ort, förlag, år, upplaga, sidor
    TAYLOR & FRANCIS LTD, 2017
    Nationell ämneskategori
    Kirurgi
    Identifikatorer
    urn:nbn:se:liu:diva-144005 (URN)10.1080/0284186X.2017.1332780 (DOI)000418118800016 ()28675067 (PubMedID)
    Anmärkning

    Funding Agencies|Merck; Linkoping University Hospital for Neuro-research; Lions Cancer Foundation; Cancer Foundation Norrland, Umea, Sweden; LIUCancer; South-East Sweden FORSS

    Tillgänglig från: 2018-01-02 Skapad: 2018-01-02 Senast uppdaterad: 2019-11-06
    3. Do we really know who has an MGMT methylated glioma?: Results of an international survey regarding use of MGMT analyses for glioma
    Öppna denna publikation i ny flik eller fönster >>Do we really know who has an MGMT methylated glioma?: Results of an international survey regarding use of MGMT analyses for glioma
    Visa övriga...
    2019 (Engelska)Ingår i: Neuro-Oncology Practice, ISSN 2054-2577, s. 1-9Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Glioma O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status informs clinical decision making. Worldwide different methods and cutoff levels are used, which can lead to discordant methylation results.We conducted an international survey to clarify which methods are regularly used and why. We also explored opinions regarding international consensus on methods and cutoff.The survey had 152 respondents from 25 countries. MGMT methylation status is determined for all glioblastomas in 37% of laboratories. The most common methods are methylation-specific polymerase chain reaction (msPCR) (37%) and pyrosequencing (34%). A method is selected for simplicity (56%), cost-effectiveness (50%), and reproducibility of results (52%). For sequencing, the number of CpG sites analyzed varies from 1–3 up to more than 16. For 50% of laboratories, the company producing the kit determines which CpG sites are examined, whereas 33% select the sites themselves. Selection of cutoff is equally distributed among a cutoff defined in the literature, by the local laboratory, or by the outside laboratory performing the analysis. This cutoff varies, reported from 1% to 30%, and in 1 laboratory tumor is determined as methylated in case of 1 methylated CpG site of 17 analyzed. Some report tumors as unmethylated or weakly vs highly methylated. An international consensus on MGMT methylation method and cutoff is warranted by 66% and 76% of respondents, respectively. The method preferred would be msPCR (45%) or pyrosequencing (42%), whereas 18% suggest next-generation sequencing.Although analysis of MGMT methylation status is routine, there is controversy regarding laboratory methods and cutoff level. Most respondents favor development of international consensus guidelines.

    Ort, förlag, år, upplaga, sidor
    Oxford: Oxford University Press, 2019
    Nationell ämneskategori
    Medicinsk biovetenskap Klinisk laboratoriemedicin
    Identifikatorer
    urn:nbn:se:liu:diva-160808 (URN)10.1093/nop/npz039 (DOI)
    Tillgänglig från: 2019-10-09 Skapad: 2019-10-09 Senast uppdaterad: 2019-11-06Bibliografiskt granskad
  • 332.
    Malmström, Annika
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Lysiak, Malgorzata
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Winther Kristensen, Bjarne
    Department of Pathology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Denmark.
    Hovey, Elizabeth
    Department of Medical Oncology, Nelune Comprehensive Cancer Centre, Prince of Wales Hospital , Randwick, Sydney, NSW, Australia University of New South Wales , Sydney, Australia.
    Henriksson, Roger
    Department of Radiation Sciences, University of Umeå , Sweden.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Do we really know who has an MGMT methylated glioma?: Results of an international survey regarding use of MGMT analyses for glioma2019Ingår i: Neuro-Oncology Practice, ISSN 2054-2577, s. 1-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Glioma O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status informs clinical decision making. Worldwide different methods and cutoff levels are used, which can lead to discordant methylation results.We conducted an international survey to clarify which methods are regularly used and why. We also explored opinions regarding international consensus on methods and cutoff.The survey had 152 respondents from 25 countries. MGMT methylation status is determined for all glioblastomas in 37% of laboratories. The most common methods are methylation-specific polymerase chain reaction (msPCR) (37%) and pyrosequencing (34%). A method is selected for simplicity (56%), cost-effectiveness (50%), and reproducibility of results (52%). For sequencing, the number of CpG sites analyzed varies from 1–3 up to more than 16. For 50% of laboratories, the company producing the kit determines which CpG sites are examined, whereas 33% select the sites themselves. Selection of cutoff is equally distributed among a cutoff defined in the literature, by the local laboratory, or by the outside laboratory performing the analysis. This cutoff varies, reported from 1% to 30%, and in 1 laboratory tumor is determined as methylated in case of 1 methylated CpG site of 17 analyzed. Some report tumors as unmethylated or weakly vs highly methylated. An international consensus on MGMT methylation method and cutoff is warranted by 66% and 76% of respondents, respectively. The method preferred would be msPCR (45%) or pyrosequencing (42%), whereas 18% suggest next-generation sequencing.Although analysis of MGMT methylation status is routine, there is controversy regarding laboratory methods and cutoff level. Most respondents favor development of international consensus guidelines.

