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  • 151.
    Fahlgren, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Bratengeier, Cornelia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Gelmi, Amy
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska fakulteten.
    Semeins, Cornelis M.
    ACTA University of Amsterdam, Netherlands; Vrije University of Amsterdam, Netherlands.
    Klein-Nulend, Jenneke
    ACTA University of Amsterdam, Netherlands; Vrije University of Amsterdam, Netherlands.
    Jager, Edwin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska fakulteten.
    Bakker, Astrid D.
    ACTA University of Amsterdam, Netherlands; Vrije University of Amsterdam, Netherlands.
    Biocompatibility of Polypyrrole with Human Primary Osteoblasts and the Effect of Dopants2015Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 7, artikkel-id e0134023Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Polypyrrole (PPy) is a conducting polymer that enables controlled drug release upon electrical stimulation. We characterized the biocompatibility of PPy with human primary osteoblasts, and the effect of dopants. We investigated the biocompatibility of PPy comprising various dopants, i.e. p-toluene sulfonate (PPy-pTS), chondroitin sulfate (PPy-CS), or dodecylbenzenesulfonate (PPy-DBS), with human primary osteoblasts. PPy-DBS showed the roughest appearance of all surfaces tested, and its wettability was similar to the gold-coated control. The average number of attached cells was 45% higher on PPy-DBS than on PPyCS or PPy-pTS, although gene expression of the proliferation marker Ki-67 was similar in osteoblasts on all surfaces tested. Osteoblasts seeded on PPy-DBS or gold showed similar vinculin attachment points, vinculin area per cell area, actin filament structure, and Ferets diameter, while cells seeded on PPY-CS or PPY-pTS showed disturbed focal adhesions and were enlarged with disorganized actin filaments. Osteoblasts grown on PPy-DBS or gold showed enhanced alkaline phosphatase activity and osteocalcin gene expression, but reduced osteopontin gene expression compared to cells grown on PPy-pTS and PPy-CS. In conclusion, PPy doped with DBS showed excellent biocompatibility, which resulted in maintaining focal adhesions, cell morphology, cell number, alkaline phosphatase activity, and osteocalcin gene expression. Taken together, conducting polymers doped with DBS are well tolerated by osteoblasts. Our results could provide a basis for the development of novel orthopedic or dental implants with controlled release of antibiotics and pharmaceutics that fight infections or focally enhance bone formation in a tightly controlled manner.

  • 152.
    Fahlgren, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Bratengeier, Cornelia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Semeins, Cornelis M.
    Univ Amsterdam, Netherlands; Vrije Univ Amsterdam, Netherlands.
    Klein-Nulend, Jenneke
    Univ Amsterdam, Netherlands; Vrije Univ Amsterdam, Netherlands.
    Bakker, Astrid D.
    Univ Amsterdam, Netherlands; Vrije Univ Amsterdam, Netherlands.
    Supraphysiological loading induces osteocyte-mediated osteoclastogenesis in a novel in vitro model for bone implant loosening2018Inngår i: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 36, nr 5, s. 1425-1434Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 153.
    Fahlgren, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Larsson, Max
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Lindahl, Mats
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Thorsell, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Kågedal, Katarina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Gunnarsson, Svante
    Linköpings universitet, Institutionen för systemteknik, Reglerteknik. Linköpings universitet, Tekniska fakulteten.
    Design and Outcome of a CDIO Syllabus Survey for a Biomedicine Program2019Inngår i: The 15th International CDIO Conference: Proceedings – Full Papers / [ed] Jens Bennedsen, Aage Birkkjær Lauritsen, Kristina Edström, Natha Kuptasthien, Janne Roslöf & Robert Songer, Aarhus: Aarhus University , 2019, s. 191-200Konferansepaper (Fagfellevurdert)
    Abstract [en]

    The CDIO Syllabus survey has successfully been applied to the Bachelor’s and Master’s programs in Experimental and Medical Biosciences, within the Faculty of Medicine and Health Sciences at Linköping University, Sweden. The programs are and have been, subject to considerable redesign with strong influence from the CDIO framework. One of the main drivers for the redesign is a shift concerning the main job market after graduation, from an academic career to industry and healthcare. One of the steps in the development process has been to carry out a Syllabus survey based on an adapted version of the CDIO Syllabus. The survey was sent out to students and to various categories of professionals, and in total 87 responses were received. The adapted version of the Syllabus and the design, execution, and outcome of the survey is presented.

  • 154.
    Farahani, Ensieh
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Patra, Hirak Kumar
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Jangamreddy, Jaganmohan Reddy
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Rashedi, Iran
    University of Toronto, ON, Canada.
    Kawalec, Martha
    University of Manitoba, Winnipeg, Canada .
    Rao Pariti, Rama K.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Batakis, Petros
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska högskolan.
    Wiechec, Emilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Cell adhesion molecules and their relation to (cancer) cell stemness2014Inngår i: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 35, nr 4, s. 747-759Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Despite decades of search for anticancer drugs targeting solid tumors, this group of diseases remains largely incurable, especially if in advanced, metastatic stage. In this review, we draw comparison between reprogramming and carcinogenesis, as well as between stem cells (SCs) and cancer stem cells (CSCs), focusing on changing garniture of adhesion molecules. Furthermore, we elaborate on the role of adhesion molecules in the regulation of (cancer) SCs division (symmetric or asymmetric), and in evolving interactions between CSCs and extracellular matrix. Among other aspects, we analyze the role and changes of expression of key adhesion molecules as cancer progresses and metastases develop. Here, the role of cadherins, integrins, as well as selected transcription factors like Twist and Snail is highlighted, not only in the regulation of epithelial-to-mesenchymal transition but also in the avoidance of anoikis. Finally, we briefly discuss recent developments and new strategies targeting CSCs, which focus on adhesion molecules or targeting tumor vasculature.

