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  • 201.
    Hadrévi, Jenny
    et al.
    Umeå University, Sweden.
    Turkina, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Carlsson, Anders
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Östergötlands Läns Landsting, Sinnescentrum, Smärt och rehabiliteringscentrum. Linköpings universitet, Medicinska fakulteten.
    Gerdle, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten. Östergötlands Läns Landsting, Sinnescentrum, Smärt och rehabiliteringscentrum.
    Larsson, Britt
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten. Östergötlands Läns Landsting, Sinnescentrum, Smärt och rehabiliteringscentrum.
    Hellström, Fredrik
    University of Gävle, Sweden.
    Ghafouri, Bijar
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten. Östergötlands Läns Landsting, Sinnescentrum, Smärt och rehabiliteringscentrum.
    Myosin light chain and calcium regulating protein differences in chronic musculoskeletal neck and shoulder pain2016Inngår i: Journal of Integrated OMICS, ISSN 2182-0287, Vol. 6, nr 1, s. 1-8Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Proteomic screening analysis has detected myosin light chain (MLC) as a protein implied to be involved in chronic musculoskeletal neck and shoulder pain. Several analyses of MLC proteins have stated a difference in phosphorylation being the determining factor for protein activation hence altered contrability of the muscle in i.e. senescence. In continuation of a previous publication, this study is an attempt to analyze the different MLC isoforms by mass spectrometry and immune-analyses in myalgic and healthy trapezius muscle. In the present study no differences in phosphorylation level between the corresponding individual proteins were detected using LC-MSMS and immunoblotting; instead we assigned different isoforms of regulatory MLCs. To further elucidate the contrability: calcium (Ca2+) regulatory proteins, sarco(endo)plasmic reticulum Ca2+ ATPase 1 (SERCA-1) and calsequestrine (CSQ) were analyzed by western blot. The analysis revealed a significantly increased abundance of SERCA-1 protein in the myalgic muscle and a significantly increased abundance of CSQ in healthy muscle. Myalgic muscle contraction patterns have in previous studies shown to differ from healthy muscle which may be connected to the Ca2+ availability in the muscle. Here we present the proteomic characterization of differences in Ca2+ regulating proteins and particularly regulatory MLCs in trapezius muscle of women with chronic musculoskeletal neck and shoulder pain.

  • 202.
    Haglund, Sofie
    et al.
    Regional Jonköping County, Sweden; Karolinska Institute, Sweden.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Almer, Sven
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Söderman, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Regional Jonköping County, Sweden.
    Combination treatment with 6-mercaptopurine and allopurinol in HepG2 and HEK293 cells - Effects on gene expression levels and thiopurine metabolism2017Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 3, artikkel-id e0173825Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Combination treatment with low-dose thiopurine and allopurinol (AP) has successfully been used in patients with inflammatory bowel disease with a so called skewed thiopurine metabolite profile. In red blood cells in vivo, it reduces the concentration of methylated metabolites and increases the concentration of the phosphorylated ones, which is associated with improved therapeutic efficacy. This study aimed to investigate the largely unknown mechanism of AP on thiopurine metabolism in cells with an active thiopurine metabolic pathway using HepG2 and HEK293 cells. Cells were treated with 6-mercaptopurine (6MP) and AP or its metabolite oxypurinol. The expression of genes known to be associated with thiopurine metabolism, and the concentration of thiopurine metabolites were analyzed. Gene expression levels were only affected by AP in the presence of 6MP. The addition of AP to 6MP affected the expression of in total 19 genes in the two cell lines. In both cell lines the expression of the transporter SLC29A2 was reduced by the combined treatment. Six regulated genes in HepG2 cells and 8 regulated genes in HEK293 cells were connected to networks with 18 and 35 genes, respectively, present at known susceptibility loci for inflammatory bowel disease, when analyzed using a protein-protein interaction database. The genes identified as regulated as well as the disease associated interacting genes represent new candidates for further investigation in the context of combination therapy with thiopurines and AP. However, no differences in absolute metabolite concentrations were observed between 6MP+AP or 6MP +oxypurinol vs. 6MP alone in either of the two cell lines. In conclusion; the effect of AP on=gene expression levels requires the presence of 6MP, at least in vitro. Previously described AP-effects on metabolite concentrations observed in red blood cells in vivo could not be reproduced in our cell lines in vitro. APs effects in relation to thiopurine metabolism are complex. The network-identified susceptibility genes represented biological processes mainly associated with purine nucleotide biosynthetic processes, lymphocyte proliferation, NF-KB activation, JAK-STAT signaling, and apoptotic signaling at oxidative stress.

  • 203.
    Hakizimana, Pierre
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Effects of salicylate on sound-evoked outer hair cell stereocilia deflections2015Inngår i: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 467, nr 9, s. 2021-2029Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hearing depends on sound-evoked deflections of the stereocilia that protrude from the sensory hair cells in the inner ear. Although sound provides an important force driving stereocilia, forces generated through mechanically sensitive ion channels and through the motor protein prestin have been shown to influence stereocilia motion in solitary hair cells. While a possible influence of prestin on mechanically sensitive ion channels has not been systematically investigated, a decrease in transducer currents is evident in solitary hair cells when prestin is blocked with salicylate, raising the question of whether a reduced prestin activity or salicylate itself affected the mechanotransduction apparatus. We used two- and three-dimensional time-resolved confocal imaging to visualize outer hair cell stereocilia during sound stimulation in the apical turn of cochlear explant preparations from the guinea pig. Surprisingly, following application of salicylate, outer hair cell stereocilia deflections increased, while cochlear microphonic potentials decreased. However, when prestin activity was altered with the chloride ionophore tributyltin, both the cochlear microphonic potential and the stereocilia deflection amplitude decreased. Neither positive nor negative current stimulation abolished the bundle movements in the presence of salicylate, indicating that the observed effects did not depend on the endocochlear potential. These data suggest that salicylate may alter the mechanical properties of stereocilia, decreasing their bending stiffness.

  • 204.
    Halvarsson, Camilla
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Eliasson, Pernilla M.
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Pyruvate dehydrogenase kinase 1 is essential for transplantable mouse bone marrow hematopoietic stem cell and progenitor function2017Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 2, artikkel-id e0171714Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Accumulating evidence suggests that hypoxic areas in the bone marrow are crucial for maintenance of hematopoietic stem cells (HSCs) by supporting a quiescent state of cell cycle and regulating the transplantation capacity of long-term (LT)-HSCs. In addition, HSCs seem to express a metabolic profile of energy production away from mitochondrial oxidative phosphorylation in favor of glycolysis. At oxygen deprivation, hypoxia inducible factor 1 alpha (HIF-1 alpha) is known to induce glycolytic enzymes as well as suppressing mitochondrial energy production by inducing pyruvate dehydrogenase kinase 1 (Pdk1) in most cell types. It has not been established whether PDK1 is essential for HSC function and mediates hypoxia-adapting functions in HSCs. While the Pdk gene family contains four members (Pdk1-4), it was recently shown that Pdk2 and Pdk4 have an important role in regulating LT-HSCs. Principle findings Here we demonstrate that PDK1 activity is crucial for transplantable HSC function. Whereas Pdkl, Pdk2, and Pdk3 transcripts were expressed at higher levels in different subtypes of HSCs compared to differentiated cells, we could not detect any major differences in expression between LT-HSCs and more short-term HSCs and multipotent progenitors. When studying HIF-1 alpha-mediated regulation of Pdk activity in vitro, Pdk1 was the most robust target regulated by hypoxia, whereas Pdk2, Pdk3, and Pdk4 were not affected. Contrary, genetic ablation in a cre-inducible Hif-1 alpha knockout mouse did not support a link between HIF-1 alpha and Pdk1. Silencing of Pdk1 by shRNA lentiviral gene transfer partially impaired progenitor colony formation in vitro and had a strong negative effect on both long-term and short-term engraftment in mice. Conclusions Our study demonstrates that PDK1 has broad effects in hematopoiesis and is a critical factor for engraftment of both HSCs and multipotent progenitors upon transplantation to recipient mice. While Pdk1 was a robust hypoxia-inducible gene mediated by HIF-1 alpha in vitro, we could not find evidence of any in vivo links between Pdk1 and HIF-1 alpha.

  • 205.
    Hamrin, Elisabeth
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Ernerudh, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Rosén, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Immunological and Quality-of-Life Profiles in Women with Breast Cancer: Complementary versus Conventional Care2018Inngår i: Complementary Medicine Research, ISSN 2504-2092, Vol. 25, s. 391-397Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Previous studies showed that women with breast cancer treated in anthroposophic clinic versus conventional care had increased quality of life (QoL) parameters, fighting spirit, and anxiety coping. We have now analyzed immune and QoL factors in these 2 groups for possible differences during the first 6 months after admission, prompted by anthroposophic studies, including mistletoe extracts, showing beneficial immune system effects.

    Patients and MethodsFourteen immunological variables, including leukocyte count, lymphocyte count, activated T cells (CD4+ and CD8+), NK cells, B cells, IL1β, IL6, IL10, and oxytocin, were longitudinally analyzed in both groups (n = 2 × 26). A panel of QoL parameters were analyzed using 3 different instruments. Statistical evaluation included that each patient was its own control.

    Results: Cytotoxic CD8+ T cell frequency (percent of lymphocytes analyzed by flow-cytometry) significantly decreased over time in the anthroposophic group versus the conventional group (repeated measures ANOVA, p = 0.05). No major differences were observed in other immunological parameters, whereas QoL variables, anxiety decreased and physical symptoms increased/improved significantly in the anthroposophic group (p = 0.04 and p = 0.05, respectively).

    Conclusion: Overall, women with breast cancer in anthroposophic or conventional therapy did not differ in their immune profiles over time, with exception of decreased cytotoxic T cells in the anthroposophic group. Improvement in physical symptoms along with less anxiety in this group may have influenced the brain-immune axis resulting in lower frequency of CD8+ T cells, a feature associated with less aggressive cancer stages. To evaluate whether this observation is associated with good or bad prognosis, further detailed analyses of memory and naïve CD8+ T cells at tumor site and in blood circulation are essential.

  • 206.
    Hamzik, Namik
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Tang, Yan-juan
    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.
    Ruud, Johan
    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.
    Nilsberth, Camilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Interleukin-6 primarily produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response2013Inngår i: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 33, s. 123-130Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Interleukin-6 (IL-6) is critical for the lipopolysaccharide (LPS)-induced febrile response. However, the exact source(s) of IL-6 involved in regulating the LPS-elicited fever is still to be identified. One known source of IL-6 is hematopoietic cells, such as monocytes. To clarify the contribution of hematopoietically derived IL-6 to fever, we created chimeric mice expressing IL-6 selectively either in cells of hematopoietic or, conversely, in cells of non-hematopoietic origin. This was performed by extinguishing hematopoietic cells in wild-type (WT) or IL-6 knockout (IL-6 KO) mice by whole-body irradiation and transplanting them with new stem cells. Mice on a WT background but lacking IL-6 in hematopoietic cells displayed normal fever to LPS and were found to have similar levels of IL-6 protein in the cerebrospinal fluid (CSF) and in plasma and of IL-6 mRNA in the brain as WT mice. In contrast, mice on an IL-6 KO background, but with intact IL-6 production in cells of hematopoietic origin, only showed a minor elevation of the body temperature after peripheral LPS injection. While they displayed significantly elevated levels of IL-6 both in plasma and CSF compared with control mice, the increase was modest compared with that seen in LPS injected mice on a WT background, the latter being approximately 20 times larger in magnitude. These results suggest that IL-6 of non-hematopoietic origin is the main source of IL-6 in LPS-induced fever, and that IL-6 produced by hematopoietic cells only plays a minor role.

  • 207.
    Haridass, Isha N.
    et al.
    Curtin Univ, Australia; Univ Queensland, Australia.
    Wei, Jonathan C. J.
    Univ Queensland, Australia; Delft Univ Technol, Netherlands.
    Mohammed, Yousuf H.
    Univ Queensland, Australia.
    Crichton, Michael L.
    Heriot Watt Univ, Scotland.
    Anderson, Chris
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Henricson, Joakim
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Akutkliniken.
    Sanchez, Washington Y.
    Univ Queensland, Australia.
    Meliga, Stefano C.
    Univ Queensland, Australia.
    Grice, Jeffrey E.
    Univ Queensland, Australia.
    Benson, Heather A. E.
    Curtin Univ, Australia.
    Kendall, Mark A. F.
    Australian Natl Univ, Australia; Univ Queensland, Australia.
    Roberts, Michael S.
    Univ Queensland, Australia; Univ South Australia, Australia.
    Cellular metabolism and pore lifetime of human skin following microprojection array mediation2019Inngår i: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 306, s. 59-68Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Skin-targeting microscale medical devices are becoming popular for therapeutic delivery and diagnosis. We used cryo-SEM, fluorescence lifetime imaging microscopy (FLIM), autofluorescence imaging microscopy and inflammatory response to study the puncturing and recovery of human skin ex vivo and in vivo after discretised puncturing by a microneedle array (Nanopatch (R)). Pores induced by the microprojections were found to close by similar to 25% in diameter within the first 30 min, and almost completely close by similar to 6 h. FLIM images of ex vivo viable epidermis showed a stable fluorescence lifetime for unpatched areas of similar to 1000 ps up to 24 h. Only the cells in the immediate puncture zones (in direct contact with projections) showed a reduction in the observed fluorescence lifetimes to between similar to 518-583 ps. The ratio of free-bound NAD(P)H (alpha 1/alpha 2) in unaffected areas of the viable epidermis was similar to 2.5-3.0, whereas the ratio at puncture holes was almost double at similar to 4.2-4.6. An exploratory pilot in vivo study also suggested similar closure rate with histamine administration to the forearms of human volunteers after Nanopatch (R) treatment, although a prolonged inflammation was observed with Tissue Viability Imaging. Overall, this work shows that the pores created by the microneedle-type medical device, Nanopatch (R), are transient, with the skin recovering rapidly within 1-2 days in the epidermis after application.