    Publikationen är tillgänglig i fulltext från 2020-09-25 08:00
  • 333.
    Malmström, Annika
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, LAH Linköping.
    Skovgaard Poulsen, Hans
    Rigshosp, Denmark.
    Henning Gronberg, Bjorn
    Norwegian University of Science and Technology, Norway; Trondheim Regional and University Hospital, Norway.
    Stragliotto, Giuseppe
    Karolinska University Hospital, Sweden.
    Hansen, Steinbjorn
    University of Southern Denmark, Denmark.
    Asklund, Thomas
    Karolinska University Hospital, Sweden; Umeå University, Sweden.
    Holmlund, Birgitta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Lysiak, Malgorzata
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Dowsett, Joseph
    University of Southern Denmark, Denmark.
    Winther Kristensen, Bjarne
    University of Southern Denmark, Denmark.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Rosell, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för verksamhetsstöd och utveckling, Regionalt Cancercentrum.
    Henriksson, Roger
    Umeå University, Sweden; Regional Cancer Centre Stockholm Gotland, Sweden.
    Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial2017Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, nr 12, s. 1776-1785Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: A pilot study of temozolomide (TMZ) given before radiotherapy (RT) for anaplastic astrocytoma (AA) and glioblastoma (GBM) resulted in prolonged survival compared to historical controls receiving RT alone. We therefore investigated neoadjuvant TMZ (NeoTMZ) in a randomized trial. During enrollment, concomitant and adjuvant radio-chemotherapy with TMZ became standard treatment. The trial was amended to include concurrent TMZ.Patients and methods: Patients, after surgery for GBM or AA, age 60 years and performance status (PS) 0-2, were randomized to either 2-3 cycles of TMZ, 200mg/m(2) days 1-5 every 28 days, followed by RT 60Gy in 30 fractions or RT only. Patients without progressive disease after two TMZ cycles, received the third cycle. From March 2005, TMZ 75mg/m(2) was administered daily concomitant with RT. TMZ was recommended first-line treatment at progression. Primary endpoint was overall survival and secondary safety.Results: The study closed prematurely after enrolling 144 patients, 103 with GBM and 41 with AA. Median age was 53 years (range 24-60) and 89 (62%) were male. PS was 0-1 for 133 (92%) patients, 53 (37%) had complete surgical resection and 18 (12%) biopsy. Ninety-two (64%) received TMZ concomitant with RT. Seventy-two (50%) were randomized to neoadjuvant treatment. For the overall study population survival was 20.3 months for RT and 17.7 months for NeoTMZ (p=.76), this not reaching the primary objective. For the preplanned subgroup analysis, we found that NeoTMZ AA patients had a median survival of 95.1 months compared to 35.2 months for RT (p=.022). For patients with GBM, no difference in survival was observed (p=.10). MGMT and IDH status affected outcome.Conclusions: No advantage of NeoTMZ was noted for the overall study population or subgroup of GBM, while NeoTMZ resulted in 5 years longer median survival for patients diagnosed as AA.

  • 334.
    Marco-Ramell, Anna
    et al.
    Universitat Autònoma de Barcelona, Spain; Univ Barcelona, Spain.
    de Almeida, Andree M
    Instituto de Biologia Experimental e Tecnologica, Oeiras, Portugal; Univ Lisbon, Fac, Lisbon, Portugal; Ross Univ, Sch Vet Med, Basseterre, St Kitts & Nevi.
    Cristobal, Susana
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Univ Basque Country, Leioa, Spain.
    Rodrigues, Pedro
    University of Algarve, Portugal.
    Roncada, Paola
    Istituto Sperimentale Italiano L. Spallanzani, Milano, Italy.
    Bassols, Anna
    Universitat Autònoma de Barcelona, Spain.
    Proteomics and the search for welfare and stress biomarkers in animal production in the one health context2016Ingår i: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 12, nr 7, s. 2024-2035Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Stress and welfare are important factors to animal production in a context of growing production optimization and scrutiny by the general public. In a context in which animal and human health are intertwined aspects of the one-health concept it is of utmost importance to define markers for stress and welfare. These are important tools for producers, retailers, regulatory agents and ultimately consumers to effectively monitor and assess the welfare state of production animals. Proteomics is the science that studies the proteins existing in a given tissue or fluid. In this review we address this topic by showing clear examples where proteomics has been used to study stress-induced changes at various levels. We adopt a multi-species (cattle, swine, small ruminants, poultry, fish and shellfish) approach under the effect of varied stress inducers (handling, transport, management, nutritional, thermal and exposure to pollutants) clearly demonstrating how Proteomics and Systems Biology are key elements to the study of stress and welfare on farm animals and a powerful tool to animal welfare, health and productivity.

  • 335.
    Martis, Mihaela-Maria
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Tarbiat, Behdad
    Swedish University of Agriculture Science SLU, Sweden.
    Tyden, Eva
    Swedish University of Agriculture Science SLU, Sweden.
    Jansson, Desiree S.
    National Vet Institute SVA, Sweden.
    Hoglund, Johan
    Swedish University of Agriculture Science SLU, Sweden.
    RNA-Seqde novo assembly and differential transcriptome analysis of the nematode Ascaridia galli in relation to in vivo exposure to flubendazole2017Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 11, artikel-id 0185182Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The nematode Ascaridia galli (order Ascaridida) is an economically important intestinal parasite responsible for increased food consumption, reduced performance and elevated mortality in commercial poultry production. This roundworm is an emerging problem in several European countries on farms with laying hens, as a consequence of the recent European Union (EU) ban on conventional battery cages. As infection is associated with slow development of low levels of acquired protective immunity, parasite control relies on repeated use of dewormers (anthelmintics). Benzimidazoles (BZ) are currently the only anthelmintic registered in the EU for use in controlling A. galli and there is an obvious risk of overuse of one drug class, selecting for resistance. Thus we developed a reference transcriptome of A. galli to investigate the response in gene expression before and after exposure to the BZ drug flubendazole (FLBZ). Transcriptional variations between treated and untreated A. galli showed that transcripts annotated as mitochondrial glutamate dehydrogenase and cytochrome P450 were significantly down-regulated in treated worms, whereas transcripts homologous to heat shock proteins (HSP), catalase, phosphofructokinase, and a multidrug resistance Pglycoprotein (PGP1) were significantly up-regulated in treated worms. Investigation of candidate transcripts responsible for anthelmintic resistance in livestock nematodes led to identification of several tubulins, including six new isoforms of beta-tubulin, and several ligandgated ionotropic receptors and ABC-transporters. We discovered several transcripts associated with drug binding and processing genes, but further characterisation using a larger set of worms exposed to BZs in functional assays is required to determine how these are involved in drug binding and metabolism.