  • 155.
    Fardell, Camilla
    et al.
    Univ Gothenburg, Sweden.
    Zettergren, Anna
    Univ Gothenburg, Sweden.
    Ran, Caroline
    Karolinska Inst, Sweden.
    Belin, Andrea Carmine
    Karolinska Inst, Sweden.
    Ekman, Agneta
    Univ Gothenburg, Sweden.
    Sydow, Olof
    Karolinska Univ Hosp, Sweden.
    Backman, Lars
    Karolinska Inst, Sweden.
    Holmberg, Bjorn
    Univ Gothenburg, Sweden.
    Dizdar Segrell, Nil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Neurologiska kliniken.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Nissbrandt, Hans
    Univ Gothenburg, Sweden.
    S100B polymorphisms are associated with age of onset of Parkinsons disease2018Inngår i: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 19, artikkel-id 42Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: In this study we investigated the association between SNPs in the S100B gene and Parkinsons disease (PD) in two independent Swedish cohorts. The SNP rs9722 has previously been shown to be associated with higher S100B concentrations in serum and frontal cortex in humans. S100B is widely expressed in the central nervous system and has many functions such as regulating calcium homeostasis, inflammatory processes, cytoskeleton assembly/disassembly, protein phosphorylation and degradation, and cell proliferation and differentiation. Several of these functions have been suggested to be of importance for the pathophysiology of PD. Methods: The SNPs rs9722, rs2239574, rs881827, rs9984765, and rs1051169 of the S100B gene were genotyped using the KASPar (R) PCR SNP genotyping system in a case-control study of two populations (431 PD patients and 465 controls, 195 PD patients and 378 controls, respectively). The association between the genotype and allelic distributions and PD risk was evaluated using Chi-Square and Cox proportional hazards test, as well as logistic regression. Linear regression and Cox proportional hazards tests were applied to assess the effect of the rs9722 genotypes on age of disease onset. Results: The S100B SNPs tested were not associated with the risk of PD. However, in both cohorts, the T allele of rs9722 was significantly more common in early onset PD patients compared to late onset PD patients. The SNP rs9722 was significantly related to age of onset, and each T allele lowered disease onset with 4.9 years. In addition, allelic variants of rs881827, rs9984765, and rs1051169, were significantly more common in early-onset PD compared to late-onset PD in the pooled population. Conclusions: rs9722, a functional SNP in the 3-UTR of the S100B gene, was strongly associated with age of onset of PD.

  • 156.
    Farnebo, Lovisa
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Region Östergötland, Sinnescentrum, Öron- näsa- och halskliniken US. Linköpings universitet, Medicinska fakulteten.
    Stjernstrom, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Fredrikson, Mats
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Ansell, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Garvin, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Thunell, Lena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    DNA repair genes XPC, XPD, XRCC1, and XRCC3 are associated with risk and survival of squamous cell carcinoma of the head and neck2015Inngår i: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 31, s. 64-72Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Head and neck squamous cell carcinomas (HNSCC) are a heterogenous group of tumors with a high rate of early recurrences, second primary tumors, and mortality. Despite advances in diagnosis and treatment over the past decades, the overall 5-year survival rate remains around 50%. Since the head-and neck-region is continuously exposed to potentially DNA-damaging exogenous and endogenous factors, it is reasonable to expect that the DNA repair genes play a part in the development, progression, and outcome of HNSCC. The aim of this study was to investigate the SNPs XPC A499V, XPD K751Q XRCC1 R399Q and XRCC3 T241M as potential risk factors and indicators of survival among Caucasian patients. One-hundred-sixty-nine patients as well as 344 healthy controls were included and genotyped with PCR-RFLP. We showed that XPC A499V was associated with increased risk of HNSCC, especially laryngeal carcinoma. Among women, XPD K751Q was associated with increased risk of oral SCC. Furthermore, XPD homozygous mutant individuals had the shortest survival time, a survival time that increased however after full dose radiotherapy. Wild-type individuals of XRCC3 T241M demonstrated an earlier age of onset. HPV-positive never smokers had lower frequencies of p53 mutation. Among HNSCC patients, HPV-positivity was significantly associated with XRCC1 R399Q homozygous mutant genotype. Moreover, combinations of putative risk alleles seemed to act synergistically, increasing the risk of HNSCC. In conclusion, our results suggest that SNPs of the DNA repair genes XPC, XPD, XRCC1, and XRCC3 may affect risk and survival of HNSCC. (C) 2015 Elsevier B.V. All rights reserved.

  • 157.
    Farnebo, Lovisa
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Öron- näsa- och halskliniken US.
    Tiefenböck, Katharina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Ansell, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet.
    Thunell, Lena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Garvin, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Öron- näsa- och halskliniken US.
    Strong expression of survivin is associated with positive response to radiotherapy and improved overall survival in head and neck squamous cell carcinoma patients2013Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 133, nr 8, s. 1994-2003Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Head and neck squamous cell carcinoma (HNSCC) is a malignancy that is associated with severe mortality despite advances in therapy. Todays standard treatment most commonly includes radiotherapy, often combined with chemotherapy or surgery. There are so far no established biomarkers to predict response to radiation, and thus the aim of this study was to investigate a series of markers that could potentially identify HNSCC patients who would benefit from radiotherapy. The selected markers, both proteins (epidermal growth factor receptor, survivin and p53), and single nucleotide polymorphisms (SNPs) in the genes of XRCC3, XRCC1, XPC, XPD, MDM2, p53 and FGFR4 were correlated to the response to radiotherapy and overall survival. Investigations were performed on pretreatment tumor biopsies from patients classified as responders or nonresponders to radiotherapy. Protein expression was examined using immunohistochemistry and the genotyping of specific SNPs was analyzed using PCR-RFLP or pyrosequencing. We found that survivin expression was significantly stronger in the responder group (p = 0.003) and that patients with a strong survivin expression had a significantly better overall survival (p andlt; 0.001). Moreover, downregulation of survivin by siRNA in two HNSCC cell lines significantly decreased their sensitivity to radiation. Among the SNPs analyzed, patients with the XPD Lys751Gln SNP had a significantly shorter overall survival (p = 0.048), and patients with the FGFR4 Gly388Arg SNP had a significantly longer overall survival (p = 0.010). In conclusion, our results suggest that survivin plays an important role in the response to radiotherapy and may be a useful marker for predicting radiotherapy response in patients with HNSCC. less thanbrgreater than less thanbrgreater thanWhats new? Resistance to radiation therapy is a significant problem in the treatment of head and neck squamous cell carcinoma (HNSCC) and has created a need for the discovery of markers predictive of radiotherapy response. One promising marker is survivin, an inhibitor of apoptosis. Here, in pre-treatment biopsies from 40 patients with HNSCC, strong survivin expression was significantly associated with response to radiotherapy and increased overall survival. The data also indicate that single nucleotide polymorphisms in the genes XPD and FGFR4 are other possible predictors of overall survival after radiotherapy.