  • 208.
    Hashem, Rasha
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Tynngård, Nahreen
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Ledningsstab Region Östergötland, Enheten för forskningsstöd.
    Lundmark, Katarzyna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Falk, Lars
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland. Region Östergötland, Ledningsstab Region Östergötland, Enheten för forskningsstöd.
    Microcystic adnexal carcinoma originating in a nevus sebaceous: a case report of a 16-year-old boy2019Inngår i: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 99Artikkel i tidsskrift (Fagfellevurdert)
  • 209.
    Hashemi, Mohammad
    et al.
    Zahedan University of Medical Sciences, Iran.
    Karami, Shima
    Zahedan University of Medical Sciences, Iran.
    Sarabandi, Sahel
    Zahedan University of Medical Sciences, Iran.
    Moazeni-Roodi, Abdolkarim
    Iranshahr University of Medical Sciences, Iran.
    Malecki, Andrzej
    The Jerzy Kukuczka Academy of Physical Education, Katowice, Poland.
    Ghavami, Saeid
    University of Manitoba, Canada.
    Wiechec, Emilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Association between PD-1 and PD-L1 polymorphisms and the risk of cancer: a meta analysis of case-control studies2019Inngår i: Cancers, ISSN 2072-6694, Vol. 11, nr 8, artikkel-id 1150Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A number of case-control studies regarding the association of the polymorphisms in the programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) genes with the risk of cancer have yielded inconsistent findings. Therefore, we have conducted a comprehensive, updated meta-analysis study to identify the impact of PD-1 and PD-L1 polymorphisms on overall cancer susceptibility. The findings revealed that PD-1 rs2227981 and rs11568821 polymorphisms significantly decreased the overall cancer risk (Odds Ratio (OR) = 0.82, 95% CI = 0.68–0.99, p = 0.04, TT vs. CT+CC; OR = 0.79, 95% CI = 0.67–0.94, p = 0.006, AG vs. GG, and OR = 0.82, 95% CI = 0.70–0.96, p = 0.020, AG+AA vs. GG, respectively), while PD-1 rs7421861 polymorphism significantly increased the risk of developing cancer (OR = 1.16, 95% CI = 1.02–1.33, p = 0.03, CT vs. TT). The PD-L1 rs4143815 variant significantly decreased the risk of cancer in homozygous (OR = 0.62, 95% CI = 0.41–0.94, p = 0.02), dominant (OR = 0.70, 95% CI = 0.50–0.97, p = 0.03), recessive (OR = 0.76, 95% CI = 0.60–0.96, p = 0.02), and allele (OR = 0.78, 95% CI = 0.63–0.96, p = 0.02) genetic models. No significant association between rs2227982, rs36084323, rs10204525, and rs2890658 polymorphisms and overall cancer risk has been found. In conclusions, the results of this meta-analysis have revealed an association between PD-1 rs2227981, rs11568821, rs7421861, as well as PD-L1 rs4143815 polymorphisms and overall cancer susceptibility. 

  • 210.
    Hayes, Sally
    et al.
    Cardiff University, Wales; Cardiff University, Wales.
    Lewis, Phillip
    Cardiff University, Wales; Cardiff University, Wales.
    Islam, Mohammad Mirazul
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    Doutch, James
    Diamond Light Source, England.
    Sorensen, Thomas
    Diamond Light Source, England.
    White, Tomas
    Cardiff University, Wales; Cardiff University, Wales.
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    Meek, Keith M.
    Cardiff University, Wales; Cardiff University, Wales.
    The structural and optical properties of type III human collagen biosynthetic corneal substitutes2015Inngår i: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 25, s. 121-130Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The structural and optical properties of clinically biocompatible, cell-free hydrogels comprised of synthetically cross-linked and moulded recombinant human collagen type III (RHCIII) with and without the incorporation of 2-methacryloyloxyethyl phosphorylcholine (MPC) were assessed using transmission electron microscopy (TEM), X-ray scattering, spectroscopy and refractometry. These findings were examined alongside similarly obtained data from 21 human donor corneas. TEM demonstrated the presence of loosely bundled aggregates of fine collagen filaments within both RHCIII and RHCIII-MPC implants, which X-ray scattering showed to lack D-banding and be preferentially aligned in a uniaxial orientation throughout. This arrangement differs from the predominantly biaxial alignment of collagen fibrils that exists in the human cornea. By virtue of their high water content (90%), very fine collagen filaments (2-9 nm) and lack of cells, the collagen hydrogels were found to transmit almost all incident light in the visible spectrum. They also transmitted a large proportion of UV light compared to the cornea which acts as an effective UV filter. Patients implanted with these hydrogels should be cautious about UV exposure prior to regrowth of the epithelium and in-growth of corneal cells into the implants. (C) 2015 Acta Materialia Inc. Published by Elsevier Ltd.

  • 211.
    He, Min
    et al.
    Harvard Medical Sch, MA USA; Shanxi Medical University, Peoples R China.
    Storr-Paulsen, Thomas
    Harvard Medical Sch, MA USA; Aarhus University Hospital NBG, Denmark.
    Wang, Annie L.
    Harvard Medical Sch, MA USA.
    Ghezzi, Chiara E.
    Tufts University, MA 02155 USA.
    Wang, Siran
    Tufts University, MA 02155 USA.
    Fullana, Matthew
    Case Western Reserve University, OH 44106 USA.
    Karamichos, Dimitrios
    University of Oklahoma, OK USA.
    Utheim, Tor P.
    Harvard Medical Sch, MA USA; University of Oslo, Norway; Vestre Viken Hospital Trust, Norway; University of Coll Southeast Norway, Norway.
    Islam, Rakibul
    Harvard Medical Sch, MA USA; University of Oslo, Norway.
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    Islam, Mohammad Mirazul Mirazul
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    Hodges, Robin R.
    Harvard Medical Sch, MA USA.
    Wnek, Gary E.
    Case Western Reserve University, OH 44106 USA.
    Kaplan, David L.
    Tufts University, MA 02155 USA.
    Dartt, Darlene A.
    Harvard Medical Sch, MA USA.
    Artificial Polymeric Scaffolds as Extracellular Matrix Substitutes for Autologous Conjunctival Goblet Cell Expansion2016Inngår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 57, nr 14, s. 6134-6146Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE. We fabricated and investigated polymeric scaffolds that can substitute for the conjunctival extracellular matrix to provide a substrate for autologous expansion of human conjunctival goblet cells in culture. METHODS. We fabricated two hydrogels and two silk films: (1) recombinant human collagen (RHC) hydrogel, (2) recombinant human collagen 2-methacryloylxyethyl phosphorylcholine (RHC-MPC) hydrogel, (3) arginine-glycine-aspartic acid (RGD) modified silk, and (4) poly-D-lysine (PDL) coated silk, and four electrospun scaffolds: (1) collagen, (2) poly(acrylic acid) (PAA), (3) poly(caprolactone) (PCL), and (4) poly(vinyl alcohol) (PVA). Coverslips and polyethylene terephthalate (PET) were used for comparison. Human conjunctival explants were cultured on scaffolds for 9 to 15 days. Cell viability, outgrowth area, and the percentage of cells expressing markers for stratified squamous epithelial cells (cytokeratin 4) and goblet cells (cytokeratin 7) were determined. RESULTS. Most of cells grown on all scaffolds were viable except for PCL in which only 3.6 +/- 2.2% of the cells were viable. No cells attached to PVA scaffold. The outgrowth was greatest on PDL-silk and PET. Outgrowth was smallest on PCL. All cells were CK7-positive on RHCMPC while 84.7 +/- 6.9% of cells expressed CK7 on PDL-silk. For PCL, 87.10 +/- 3.17% of cells were CK7-positive compared to PET where 67.10 +/- 12.08% of cells were CK7-positive cells. CONCLUSIONS. Biopolymer substrates in the form of hydrogels and silk films provided for better adherence, proliferation, and differentiation than the electrospun scaffolds and could be used for conjunctival goblet cell expansion for eventual transplantation once undifferentiated and stratified squamous cells are included. Useful polymer scaffold design characteristics have emerged from this study.

  • 212.
    Hedman, Christina A
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrinmedicinska enheten.
    Frystyk, Jan
    Aarhus University and Aarhus University Hospital, Denmark.
    Lindström, Torbjörn
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrinmedicinska enheten.
    Oskarsson, Per
    Karolinska University Hospital, Stockholm, Sweden.
    Arnqvist, Hans J
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrinmedicinska enheten.
    Intraperitoneal insulin delivery to patients with type 1 diabetes results in higher serum IGF-I bioactivity than continuous subcutaneous insulin infusion2014Inngår i: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 81, nr 1, s. 58-62Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective

    Type 1 diabetes (T1D) is associated with low IGF-I and altered levels of IGF-binding proteins (IGFBPs) in plasma. This may be of importance for insulin sensitivity and the risk of developing diabetic complications. We hypothesized that IGF-I bioactivity is affected by the route of insulin administration and that continuous intraperitoneal insulin infusion (CIPII) has a more pronounced effect than continuous subcutaneous insulin infusion (CSII).

    Design and methods

    We compared 10 patients with T1D on CIPII with 20 age- and sex-matched patients on CSII. Blood sampling was carried out 7–9 am after an overnight fast. All patients were C-peptide negative. IGF-I bioactivity was measured in vitro using a specific IGF-I kinase receptor activation (KIRA) assay. IGF-I was also measured by immunoassay together with IGF-II, IGFBP-1 and IGFBP-2.

    Results

    When compared with subcutaneous insulin, intraperitoneal insulin resulted in (CIPII vs CSII) higher IGF-I bioactivity (1·83 ± 0·76 vs 1·16 ± 0·24 μg/l; P = 0·02), IGF-I (120 ± 35 vs 81 ± 19 μg/l; P = 0·01) and IGF-II (1050 ± 136 vs 879 ± 110 μg/l; P = 0·02). By contrast, log-transformed IGFBP-1 was reduced (P = 0·013), whereas log-transformed IGFBP-2 was not different (P = 0·12). There was a positive correlation between IGF bioactivity and IGF-I (r = 0·69; P < 0·001) and an inverse correlation between IGF-I bioactivity and log10 IGFBP-1 (r = −0·68, P < 0·001).

    Conclusion

    The in vitro IGF-I bioactivity was higher in patients treated with CIPII compared with CSII supporting the theory that the route of insulin administration is of importance for the activity of the IGF system. Intraperitoneal insulin administration may therefore be beneficial by correcting the alterations of the IGF system in T1D.

  • 213.
    Helander, Sara
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Montecchio, Meri
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Pilstål, Robert
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Su, Yulong
    Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA.
    Kuruvilla, Jacob
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Sweden.
    Johansson, Malin
    Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Sweden.
    Mohammed, Javed
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Cristobal, Susana
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Lundström, Patrik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Sears, Rosalie
    Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA.
    Wallner, Björn
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Institutionen för samhälls- och välfärdsstudier, Lärande, Estetik, Naturvetenskap (LEN). Linköpings universitet, Utbildningsvetenskap. Linköpings universitet, Tekniska fakulteten.
    Sunnerhagen, Maria
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Pre-Anchoring of Pin1 to Unphosphorylated c-Myc in a Fuzzy Complex Regulates c-Myc Activity2015Inngår i: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 23, nr 12, s. 2267-2279Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hierarchic phosphorylation and concomitant Pin1-mediated proline isomerization of the oncoprotein c-Myc controls its cellular stability and activity. However, the molecular basis for Pin1 recognition and catalysis of c-Myc and other multisite, disordered substrates in cell regulation and disease is unclear. By nuclear magnetic resonance, surface plasmon resonance, and molecular modeling, we show that Pin1 subdomains jointly pre-anchor unphosphorylated c-Myc1–88 in the Pin1 interdomain cleft in a disordered, or “fuzzy”, complex at the herein named Myc Box 0 (MB0) conserved region N-terminal to the highly conserved Myc Box I (MBI). Ser62 phosphorylation in MBI intensifies previously transient MBI-Pin1 interactions in c-Myc1–88 binding, and increasingly engages Pin1PPIase and its catalytic region with maintained MB0 interactions. In cellular assays, MB0 mutated c-Myc shows decreased Pin1 interaction, increased protein half-life, but lowered rates of Myc-driven transcription and cell proliferation. We propose that dynamic Pin1 recognition of MB0 contributes to the regulation of c-Myc activity in cells

  • 214.
    Helmfors, Linda
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Armstrong, Andrea
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Civitelli, Livia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Sandin, Linnea
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Nath, Sangeeta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Janefjord, Camilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Zetterberg, Henrik
    Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden.
    Blennow, Kaj
    Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden.
    Garner, Brett
    Illawarra Health and Medical Research Institute University of Wollongong, Australia.
    Brorsson, Ann-Christin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Kågedal, Katarina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    A protective role of lysozyme in Alzheimer diseaseManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Alzheimer disease (AD) is a devastating neurodegenerative disorder where extracellular plaques composed of amyloid β (Aβ) peptides and neuroinflammation are some of the main hallmarks of the disease. Activated microglial cells, which are the resident macrophages in the central nervous system, are suggested to trigger the inflammation response in AD. To discover neuroinflammation biomarkers would be important to reveal the pathological mechanisms of AD and develop therapies that target inflammation mediators. Lysozyme is part of the innate immune system and is secreted from macrophages during various inflammation conditions. However, the involvement of lysozyme in AD pathology has not been explored previously. We have discovered that lysozyme is up-regulated in cerebrospinal fluid from AD patients. Cells exposed to Aβ increased the expression of lysozyme indicating that Aβ might be responsible for the upregulation of lysozyme detected in cerebrospinal fluid. In vitro studies revealed that lysozyme binds to monomeric Aβ1-42 and alters the aggregation pathway counteracting formation of toxic Aβ species. In a newly developed Drosophila model, co-expression of lysozyme with Aβ in brain neurons reduced the formation of insoluble Aβ species, prolonged the survival and improved the activity of the double transgenic flies compared to flies only expressing Aβ. Our findings identify lysozyme as a modulator of Aβ aggregation and toxicity and our discoveries has the potential to be used for development of new treatment strategies and to use lysozyme as a biomarker for AD.