  • 336.
    Matsuwaki, Takashi
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Eskilsson, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Örtegren Kugelberg, Unn
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Interleukin-1 beta induced activation of the hypothalamus-pituitary-adrenal axis is dependent on interleukin-1 receptors on non-hematopoietic cells2014Ingår i: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 40, s. 166-173Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The proinflammatory cytokine interleukin-1 beta (IL-beta) plays a major role in the signal transduction of immune stimuli from the periphery to the central nervous system, and has been shown to be an important mediator of the immune-induced stress hormone release. The signaling pathway by which IL-1 beta exerts this function involves the blood-brain-barrier and induced central prostaglandin synthesis, but the identity of the blood-brain-barrier cells responsible for this signal transduction has been unclear, with both endothelial cells and perivascular macrophages suggested as critical components. Here, using an irradiation and transplantation strategy, we generated mice expressing IL-1 type 1 receptors (IL-1 RI) either in hematopoietic or non-hematopoietic cells and subjected these mice to peripheral immune challenge with IL-beta. Following both intraperitoneal and intravenous administration of IL-beta, mice lacking IL-1R1 in hematopoietic cells showed induced expression of the activity marker c-Fos in the paraventricular hypothalamic nucleus, and increased plasma levels of ACTH and corticosterone. In contrast, these responses were not observed in mice with IL-1R1 expression only in hematopoietic cells. Immunoreactivity for IL-1R1 was detected in brain vascular cells that displayed induced expression of the prostaglandin synthesizing enzyme cyclooxygenase-2 and that were immunoreactive for the endothelial cell marker CD31, but was not seen in cells positive for the brain macrophage marker CD206. These results imply that activation of the HPA-axis by IL-1 beta is dependent on IL-1R1 s on non-hematopoietic cells, such as brain endothelial cells, and that IL-1R1 on perivascular macrophages are not involved.

  • 337.
    Melissaridou, Styliani
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Wiechec, Emilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Magan, Mustafa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Jain, Mayur Vilas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
    Chung, Man Ki
    Department of Otorhinolaryngology-Head & Neck Surgery, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, South Korea.
    Farnebo, Lovisa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Öron- näsa- och halskliniken US.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Öron- näsa- och halskliniken US.
    The effect of 2D and 3D cell cultures on treatment response, EMT profile and stem cell features in head and neck cancer.2019Ingår i: Cancer Cell International, ISSN 1475-2867, E-ISSN 1475-2867, Vol. 19, nr 16Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Head and Neck Squamous Cell Carcinoma (HNSCC) tumors are often resistant to therapies. Therefore searching for predictive markers and new targets for treatment in clinically relevant in vitro tumor models is essential. Five HNSCC-derived cell lines were used to assess the effect of 3D culturing compared to 2D monolayers in terms of cell proliferation, response to anti-cancer therapy as well as expression of EMT and CSC genes.

    Methods

    The viability and proliferation capacity of HNSCC cells as well as induction of apoptosis in tumor spheroids cells after treatment was assessed by MTT assay, crystal violet- and TUNEL assay respectively. Expression of EMT and CSC markers was analyzed on mRNA (RT-qPCR) and protein (Western blot) level.

    Results

    We showed that HNSCC cells from different tumors formed spheroids that differed in size and density in regard to EMT-associated protein expression and culturing time. In all spheroids, an up regulation of CDH1, NANOG and SOX2 was observed in comparison to 2D but changes in the expression of EGFR and EMT markers varied among the cell lines. Moreover, most HNSCC cells grown in 3D showed decreased sensitivity to cisplatin and cetuximab (anti-EGFR) treatment.

    Conclusions

    Taken together, our study points at notable differences between these two cellular systems in terms of EMT-associated gene expression profile and drug response. As the 3D cell cultures imitate the in vivo behaviour of neoplastic cells within the tumor, our study suggest that 3D culture model is superior to 2D monolayers in the search for new therapeutic targets.

  • 338.
    Merrett, Kimberly
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Kozak Ljunggren, Monika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Mondal, Debasish
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Rafat, Mehrdad
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Collagen Type I: A Promising Scaffold Material for Tissue Engineering and Regenerative Medicine2012Ingår i: Type I collagen: biological functions, synthesis & medicinal applications / [ed] Maria Eduarda Henriques and Marcio Pinto, Nova Science Publishers, Inc., 2012, s. 1-43Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    Abstract [en]

    It is now recognized that biological macromolecules such as components of the extracellular matrix (ECM) are important as instructive templates in Regenerative Medicine applications. They are now increasingly used in the development of a new generation of bio-mimetic materials that allow for restoration of function when the self-renewal capacity of a tissue or organ cannot overcome degeneration caused by disease, injury or age-related wear. For example, macromolecules derived from connective tissue have been isolated, chemically modified, and used in medical applications ranging from tissue repair and reconstruction to drug and cell delivery systems. Common ECM macromolecules of vertebrates include collagen, proteoglycans, elastin, and other cell-interactive proteins such as fibronectin and laminin. Of these, type I collagen is the most abundant ECM macromolecule and is the primary scaffolding material that maintains the 3-dimensional structure of tissues and organs within the body. It also provides the micro-environmental milieu for cellular attachment, migration, and proliferation.