  • 158.
    Fernando, Germain J. P.
    et al.
    Vaxxas Pty Ltd, Australia.
    Hickling, Julian
    Working Tandem Ltd, England.
    Flores, Cesar M. Jayashi
    Vaxxas Pty Ltd, Australia.
    Griffin, Paul
    QIMR Berghofer Med Res Inst, Australia; Q Pharm Pry Ltd, Australia; Mater Hosp, Australia; Mater Res Inst, Australia; Univ Queensland, Australia.
    Anderson, Chris D
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Skinner, S. Rachel
    Univ Sydney, Australia; Childrens Hosp Westmead, Australia.
    Davies, Cristyn
    Univ Sydney, Australia; Childrens Hosp Westmead, Australia.
    Witham, Katey
    Vaxxas Pty Ltd, Australia.
    Pryor, Melinda
    360Biolabs Pry Ltd, Australia.
    Bodle, Jesse
    Seqirus Pty Ltd, Australia.
    Rockman, Steve
    Seqirus Pty Ltd, Australia; Univ Melbourne, Australia.
    Frazer, Ian H.
    Not Found:[Fernando, Germain J. P.; Flores, Cesar M. Jayashi; Witham, Katey; Forster, Angus H.] Vaxxas Pty Ltd, Translat Res Inst, 37 Kent St, Brisbane, Qld 4102, Australia; [Hickling, Julian] Working Tandem Ltd, Cambridge, England; [Griffin, Paul] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia; [Griffin, Paul] Q Pharm Pry Ltd, Brisbane, Qld, Australia; [Griffin, Paul] Mater Hosp, Dept Med and Infect Dieases, Brisbane, Qld, Australia; [Griffin, Paul] Mater Res Inst, Brisbane, Qld, Australia; [Griffin, Paul] Univ Queensland, Brisbane, Qld, Australia; [Anderson, Christopher D.] Linkoping Univ, Dept Clin and Expt Med, Fac Hlth Sci, Linkoping, Sweden; [Anderson, Christopher D.] Heart and Med Ctr, Dept Dermatol and Venereol, Region Ostergotland, Sweden; [Skinner, S. Rachel; Davies, Cristyn] Univ Sydney, Sydney Med Sch, Discipline Child and Adolescent Hlth, Sydney, NSW, Australia; [Skinner, S. Rachel; Davies, Cristyn] Childrens Hosp Westmead, Sydney, NSW, Australia; [Pryor, Melinda] 360Biolabs Pry Ltd, Burnet Inst, Melbourne, Vic, Australia; [Bodle, Jesse; Rockman, Steve] Seqirus Pty Ltd, Melbourne, Vic, Australia; [Rockman, Steve] Univ Melbourne, Melbourne, Vic, Australia;.
    Forster, Angus H.
    Vaxxas Pty Ltd, Australia.
    Safety, tolerability, acceptability and immunogenicity of an influenza vaccine delivered to human skin by a novel high-density microprojection array patch (Nanopatch (TM))2018Inngår i: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 36, nr 26, s. 3779-3788Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Injection using needle and syringe (Namp;S) is the most widely used method for vaccination, but requires trained healthcare workers. Fear of needles, risk of needle-stick injury, and the need to reconstitute lyophilised vaccines, are also drawbacks. The Nanopatch (NP) is a microarray skin patch comprised of a high-density array of microprojections dry-coated with vaccine that is being developed to address these shortcomings. Here we report a randomised, partly-blinded, placebo-controlled trial that represents the first use in humans of the NP to deliver a vaccine. Methods: Healthy volunteers were vaccinated once with one of the following: (1) NPs coated with split inactivated influenza virus (A/California/07/2009 [H1N1], 15 mu g haemagglutinin (HA) per dose), applied to the volar forearm (NP-HAIFA), n = 15; (2) NPs coated with split inactivated influenza virus (A/California/07/2009 11-11N1 I, 15 mu g HA per dose), applied to the upper arm (NP-HA/UA), n = 15; (3) Fluvaxe (R) 2016 containing 15 mu g of the same H1N1 HA antigen injected intramuscularly (IM) into the deltoid (IM-HA/D), n = 15; (4) NPs coated with excipients only, applied to the volar forearm (NP-placebo/FA), n = 5; (5) NPs coated with excipients only applied to the upper arm (NP-placebo/UA), n = 5; or (6) Saline injected IM into the deltoid (IM-placebo/D), n = 5. Antibody responses at days 0, 7, and 21 were measured by haemagglutination inhibition (HAI) and microneutralisation (MN) assays. Findings: NP vaccination was safe and acceptable; all adverse events were mild or moderate. Most subjects (55%) receiving patch vaccinations (HA or placebo) preferred the NP compared with their past experience of IM injection with Namp;S (preferred by 24%). The antigen-vaccinated groups had statistically higher HAI titres at day 7 and 21 compared with baseline (p amp;lt; 0.0001), with no statistical differences between the treatment groups (p amp;gt; 0.05), although the group sizes were small. The geometric mean HAI titres at day 21 for the NP-HA/FA, NP-HA/UA and IM-HA/D groups were: 335 (189-593 95% CI), 160 (74-345 95% CI), and 221 (129-380 95% CI) respectively. A similar pattern of responses was seen with the MN assays. Application site reactions were mild or moderate, and more marked with the influenza vaccine NPs than with the placebo or IM injection. Interpretation: Influenza vaccination using the NP appeared to be safe, and acceptable in this first time in humans study, and induced similar immune responses to vaccination by IM injection. (C) 2018 The Author(s). Published by Elsevier Ltd.