  • 215.
    Helmfors, Linda
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär Bioteknik. Linköpings universitet, Tekniska fakulteten.
    Boman, Andrea
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Civitelli, Livia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Nath, Sangeeta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Sandin, Linnea
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Janefjord, Camilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    McCann, Heather
    Neuroscience Research Australia and University of New South Wales, Australia.
    Zetterberg, Henrik
    Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden / UCL Institute of Neurology, Queen Square, London, United Kingdom.
    Blennow, Kaj
    Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden.
    Halliday, Glenda
    UCL Institute of Neurology, Queen Square, London, United Kingdom.
    Brorsson, Ann-Christin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär Bioteknik. Linköpings universitet, Tekniska fakulteten.
    Kågedal, Katarina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Protective properties of lysozyme on β-amyloid pathology: implications for Alzheimer disease2015Inngår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 83, s. 122-133Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 216.
    Henningsson, Anna J
    et al.
    Ryhov County Hospital, Jönköping.
    Wilhelmsson, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Gyllemark, Paula
    Ryhov County Hospital, Jönköping.
    Kozak Ljunggren, Monika
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi.
    Matussek, Andreas
    Ryhov County Hospital, Jönköping.
    Nyman, Dag
    Ryhov County Hospital, Jönköping.
    Ekerfelt, Christina
    Bimelix Biomedical Laboratory, Mariehamn, Åland, Finland .
    Lindgren, Per-Eric
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Ryhov County Hospital, Jönköping.
    Forsberg, Pia
    Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Infektionskliniken i Östergötland. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin.
    Low risk of seroconversion or clinical disease in humans after a bite by an Anaplasma phagocytophilum-infected tick2015Inngår i: Ticks and Tick-borne Diseases, ISSN 1877-959X, E-ISSN 1877-9603, Vol. 6, nr 6, s. 787-792Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The risk of contracting human granulocytic anaplasmosis (HGA) after a tick bite is mainly unknown. In this study we investigated the clinical and serological response in 30 humans bitten by ticks positive for Anaplasma phagocytophilum (Group A), 30 humans bitten by Borrelia burgdorferi sensu lato (s.l.)-positive ticks (Group B), and 30 humans bitten by ticks negative for both A. phagocytophilum and B. burgdorferi s.l. (Group C). Ticks, blood samples and questionnaires were collected from tick-bitten humans at 34 primary healthcare centres in Sweden and in the Åland Islands, Finland, at the time of the tick bite and after three months. A total of 2553 ticks detached from humans in 2007-2009 were analyzed by polymerase chain reaction, and 31 (1.2%) were positive for A. phagocytophilum, 556 (21.8%) were positive for B. burgdorferi s.l., and eight (0.3%) were co-infected by A. phagocytophilum and B. burgdorferi s.l. The overall prevalence of Anaplasma IgG antibodies in the included participants (n=90) was 17%, and there was no significant difference between the groups A-C. Only one of the participants (in Group C) showed a four-fold increase of IgG antibodies against A. phagocytophilum at the three-month follow-up, but reported no symptoms. The frequency of reported symptoms did not differ between groups A-C, and was unrelated to the findings of A. phagocytophilum and B. burgdorferi s.l. in the detached ticks. We conclude that the risk for HGA or asymptomatic seroconversion after a tick bite in Sweden or in the Åland Islands is low, even if the tick is infected by A. phagocytophilum.

  • 217.
    Henricson, Joakim
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Toll John, Rani
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Anderson, Chris
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Björk Wilhelms, Daniel
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Akutkliniken.
    Diffuse Reflectance Spectroscopy: Getting the Capillary Refill Test Under Ones Thumb2017Inngår i: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, nr 130, artikkel-id e56737Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The capillary refill test was introduced in 1947 to help estimate circulatory status in critically ill patients. Guidelines commonly state that refill should occur within 2 s after releasing 5 s of firm pressure (e.g., by the physicians finger) in the normal healthy supine patient. A slower refill time indicates poor skin perfusion, which can be caused by conditions including sepsis, blood loss, hypoperfusion, and hypothermia. Since its introduction, the clinical usefulness of the test has been debated. Advocates point out its feasibility and simplicity and claim that it can indicate changes in vascular status earlier than changes in vital signs such as heart rate. Critics, on the other hand, stress that the lack of standardization in how the test is performed and the highly subjective nature of the naked eye assessment, as well as the tests susceptibility to ambient factors, markedly lowers the clinical value. The aim of the present work is to describe in detail the course of the refill event and to suggest potentially more objective and exact endpoint values for the capillary refill test using diffuse polarization spectroscopy.

  • 218.
    Henriksson, Pontus
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Lof, M.
    Karolinska Institute, Sweden.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Forsum, Elisabet
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Variation in the fat mass and obesity-related (FTO) genotype is not associated with body fatness in infants, but possibly with their length2014Inngår i: Pediatric Obesity, ISSN 2047-6302, E-ISSN 2047-6310, Vol. 9, nr 5, s. E112-E115Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BackgroundData relating variation at the fat mass and obesity-related (FTO) locus (rs9939609) to fat mass in infancy are inconclusive. ObjectiveTo study relationships between FTO genotype and infant size (at 1 and 12 weeks and at 1 year of age) and body composition (at 1 and 12 weeks). MethodsBody composition was assessed using air displacement plethysmography in 207 infants. FTO was genotyped using the TaqMan assay. ResultsThe number of risk alleles was related to length at 1 and 12 weeks (P=0.007-0.033) but not to fat mass. The relationship to length was stronger in boys than in girls. ConclusionsOur results suggest that the FTO genotype is not related during infancy to fat mass but is related to length in boys but not in girls.

  • 219.
    Henrion, Ulrike
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi.
    Renhorn, Jakob
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Börjesson, Sara
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Nelson, Erin M
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Schwaiger, Christine S
    Royal Institute of Technology, Sweden .
    Bjelkmar, Par
    Royal Institute of Technology, Sweden Stockholm University, Sweden .
    Wallner, Björn
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Lindahl, Erik
    Royal Institute of Technology, Sweden Stockholm University, Sweden .
    Elinder, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Tracking a complete voltage-sensor cycle with metal-ion bridges2012Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, nr 22, s. 8552-8557Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Voltage-gated ion channels open and close in response to changes in membrane potential, thereby enabling electrical signaling in excitable cells. The voltage sensitivity is conferred through four voltage-sensor domains (VSDs) where positively charged residues in the fourth transmembrane segment (S4) sense the potential. While an open state is known from the Kv1.2/2.1 X-ray structure, the conformational changes underlying voltage sensing have not been resolved. We present 20 additional interactions in one open and four different closed conformations based on metal-ion bridges between all four segments of the VSD in the voltage-gated Shaker K channel. A subset of the experimental constraints was used to generate Rosetta models of the conformations that were subjected to molecular simulation and tested against the remaining constraints. This achieves a detailed model of intermediate conformations during VSD gating. The results provide molecular insight into the transition, suggesting that S4 slides at least 12 angstrom along its axis to open the channel with a 3(10) helix region present that moves in sequence in S4 in order to occupy the same position in space opposite F290 from open through the three first closed states.

  • 220.
    Herman, Jeremy S.
    et al.
    National Museums Scotland, Scotland .
    McDevitt, Allan D.
    Polish Academic Science, Poland .
    Kawalko, Agata
    Polish Academic Science, Poland Centre Forestry and Preservat Nat, Poland .
    Jaarola, Maarit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Wojcik, Jan M.
    Polish Academic Science, Poland .
    Searle, Jeremy B.
    Cornell University, NY USA .
    Land-Bridge Calibration of Molecular Clocks and the Post-Glacial Colonization of Scandinavia by the Eurasian Field Vole Microtus agrestis2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 8, s. e103949-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Phylogeography interprets molecular genetic variation in a spatial and temporal context. Molecular clocks are frequently used to calibrate phylogeographic analyses, however there is mounting evidence that molecular rates decay over the relevant timescales. It is therefore essential that an appropriate rate is determined, consistent with the temporal scale of the specific analysis. This can be achieved by using temporally spaced data such as ancient DNA or by relating the divergence of lineages directly to contemporaneous external events of known time. Here we calibrate a Eurasian field vole ( Microtus agrestis) mitochondrial genealogy from the well-established series of post-glacial geophysical changes that led to the formation of the Baltic Sea and the separation of the Scandinavian peninsula from the central European mainland. The field vole exhibits the common phylogeographic pattern of Scandinavian colonization from both the north and the south, however the southernmost of the two relevant lineages appears to have originated in situ on the Scandinavian peninsula, or possibly in the adjacent island of Zealand, around the close of the Younger Dryas. The mitochondrial substitution rate and the timescale for the genealogy are closely consistent with those obtained with a previous calibration, based on the separation of the British Isles from mainland Europe. However the result here is arguably more certain, given the level of confidence that can be placed in one of the central assumptions of the calibration, that field voles could not survive the last glaciation of the southern part of the Scandinavian peninsula. Furthermore, the similarity between the molecular clock rate estimated here and those obtained by sampling heterochronous (ancient) DNA ( including that of a congeneric species) suggest that there is little disparity between the measured genetic divergence and the population divergence that is implicit in our land-bridge calibration.

  • 221.
    Hernandez, Aura Rocio
    et al.
    Malmo Univ, Sweden; Univ Nacl Colombia, Colombia.
    Boutonnet, Marine
    Malmo Univ, Sweden.
    Svensson, Birgitta
    Bioglan AB, Sweden.
    Butler, Eile
    Biogaia AB, Sweden.
    Lood, Rolf
    Lund Univ, Sweden.
    Blom, Kristina
    Medibiome AB, Sweden.
    Vallejo, Bibiana
    Univ Nacl Colombia, Colombia.
    Anderson, Chris
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Engblom, Johan
    Malmo Univ, Sweden.
    Ruzgas, Tautgirdas
    Malmo Univ, Sweden.
    Bjorklund, Sebastian
    Malmo Univ, Sweden.
    New concepts for transdermal delivery of oxygen based on catalase biochemical reactions studied by oxygen electrode amperometry2019Inngår i: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 306, s. 121-129Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The development of formulation concepts for improved skin tissue oxygenation, including methods for measuring oxygen (O-2) transport across biological barriers, are important research topics with respect to all processes that are affected by the O-2 concentration, such as radiation therapy in oncology treatments, wound healing, and the general health status of skin. In this work we approach this topic by a novel strategy based on the antioxidative enzyme catalase, which is naturally present in the skin organ where it enables conversion of the reactive oxygen species hydrogen peroxide (H2O2) into O-2. We introduce various applications of the skin covered oxygen electrode (SCOE) as an in-vitro tool for studies of catalase activity and function. The SCOE is constructed by placing an excised skin membrane directly on an O-2 electrode and the methodology is based on measurements of the electrical current generated by reduction of O-2 as a function of time (i.e. chronoamperometry). The results confirm that a high amount of native catalase is present in the skin organ, even in the outermost stratum corneum (SC) barrier, and we conclude that excised pig skin (irrespective of freeze-thaw treatment) represents a valid model for ex vivo human skin for studying catalase function by the SCOE setup. The activity of native catalase in skin is sufficient to generate considerable amounts of O-2 by conversion from H2O2 and proof-of-concept is presented for catalase-based transdermal O-2 delivery from topical formulations containing H2O2. In addition, we show that this concept can be further improved by topical application of external catalase on the skin surface, which enables transdermal O-2 delivery from 50 times lower concentrations of H2O2. These important results are promising for development of novel topical or transdermal formulations containing low and safe concentrations of H2O2 for skin tissue oxygenation. Further, our results indicate that the O-2 production by catalase, derived from topically applied S. epidermidis (a simple model for skin microbiota) is relatively low as compared to the O-2 produced by the catalase naturally present in skin. Still, the catalase activity derived from S. epidermidis is measurable. Taken together, this work illustrates the benefits and versatility of the SCOE as an in vitro skin research tool and introduces new and promising strategies for transdermal oxygen delivery, with simultaneous detoxification of H2O2, based on native or topically applied catalase.

  • 222.
    Holm, Lovisa
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Liang, Wen
    TNO Metabolic Health Research, Leiden, Netherlands.
    Thorsell, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Hilke, Susanne
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Acute effects on brain cholecystokinin-like concentration and anxiety-like behaviour in the female rat upon a single injection of 17β-estradiol2014Inngår i: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 122, s. 222-227Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The neuropeptide cholecystokinin (CCK) has been implicated in the neurobiology of anxiety and panic disorders, as well as in dopamine-related behaviours. Anxiety and panic-disorders are twice as common in females compared to males, but studies of females are rare, although increasing in number. Limited studies have found that CCK fluctuates in limbic regions during the estrous cycle, and that CCK and its receptors are sensitive to estrogen.