    Animal-derived collagen is frequently used in tissue engineering applications due to its biocompatibility, but there are significant concerns about the immunogenicity of xenogeneic material as well as the possibility of pathogen transmission. Most recently, synthetic collagens and recombinant human collagens have been produced for medical application. Regardless of the source, however, macromolecules require processing and chemical treatment in order to improve their stability both in vitro and in vivo. This is most commonly achieved by cross-linking using a variety of agents. Cross-linking also allows for the development of “tailor-made” collagen-based biomaterials that possess specific properties for tissue engineering. Chemical cross-linkers such as glutaraldehyde and epoxy compounds are frequently used but their cytotoxicities have limited their clinical application. This has led to the use of zero-length cross-linkers such as carbodiimides and naturally derived agents such as genipin. Enzymatic cross-linking is becoming an attractive method to induce in situ biomaterial formation due to the mildness of the reaction. Naturally occurring enzymes such as transglutaminase are now commonly used. Photosensitizers used in combination with ultra-violet light irradiation can be used as exogenous cross-linkers. For example, riboflavin in combination with ultra-violet light is used clinically to augment the properties of collagen-based tissues such as the sclera and the cornea.

    Collagen type I is a good candidate for tissue engineering and in vivo delivery systems for cells, proteins, and drugs. Important to its versatile and functional nature are its chemotactic properties, which promote cellular proliferation and differentiation, richness in cross-linking sites, and biodegradability. Collagen based delivery matrices have been reported to improve the results of cell delivery by improving cell viability.

  • 339.
    Milovanovic, Micha
    et al.
    Linköpings universitet, Institutionen för samhälls- och välfärdsstudier, Hälsa, Aktivitet, Vård (HAV). Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i östra Östergötland, Medicinkliniken ViN.
    Eriksson, Kristoffer
    Östergötlands Läns Landsting, Närsjukvården i östra Östergötland, Medicinkliniken ViN.
    Winblad, Bengt
    Karolinska Institute, Sweden.
    Nilsson, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i östra Östergötland, Primärvården i östra länsdelen.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Post, Claes
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Järemo, Petter
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i östra Östergötland, Medicinkliniken ViN.
    Alzheimer and platelets: Low-density platelet populations reveal increased serotonin content in Alzheimer type dementia2014Ingår i: Clinical Biochemistry, ISSN 0009-9120, E-ISSN 1873-2933, Vol. 47, nr 15, s. 51-53Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: Alzheimers disease (AD) is a progressive form of dementia characterized by an increase in the toxic substance beta-amyloid in the brain. Platelets display a substantial heterogeneity with respect to density. They further contain a substantial amount of beta-amyloid precursor protein. Platelets take up and store serotonin (5-HT) that plays an important role in the pathogenesis of severe depression. The current study aims to investigate platelet serotonin content in different platelet density populations. Material and methods: The study involved 8 patients (age 70 +/- 8 (SD) years) (3 females/5 males) with moderate AD. 6 healthy elderly subjects (age 66 +/- 9 (SD) years) (3 females/3 males) served as controls. The platelet population was divided into 17 subpopulations according to density, using a linear Percoll (TM) gradient. Platelets were counted in all fractions. After cell lysis an ELISA technique was employed to determine the 5-HT content in each platelet subfraction. Results: The two study groups did not differ significantly regarding platelet distribution in the gradients, but AD sufferers have a significantly higher 5-HT content (p less than 0.05) in the lighter platelet populations. Discussion: AD-type dementia proved to be associated with lighter platelets containing more 5-HT. It is possible that platelets from AD patients release less 5-HT. It is speculated that AD synapses are affected in a manner comparable to platelets, which could explain why 5-HT reuptake inhibitors are less effective in AD dementia.

  • 340.
    Mobacken, Håkan
    et al.
    Hudmottagningen, Göteborg, Sweden.
    Berg, Mats
    Uppsala, Sweden.
    Angesjö, Eva
    Brämhults Vårdcentral - Borås, Sweden.
    Dunér, Kari
    Infektions och Hudkliniken, Blekingesjukhuset - Karlskrona, Sweden.
    Svensson, Margareta
    Stockholm Hud - Stockholm, Sweden.
    Synnerstad, Ingrid
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Dags att minska användningen av antibiotika vid rosacea [Time to limit the use of antibiotics in rosacea!]2018Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 115Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Rosacea is a chronic inflammatory disease with facial erythema and papulopustules. It is common in middle-aged/elderly persons and often affects self-perception and social well-being. It is generally classified into four subtypes. Improved understanding of pathophysiology has resulted in novel treatment approaches, but routine management in health care usually follows old trails. Most patients are managed in primary care. Greater attention to the reduced skin barrier, avoidance of exacerbating factors, better topicals and encouragement to topical maintenance treatment should reduce the use of oral tetracyclines. Low-dose isotretinoin is reserved for treatment-resistant patients, but relapses are frequent unlike its use in acne. In order to reduce antibiotic use, we propose that patients should be referred to a dermatologist for optimization of therapy including consideration of isotretinoin following tetracycline treatment of a maximum of 4-6 months.