  • 159.
    Fernlund, Eva
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus Linköping/Motala. Lund Univ, Sweden.
    Andersson, Oskar
    Vrinnevi Hosp, Sweden.
    Ellegård, Rada
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för hematopoes och utvecklingsbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Klang Årstrand, Hanna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Olsson, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Gunnarsson, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    The congenital disorder of glycosylation in PGM1 (PGM1-CDG) can cause severe cardiomyopathy and unexpected sudden cardiac death in childhood2019Inngår i: Forensic Science International: Genetics, ISSN 1872-4973, E-ISSN 1878-0326, Vol. 43, artikkel-id UNSP 102111Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: Sudden cardiac death (SCD) in the young is rare and should always lead to suspicion of a genetic cardiac disorder. We describe a family, in which the proband was a girl deceased by sudden cardiac death in the playground at thirteen years of age. The index-patient had short stature, cleft palate but no previous cardiac symptoms. We found an uncommon cause of cardiomyopathy, due to a congenital disorder of glycosylation (CDG), previously described to cause a variable range of usually mild symptoms, and not previously found to cause SCD as the first symptom of the condition. Methods: The index patient underwent postmortem genetic testing/molecular autopsy for genes known to cause SCD, without a detection of causative agent, why two siblings of similar phenotype as the deceased sister underwent clinical-exome genetic sequencing (next generation sequencing). All first-degree relatives underwent clinical examination including cardiac ultrasound, Holzer-ECG, exercise stress test and biochemistry panel. Results: A genetic variant in the gene for phosphoglucomutase 1 (PGM1) was identified in the index patient and her two brothers, all were found to be homozygous for the genetic variant (G230E) NM_002633.2:c.689 G amp;gt; A in PGM1. This variant has been linked to a congenital disorder of glycosylation (PGM1-CDG), explaining the clinical picture of short stature, cleft palate, liver engagement and cardiomyopathy. During follow-up one of the brothers died unexpectedly after physical exertion during daily life at the age of twelve years. The other brother fainted during similar circumstances at the age of thirteen years. Both parents and three other siblings were found to be heterozygous gene carriers without risk for the disease. Conclusion: Our findings suggest that there is a need of multidisciplinary discussion and genetic testing after unexpected cardiac death in the young. We have to be more flexible in our evaluation of diseases and to consider even uncommon diseases including rare recessive inherited disorders. Our findings also suggest that the autosomal recessive PGM1-CDG might be highly associated with life-threatening cardiomyopathy with arrhythmia or sudden cardiac death as the first symptom presenting from childhood and adolescence.

  • 160.
    Fernlund, Eva
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus. Lund University, Sweden.
    Wålinder Österberg, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Kuchinskaya, Ekaterina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Gustafsson, Mikael
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Kardiologiska kliniken US.
    Jansson, Kjell
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Kardiologiska kliniken US.
    Gunnarsson, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik. Region Östergötland, Centrum för verksamhetsstöd och utveckling.
    Novel Genetic Variants in BAG3 and TNNT2 in a Swedish Family with a History of Dilated Cardiomyopathy and Sudden Cardiac Death2017Inngår i: Pediatric Cardiology, ISSN 0172-0643, E-ISSN 1432-1971, Vol. 38, nr 6, s. 1262-1268Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Familial dilated cardiomyopathy is a rare cause of dilated cardiomyopathy (DCM), especially in childhood. Our aim was to describe the clinical course and the genetic variants in a family where the proband was a four-month-old infant presenting with respiratory problems due to DCM. In the family, there was a strong family history of DCM and sudden cardiac death in four generations. DNA was analyzed initially from the deceased girl using next-generation sequencing including 50 genes involved in cardiomyopathy. A cascade family screening was performed in the family after identification of the TNNT2 and the BAG3 variants in the proband. The first-degree relatives underwent clinical examination including biochemistry panel, cardiac ultrasound, Holter ECG, exercise stress test, and targeted genetic testing. The index patient presented with advanced DCM. After a severe clinical course, the baby had external left ventricular assist as a bridge to heart transplantation. 1.5 months after transplantation, the baby suffered sudden cardiac death (SCD) despite maximal treatment in the pediatric intensive care unit. The patient was shown to carry two heterozygous genetic variants in the TNNT2 gene [TNNT2 c.518G amp;gt; A(p.Arg173Gln)] and BAG3 [BAG3 c.785C amp;gt; T(p.Ala262Val)]. Two of the screened individuals (two females) appeared to carry both the familial variants. All the individuals carrying the TNNT2 variant presented with DCM, the two adult patients had mild or moderate symptoms of heart failure and reported palpitations but no syncope or presyncopal attacks prior to the genetic diagnosis. The female carriers of TNNT2 and BAG3 variants had more advanced DCM. In the family history, there were three additional cases of SCD due to DCM, diagnosed by autopsy, but no genetic analysis was possible in these cases. Our findings suggest that the variants in TNNT2 and BAG3 are associated with a high propensity to life-threatening cardiomyopathy presenting from childhood and young adulthood.

  • 161.
    Fieblinger, Tim
    et al.
    Lund University, Sweden .
    Sebastianutto, Irene
    Lund University, Sweden .
    Alcacer, Cristina
    Lund University, Sweden .
    Bimpisidis, Zisis
    Lund University, Sweden .
    Maslava, Natallia
    Lund University, Sweden .
    Sandberg, Sabina
    Lund University, Sweden .
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Cenci, M. Angela
    Lund University, Sweden .
    Mechanisms of Dopamine D1 Receptor-Mediated ERK1/2 Activation in the Parkinsonian Striatum and Their Modulation by Metabotropic Glutamate Receptor Type 52014Inngår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, nr 13, s. 4728-4740Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In animal models of Parkinsons disease, striatal overactivation of ERK1/2 via dopamine (DA) D1 receptors is the hallmark of a supersensitive molecular response associated with dyskinetic behaviors. Here we investigate the pathways involved in D1 receptor-dependent ERK1/2 activation using acute striatal slices from rodents with unilateral 6-hydroxydopamine (6-OHDA) lesions. Application of the dopamine D1-like receptor agonist SKF38393 induced ERK1/2 phosphorylation and downstream signaling in the DA-denervated but not the intact striatum. This response was mediated through a canonical D1R/PKA/MEK1/2 pathway and independent of ionotropic glutamate receptors but blocked by antagonists of L-type calcium channels. Coapplication of an antagonist of metabotropic glutamate receptor type 5 (mGluR5) or its downstream signaling molecules (PLC, PKC, IP3 receptors) markedly attenuated SKF38393-induced ERK1/2 activation. The role of striatal mGluR5 in D1-dependent ERK1/2 activation was confirmed in vivo in 6-OHDA-lesioned animals treated systemically with SKF38393. In one experiment, local infusion of the mGluR5 antagonistMTEPin the DA-denervated rat striatum attenuated the activation of ERK1/2 signaling by SKF38393. In another experiment, 6-OHDA lesions were applied to transgenic mice with a cell-specific knockdown of mGluR5 in D1 receptor-expressing neurons. These mice showed a blunted striatal ERK1/2 activation in response to SFK38393 treatment. Our results reveal that D1-dependent ERK1/2 activation in the DA-denervated striatum depends on a complex interaction between PKA-and Ca2+ -dependent signaling pathways that is critically modulated by striatal mGluR5.