    AIM/PURPOSE: The aim of the present work was to study the acute effects of 17β-estradiol on anxiety-like behaviour and on CCK-like immunoreactivity (LI) in the female rat brain (amygdala, hippocampus, nucleus accumbens, and cingulate cortex).

    METHODS: Four groups of female Sprague-Dawley rats were used: ovariectomized, ovariectomized+17β-estradiol-replacement, sham, and sham+17β-estradiol-replacement. The effect of 17β-estradiol-replacement on anxiety-related behaviour was measured in all animals on the elevated plus maze 2-24h after injection. CCK-LI concentration was measured in punch biopsies by means of radioimmunoassay.

    RESULTS: 17β-estradiol decreased anxiety-like behaviour 2h after administration in ovariectomized and sham-operated animals, as demonstrated by increased exploration of the open arms compared to respective sesame oil-treated controls. This effect was not present when testing occurred 24h post-treatment. The rapid behavioural effect of 17β-estradiol was accompanied by changes in CCK-LI concentrations in regions of the limbic system including cingulate cortex, hippocampus, amygdala and nucleus accumbens.

    CONCLUSION: Although the interpretation of these data requires caution since the data were collected from two different experiments, our results suggest that estrogen-induced anxiolytic effects may be associated with changes of the CCK-system in brain regions controlling anxiety-like behaviour.

  • 223.
    Hombach-Klonisch, Sabine
    et al.
    Univ Manitoba, Canada.
    Mehrpour, Maryam
    CNRS, France; Univ Paris 05, France.
    Shojaei, Shahla
    Univ Manitoba, Canada; Isfahan Univ Med Sci, Iran.
    Harlos, Craig
    Univ Manitoba, Canada; CancerCare Manitoba, Canada.
    Pitz, Marshall
    Univ Manitoba, Canada; CancerCare Manitoba, Canada.
    Hamai, Ahmed
    CNRS, France; Univ Paris 05, France.
    Siemianowicz, Krzysztof
    Med Univ Silesia, Poland.
    Likus, Wirginia
    Med Univ Silesia, Poland.
    Wiechec, Emilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Toyota, Brian D.
    Univ British Columbia, Canada.
    Hoshyar, Reyhane
    Blrjand Univ Med Sci, Iran; Birjand Univ Med Sci, Iran.
    Seyfoori, Amir
    Univ Victoria, Canada.
    Sepehri, Zahra
    Univ Manitoba, Canada; Zabol Univ Med Sci, Iran.
    Ande, Sudharsana R.
    Univ Manitoba, Canada.
    Khadem, Forough
    Univ Manitoba, Canada.
    Akbari, Mohsen
    Univ Victoria, Canada.
    Gorman, Adrienne M.
    Natl Univ Ireland, Ireland; Natl Univ Ireland, Ireland.
    Samali, Afshin
    Natl Univ Ireland, Ireland; Natl Univ Ireland, Ireland.
    Klonisch, Thomas
    Univ Manitoba, Canada; CancerCare Manitoba, Canada.
    Ghavami, Saeid
    Univ Manitoba, Canada; Shiraz Med Univ Med Sci, Iran.
    Glioblastoma and chemoresistance to alkylating agents: Involvement of apoptosis, autophagy, and unfolded protein response2018Inngår i: Pharmacology and Therapeutics, ISSN 0163-7258, E-ISSN 1879-016X, Vol. 184, s. 13-41Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Despite advances in neurosurgical techniques and radio-/chemotherapy, the treatment of brain tumors remains a challenge. This is particularly true for the most frequent and fatal adult brain tumor, glioblastoma (GB). Upon diagnosis, the average survival time of GB patients remains only approximately 15 months. The alkylating drug temozolomide (TMZ) is routinely used in brain tumor patients and induces apoptosis, autophagy and unfolded protein response (UPR). Here, we review these cellular mechanisms and their contributions to TMZ chemoresistance in brain tumors, with a particular emphasis on TMZ chemoresistance in glioma stem cells and GB.

  • 224.
    Hug, S.
    et al.
    Helmholtz Zentrum Munchen, Germany Technical University of Munich, Germany .
    Raue, A.
    Helmholtz Zentrum Munchen, Germany University of Freiburg, Germany .
    Hasenauer, J.
    Helmholtz Zentrum Munchen, Germany .
    Bachmann, J.
    German Cancer Research Centre, Germany .
    Klingmueller, U.
    German Cancer Research Centre, Germany .
    Timmer, Jens
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Theis, F .J.
    Helmholtz Zentrum Munchen, Germany Technical University of Munich, Germany .
    High-dimensional Bayesian parameter estimation: Case study for a model of JAK2/STAT5 signaling2013Inngår i: Mathematical Biosciences, ISSN 0025-5564, E-ISSN 1879-3134, Vol. 246, nr 2, s. 293-304Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In this work we present results of a detailed Bayesian parameter estimation for an analysis of ordinary differential equation models. These depend on many unknown parameters that have to be inferred from experimental data. The statistical inference in a high-dimensional parameter space is however conceptually and computationally challenging. To ensure rigorous assessment of model and prediction uncertainties we take advantage of both a profile posterior approach and Markov chain Monte Carlo sampling. We analyzed a dynamical model of the JAK2/STAT5 signal transduction pathway that contains more than one hundred parameters. Using the profile posterior we found that the corresponding posterior distribution is bimodal. To guarantee efficient mixing in the presence of multimodal posterior distributions we applied a multi-chain sampling approach. The Bayesian parameter estimation enables the assessment of prediction uncertainties and the design of additional experiments that enhance the explanatory power of the model. This study represents a proof of principle that detailed statistical analysis for quantitative dynamical modeling used in systems biology is feasible also in high-dimensional parameter spaces.

  • 225.
    Ihnatko, Robert
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Post, Claes
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Proteomic profiling of the hypothalamus in a mouse model of cancer-induced anorexia-cachexia2013Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 109, nr 7, s. 1867-1875Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background:

    Anorexia-cachexia is a common and severe cancer-related complication but the underlying mechanisms are largely unknown. Here, using a mouse model for tumour-induced anorexia-cachexia, we screened for proteins that are differentially expressed in the hypothalamus, the brain’s metabolic control centre.

    Methods:

    The hypothalamus of tumour-bearing mice with implanted methylcholanthrene-induced sarcoma (MCG 101) displaying anorexia and their sham-implanted pair-fed or free-fed littermates was examined using two-dimensional electrophoresis (2-DE)-based comparative proteomics. Differentially expressed proteins were identified by liquid chromatography-tandem mass spectrometry.

    Results:

    The 2-DE data showed an increased expression of dynamin 1, hexokinase, pyruvate carboxylase, oxoglutarate dehydrogenase, and N-ethylmaleimide-sensitive factor in tumour-bearing mice, whereas heat-shock 70 kDa cognate protein, selenium-binding protein 1, and guanine nucleotide-binding protein Gα0 were downregulated. The expression of several of the identified proteins was similarly altered also in the caloric-restricted pair-fed mice, suggesting an involvement of these proteins in brain metabolic adaptation to restricted nutrient availability. However, the expression of dynamin 1, which is required for receptor internalisation, and of hexokinase, and pyruvate carboxylase were specifically changed in tumour-bearing mice with anorexia.

    Conclusion:

    The identified differentially expressed proteins may be new candidate molecules involved in the pathophysiology of tumour-induced anorexia-cachexia.

  • 226.
    Ingelsson, Björn
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Fristedt, Rikard
    Biophysics of Photosynthesis Physics and Astronomy Faculty of Sciences, VU University Amsterdam, Amsterdam, The Netherlands.
    Turkina, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Phosphorylation stoichiometry determination in plant photosynthetic membranes.2015Inngår i: Plant Phosphoproteomics: Methods and Protocols / [ed] Waltraud X. Schulze, New York: Springer-Verlag New York, 2015, s. 121-134Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    This chapter describes different strategies for the study of phosphorylation dynamics and stoichiometry in photosynthetic membranes. Detailed procedures for the detection, large-scale identification, and quantification of phosphorylated proteins optimized for plant thylakoid proteins are given.

  • 227.
    Ingelsson, Björn
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Söderberg, Daniel
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Strid, Tobias
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Söderberg, Anita
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Bergh, Ann-Charlotte
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Loitto, Vesa-Matti
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Segelmark, Mårten
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Njurmedicinska kliniken US.
    Spyrou, Giannis
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Rosén, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C2018Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, nr 3, s. E478-E487Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Circulating mitochondrial DNA (mtDNA) is receiving increasing attention as a danger-associated molecular pattern in conditions such as autoimmunity, cancer, and trauma. We report here that human lymphocytes [B cells, T cells, natural killer (NK) cells], monocytes, and neutrophils derived from healthy blood donors, as well as B cells from chronic lymphocytic leukemia patients, rapidly eject mtDNA as web filament structures upon recognition of CpG and non-CpG oligodeoxynucleotides of class C. The release was quenched by ZnCl2, independent of cell death (apoptosis, necrosis, necroptosis, autophagy), and continued in the presence of TLR9 signaling inhibitors. B-cell mtDNA webs were distinct from neutrophil extracellular traps concerning structure, reactive oxygen species (ROS) dependence, and were devoid of antibacterial proteins. mtDNA webs acted as rapid (within minutes) messengers, priming antiviral type I IFN production. In summary, our findings point at a previously unrecognized role for lymphocytes in antimicrobial defense, utilizing mtDNA webs as signals in synergy with cytokines and natural antibodies, and cast light on the interplay between mitochondria and the immune system.

  • 228.
    Iresjö, Britt‐Marie
    et al.
    Department of Surgery, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden..
    Wang, Wenhua
    Department of Surgery, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden..
    Nilsberth, Camilla
    Region Östergötland, Närsjukvården i centrala Östergötland, Geriatriska kliniken. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Andersson, Marianne
    Department of Surgery, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden..
    Lönnroth, Christina
    Department of Surgery, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden..
    Smedh, Ulrika
    Department of Surgery, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden..
    Food intake, tumor growth, and weight loss in EP2 receptor subtype knockout mice bearing PGE2-producing tumors2015Inngår i: Physiological Reports, E-ISSN 2051-817X, ISSN 2051-817X, Vol. 3, nr 7, s. 1-7, artikkel-id e12441Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Previous studies in our laboratory have demonstrated that prostaglandin (PG) E2 is involved in anorexia/cachexia development in MCG 101 tumor‐bearing mice. In the present study, we investigate the role of PGE receptor subtype EP2 in the development of anorexia after MCG 101 implantation in wild‐type (EP2+/+) or EP2‐receptor knockout (EP2−/−) mice. Our results showed that host absence of EP2 receptors attenuated tumor growth and development of anorexia in tumor‐bearing EP2 knockout mice compared to tumor‐bearing wild‐type animals. Microarray profiling of the hypothalamus revealed a relative twofold change in expression of around 35 genes including mRNA transcripts coding for Phospholipase A2 and Prostaglandin D2 synthase (Ptgds) in EP2 receptor knockout mice compared to wild‐type mice. Prostaglandin D2 synthase levels were increased significantly in EP2 receptor knockouts, suggesting that improved food intake may depend on altered balance of prostaglandin production in hypothalamus since PGE2 and PGD2 display opposing effects in feeding control.

  • 229.
    Islam, Mohammad M.
    et al.
    Swedish Medical Nanoscience Center, Karolinska Institutet, Stockholm, Sweden.
    Cėpla, Vytautas
    Center for Physical Sciences and Technology, Vilnius, Lithuania.
    He, Chaoliang
    Ottawa Hospital Research Institute, Ontario, Canada.
    Edin, Joel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Rakickas, Tomas
    Center for Physical Sciences and Technology, Vilnius, Lithuania.
    Kobuch, Karin
    Technische Universität München, Germany.
    Ruželė, Živilė
    Center for Physical Sciences and Technology, Vilnius, Lithuania.
    Jackson, Bruce W.
    Ottawa Hospital Research Institute, Ontario, Canada.
    Rafat, Mehrdad
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Institutionen för medicinsk teknik. Linköpings universitet, Hälsouniversitetet. Ottawa Hospital Research Institute, Ontario, Canada.
    Lohmann, Chris P.
    Technische Universität München, Germany.
    Valiokas, Ramūnas
    Center for Physical Sciences and Technology, Vilnius, Lithuania.
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Swedish Medical Nanoscience Center, Karolinska Institutet, Stockholm, Sweden; Ottawa Hospital Research Institute, Ontario, Canada.
    Functional fabrication of recombinant human collagen–phosphorylcholine hydrogels for regenerative medicine applications2015Inngår i: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 12, s. 70-80Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The implant-host interface is a critical element in guiding tissue or organ regeneration. We previously developed hydrogels comprising interpenetrating networks of recombinant human collagen type III and 2-methacryloyloxyethyl phosphorylcholine (RHCIII-MPC) as substitutes of the corneal extracellular matrix that promote endogenous regeneration of corneal tissue. To render them functional for clinical application, we have now optimized their composition and thereby enhanced their mechanical properties. We have demonstrated that such optimized RHCIII-MPC hydrogels are suitable for precision femtosecond laser cutting to produce complementing implants and host surgical beds for subsequent tissue welding. This avoids the tissue damage and inflammation associated with manual surgical techniques, thereby leading to more efficient healing. Although we previously demonstrated in clinical testing that RHCIII-based implants stimulated cornea regeneration in patients, the rate of epithelial cell coverage of the implants needs improvement, e.g. modification of the implant surface. We now show that our 500 μm thick RHCIII-MPC constructs comprising over 85% water, are suitable for microcontact printing with fibronectin. The resulting fibronectin micropatterns promote cell adhesion, as compared to the bare RHCIII-MPC hydrogel. Interestingly, a pattern of 30 μm wide fibronectin stripes enhanced cell attachment and showed highest mitotic rates, an effect that potentially can be utilized for faster integration of the implant. We have therefore shown that laboratory-produced mimics of naturally occurring collagen and phospholipids can be fabricated into robust hydrogels that can be laser profiled and patterned to enhance their potential function as artificial substitutes of donor human corneas.