  • 341.
    Moelzer, Christine
    et al.
    Univ Aberdeen, Scotland.
    Shankar, Sucharita P.
    Univ Aberdeen, Scotland; UCB Pharma, England.
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Univ Montreal, Canada.
    Mirazul Islam, Mohammad Mirazul
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Harvard Med Sch, MA 02115 USA; Harvard Med Sch, MA 02115 USA.
    Forrester, John V
    Univ Aberdeen, Scotland.
    Kuffova, Lucia
    Univ Aberdeen, Scotland.
    Activation of dendritic cells by crosslinked collagen hydrogels (artificial corneas) varies with their composition2019Ingår i: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Activated T cells are known to promote fibrosis, a major complication limiting the range of polymeric hydrogels as artificial corneal implants. As T cells are activated by dendritic cells (DC), minimally activating hydrogels would be optimal. In this study, we evaluated the ability of a series of engineered (manufactured/fabricated) and natural collagen matrices to either activate DC or conversely induce DC apoptosis in vitro. Bone marrow DC were cultured on a series of singly and doubly crosslinked hydrogels (made from recombinant human collagen III [RHCIII] or collagen mimetic peptide [CMP]) or on natural collagen-containing matrices, Matrigel(TM) and de-cellularised mouse corneal stroma. DC surface expression of major histocompatibility complex Class II and CD86 as well as apoptosis markers were examined. Natural matrices induced low levels of DC activation and maintained a "tolerogenic" phenotype. The same applied to singly crosslinked CMP-PEG gels. RHCIII gels singly crosslinked using either N-(3-dimethylaminopropyl)-N -ethylcarbodiimide with the coinitiator N-hydroxy succinimide (EDC-NHS) or N-cyclohexyl-N-(2-morpholinoethyl)carbodiimide metho-p-toulenesulfonate with NHS (CMC-NHS) induced varying levels of DC activation. In contrast, however, RHCIII hydrogels incorporating an additional polymeric network of 2-methacryloyloxyethyl phosphorylcholine did not activate DC but instead induced DC apoptosis, a phenomenon observed in natural matrices. This correlated with increased DC expression of leukocyte-associated immunoglobulin-like receptor-1. Despite low immunogenic potential, viable tolerogenic DC migrated into and through both natural and manufactured RHCIII gels. These data show that the immunogenic potential of RHCIII gels varies with the nature and composition of the gel. Preclinical evaluation of hydrogel immunogenic/fibrogenic potential is recommended.

  • 342.
    Mohan Kumar, Dipu
    et al.
    Ohio State University, Columbus, USA.
    Yamaguchi, Mamoru
    Ohio State University, Columbus, USA.
    Miura, Koshiro
    Ohio State University, Columbus, USA.
    Lin, Mingqun
    Ohio State University, Columbus, USA.
    Los, Marek
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Coy, Johannes F.
    Vorstand/CSO TAVARLIN AG, Darmstadt, Germany .
    Rikihisa, Yasuko
    Ohio State University, Columbus, USA.
    Ehrlichia chaffeensis Uses Its Surface Protein EtpE to Bind GPI-Anchored Protein DNase X and Trigger Entry into Mammalian Cells2013Ingår i: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 9, nr 10, s. e1003666-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ehrlichia chaffeensis, an obligatory intracellular rickettsial pathogen, enters and replicates in monocytes/macrophages and several non-phagocytic cells. E. chaffeensis entry into mammalian cells is essential not only for causing the emerging zoonosis, human monocytic ehrlichiosis, but also for its survival. It remains unclear if E. chaffeensis has evolved a specific surface protein that functions as an 'invasin' to mediate its entry. We report a novel entry triggering protein of Ehrlichia, EtpE that functions as an invasin. EtpE is an outer membrane protein and an antibody against EtpE (the C-terminal fragment, EtpE-C) greatly inhibited E. chaffeensis binding, entry and infection of both phagocytes and non-phagocytes. EtpE-C-immunization of mice significantly inhibited E. chaffeensis infection. EtpE-C-coated latex beads, used to investigate whether EtpE-C can mediate cell invasion, entered both phagocytes and non-phagocytes and the entry was blocked by compounds that block E. chaffeensis entry. None of these compounds blocked uptake of non-coated beads by phagocytes. Yeast two-hybrid screening revealed that DNase X, a glycosylphosphatidyl inositol-anchored mammalian cell-surface protein binds EtpE-C. This was confirmed by far-Western blotting, affinity pull-down, co-immunoprecipitation, immunofluorescence labeling, and live-cell image analysis. EtpE-C-coated beads entered bone marrow-derived macrophages (BMDMs) from wild-type mice, whereas they neither bound nor entered BMDMs from DNase X-/- mice. Antibody against DNase X or DNase X knock-down by small interfering RNA impaired E. chaffeensis binding, entry, and infection. E. chaffeensis entry and infection rates of BMDMs from DNase X-/- mice and bacterial load in the peripheral blood in experimentally infected DNase X-/- mice, were significantly lower than those from wild-type mice. Thus this obligatory intracellular pathogen evolved a unique protein EtpE that binds DNase X to enter and infect eukaryotic cells. This study is the first to demonstrate the invasin and its mammalian receptor, and their in vivo relevance in any ehrlichial species.