  • 162.
    Fleenor, Courtney J.
    et al.
    Natl Jewish Hlth, CO 80206 USA; Univ Colorado, CO 80045 USA; Globeimmune Inc, CO USA.
    Arends, Tessa
    Univ Colorado, CO 80045 USA.
    Lei, Hong
    Natl Jewish Hlth, CO 80206 USA; Univ Colorado, CO 80045 USA.
    Åhsberg, Josefine
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Okuyama, Kazuki
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Kuruvilla, Jacob
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Cristobal, Susana
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Rabe, Jennifer L.
    Univ Colorado, CO 80045 USA.
    Pandey, Ahwan
    Univ Colorado, CO USA; Univ Colorado, CO USA.
    Danhorn, Thomas
    Natl Jewish Hlth, CO USA.
    Straign, Desiree
    Natl Jewish Hlth, CO 80206 USA.
    Espinosa, Joaquin M.
    Univ Colorado, CO USA; Univ Colorado, CO USA.
    Warming, Soren
    Genentech Inc, CA 94080 USA.
    Pietras, Eric M.
    Univ Colorado, CO USA.
    Sigvardsson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Hagman, James R.
    Natl Jewish Hlth, CO 80206 USA; Univ Colorado, CO 80045 USA; Univ Colorado, CO 80045 USA.
    Zinc Finger Protein 521 Regulates Early Hematopoiesis through Cell-Extrinsic Mechanisms in the Bone Marrow Microenvironment2018Inngår i: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 38, nr 17, artikkel-id UNSP e00603-17Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Zinc finger protein 521 (ZFP521), a DNA-binding protein containing 30 Kruppel-like zinc fingers, has been implicated in the differentiation of multiple cell types, including hematopoietic stem and progenitor cells (HSPC) and B lymphocytes. Here, we report a novel role for ZFP521 in regulating the earliest stages of hematopoiesis and lymphoid cell development via a cell-extrinsic mechanism. Mice with inactivated Zfp521 genes (Zfp521(-/-)) possess reduced frequencies and numbers of hematopoietic stem and progenitor cells, common lymphoid progenitors, and B and T cell precursors. Notably, ZFP521 deficiency changes bone marrow microenvironment cytokine levels and gene expression within resident HSPC, consistent with a skewing of hematopoiesis away from lymphopoiesis. These results advance our understanding of ZFP521s role in normal hematopoiesis, justifying further research to assess its potential as a target for cancer therapies.

  • 163.
    Forsgren, Mikael
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Dahlqvist Leinhard, Olof
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Dahlström, Nils
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Röntgenkliniken i Linköping. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Cedersund, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Lundberg, Peter
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US. Östergötlands Läns Landsting, Diagnostikcentrum, Röntgenkliniken i Linköping.
    Physiologically Realistic and Validated Mathematical Liver Model Revels Hepatobiliary Transfer Rates for Gd-EOB-DTPA Using Human DCE-MRI Data2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 4, s. 0095700-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: Diffuse liver disease (DLD), such as non-alcoholic fatty liver disease (NASH) and cirrhosis, is a rapidly growing problem throughout the Westernized world. Magnetic resonance imaging (MRI), based on uptake of the hepatocyte-specific contrast agent (CA) Gd-EOB-DTPA, is a promising non-invasive approach for diagnosing DLD. However, to fully utilize the potential of such dynamic measurements for clinical or research purposes, more advanced methods for data analysis are required. Methods: A mathematical model that can be used for such data-analysis was developed. Data was obtained from healthy human subjects using a clinical protocol with high spatial resolution. The model is based on ordinary differential equations and goes beyond local diffusion modeling, taking into account the complete system accessible to the CA. Results: The presented model can describe the data accurately, which was confirmed using chi-square statistics. Furthermore, the model is minimal and identifiable, meaning that all parameters were determined with small degree of uncertainty. The model was also validated using independent data. Conclusions: We have developed a novel approach for determining previously undescribed physiological hepatic parameters in humans, associated with CA transport across the liver. The method has a potential for assessing regional liver function in clinical examinations of patients that are suffering of DLD and compromised hepatic function.

  • 164.
    Fotouhi, Omid
    et al.
    Karolinska Inst, Sweden.
    Kjellin, Hanna
    Karolinska Inst, Sweden.
    Juhlin, C. Christofer
    Karolinska Inst, Sweden; Karolinska Univ Hosp Solna, Sweden.
    Pan, Yanbo
    Karolinska Inst, Sweden; SciLifeLab, Sweden.
    Vesterlund, Mattias
    Karolinska Inst, Sweden; SciLifeLab, Sweden.
    Ghaderi, Mehran
    Karolinska Inst, Sweden.
    Yousef, Abdelhamid
    Univ Cambridge, England.
    Andersson-Sand, Hillevi
    SciLifeLab, Sweden.
    Kharaziha, Pedram
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Caramuta, Stefano
    Uppsala Univ, Sweden.
    Kjellman, Magnus
    Karolinska Inst, Sweden; Karolinska Univ Hosp Solna, Sweden.
    Zedenius, Jan
    Karolinska Inst, Sweden; Karolinska Univ Hosp Solna, Sweden.
    Larsson, Catharina
    Karolinska Inst, Sweden.
    Orre, Lukas M.
    Karolinska Inst, Sweden; SciLifeLab, Sweden.
    Proteomics identifies neddylation as a potential therapy target in small intestinal neuroendocrine tumors2019Inngår i: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 38, nr 43, s. 6881-6897Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Patients with small intestinal neuroendocrine tumors (SI-NETs) frequently develop spread disease; however, the underlying molecular mechanisms of disease progression are not known and effective preventive treatment strategies are lacking. Here, protein expression profiling was performed by HiRIEF-LC-MS in 14 primary SI-NETs from patients with and without liver metastases detected at the time of surgery and initial treatment. Among differentially expressed proteins, overexpression of the ubiquitin-like protein NEDD8 was identified in samples from patients with liver metastasis. Further, NEDD8 correlation analysis indicated co-expression with RBX1, a key component in cullin-RING ubiquitin ligases (CRLs). In vitro inhibition of neddylation with the therapeutic agent pevonedistat (MLN4924) resulted in a dramatic decrease of proliferation in SI-NET cell lines. Subsequent mass spectrometry-based proteomics analysis of pevonedistat effects and effects of the proteasome inhibitor bortezomib revealed stabilization of multiple targets of CRLs including p27, an established tumor suppressor in SI-NET. Silencing of NEDD8 and RBX1 using siRNA resulted in a stabilization of p27, suggesting that the cellular levels of NEDD8 and RBX1 affect CRL activity. Inhibition of CRL activity, by either NEDD8/RBX1 silencing or pevonedistat treatment of cells resulted in induction of apoptosis that could be partially rescued by siRNA-based silencing of p27. Differential expression of both p27 and NEDD8 was confirmed in a second cohort of SI-NET using immunohistochemistry. Collectively, these findings suggest a role for CRLs and the ubiquitin proteasome system in suppression of p27 in SI-NET, and inhibition of neddylation as a putative therapeutic strategy in SI-NET.