  • 230.
    Islam, Mohammad Mirazul
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Harvard Medical School, Boston, MA USA.
    Buznyk, Oleksiy
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Filatov Institute of Eye Diseases and Tissue Therapy of the NAMS of Ukraine, Odessa, Ukraine.
    Reddy, Jagadesh C
    Tej Kohli Cornea Institute, LV Prasad Eye Institute, Hyderabad, India.
    Pasyechnikova, Nataliya
    Filatov Institute of Eye Diseases and Tissue Therapy of the NAMS of Ukraine, Odessa, Ukraine.
    Alarcon, Emilio I
    Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, ON Canada.
    Hayes, Sally
    School of Optometry and Vision Sciences College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK; 7Cardiff Institute for Tissue Engineering and Repair (CITER), Cardiff University, Cardiff, UK.
    Lewis, Philip
    School of Optometry and Vision Sciences College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK; 7Cardiff Institute for Tissue Engineering and Repair (CITER), Cardiff University, Cardiff, UK.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    He, Chaoliang
    Key Laboratory of Polymer Eco-materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
    Iakymenko, Stanislav
    Filatov Institute of Eye Diseases and Tissue Therapy of the NAMS of Ukraine, Odessa, Ukraine.
    Liu, Wenguang
    School of Materials Science and Engineering, Tianjin University, Tianjin, China.
    Meek, Keith M
    School of Optometry and Vision Sciences College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK; 7Cardiff Institute for Tissue Engineering and Repair (CITER), Cardiff University, Cardiff, UK.
    Sangwan, Virender S
    Tej Kohli Cornea Institute, LV Prasad Eye Institute, Hyderabad, India.
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. University of Montreal, Montreal, Canada.
    Biomaterials-enabled cornea regeneration in patients at high risk for rejection of donor tissue transplantation2018Inngår i: NPJ Regenerative medicine, ISSN 2057-3995, Vol. 3, artikkel-id 2Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The severe worldwide shortage of donor organs, and severe pathologies placing patients at high risk for rejecting conventional cornea transplantation, have left many corneal blind patients untreated. Following successful pre-clinical evaluation in mini-pigs, we tested a biomaterials-enabled pro-regeneration strategy to restore corneal integrity in an open-label observational study of six patients. Cell-free corneal implants comprising recombinant human collagen and phosphorylcholine were grafted by anterior lamellar keratoplasty into corneas of unilaterally blind patients diagnosed at high-risk for rejecting donor allografts. They were followed-up for a mean of 24 months. Patients with acute disease (ulceration) were relieved of pain and discomfort within 1-2 weeks post-operation. Patients with scarred or ulcerated corneas from severe infection showed better vision improvement, followed by corneas with burns. Corneas with immune or degenerative conditions transplanted for symptom relief only showed no vision improvement overall. However, grafting promoted nerve regeneration as observed by improved touch sensitivity to near normal levels in all patients tested, even for those with little/no sensitivity before treatment. Overall, three out of six patients showed significant vision improvement. Others were sufficiently stabilized to allow follow-on surgery to restore vision. Grafting outcomes in mini-pig corneas were superior to those in human subjects, emphasizing that animal models are only predictive for patients with non-severely pathological corneas; however, for establishing parameters such as stable corneal tissue and nerve regeneration, our pig model is satisfactory. While further testing is merited, we have nevertheless shown that cell-free implants are potentially safe, efficacious options for treating high-risk patients.

  • 231.
    Islam, Mohammad Mirazul
    et al.
    Swedish Medical Nanoscience Center, Karolinska Institute, Stockholm, Sweden.
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Merrett, Kimberley
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Fabrication of a human recombinant collagen-based corneal substitute using carbodiimide chemistry2013Inngår i: Methods in Molecular Biology, ISSN 1064-3745, E-ISSN 1940-6029, Vol. 1014, s. 157-164Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human recombinant collagen can be cross-linked with a variety of chemical cross-linking agents. Cross-linking methods can be tuned to confer collagen-based scaffolds with specific physical properties, improved antigenicity and thermal stability without impeding the ability of the material to integrate into the surrounding tissue and to promote regeneration. Here, we describe a method to cross-link human recombinant collagen using a water soluble carbodiimide. Carbodiimides are referred to as zero-length cross-linking agents as they are not incorporated into the final cross-link and thus pose minimal risk with respect to cytotoxicity. The resulting collagen-based scaffold possesses properties comparable to that of the human cornea and is thus suitable for use as a corneal substitute.

  • 232.
    Islam, Mohammad Mirazul
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    Ravichandran, Ranjithkumar
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär fysik. Linköpings universitet, Tekniska fakulteten.
    Olsen, D.
    FibroGen Inc, CA 94158 USA.
    Kozak Ljunggren, Monika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Lee, Chyan-Jang
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Sensorvetenskap och Molekylfysik. Linköpings universitet, Tekniska högskolan. 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. Karolinska Institute, Sweden.
    Phopase, Jaywant
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär fysik. Linköpings universitet, Tekniska fakulteten.
    Self-assembled collagen-like-peptide implants as alternatives to human donor corneal transplantation2016Inngår i: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 6, nr 61, s. 55745-55749Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Extracellular matrix proteins like collagen promote regeneration as implants in clinical studies. However, collagens are large and unwieldy proteins, making small functional peptide analogs potentially ideal substitutes. Self-assembling collagen-like-peptides conjugated with PEG-maleimide were assembled into hydrogels. When tested pre-clinically as corneal implants in mini-pigs, they promoted cell and nerve regeneration, forming neo-corneas structurally and functionally similar to natural corneas.

  • 233.
    Islam, Rakibul
    et al.
    University of Oslo, Norway; Oslo University Hospital, Norway; Harvard University, MA USA.
    Jackson, Catherine
    Oslo University Hospital, Norway.
    Eidet, Jon R.
    Oslo University Hospital, Norway.
    Messelt, Edward B.
    University of Oslo, Norway.
    Maria Corraya, Rima
    Oslo University Hospital, Norway; Harvard University, MA USA.
    Lyberg, Torstein
    Oslo University Hospital, Norway.
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Dartt, Darlene A.
    Harvard University, MA USA.
    Utheim, Tor P.
    University of Oslo, Norway; Oslo University Hospital, Norway; Harvard University, MA USA.
    Effect of Storage Temperature on Structure and Function of Cultured Human Oral Keratinocytes2015Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 6, s. e0128306-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose/Aims To assess the effect of storage temperature on the viability, phenotype, metabolism, and morphology of cultured human oral keratinocytes (HOK). Materials and Methods Cultured HOK cells were stored in HEPES- and sodium bicarbonate-buffered Minimum Essential Medium (MEM) at nine temperatures in approximately 4 degrees C increments from 4 degrees C to 37 degrees C for seven days. Cells were characterized for viability by calcein fluorescence, phenotype retention by immunocytochemistry, metabolic parameters (pH, glucose, lactate, and O-2) within the storage medium by blood gas analysis, and morphology by scanning electron microscopy and light microscopy. Results Relative to the cultured, but non-stored control cells, a high percentage of viable cells were retained only in the 12 degrees C and 16 degrees C storage groups (85%+/- 13% and 68%+/- 10%, respectively). Expression of ABCG2, Bmi1, C/EBP delta, PCNA, cytokeratin 18, and caspase-3 were preserved after storage in the 5 groups between 4 degrees C and 20 degrees C, compared to the non-stored control. Glucose, pH and pO(2) in the storage medium declined, whereas lactate increased with increasing storage temperature. Morphology was best preserved following storage of the three groups between 12 degrees C, 16 degrees C, and 20 degrees C. Conclusion We conclude that storage temperatures of 12 degrees C and 16 degrees C were optimal for maintenance of cell viability, phenotype, and morphology of cultured HOK. The storage method described in the present study may be applicable for other cell types and tissues; thus its significance may extend beyond HOK and the field of ophthalmology.

  • 234.
    Islam, Rakibul
    et al.
    Harvard Medical Sch, MA USA; University of Oslo, Norway; Oslo University Hospital, Norway.
    Roger Eidet, Jon
    Oslo University Hospital, Norway.
    Badian, Reza A.
    Harvard Medical Sch, MA USA; University of Coll Southeast Norway, Norway; Innlandet Hospital Trust, Norway.
    Lippestad, Marit
    Harvard Medical Sch, MA USA; Oslo University Hospital, Norway; University of Oslo, Norway.
    Messelt, Edward
    University of Oslo, Norway.
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Dartt, Darlene A.
    Harvard Medical Sch, MA USA; University of Oslo, Norway.
    Paaske Utheim, Tor
    Harvard Medical Sch, MA USA; University of Oslo, Norway; Oslo University Hospital, Norway; Innlandet Hospital Trust, Norway.
    Tissue Harvesting Site and Culture Medium Affect Attachment, Growth, and Phenotype of Ex Vivo Expanded Oral Mucosal Epithelial Cells2017Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikkel-id 674Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Transplantation of cultured oral mucosal epithelial cells (OMECs) is a promising treatment strategy for limbal stem cell deficiency. In order to improve the culture method, we investigated the effects of four culture media and tissue harvesting sites on explant attachment, growth, and phenotype of OMECs cultured from Sprague-Dawley rats. Neither choice of media or harvesting site impacted the ability of the explants to attach to the culture well. Dulbeccos modified Eagles medium/Hams F12 (DMEM) and Roswell Park Memorial Institute 1640 medium (RPMI) supported the largest cellular outgrowth. Fold outgrowth was superior from LL explants compared to explants from the buccal mucosa (BM), HP, and transition zone of the lower lip (TZ) after six-day culture. Putative stem cell markers were detected in cultures grown in DMEM and RPMI. In DMEM, cells from TZ showed higher colony-forming efficiency than LL, BM, and HP. In contrast to RPMI, DMEM both expressed the putative stem cell marker Bmi-1 and yielded cell colonies. Our data suggest that OMECs from LL and TZ cultured in DMEM give rise to undifferentiated cells with high growth capacity, and hence are the most promising for treatment of limbal stem cell deficiency.

  • 235.
    Jafari, Shadi
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Mechanisms of Olfactory sensory neuron class maintenance in Drosophila: It is all about design and equilibrium2015Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    How the cellular diversity of our body is generated and maintained is still a great mystery regardless of the wealth of research that has been done on this issue. The greatest complexity is found in the nervous system that contains a vast number of neurons and displays a great diversity in cell types and classes. For example the Drosophila olfactory system is a complex but defined set of neurons with extremely high specificity and sensitivity. The 34 OSN classes are each defined by their expression of a specific odorant receptor (OR). During development each OSN chooses one OR from 60 different OR genes in the genome to express. Furthermore, a cell is subject to immense challenges during its life cycle. Confronting each challenge the cell needs to perform its function and maintain its fate. OSNs continue to express the same OR during their  whole life regardless of fluctuations in the environment.

    Although the olfactory system is remarkably conserved across the phyla, it is still unclear how an OSN chooses to express a particular OR from a large genomic repertoire. In this thesis the final steps of the specification and diversification for establishing an OSN identity is addressed. We find seven transcription factors that are continuously required in different combinations for the expression of the Drosophila ORs. The TFs can in different background context both activate and repress OR expression, making the regulation more economical. We also imply that repression is crucial for correct OR gene expression. We further show that short DNA sequences from OR gene promoters are sufficient to drive OSN class specific expression. These regions contain clusters of TF binding motifs, which we show to be sensitive to any change in their composition or to changes of the internal or external environment. We demonstrate that the chromatin state is responsible for the clusters response to environmental challenges. We reveal that Su(var)3-9 controls the OSN response to environmental stresses. We address the epigenetic mechanisms that initiate and pertain the single OR expression to a single OSN class. Our results show that OSNs have an epigenetic switch marking the end of development and the transition to mature OSNs. This switch supplies the expression of a single OR gene.