  • 343.
    Mohseni, Simin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Neurologic damage in hypoglycemia.2014Ingår i: Handbook of Clinical Neurology, Elsevier, 2014, Vol. 126, s. 513-32Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    Hypoglycemia occurs in diabetic patients as a consequence of treatment with hypoglycemic agents, in insulinoma patients as a result of excessive insulin production, and in infants as a result of abnormal regulation of metabolism. Profound hypoglycemia can cause structural and functional disturbances in both the central (CNS) and the peripheral nervous system (PNS). The brain is damaged by a short and severe episode of hypoglycemia, whereas PNS pathology appears after a mild and prolonged episode. In the CNS, damaged mitochondria, elevated intracellular Ca2(+) level, released cytochrome c to the cytosol, extensive production of superoxide, increased caspase-3 activity, release of aspartate and glutamate from presynaptic terminals, and altered biosynthetic machinery can lead to neuronal cell death in the brain. Considering the PNS, chronic hypoglycemia is associated with delayed motor and sensory conduction velocities in peripheral nerves. With respect to pathology, hypoglycemic neuropathy in the PNS is characterized by Wallerian-like axonal degeneration that starts at the nerve terminal and progresses to a more proximal part of the axon, and motor axons to the muscles may be more severely damaged than sensory axons. Since excitatory neurotransmitters primarily involve the neuron in the CNS, this "dying back" pattern of axonal damage in the PNS may involve mechanisms other than excitotoxicity.

  • 344.
    Mohseni, Simin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Badii, Medeea
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Kylhammar, Axel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Thomsen, Niels O. B.
    Department of Hand Surgery, Skåne University Hospital, Malmö, Sweden.
    Eriksson, Karl‐Fredrik
    Vascular Department of Angiology, Skåne University Hospital, Malmö, Sweden.
    Malik, Rayaz A.
    Weill Cornell Medicine-Qatar, Qatar Foundation, Doha, Qatar; Division of Cardiovascular Sciences, Manchester Academic Health Science Centre, Central Manchester University Hospitals.
    Rosén, Ingmar
    Department of Neurophysiology, Skåne University Hospital, Lund, Sweden.
    Dahlin, Lars B.
    Department of Hand Surgery, Skåne University Hospital, Malmö, Sweden; Department of Translational Medicine – Hand Surgery, Lund University, Malmö, Sweden .
    Longitudinal study of neuropathy, microangiopathy, and autophagy in sural nerve: Implications for diabetic neuropathy2017Ingår i: Brain and Behavior, ISSN 2162-3279, E-ISSN 2162-3279, Vol. 7, nr 8, artikel-id e00763Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The progression and pathophysiology of neuropathy in impaired glucose tolerance (IGT) and type 2 diabetes (T2DM) is poorly understood, especially in relation to autophagy. This study was designed to assess whether the presence of autophagy-related structures was associated with sural nerve fiber pathology, and to investigate if endoneurial capillary pathology could predict the development of T2DM and neuropathy. Sural nerve physiology and ultrastructural morphology were studied at baseline and 11 years later in subjects with normal glucose tolerance (NGT), IGT, and T2DM. Subjects with T2DM had significantly lower sural nerve amplitude compared to subjects with NGT and IGT at baseline. Myelinated and unmyelinated fiber, endoneurial capillary morphology, and the presence and distribution of autophagy structures were comparable between groups at baseline, except for a smaller myelinated axon diameter in subjects with T2DM and IGT compared to NGT. The baseline values of the subjects with NGT and IGT who converted to T2DM 11 years later demonstrated healthy smaller endoneurial capillary and higher g-ratio versus subjects who remained NGT. At follow-up, T2DM showed a reduction in nerve conduction, amplitude, myelinated fiber density, unmyelinated axon diameter, and autophagy structures in myelinated axons. Endothelial cell area and total diffusion barrier was increased versus baseline. We conclude that small healthy endoneurial capillary may presage the development of T2DM and neuropathy. Autophagy occurs in human sural nerves and can be affected by T2DM. Further studies are warranted to understand the role of autophagy in diabetic neuropathy.

  • 345.
    Molzer, Christine
    et al.
    Univ Aberdeen, Scotland.
    Shankar, Sucharita P.
    Univ Aberdeen, Scotland; UCB Pharma, England.
    Masalski, Vlad
    Univ Aberdeen, Scotland.
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Univ Montreal, Canada; Maisonneuve Rosemont Hosp Res Ctr, Canada.
    Kuffova, Lucia
    Univ Aberdeen, Scotland.
    Forrester, John V
    Univ Aberdeen, Scotland.
    TGF-beta 1-activated type 2 dendritic cells promote wound healing and induce fibroblasts to express tenascin c following corneal full-thickness hydrogel transplantation2019Ingår i: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We showed previously that 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDC) cross-linked recombinant human collagen III hydrogels promoted stable regeneration of the human cornea (continued nerve and stromal cell repopulation) for over 4 years. However, as EDC cross linking kinetics were difficult to control, we additionally tested a sterically bulky carbodiimide. Here, we compared the effects of two carbodiimide cross linkers-bulky, aromatic N-cyclohexyl-N0-(2-morpholinoethyl)-carbodiimide (CMC), and nonbulky EDC-in a mouse corneal graft model. Murine corneas undergoing full-thickness implantation with these gels became opaque due to dense retro-corneal membranes (RCM). Corneal epithelial cytokeratin 12 and alpha smooth muscle actin indicative of functional tissue regeneration and wound contraction were observed in RCM surrounding both hydrogel types. However, quantitatively different levels of infiltrating CD11c(+) dendritic cells (DC) were found, suggesting a hydrogel-specific innate immune response. More DC infiltrated the stroma surrounding EDC-N-hydroxysuccinimide (NHS) hydrogels concurrently with higher fibrosis-associated tenascin c expression. The opposite was true for CMC-NHS gels that had previously been shown to be more tolerising to DC. In vitro studies showed that DC cultured with transforming growth factor beta 1 (TGF-beta 1) induced fibroblasts to secrete more tenascin c than those cultured with lipopolysaccharide and this effect was blocked by TGF-beta 1 neutralisation. Furthermore, tenascin c staining was found in 40- to 50 mu m long membrane nanotubes formed in fibroblast/DC cocultures. We suggest that TGF-beta 1 alternatively activated (tolerising) DC regulate fibroblast-mediated tenascin c secretion, possibly via local production of TGF-beta 1 in early wound contraction, and that this is indirectly modulated by different hydrogel chemistries.