  • 165.
    Fridberger, Anders
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Oregon Health and Science University, OR 97201 USA.
    Guinan, John J. Jr.
    Harvard MIT Div Health Science and Technology, MA USA; Massachusetts Eye and Ear Infirm, MA 02114 USA; Harvard University, MA 02115 USA.
    What Shapes the Stimulus to the Inner Hair Cell?: A Moderated Discussion2015Inngår i: MECHANICS OF HEARING: PROTEIN TO PERCEPTION, AMER INST PHYSICS , 2015, Vol. 1703, nr 080006Konferansepaper (Fagfellevurdert)
    Abstract [en]

    The following is an edited transcript of a recorded discussion session on the topic of "What Shapes the Stimulus to the Inner Hair Cell?". The discussion, moderated by the authors, took place at the 12th International Workshop on the Mechanics of Hearing held at Cape Sounio, Greece, in June 2014. All participants knew that the session was being recorded. In view of both the spontaneous nature of the discussion and the editing, however, this transcript may not represent the considered or final views of the participants, and may not represent a consensus of experts in the field. The reader is advised to consult additional independent publications.

  • 166.
    Fritz, Michael
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Klawonn, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Nilsson, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Kumar Singh, Anand
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Zajdel, Joanna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Wilhelms, Daniel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Akutkliniken.
    Lazarus, Michael
    University of Tsukuba, Japan.
    Löfberg, Andreas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Jaarola, Maarit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Örtegren Kugelberg, Unn
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Billiar, Timothy R.
    University of Pittsburgh, PA USA.
    Hackam, David J.
    Johns Hopkins University, MD USA.
    Sodhi, Chhinder P.
    Johns Hopkins University, MD USA.
    Breyer, Matthew D.
    Lilly Research Labs, IN USA.
    Jakobsson, Johan
    Lund University, Sweden; Lund University, Sweden.
    Schwaninger, Markus
    University of Lubeck, Germany.
    Schuetz, Gunther
    German Cancer Research Centre, Germany.
    Rodriguez Parkitna, Jan
    Polish Academic Science, Poland.
    Saper, Clifford B.
    Beth Israel Deaconess Medical Centre, MA 02215 USA; Harvard University, MA USA.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice2016Inngår i: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 126, nr 2, s. 695-705Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Systemic inflammation causes malaise and general feelings of discomfort. This fundamental aspect of the sickness response reduces the quality of life for people suffering from chronic inflammatory diseases and is a nuisance during mild infections like common colds or the flu. To investigate how inflammation is perceived as unpleasant and causes negative affect, we used a behavioral test in which mice avoid an environment that they have learned to associate with inflammation-induced discomfort. Using a combination of cell-type-specific gene deletions, pharmacology, and chemogenetics, we found that systemic inflammation triggered aversion through MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E-2 (PGE(2)) synthesis. Further, we showed that inflammation-induced PGE(2) targeted EP1 receptors on striatal dopamine D1 receptor-expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, we demonstrated that inflammation-induced aversion was not an indirect consequence of fever or anorexia but that it constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE(2)-mediated modulation of the dopaminergic motivational circuitry is a key mechanism underlying the negative affect induced by inflammation.