    Delarbeid
    1. Combinatorial Activation and Repression by Seven Transcription Factors Specify Drosophila Odorant Receptor Expression
    Åpne denne publikasjonen i ny fane eller vindu >>Combinatorial Activation and Repression by Seven Transcription Factors Specify Drosophila Odorant Receptor Expression
    Vise andre…
    2012 (engelsk)Inngår i: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 10, nr 3, s. e1001280-Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The mechanism that specifies olfactory sensory neurons to express only one odorant receptor (OR) from a large repertoire is critical for odor discrimination but poorly understood. Here, we describe the first comprehensive analysis of OR expression regulation in Drosophila. A systematic, RNAi-mediated knock down of most of the predicted transcription factors identified an essential function of acj6, E93, Fer1, onecut, sim, xbp1, and zf30c in the regulation of more than 30 ORs. These regulatory factors are differentially expressed in antennal sensory neuron classes and specifically required for the adult expression of ORs. A systematic analysis reveals not only that combinations of these seven factors are necessary for receptor gene expression but also a prominent role for transcriptional repression in preventing ectopic receptor expression. Such regulation is supported by bioinformatics and OR promoter analyses, which uncovered a common promoter structure with distal repressive and proximal activating regions. Thus, our data provide insight into how combinatorial activation and repression can allow a small number of transcription factors to specify a large repertoire of neuron classes in the olfactory system.

    sted, utgiver, år, opplag, sider
    Public Library of Science, 2012
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-76960 (URN)10.1371/journal.pbio.1001280 (DOI)000302239700004 ()
    Merknad
    Funding Agencies|Marie Curie Actions (European Commission)||Swedish Research Council||Swedish Strategic Research Foundation||Boehringer Ingelheim GmbH||DFG||Schram-Foundation||Tilgjengelig fra: 2012-04-27 Laget: 2012-04-27 Sist oppdatert: 2017-12-07
    2. Cis-Regulatory Mechanisms for Robust Olfactory Sensory Neuron Class-restricted Odorant Receptor Gene Expression in Drosophila
    Åpne denne publikasjonen i ny fane eller vindu >>Cis-Regulatory Mechanisms for Robust Olfactory Sensory Neuron Class-restricted Odorant Receptor Gene Expression in Drosophila
    2015 (engelsk)Inngår i: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, nr 3, s. e1005051-Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Odor perception requires that each olfactory sensory neuron (OSN) class continuously express a single odorant receptor (OR) regardless of changes in the environment. However, little is known about the control of the robust, class-specific OR expression involved. Here, we investigate the cis-regulatory mechanisms and components that generate robust and OSN class-specific OR expression in Drosophila. Our results demonstrate that the spatial restriction of expression to a single OSN class is directed by clusters of transcription-factor DNA binding motifs. Our dissection of motif clusters of differing complexity demonstrates that structural components such as motif overlap and motif order integrate transcription factor combinations and chromatin status to form a spatially restricted pattern. We further demonstrate that changes in metabolism or temperature perturb the function of complex clusters. We show that the cooperative regulation between motifs around and within the cluster generates robust, class-specific OR expression.

    sted, utgiver, år, opplag, sider
    Public Library of Science, 2015
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-117811 (URN)10.1371/journal.pgen.1005051 (DOI)000352197100039 ()25760344 (PubMedID)
    Merknad

    Funding Agencies|Swedish Foundation for Strategic Research [F06-0013]; Swedish Research Council [522-2006-6364 / K2007-66P-20436-01-04]

    Tilgjengelig fra: 2015-05-11 Laget: 2015-05-08 Sist oppdatert: 2017-12-04
    3. Drosophila olfactory sensory neurons have two phases of gene expression regulation
    Åpne denne publikasjonen i ny fane eller vindu >>Drosophila olfactory sensory neurons have two phases of gene expression regulation
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Here, we investigate the gene regulatory mechanisms that buffer environmental challenges and are required for Drosophila OSNs to maintain their fate. Each OSN expresses one odorant receptor (OR) gene from a large OR gene repertoire and the expression is maintained throughout the life of the neuron. We demonstrate that OSNs transit from a permissive gene regulatory state at the end of development to a robust continuous regulatory state in mature OSNs that secure the expression of a single OR gene. We provide evidence that the switch is associated to a change in the H3K9 methylation state. We show that the H3K9 demetylase su(var)3-3 is required for the permissive phase and the robust phase require the H3K9 methylase, su(var) 3-9. We further show that H3K9 methylation status has a role in the regulation of gene expression during the environmental challenges. Thus, our data demonstrate that OSNs go through two separate phases that compensate the environmental fluctuations differently.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-120991 (URN)
    Tilgjengelig fra: 2015-09-01 Laget: 2015-09-01 Sist oppdatert: 2018-01-11bibliografisk kontrollert
  • 236.
    Jafari, Shadi
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Alenius, Mattias
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Cis-Regulatory Mechanisms for Robust Olfactory Sensory Neuron Class-restricted Odorant Receptor Gene Expression in Drosophila2015Inngår i: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, nr 3, s. e1005051-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Odor perception requires that each olfactory sensory neuron (OSN) class continuously express a single odorant receptor (OR) regardless of changes in the environment. However, little is known about the control of the robust, class-specific OR expression involved. Here, we investigate the cis-regulatory mechanisms and components that generate robust and OSN class-specific OR expression in Drosophila. Our results demonstrate that the spatial restriction of expression to a single OSN class is directed by clusters of transcription-factor DNA binding motifs. Our dissection of motif clusters of differing complexity demonstrates that structural components such as motif overlap and motif order integrate transcription factor combinations and chromatin status to form a spatially restricted pattern. We further demonstrate that changes in metabolism or temperature perturb the function of complex clusters. We show that the cooperative regulation between motifs around and within the cluster generates robust, class-specific OR expression.

  • 237.
    Jafari, Shadi
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Alenius, Mattias
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Drosophila olfactory sensory neurons have two phases of gene expression regulationManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Here, we investigate the gene regulatory mechanisms that buffer environmental challenges and are required for Drosophila OSNs to maintain their fate. Each OSN expresses one odorant receptor (OR) gene from a large OR gene repertoire and the expression is maintained throughout the life of the neuron. We demonstrate that OSNs transit from a permissive gene regulatory state at the end of development to a robust continuous regulatory state in mature OSNs that secure the expression of a single OR gene. We provide evidence that the switch is associated to a change in the H3K9 methylation state. We show that the H3K9 demetylase su(var)3-3 is required for the permissive phase and the robust phase require the H3K9 methylase, su(var) 3-9. We further show that H3K9 methylation status has a role in the regulation of gene expression during the environmental challenges. Thus, our data demonstrate that OSNs go through two separate phases that compensate the environmental fluctuations differently.

  • 238.
    Jain, Mayur V.
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Los, Marek Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. BioApplications Ent., Winnipeg, MB, Canada; Department of Pathomorphology, Pomeranian Medical University, Szczecin, Poland.
    Spatiotemporal cytometry—Simultaneous analysis of DNA replication and damage2013Inngår i: Cytometry Part A, ISSN 1552-4922, E-ISSN 1552-4930, Vol. 83, nr 11, s. 975-976Artikkel i tidsskrift (Fagfellevurdert)
  • 239.
    Jain, Mayur Vilas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    PKB/Akt kinase localization and role in stemness maintenance in cancer2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Cancer incidence rates have increased over the last decade. Currently available therapies are only moderately effective in targeting cancer cells. Established cancer treatment protocols fail to eliminate populations of cancer stem cells (CSCs), which develop resistance against the chemotherapeutic drugs and lead to cancer recurrence. Therefore, understanding the mechanisms by which CSCs resist drugs and identifying molecular markers are both necessary to further improve prognosis and to develop new treatment strategies. Increased protein kinase B/Akt1 gene expression and/or activity have been found increased in majority of cancer types. Akt1 is a key player in PI3K-AktmTOR pathway that is vital for cell survival, proliferation, migration, invasion, metastasis, angiogenesis and apoptosis. In this study, we investigated a series of novel markers to improve the characterization of CSCs, with particular focus the roles of Akt in CSC maintenance and the regulatory role of micro-RNA (miR) in cancer cells. While utilizing in breast cancer cells as models, we found that luminescent conjugated oligothiophenes (LCOs), p-HTMI and p-HTAA have the potential to differentially stain various subpopulations of cancer cells, presumably also CSCs among breast cancer cells. However, further studies are needed to confirm these results. Additionally, when we investigated the effect of Akt intracellular compartmentalization on CSC development, the results revealed that nuclear Akt enhances CSC proliferation (ALDH +/High CD44+/High/CD24-/Low) and clonogenicity, which was counter examined and confirmed by using the Aktspecific inibitor triciribine. Furthermore, while investigating the impact of Akt on miR regulation in cancer cells, we found that Akt overexpression decreased.

    Delarbeid
    1. Cell Type Related Differences in Staining with Pentameric Thiophene Derivatives
    Åpne denne publikasjonen i ny fane eller vindu >>Cell Type Related Differences in Staining with Pentameric Thiophene Derivatives
    Vise andre…
    2014 (engelsk)Inngår i: Cytometry Part A, ISSN 1552-4922, E-ISSN 1552-4930, Vol. 85A, nr 7, s. 628-635Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Fluorescent compounds capable of staining cells selectively without affecting their viability are gaining importance in biology and medicine. Recently, a new family of optical dyes, denoted luminescent conjugated oligothiophenes (LCOs), has emerged as an interesting class of highly emissive molecules for studying various biological phenomena. Properly functionalized LCOs have been utilized for selective identification of disease-associated protein aggregates and for selective detection of distinct cells. Herein, we present data on differential staining of various cell types, including cancer cells. The differential staining observed with newly developed pentameric LCOs is attributed to distinct side chain functionalities along the thiophene backbone. Employing flow cytometry and fluorescence microscopy we examined a library of LCOs for stainability of a variety of cell lines. Among tested dyes we found promising candidates that showed strong or moderate capability to stain cells to different extent, depending on target cells. Hence, LCOs with diverse imidazole motifs along the thiophene backbone were identified as an interesting class of agents for staining of cancer cells, whereas LCOs with other amino acid side chains along the backbone showed a complete lack of staining for the cells included in the study. Furthermore, for p-HTMI,a LCO functionalized with methylated imidazole moieties, the staining was dependent on the p53 status of the cells, indicating that the molecular target for the dye is a cellular component regulated by p53. We foresee that functionalized LCOs will serve as a new class of optical ligands for fluorescent classification of cells and expand the toolbox of reagents for fluorescent live imaging of different cells.

    sted, utgiver, år, opplag, sider
    John Wiley & Sons, 2014
    Emneord
    cancer stem cells; luminescent conjugated oligothiophenes; fluorescent probes
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-109171 (URN)10.1002/cyto.a.22437 (DOI)000338007700010 ()24500794 (PubMedID)
    Tilgjengelig fra: 2014-08-12 Laget: 2014-08-11 Sist oppdatert: 2018-01-11bibliografisk kontrollert
    2. Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21(Waf1/Cip1) and p27(kip1)
    Åpne denne publikasjonen i ny fane eller vindu >>Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21(Waf1/Cip1) and p27(kip1)
    Vise andre…
    2015 (engelsk)Inngår i: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 14, nr 13, s. 2109-2120Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Cancer stem-like cells (CSCs) are a rare subpopulation of cancer cells capable of propagating the disease and causing cancer recurrence. In this study, we found that the cellular localization of PKB/Akt kinase affects the maintenance of CSCs. When Akt tagged with nuclear localization signal (Akt-NLS) was overexpressed in SKBR3 and MDA-MB468 cells, these cells showed a 10-15% increase in the number of cells with CSCs enhanced ALDH activity and demonstrated a CD44(+High)/CD24(-Low) phenotype. This effect was completely reversed in the presence of Akt-specific inhibitor, triciribine. Furthermore, cells overexpressing Akt or Akt-NLS were less likely to be in G0/G1 phase of the cell cycle by inactivating p21(Waf1/Cip1) and exhibited increased clonogenicity and proliferation as assayed by colony-forming assay (mammosphere formation). Thus, our data emphasize the importance the intracellular localization of Akt has on stemness in human breast cancer cells. It also indicates a new robust way for improving the enrichment and culture of CSCs for experimental purposes. Hence, it allows for the development of simpler protocols to study stemness, clonogenic potency, and screening of new chemotherapeutic agents that preferentially target cancer stem cells. Summary: The presented data, (i) shows new, stemness-promoting role of nuclear Akt/PKB kinase, (ii) it underlines the effects of nuclear Akt on cell cycle regulation, and finally (iii) it suggests new ways to study cancer stem-like cells.

    sted, utgiver, år, opplag, sider
    Taylor and Francis: STM, Behavioural Science and Public Health Titles, 2015
    Emneord
    Akt-NLS; cancer stem-like cells; mTOR; PI3K; stemness
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-120274 (URN)10.1080/15384101.2015.1041692 (DOI)000356959800021 ()26030190 (PubMedID)
    Merknad

    Funding Agencies|Linkoping University; Integrative Regenerative Medicine Center (IGEN); VR-NanoVision [K2012-99X-22325-01-5]; Cancerfonden [2013/391]; Canadian Breast Cancer Foundation (CBCF); Natural Sciences and Engineering Research Council of Canada (NSERC); [BK/265/RAU1/2014/t.10]

    Tilgjengelig fra: 2015-07-24 Laget: 2015-07-24 Sist oppdatert: 2018-01-11
    3. Inhibition of miR301 enhances Akt-mediated cell proliferation by accumulation of PTEN in nucleus and its effects on cell-cycle regulatory proteins
    Åpne denne publikasjonen i ny fane eller vindu >>Inhibition of miR301 enhances Akt-mediated cell proliferation by accumulation of PTEN in nucleus and its effects on cell-cycle regulatory proteins
    Vise andre…
    2016 (engelsk)Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 15, s. 20953-20965Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Micro-RNAs (miRs) represent an innovative class of genes that act as regulators of gene expression. Recently, the aberrant expression of several miRs has been associated with different types of cancers. In this study, we show that miR301 inhibition influences PI3K-Akt pathway activity. Akt overexpression in MCF7 and MDAMB468 cells caused downregulation of miR301 expression. This effect was confirmed by co-transfection of miR301-modulators in the presence of Akt. Cells overexpressing miR301-inhibitor and Akt, exhibited increased migration and proliferation. Experimental results also confirmed PI3K, PTEN and FoxF2 as regulatory targets for miR301. Furthermore, Akt expression in conjunction with miR301-inhibitor increased nuclear accumulation of PTEN, thus preventing it from downregulating the PI3K-signalling. In summary, our data emphasize the importance of miR301 inhibition on PI3K-Akt pathway-mediated cellular functions. Hence, it opens new avenues for the development of new anti-cancer agents preferentially targeting PI3K-Akt pathway.