  • 346.
    Mondal, Debasish
    et al.
    Singapore Eye Research Institute, Singapore.
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Venkatraman, Subbu S.
    Nanyang Technology University, Singapore.
    Polycaprolactone-based biomaterials for tissue engineering and drug delivery: Current scenario and challenges2016Ingår i: International Journal of Polymeric Materials, ISSN 0091-4037, E-ISSN 1563-535X, Vol. 65, nr 5, s. 255-265Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recently, poly (epsilon-caprolactone) (PCL) has gained a lot of attention, and shown great potential in biomedical applications. Among synthetic polymers, PCL is one of the easiest to process and manipulate into a large range of shapes and sizes due to its low melting temperature and its superior viscoelastic properties. In this review article the authors focus mainly on the properties of PCL-based biomaterials relevant to drug delivery and tissue engineering applications. The authors provide an insight into the recent developments and challenges of PCL-based biomaterials as a critical component of new therapeutic strategies for many diseases.

  • 347.
    Mosrati, Mohamed Ali
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Malmström, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Region Östergötland, Närsjukvården i centrala Östergötland, LAH Linköping. Linköpings universitet, Medicinska fakulteten.
    Lysiak, Malgorzata
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Krysztofiak, Adam
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Hallbeck, Martin
    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.
    Milos, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Region Östergötland, Sinnescentrum, Neurokirurgiska kliniken US. Linköpings universitet, Medicinska fakulteten.
    Hallbeck, Anna-Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Linköpings universitet, Medicinska fakulteten.
    Bratthall, Charlotte
    Dist Hospital, Sweden.
    Strandeus, Michael
    Ryhov Hospital, Sweden.
    Stenmark Askmalm, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    TERT promoter mutations and polymorphisms as prognostic factors in primary glioblastoma2015Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, nr 18, s. 16663-16673Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Telomerase reverse transcriptase (TERT) activity is up-regulated in several types of tumors including glioblastoma (GBM). In the present study, 128 primary glioblastoma patients were examined for single nucleotide polymorphisms of TERT in blood and in 92 cases for TERT promoter mutations in tumors. TERT promoter mutations were observed in 86% of the tumors and of these, C228T (-124 bp upstream start codon) was detected in 75% and C250T (-146 bp) in 25% of cases. TERT promoter mutations were associated with shorter overall survival (11 vs. 20 months p = 0.002 and 12 vs. 20, p = 0.04 for C228T and C250T, respectively). The minor alleles of rs2736100 and rs10069690 SNPs, located in intron 2 and the promotor regions, respectively, were associated with an increased risk of developing GBM (p = 0.004 and 0.001). GBM patients having both TERT promoter mutations and being homozygous carriers of the rs2853669 C-allele displayed significantly shorter overall survival than those with the wild type allele. The rs2853669 SNP is located in a putative Ets2 binding site in the promoter (-246 bp upstream start codon) close to the C228T and C250T mutation hot spots. Interleukin-6 (IL-6) expression regulated by TERT promoter status and polymorphism, what leads us to think that TERT and IL-6 plays a significant role in GBM, where specific SNPs increase the risk of developing GBM while the rs2853669 SNP and specific mutations in the TERT promoter of the tumor lead to shorter survival.

  • 348.
    Mosrati, Mohamed Ali
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Willander, Kerstin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Jakobsen Falk, Ingrid
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Hermanson, Monica
    Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Höglund, Martin
    Division of Hematology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Stockelberg, Dick
    Section for Hematology and Coagulation, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Wei, Yuan
    Section for Hematology and Coagulation, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Association between TERT promoter polymorphisms and acute myeloid leukemia risk and prognosis2015Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, nr 28, s. 25109-25120Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Telomerase reverse transcriptase gene (TERT) promoter mutations are identified in many malignancies but not in hematological malignancies. Here we analyzed TERT and protection of telomeres 1 gene (POT1) mutations, and four different TERT SNVs in 226 acute myeloid leukemia (AML) patients and 806 healthy individuals in a case referent design, where also overall survival was assessed. A significant association for increased risk of AML was found for TERT SNVs, rs2853669 (OR = 2.45, p = 0.00015) and rs2736100 (OR = 1.5, p = 0.03). The overall survival for patients with CC genotype of rs2853669 was significantly shorter compared to those with TT or TC genotypes (p = 0.036 and 0.029 respectively). The influence of TERT rs2853669 CC on survival was confirmed in multivariable Cox regression analysis as an independent risk biomarker in addition to high risk group, higher age and treatment. No hot spot TERT promoter mutations at -228Cgreater thanT or -250Cgreater thanT or POT1 mutations could be identified in this AML cohort. We show that rs2853669 CC may be a risk factor for the development of AML that may also be used as a prognostic marker to identify high risk normal karyotype -AML (NK-AML) patients, for treatment guidance.