  • 167.
    Fucho, Raquel
    et al.
    IIBB-CSIC, Barcelona, Spain; IDIBAPS Hospital Clinic de Barcelona and CIBEREHD, Barcelona, Spain.
    Martinez, Laura
    IIBB-CSIC, Barcelona, Spain; IDIBAPS Hospital Clinic de Barcelona and CIBEREHD, Barcelona, Spain.
    Baulies, Anna
    IIBB-CSIC, Barcelona, Spain; IDIBAPS Hospital Clinic de Barcelona and CIBEREHD, Barcelona, Spain.
    Torres, Sandra
    IIBB-CSIC, Barcelona, Spain; IDIBAPS Hospital Clinic de Barcelona and CIBEREHD, Barcelona, Spain.
    Tarrats, Nuria
    IIBB-CSIC, Barcelona, Spain; IDIBAPS Hospital Clinic de Barcelona and CIBEREHD, Barcelona, Spain.
    Fernandez, Anna
    IIBB-CSIC, Barcelona, Spain; IDIBAPS Hospital Clinic de Barcelona and CIBEREHD, Barcelona, Spain.
    Ribas, Vicente
    IIBB-CSIC, Barcelona, Spain; IDIBAPS Hospital Clinic de Barcelona and CIBEREHD, Barcelona, Spain.
    Astudillo, Alma M.
    University of Valladolid and CIBERDEM, Valladolid, Spain.
    Balsinde, Jesus
    University of Valladolid and CIBERDEM, Valladolid, Spain.
    Garcia-Roves, Pablo
    IDIBAPS-Hospital Clinic de Barcelona, Spain.
    Elena, Montserrat
    Hospital Clinic de Barcelona, Spain.
    Bergheim, Ina
    Friedrich-Schiller-University, Jena, Germany.
    Lotersztajn, Sophie
    UPEC, France.
    Trautwein, Christian
    University Hospital, RWTH Aachen, Germany.
    Appelqvist, Hanna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Paton, Adrienne W.
    University of Adelaide, Australia.
    Paton, James C.
    University of Adelaide, Australia.
    Czaja, Mark J.
    Albert Einstein College of Medicine, Bronx, NY, USA.
    Kaplowitz, Neil
    University of Southern California, Los Angeles, USA.
    Fernandez-Checa, Jose C.
    IIBB-CSIC, Barcelona, Spain; IDIBAPS Hospital Clinic de Barcelona and CIBEREHD, Barcelona, Spain; University of Southern California, Los Angeles, USA.
    Garcia-Ruiz, Carmen
    IIBB-CSIC, Barcelona, Spain; IDIBAPS Hospital Clinic de Barcelona and CIBEREHD, Barcelona, Spain; University of Southern California, Los Angeles, USA.
    ASMase regulates autophagy and lysosomal membrane permeabilization and its inhibition prevents early stage non-alcoholic steatohepatitis2014Inngår i: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 61, nr 5, s. 1126-1134Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and Aims: Acid sphingomyelinase (ASMase) is activated in non-alcoholic steatohepatitis (NASH). However, the contribution of ASMase to NASH is poorly understood and limited to hepatic steatosis and glucose metabolism. Here we examined the role of ASMase in high fat diet (HFD)-induced NASH. Methods: Autophagy, endoplasmic reticulum (ER) stress and lysosomal membrane permeabilization (LMP) were determined in ASMase(-/-) mice fed a HFD. The impact of pharmacological ASMase inhibition on NASH was analyzed in wild type mice fed a HFD. Results: ASMase deficiency determined resistance to hepatic steatosis mediated by a HFD or methionine-choline deficient diet. ASMase(-/-) mice were resistant to HFD-induced hepatic ER stress, but sensitive to tunicamycin-mediated ER stress, indicating selectivity in the resistance of ASMase(-/-) mice to ER stress and steatosis. Autophagic flux, determined in the presence of rapamycin and/or chloroquine, was lower in primary mouse hepatocytes (PMH) from ASMase(-/-) mice and accompanied by increased p62 levels, suggesting autophagic impairment. Moreover, autophagy suppression by chloroquine and brefeldin A caused ER stress in PMH from ASMase(+/+) mice but not in ASMase(-/-) mice. ASMase(-/-) PMH exhibited increased lysosomal cholesterol loading, decreased LMP and apoptosis resistance induced by 0-methylserine dodecylamide hydrochloride or palmitic acid, effects that were reversed by decreasing cholesterol levels by oxysterol 25-hydroxycholesterol. In vivo pharmacological ASMase inhibition by amitriptyline, a widely used tricyclic antidepressant, protected wild type mice against HFD-induced hepatic steatosis, fibrosis, and liver damage, effects indicative of early-stage NASH, Conclusions: These findings underscore a critical role for ASMase in diet-induced NASH and suggest the potential of amitriptyline as a treatment for patients with NASH.

  • 168.
    Gacic, Jelena
    et al.
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi.
    Vorkapic, Emina
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Slind Olsen, Renate
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. County Hospital Ryhov, Sweden.
    Söderberg, Daniel
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Gustafsson, Therese
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Geffers, Robert
    Helmholtz Centre Infect Research, Germany.
    Skoglund, Karin
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Matussek, Andreas
    County Hospital Ryhov, Sweden.
    Wågsäter, Dick
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Imatinib reduces cholesterol uptake and matrix metalloproteinase activity in human THP-1 macrophages2016Inngår i: Pharmacological Reports, ISSN 1734-1140, E-ISSN 2299-5684, Vol. 68, nr 1, s. 1-6Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Imatinib mesylate (Glivec, formerly STI-571) is a selective tyrosine kinase inhibitor used for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. However, there are reports suggesting that imatinib could be atheroprotective by lowering plasma low-density lipoprotein (LDL). Aim: To investigate the potential inhibitory effect of imatinib on cholesterol uptake in human macrophages as well as its effect on matrix metalloproteinase (MMP) activity. Methods and results: Uptake of fluorescence-labeled LDL was analyzed using flow cytometry. Macrophages treated with imatinib showed a 23.5%, 27%, and 15% decrease in uptake of native LDL (p < 0.05), acetylated LDL (p < 0.01), and copper-modified oxidized LDL (p < 0.01), respectively. Gel based zymography showed that secretion and activity of MMP-2 and MMP-9 were inhibited by imatinib. Using GeneChip Whole Transcript Expression array analysis, no obvious gene candidates involved in the mechanisms of cholesterol metabolism or MMP regulation were found to be affected by imatinib. Instead, we found that imatinib up-regulated microRNA 155 (miR155) by 43.8% and down-regulated ADAM metallopeptidase domain 28 (ADAM28) by 41.4%. Both genes could potentially play an atheroprotective role and would be interesting targets in future studies. Conclusion: Our results indicate that imatinib causes post-translational inhibition with respect to cholesterol uptake and regulation of MMP-2 and MMP-9. More research is needed to further evaluate the role of imatinib in the regulation of other genes and processes. (c) 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.

  • 169.
    Garcia-Sanchez, Susana
    et al.
    University of Basque Country UPV EHU, Spain.
    Bernales, Irantzu
    University of Basque Country UPV EHU, Spain.
    Cristobal, Susana
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. University of Basque Country UPV EHU, Spain.
    Early response to nanoparticles in the Arabidopsis transcriptome compromises plant defence and root-hair development through salicylic acid signalling2015Inngår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, nr 341Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The impact of nano-scaled materials on photosynthetic organisms needs to be evaluated. Plants represent the largest interface between the environment and biosphere, so understanding how nanoparticles affect them is especially relevant for environmental assessments. Nanotoxicology studies in plants allude to quantum size effects and other properties specific of the nano-stage to explain increased toxicity respect to bulk compounds. However, gene expression profiles after exposure to nanoparticles and other sources of environmental stress have not been compared and the impact on plant defence has not been analysed. Results: Arabidopsis plants were exposed to TiO2-nanoparticles, Ag-nanoparticles, and multi-walled carbon nanotubes as well as different sources of biotic (microbial pathogens) or abiotic (saline, drought, or wounding) stresses. Changes in gene expression profiles and plant phenotypic responses were evaluated. Transcriptome analysis shows similarity of expression patterns for all plants exposed to nanoparticles and a low impact on gene expression compared to other stress inducers. Nanoparticle exposure repressed transcriptional responses to microbial pathogens, resulting in increased bacterial colonization during an experimental infection. Inhibition of root hair development and transcriptional patterns characteristic of phosphate starvation response were also observed. The exogenous addition of salicylic acid prevented some nano-specific transcriptional and phenotypic effects, including the reduction in root hair formation and the colonization of distal leaves by bacteria. Conclusions: This study integrates the effect of nanoparticles on gene expression with plant responses to major sources of environmental stress and paves the way to remediate the impact of these potentially damaging compounds through hormonal priming.