    sted, utgiver, år, opplag, sider
    Impact Journals, LLC, 2016
    Emneord
    AKT; PI3K; PTEN; mTOR; miR301
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-127476 (URN)10.18632/oncotarget.7996 (DOI)000375804000140 ()26967567 (PubMedID)
    Merknad

    Funding agencies: Cancerfonden [2013/391]; GeCONiI [POIG.02.03.01-24-099/13]

    Tilgjengelig fra: 2016-04-27 Laget: 2016-04-27 Sist oppdatert: 2019-02-11bibliografisk kontrollert
  • 240.
    Jain, Mayur Vilas
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Shareef, Ahmad
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Likus, Wirginia
    Department of Human Anatomy, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.
    Cieślar-Pobuda, Artur
    Institute of Automatic Control, Silesian University of Technology, Gliwice, Poland.
    Ghavami, Saeid
    Department of Human Anatomy and Cell Science, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
    Łos, Marek J.
    Department of Pathology, Pomeranian Medical University, Szczecin, Poland / LinkoCare Life Sciences AB, Linköping, Sweden.
    Inhibition of miR301 enhances Akt-mediated cell proliferation by accumulation of PTEN in nucleus and its effects on cell-cycle regulatory proteins2016Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 15, s. 20953-20965Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Micro-RNAs (miRs) represent an innovative class of genes that act as regulators of gene expression. Recently, the aberrant expression of several miRs has been associated with different types of cancers. In this study, we show that miR301 inhibition influences PI3K-Akt pathway activity. Akt overexpression in MCF7 and MDAMB468 cells caused downregulation of miR301 expression. This effect was confirmed by co-transfection of miR301-modulators in the presence of Akt. Cells overexpressing miR301-inhibitor and Akt, exhibited increased migration and proliferation. Experimental results also confirmed PI3K, PTEN and FoxF2 as regulatory targets for miR301. Furthermore, Akt expression in conjunction with miR301-inhibitor increased nuclear accumulation of PTEN, thus preventing it from downregulating the PI3K-signalling. In summary, our data emphasize the importance of miR301 inhibition on PI3K-Akt pathway-mediated cellular functions. Hence, it opens new avenues for the development of new anti-cancer agents preferentially targeting PI3K-Akt pathway.

  • 241.
    Jakobsen Falk, Ingrid
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning.
    Willander, Kerstin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Chaireti, Roza
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Medicinska akutkliniken.
    Lund, Johan
    Division of hematology, Department of Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden.
    Monica, Hermanson
    Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Gréen, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    TP53 mutations identify a subgroup of AML patients with dramatically impaired outcome2014Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    TP53 is commonly mutated in several cancers and confers treatment resistance and poor prognosis. Altered expression of MDM2 (mouse double minute 2), a negative regulator of p53, may also attenuate normal p53 signaling, thereby enhancing tumor transformation and resistance to apoptosis. The single nucleotide polymorphism (SNP) 309 has been reported to increase MDM2 expression and impair normal p53 response. We investigated the frequency and impact of TP53 mutations (TP53mut) and MDM2SNP309 on treatment outcome and overall survival (OS) in 207 Swedish AML patients. We found a high frequency (22%) of TP53mut in patients with cytogenetic aberrations, with strong association to high risk cytogenetics (p<0.001). TP53mut patients had lower response rates compared to TP53 wild-type (wt) patients (22% and 76% CR, respectively, p<0.001) and reduced OS (5 and 21 months, respectively, p<0.001). In TP53wt patients with abnormal karyotype, the MDM2SNP309 conferred an impaired outcome, with patients carrying the alternative G allele  having shorter OS compared to T/T patients (13 and 29 months, p=0.031). In conclusion, our results show that TP53mut analysis as well as MDM2SNP309 genotyping may be useful tools for prognostication, risk stratification and selection of patients most likely to benefit from new drugs targeting the p53 signaling pathway.

  • 242.
    Jakobsen Falk, Ingrid
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Willander, Kerstin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Chaireti, Roza
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Region Östergötland, Närsjukvården i centrala Östergötland, Medicinska akutkliniken. Karolinska University Hospital, Sweden.
    Lund, Johan
    Huddinge University Hospital, Sweden.
    Nahi, Hareth
    Huddinge University Hospital, Sweden.
    Hermanson, Monica
    Uppsala University, Sweden.
    Green, Henrik
    National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    TP53 mutations and MDM2(SNP309) identify subgroups of AML patients with impaired outcome2015Inngår i: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 94, nr 4, s. 355-362Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BackgroundTP53 is commonly mutated in several cancers and confers treatment resistance and poor prognosis. Altered expression of mouse double minute 2 (MDM2), a negative regulator of p53, may also attenuate normal p53 signaling, thereby enhancing tumor transformation and resistance to apoptosis. The single nucleotide polymorphism (SNP) 309 has been reported to increase MDM2 expression and impair normal p53 response. Experimental designWe investigated the frequency and impact of TP53 mutations (TP53mut) and MDM2(SNP309) on treatment outcome and overall survival (OS) in 189 Swedish acute myeloid leukemia patients. The genetic analyses were performed using SSCA and direct sequencing (for mutations in exon 5-8 of TP53) and Pyrosequencing (for the MDM2(SNP309)). ResultsWe found a high frequency (22%) of TP53mut in patients with cytogenetic aberrations, with association to high-risk cytogenetics (Pless than0.001). TP53mut patients had lower response rates (22% compared with 76% CR in TP53 wild-type (wt) patients, Pless than0.001) and reduced OS (2 and 16months, respectively, Pless than0.001). In TP53wt patients with high or intermediate risk cytogenetic aberrations, the MDM2(SNP309) conferred an impaired outcome, with patients carrying the alternative G-allele having shorter OS compared with T/T patients (median 9 vs. 50months, P=0.020). ConclusionsOur results show that TP53mut analysis and MDM2(SNP309) genotyping may be useful tools for prognostication, risk stratification, and selection of patients most likely to benefit from new drugs targeting the p53 signaling pathway.

  • 243.
    Jangamreddy, Jaganmohan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. LV Prasad Eye Inst, India.
    Haagdorens, Michel K. C.
    Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Mirazul Islam, Mohammad Mirazul
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Lewis, Philip
    Cardiff Univ, Wales.
    Samanta, Ayan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Liszka, Aneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Kozak Ljunggren, Monika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Buznyk, Oleksiy
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Alarcon, Emilio I.
    Univ Ottawa, Canada.
    Zakaria, Nadia
    Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Meek, Keith M.
    Cardiff Univ, Wales.
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Univ Montreal, Canada; Univ Montreal, Canada.
    Correction: Short peptide analogs as alternatives to collagen in pro-regenerative corneal implants (vol 69, pg 120, 2018)2018Inngår i: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 81, s. 330-331Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    n/a

  • 244.
    Jangamreddy, Jaganmohan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. LV Prasad Eye Inst, India.
    Haagdorens, Michel K. C.
    Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Mirazul Islam, Mohammad Mirazul
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Lewis, Philip
    Cardiff Univ, Wales.
    Samanta, Ayan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Liszka, Aneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Kozak Ljunggren, Monika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Buznyk, Oleksiy
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Alarcon, Emilio I.
    Univ Ottawa, Canada.
    Zakaria, Nadia
    Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Meek, Keith M.
    Cardiff Univ, Wales.
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Univ Montreal, Canada; Univ Montreal, Canada.
    Short peptide analogs as alternatives to collagen in pro-regenerative corneal implants2018Inngår i: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 69, s. 120-130Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Short collagen-like peptides (CLPs) are being proposed as alternatives to full-length collagen for use in tissue engineering, on their own as soft hydrogels, or conjugated to synthetic polymer for mechanical strength. However, despite intended clinical use, little is known about their safety and efficacy, mechanism of action or degree of similarity to the full-length counterparts they mimic. Here, we show the functional equivalence of a CLP conjugated to polyethylene glycol (CLP-PEG) to full-length recombinant human collagen in vitro and in promoting stable regeneration of corneal tissue and nerves in a pre- clinicalmini-pig model. We also show that these peptide analogs exerted their pro-regeneration effects through stimulating extracellular vesicle production by host cells. Our results support future use of CLP-PEG implants for corneal regeneration, suggesting the feasibility of these or similar peptide analogs in clinical application in the eye and other tissues. Statement of significance Although biomaterials comprising full-length recombinant human collagen and extracted animal collagen have been evaluated and used clinically, these macromolecules provide only a limited number of functional groups amenable to chemical modification or crosslinking and are demanding to process. Synthetic, customizable analogs that are functionally equivalent, and can be readily scaled-up are therefore very desirable for pre-clinical to clinical translation. Here, we demonstrate, using cornea regeneration as our test bed, that collagen-like-peptides conjugated to multifunctional polyethylene glycol (CLP-PEG) when grafted into mini-pigs as corneal implants were functionally equivalent to recombinant human collagen-based implants that were successfully tested in patients. We also show for the first time that these materials affected regeneration through stimulation of extracellular vesicle production by endogenous host cells that have migrated into the CLP-PEG scaffolds. (C) 2018 Acta Materialia Inc. Published by Elsevier Ltd.

  • 245.
    Jangamreddy, Jaganmohan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Haagdorens, Michel K. C.
    Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Mirazul Islam, Mohammad Mirazul
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Lewis, Philip
    Cardiff Univ, Wales.
    Samanta, Ayan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Liszka, Aneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Kozak Ljunggren, Monika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Buznyk, Oleksiy
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Alarcon, Emilio I.
    Univ Ottawa Heart Inst, Canada.
    Zakaria, Nadia
    Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Meek, Keith M.
    Univ Ottawa Heart Inst, Canada.
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Univ Montreal, Canada; Univ Montreal, Canada.
    Short peptide analogs as alternatives to collagen in pro-regenerative corneal implants (vol 69, pg 120, 2018)2019Inngår i: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 88, s. 556-557Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    n/a

  • 246.
    Jangamreddy, Jaganmohan Reddy
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Cancer and cancer stem cell targeting agents: A focus on salinomycin and apoptin2015Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Current cancer treatments involving surgery, radiotherapy, and chemotherapy target the vast majority of cancer cells, but they are only partially effective in eliminating the disease. Failure to eliminate cancer with conventional treatments can lead to recurrence, which usually kills patient. This often occurs when cancer cells develop resistance to cancer drugs or when cancer-initiating cells (cancer stem cells), unaffected by existing treatment procedures, are present. Here, we studied two drugs, salinomycin and apoptin, that exhibit great potential in the future of cancer treatment not only for restricting malignancy, but also in preventing tumor recurrence. Salinomycin is an antibiotic that was used in poultry farming that is now used clinically to target cancer stem cells, and apoptin is a chicken anemia virus-derived protein that is capable of detecting and killing transformed cells. In this study, we delved into the molecular mechanism of salinomycin action leading to cancer cell death. We showed that salinomycin induces autophagy in both cancer and normal primary cells. We further demonstrated that salinomycin promotes mitochondrial fission, thus increasing mitochondrial mass and mitochondria-specific autophagy, mitophagy. Salinomycin-induced cell death was both necrotic and apoptotic as determined by increased release of HMGB1 and caspase-3, -8 and -9 activation. We also found that stress responses of normal and cancer cells to salinomycin differ and this difference is aggravated by starvation conditions. We proposed that a combinational treatment with glucose starvation, or glucose analogues such as 2DG or 2FDG, might enhance the effects of salinomycin on cancer cells while protecting normal cells. We previously reported that apoptin interacts with BCRABL1, a protein that is expressed in patients with chronic myeloid leukemia (CML). We located a minimal region on the apoptin protein that triggers inhibition of downstream BCR-ABL1 signaling effects. This deca-peptide region was tested on patient samples and was shown to effectively kill cancer cells derived from patients, similar to the drug Imatinib. We further show that the apoptin decapeptide is cytotoxic to Imatinib-resistant patient-derived cancer cells. Thus, we identified a novel therapeutic targeting agent that can not only overcome drug resistance, but it can also induce cancer cell death without affecting normal cells.

    Delarbeid
    1. Salinomycin induces activation of autophagy, mitophagy and affects mitochondrial polarity: Differences between primary and cancer cells
    Åpne denne publikasjonen i ny fane eller vindu >>Salinomycin induces activation of autophagy, mitophagy and affects mitochondrial polarity: Differences between primary and cancer cells
    Vise andre…
    2013 (engelsk)Inngår i: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1833, nr 9, s. 2057-2069Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The molecular mechanism of Salinomycin's toxicity is not fully understood. Various studies reported that Ca2 +, cytochrome c, and caspase activation play a role in Salinomycin-induced cytotoxicity. Furthermore, Salinomycin may target Wnt/β-catenin signaling pathway to promote differentiation and thus elimination of cancer stem cells. In this study, we show a massive autophagic response to Salinomycin (substantially stronger than to commonly used autophagic inducer Rapamycin) in prostrate-, breast cancer cells, and to lesser degree in human normal dermal fibroblasts. Interestingly, autophagy induced by Salinomycin is a cell protective mechanism in all tested cancer cell lines. Furthermore, Salinomycin induces mitophagy, mitoptosis and increased mitochondrial membrane potential (∆Ψ) in a subpopulation of cells. Salinomycin strongly, and in time-dependent manner decreases cellular ATP level. Contrastingly, human normal dermal fibroblasts treated with Salinomycin show some initial decrease in mitochondrial mass, however they are largely resistant to Salinomycin-triggered ATP-depletion. Our data provide new insight into the molecular mechanism of preferential toxicity of Salinomycin towards cancer cells, and suggest possible clinical application of Salinomycin in combination with autophagy inhibitors (i.e. clinically-used Chloroquine). Furthermore, we discuss preferential Salinomycins toxicity in the context of Warburg effect.