  • 349.
    Nawaz, Imran
    et al.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Department of Microbiology, Faculty of Life Sciences, University of Balochistan, Quetta, Pakistan.
    Hu, Li-Fu
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Du, Zi-Ming
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; State Key Laboratory of Oncology in South China, and Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, P.R. China.
    Moumad, Khalid
    Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Oncovirology Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco.
    Ignatyev, Ilya
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Pavlova, Tatiana V.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Kashuba, Vladimir
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Almgren, Malin
    Department Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Centre for Molecular Medicine, Stockholm, Sweden.
    Zabarovsky, Eugene R.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Ernberg, Ingemar
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Integrin α9 gene promoter is hypermethylated and downregulated in nasopharyngeal carcinoma2015Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, nr 31, s. 31493-31507Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Epigenetic silencing of tumor suppressor genes (TSGs) by promoter methylation can be an early event in the multi-step process of carcinogenesis. Human chromosome 3 contains clusters of TSGs involved in many cancer types including nasopharyngeal carcinoma (NPC), the most common cancer in Southern China. Among ten candidate TSGs identified in chromosome 3 using NotI microarray, ITGA9 and WNT7A could be validated. 5-aza-2 deoxycytidine treatment restored the expression of ITGA9 and WNT7A in two NPC cell lines. Immunostaining showed strong expression of these genes in the membrane and cytoplasm of adjacent control nasopharyngeal epithelium cells, while they were weakly expressed in NPC tumor cells. The ITGA9 promoter showed marked differentially methylation between tumor and control tissue, whereas no differentially methylation could be detected for the WNT7A promoter. The expression level of ITGA9 in NPC tumors was downregulated 4.9-fold, compared to the expression in control. ITGA9 methylation was detected by methylation specific PCR (MSP) in 56% of EBV positive NPC-cases with 100% specificity. Taken together, this suggests that ITGA9 might be a TSG in NPC that is involved in tumor cell biology. The possibility of using ITGA9 methylation as a marker for early detection of NPC should further be explored.

  • 350.
    Nazaryan-Petersen, Lusine
    et al.
    Univ Copenhagen, Denmark.
    Eisfeldt, Jesper
    Karolinska Inst, Sweden; Karolinska Inst Sci Pk, Sweden.
    Pettersson, Maria
    Karolinska Inst, Sweden.
    Lundin, Johanna
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Nilsson, Daniel
    Karolinska Inst, Sweden; Karolinska Inst Sci Pk, Sweden; Karolinska Univ Hosp, Sweden.
    Wincent, Josephine
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Lieden, Agne
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Lovmar, Lovisa
    Sahlgrens Univ Hosp, Sweden.
    Ottosson, Jesper
    Sahlgrens Univ Hosp, Sweden.
    Gacic, Jelena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Makitie, Outi
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; Univ Helsinki, Finland; Helsinki Univ Hosp, Finland; Folkhalsan Inst Genet, Finland.
    Nordgren, Ann
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Vezzi, Francesco
    Stockholm Univ, Sweden; Devyser AB, Sweden.
    Wirta, Valtteri
    KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Kaller, Max
    KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Hjortshoj, Tina Duelund
    Rigshosp, Denmark.
    Jespersgaard, Cathrine
    Rigshosp, Denmark.
    Houssari, Rayan
    Rigshosp, Denmark.
    Pignata, Laura
    Rigshosp, Denmark.
    Bak, Mads
    Univ Copenhagen, Denmark.
    Tommerup, Niels
    Univ Copenhagen, Denmark.
    Lundberg, Elisabeth Syk
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Tumer, Zeynep
    Rigshosp, Denmark; Univ Copenhagen, Denmark.
    Lindstrand, Anna
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Replicative and non-replicative mechanisms in the formation of clustered CNVs are indicated by whole genome characterization2018Ingår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 14, nr 11, artikel-id e1007780Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Clustered copy number variants (CNVs) as detected by chromosomal microarray analysis (CMA) are often reported as germline chromothripsis. However, such cases might need further investigations by massive parallel whole genome sequencing (WGS) in order to accurately define the underlying complex rearrangement, predict the occurrence mechanisms and identify additional complexities. Here, we utilized WGS to delineate the rearrangement structure of 21 clustered CNV carriers first investigated by CMA and identified a total of 83 breakpoint junctions (BPJs). The rearrangements were further sub-classified depending on the patterns observed: I) Cases with only deletions (n = 8) often had additional structural rearrangements, such as insertions and inversions typical to chromothripsis; II) cases with only duplications (n = 7) or III) combinations of deletions and duplications (n = 6) demonstrated mostly interspersed duplications and BPJs enriched with microhomology. In two cases the rearrangement mutational signatures indicated both a breakage-fusion-bridge cycle process and haltered formation of a ring chromosome. Finally, we observed two cases with Alu- and LINE-mediated rearrangements as well as two unrelated individuals with seemingly identical clustered CNVs on 2p25.3, possibly a rare European founder rearrangement. In conclusion, through detailed characterization of the derivative chromosomes we show that multiple mechanisms are likely involved in the formation of clustered CNVs and add further evidence for chromoanagenesis mechanisms in both "simple" and highly complex chromosomal rearrangements. Finally, WGS characterization adds positional information, important for a correct clinical interpretation and deciphering mechanisms involved in the formation of these rearrangements.

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