    Emneord
    cancer stem cells; mitofusin; mitophagy; mTOR; PGC1α; salinomycin
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-91756 (URN)10.1016/j.bbamcr.2013.04.011 (DOI)000321173900004 ()23639289 (PubMedID)
    Tilgjengelig fra: 2013-05-01 Laget: 2013-05-01 Sist oppdatert: 2017-12-06
    2. Monitoring of autophagy is complicated: Salinomycin as an example
    Åpne denne publikasjonen i ny fane eller vindu >>Monitoring of autophagy is complicated: Salinomycin as an example
    2015 (engelsk)Inngår i: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, ISSN 0167-4889, Vol. 1853, nr 3, s. 604-610Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Monitoring of autophagy is challenging because of its multiple steps and lack of single befitting technique for a complete mechanistic understanding, which makes the task complicated. Here, we evaluate the functionality of autophagy triggered by salinomycin (anti-cancer stem cell agent) using flow cytometry and advanced microscopy. We show that salinomycin does induce functional autophagy at lower concentrations and such a dose is cell type-dependent. For example, PC3 cells show active autophagic flux at 10μM concentration of salinomycin while murine embryonic fibroblasts already show an inhibition of flux at such doses. A higher concentration of salinomycin (i.e. 30μM) inhibits autophagic flux in both cell types. The data confirms our previous findings that salinomycin is an inducer of autophagy, whereas autophagic flux inhibition is a secondary response.

    sted, utgiver, år, opplag, sider
    Elsevier, 2015
    Emneord
    Autophagic flux; GFP-LC3; Salinomycin; Vacuolization; mTandem GFP-RFP LC3; p62/SQSTRM1
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-113565 (URN)10.1016/j.bbamcr.2014.12.022 (DOI)000349878500007 ()25541282 (PubMedID)
    Tilgjengelig fra: 2015-01-23 Laget: 2015-01-23 Sist oppdatert: 2018-01-11bibliografisk kontrollert
    3. Glucose starvation-mediated inhibition of salinomycin induced autophagy amplifies cancer cell specific cell death
    Åpne denne publikasjonen i ny fane eller vindu >>Glucose starvation-mediated inhibition of salinomycin induced autophagy amplifies cancer cell specific cell death
    Vise andre…
    2015 (engelsk)Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, nr 12, s. 10134-10145Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Salinomycin has been used as treatment for malignant tumors in a small number of humans, causing far less side effects than standard chemotherapy. Several studies show that Salinomycin targets cancer-initiating cells (cancer stem cells, or CSC) resistant to conventional therapies. Numerous studies show that Salinomycin not only reduces tumor volume, but also decreases tumor recurrence when used as an adjuvant to standard treatments. In this study we show that starvation triggered different stress responses in cancer cells and primary normal cells, which further improved the preferential targeting of cancer cells by Salinomycin. Our in vitro studies further demonstrate that the combined use of 2-Fluoro 2-deoxy D-glucose, or 2-deoxy D-glucose with Salinomycin is lethal in cancer cells while the use of Oxamate does not improve cell death-inducing properties of Salinomycin. Furthermore, we show that treatment of cancer cells with Salinomycin under starvation conditions not only increases the apoptotic caspase activity, but also diminishes the protective autophagy normally triggered by the treatment with Salinomycin alone. Thus, this study underlines the potential use of Salinomycin as a cancer treatment, possibly in combination with short-term starvation or starvation-mimicking pharmacologic intervention.

    sted, utgiver, år, opplag, sider
    IMPACT JOURNALS LLC, 2015
    Emneord
    Glucose starvation, 2DG, 2FDG, Normoxia and Hypoxia, Differential Stress Response, autophagy, Akt, Tricirabine, Salinomycin
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-113707 (URN)000358874600039 ()
    Tilgjengelig fra: 2015-01-29 Laget: 2015-01-29 Sist oppdatert: 2018-01-11bibliografisk kontrollert
    4. Mapping of Apoptin interaction with BCR-ABL1, and development of apoptin-based targeted therapy
    Åpne denne publikasjonen i ny fane eller vindu >>Mapping of Apoptin interaction with BCR-ABL1, and development of apoptin-based targeted therapy
    Vise andre…
    2014 (engelsk)Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 5, nr 16, s. 7198-7211Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Majority of chronic myeloid leukemia patients experience an adequate therapeutic effect from imatinib however, 26-37% of patients discontinue imatinib therapy due to a suboptimal response or intolerance. Here we investigated derivatives of apoptin, a chicken anemia viral protein with selective toxicity towards cancer cells, which can be directed towards inhibiting multiple hyperactive kinases including BCR-ABL1. Our earlier studies revealed that a proline-rich segment of apoptin interacts with the SH3 domain of fusion protein BCR-ABL1 (p210) and acts as a negative regulator of BCR-ABL1 kinase and its downstream targets. In this study we show for the first time, the therapeutic potential of apoptin-derived decapeptide for the treatment of CML by establishing the minimal region of apoptin interaction domain with BCR-ABL1. We further show that the apoptin decapeptide is able to inhibit BCR-ABL1 down stream target c-Myc with a comparable efficacy to full-length apoptin and Imatinib. The synthetic apoptin is able to inhibit cell proliferation in murine (32Dp210), human cell line (K562), and ex vivo in both imatinib-resistant and imatinib sensitive CML patient samples. The apoptin based single or combination therapy may be an additional option in CML treatment and eventually be feasible as curative therapy.

    Emneord
    apoptin, BCR-ABL1, CML, imatinib, STAT5
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-111667 (URN)000347920100055 ()25216532 (PubMedID)
    Tilgjengelig fra: 2014-10-28 Laget: 2014-10-28 Sist oppdatert: 2018-01-11bibliografisk kontrollert
  • 247.
    Jangamreddy, Jaganmohan Reddy
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Jain, Mayur V.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Hallbeck, Anna-Lotta
    Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Öron- näsa- och halskliniken US.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Los, Marek Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Pomeranian Medical University, Szczecin, Poland.
    Glucose starvation-mediated inhibition of salinomycin induced autophagy amplifies cancer cell specific cell death2015Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, nr 12, s. 10134-10145Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Salinomycin has been used as treatment for malignant tumors in a small number of humans, causing far less side effects than standard chemotherapy. Several studies show that Salinomycin targets cancer-initiating cells (cancer stem cells, or CSC) resistant to conventional therapies. Numerous studies show that Salinomycin not only reduces tumor volume, but also decreases tumor recurrence when used as an adjuvant to standard treatments. In this study we show that starvation triggered different stress responses in cancer cells and primary normal cells, which further improved the preferential targeting of cancer cells by Salinomycin. Our in vitro studies further demonstrate that the combined use of 2-Fluoro 2-deoxy D-glucose, or 2-deoxy D-glucose with Salinomycin is lethal in cancer cells while the use of Oxamate does not improve cell death-inducing properties of Salinomycin. Furthermore, we show that treatment of cancer cells with Salinomycin under starvation conditions not only increases the apoptotic caspase activity, but also diminishes the protective autophagy normally triggered by the treatment with Salinomycin alone. Thus, this study underlines the potential use of Salinomycin as a cancer treatment, possibly in combination with short-term starvation or starvation-mimicking pharmacologic intervention.

  • 248.
    Jangamreddy, Jaganmohan Reddy
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Panigrahi, Soumya
    Case Western Reserve University, Cleveland, OH, USA.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Yadav, Manisha
    CSIR-Central Drug Research Institute, Lucknow, India.
    Maddika, Subbareddy
    Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India.
    Tripathi, Anil Kumar
    King George's Medical University, Lucknow, India.
    Sanyal, Sabyasachi
    CSIR-Central Drug Research Institute, Lucknow, India.
    Los, Marek Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Pomeranian Medical University, Szczecin, Poland.
    Mapping of Apoptin interaction with BCR-ABL1, and development of apoptin-based targeted therapy2014Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 5, nr 16, s. 7198-7211Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Majority of chronic myeloid leukemia patients experience an adequate therapeutic effect from imatinib however, 26-37% of patients discontinue imatinib therapy due to a suboptimal response or intolerance. Here we investigated derivatives of apoptin, a chicken anemia viral protein with selective toxicity towards cancer cells, which can be directed towards inhibiting multiple hyperactive kinases including BCR-ABL1. Our earlier studies revealed that a proline-rich segment of apoptin interacts with the SH3 domain of fusion protein BCR-ABL1 (p210) and acts as a negative regulator of BCR-ABL1 kinase and its downstream targets. In this study we show for the first time, the therapeutic potential of apoptin-derived decapeptide for the treatment of CML by establishing the minimal region of apoptin interaction domain with BCR-ABL1. We further show that the apoptin decapeptide is able to inhibit BCR-ABL1 down stream target c-Myc with a comparable efficacy to full-length apoptin and Imatinib. The synthetic apoptin is able to inhibit cell proliferation in murine (32Dp210), human cell line (K562), and ex vivo in both imatinib-resistant and imatinib sensitive CML patient samples. The apoptin based single or combination therapy may be an additional option in CML treatment and eventually be feasible as curative therapy.

  • 249.
    Jastrzebska, Kamila
    et al.
    Polish Academic Science, Poland.
    Walczak, Magdalena
    Jagiellonian University, Poland.
    Eligiusz Cieslak, Przemyslaw
    Polish Academic Science, Poland.
    Szumiec, Lukasz
    Polish Academic Science, Poland.
    Turbasa, Mateusz
    Polish Academic Science, Poland.
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Blasiak, Tomasz
    Jagiellonian University, Poland.
    Rodriguez Parkitna, Jan
    Polish Academic Science, Poland.
    Loss of NMDA receptors in dopamine neurons leads to the development of affective disorder-like symptoms in mice2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikkel-id 37171Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The role of changes in dopamine neuronal activity during the development of symptoms in affective disorders remains controversial. Here, we show that inactivation of NMDA receptors on dopaminergic neurons in adult mice led to the development of affective disorder-like symptoms. The loss of NMDA receptors altered activity and caused complete NMDA-insensitivity in dopamine-like neurons. Mutant mice exhibited increased immobility in the forced swim test and a decrease in social interactions. Mutation also led to reduced saccharin intake, however the preference of sweet taste was not significantly decreased. Additionally, we found that while mutant mice were slower to learn instrumental tasks, they were able to reach the same performance levels, had normal sensitivity to feedback and showed similar motivation to exert effort as control animals. Taken together these results show that inducing the loss of NMDA receptor-dependent activity in dopamine neurons is associated with development of affective disorder-like symptoms.

  • 250.
    Jedlinski, Adam
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Öron- näsa- och halskliniken US.
    Garvin, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Johansson, Ann-Charlotte
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Edqvist, Per-Henrik
    Uppsala University, Uppsala, Sweden.
    Pontén, Fredrik
    Uppsala University, Uppsala, Sweden.
    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.
    Cetuximab sensitivity of head and neck squamous cell carcinoma xenografts is associated with treatment-induced reduction of EGFR, pEGFR, and pSrc2017Inngår i: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, nr 9, s. 717-724Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The aim of this study was to validate in vitro drug sensitivity testing of head and neck squamous cell carcinoma (HNSCC)cell lines in an in vivo xenograft model, and to identify treatment-induced changes in the EGFR signaling pathway that could be used as markersfor cetuximab treatment response.

    METHODS: The in vitro cetuximab sensitivity of two HNSCC cell lines, UT-SCC-14 and UTSCC-45, was assessed using a crystal violet assay. In order to determine the corresponding in vivo sensitivity, UT-SCC-14 and UT-SCC-45 xenografts were generated in female BALB/c (nu/nu) nude mice. Mice were given three injections of intraperitoneal cetuximab or PBS and the tumor volume was recorded continuously. The expression of epidermal growth factor receptor (EGFR), phosphorylated EGFR (pEGFR), phosphorylated Src (pSrc), and Ki67 was investigated by immunohistochemistry.

    RESULTS: The treatment sensitive UT-SCC-14 cells were found to have an intrinsic cetuximab sensitivity (ICmabS) of 0.15 whereas the ICmabS of the insensitive cell line UT-SCC-45 was 0.78. The corresponding size ratio between untreated and cetuximab treated xenografts was 0.22 and 0.83 for UT-SCC-14 and UT-SCC-45, respectively. UT-SCC-14 cells had a higher baseline expression of pEGFR as compared to UT-SCC-45. Furthermore, in UT-SCC-14 xenografts there was a decrease in EGFR, pEGFR and pSrc upon cetuximab treatment. In contrast, a slight cetuximab-induced increase in EGFR, pEGFR and pSrc was observed in treatment-resistant UT-SCC-45 xenografts.

    CONCLUSIONS: The in vitro treatment sensitivity was reproduced in the in vivo model and cetuximab sensitivity was found to associate with a treatment-induced reduction in pEGFR and pSrc.

2345678 201 - 250 of 590
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