  • 170.
    Garvin, Stina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Oda, Husam
    Cty Hosp Ryhov, Sweden; Umea Univ, Sweden.
    Arnesson, Lars-Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Lindström, Annelie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Shabo, Ivan
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Tumor cell expression of CD163 is associated to postoperative radiotherapy and poor prognosis in patients with breast cancer treated with breast-conserving surgery2018Inngår i: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 144, nr 7, s. 1253-1263Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cancer cell fusion with macrophages results in highly tumorigenic hybrids that acquire genetic and phenotypic characteristics from both maternal cells. Macrophage traits, exemplified by CD163 expression, in tumor cells are associated with advanced stages and poor prognosis in breast cancer (BC). In vitro data suggest that cancer cells expressing CD163 acquire radioresistance. Tissue microarray was constructed from primary BC obtained from 83 patients treated with breast-conserving surgery, 50% having received postoperative radiotherapy (RT) and none of the patients had lymph node or distant metastasis. Immunostaining of CD163 in cancer cells and macrophage infiltration (MI) in tumor stroma were evaluated. Macrophage:MCF-7 hybrids were generated by spontaneous in vitro cell fusion. After irradiation (0, 2.5 and 5 Gy gamma-radiation), both hybrids and their maternal MCF-7 cells were examined by clonogenic survival. CD163-expression by cancer cells was significantly associated with MI and clinicopathological data. Patients with CD163-positive tumors had significantly shorter disease-free survival (DFS) after RT. In vitro generated macrophage:MCF-7 hybrids developed radioresistance and exhibited better survival and colony forming ability after radiation compared to maternal MCF-7 cancer cells. Our results suggest that macrophage phenotype in tumor cells results in radioresistance in breast cancer and shorter DFS after radiotherapy.

  • 171.
    Garvin, Stina
    et al.
    Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik. 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.
    Tiefenböck, Katharina
    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.
    Farnebo, Lovisa
    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.
    Thunell, Lena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Farnebo, Marianne
    Karolinska Institute, Sweden.
    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.
    Nuclear expression of WRAP53 beta is associated with a positive response to radiotherapy and improved overall survival in patients with head and neck squamous cell carcinoma2015Inngår i: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 51, nr 1, s. 24-30Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: Today there are no reliable predictive markers for radiotherapy response in head and neck squamous cell carcinoma (HNSCC), leading to both under-and over-treatment of patients, personal suffering, and negative socioeconomic effects. Inherited mutation in WRAP53 beta (WD40 encoding RNA Antisense to p53), a protein involved in intracellular trafficking, dramatically increases the risk of developing HNSCC. The purpose of this study was to investigate whether WRAP53 beta can predict response to radiotherapy in patients with HNSCC. Materials and methods: Tumor biopsies from patients with HNSCC classified as responders or non-responders to radiotherapy were examined for the expression of the WRAP53 beta protein and single nucleotide polymorphisms in the corresponding gene employing immunohistochemistry and allelic discrimination, respectively. In addition, the effect of RNAi-mediated downregulation of WRAP53 beta on the intrinsic radiosensitivity of two HNSCC cell lines was assed using crystal violet and clonogenic assays. Results: Nuclear expression of WRAP53 beta was significantly associated with better response to radiotherapy and improved patient survival. Downregulation of WRAP53 beta with siRNA in vitro enhanced cellular resistance to radiation. Conclusions: Our findings suggest that nuclear expression of WRAP53 beta promotes tumor cell death in response to radiotherapy and is a promising predictor of radiotherapy response in patients with HNSCC.

  • 172.
    Garvin, Stina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Vikhe Patil, Eva
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Arnesson, Lars-Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Oda, Husam
    Umea Univ, Sweden.
    Hedayati, Elham
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Lindström, Annelie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Shabo, Ivan
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Differences in intra-tumoral macrophage infiltration and radiotherapy response among intrinsic subtypes in pT1-T2 breast cancers treated with breast-conserving surgery2019Inngår i: Virchows Archiv, ISSN 0945-6317, E-ISSN 1432-2307, Vol. 475, nr 2, s. 151-162Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Breast cancer (BC) intrinsic subtype classification is based on the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and proliferation marker Ki-67. The expression of these markers depends on both the genetic background of the cancer cells and the surrounding tumor microenvironment. In this study, we explore macrophage traits in cancer cells and intra-tumoral M2-macrophage infiltration (MI) in relation to intrinsic subtypes in non-metastatic invasive BC treated with breast conserving surgery, with and without postoperative radiotherapy (RT). Immunostaining of M2-macrophage-specific antigen CD163 in cancer cells and MI were evaluated, together with ER, PR, HER2, and Ki-67-expression in cancer cells. The tumors were classified into intrinsic subtypes according to the ESMO guidelines. The immunostaining of these markers, MI, and clinical data were analyzed in relation to ipsilateral local recurrence (ILR) as well as recurrence-free (RFS) and disease-free specific (DFS) survival. BC intrinsic subtypes are associated with T-stage, Nottingham Histologic Grade (NHG), and MI. Macrophage phenotype in cancer cells is significantly associated with NHG3-tumors. Significant differences in macrophage infiltration were observed among the intrinsic subtypes of pT1-T2 stage BC. Shorter RFS was observed in luminal B HER2neg tumors after RT, suggesting that this phenotype may be more resistant to irradiation. Ki-67-expression was significantly higher in NHG3 and CD163-positive tumors, as well as those with moderate and high MI. Cancer cell ER expression is inversely related to MI and thus might affect the clinical staging and assessment of BC.

  • 173.
    Gawel, Danuta
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Serra-Musach, Jordi
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Lilja, Sandra
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Aagesen, Jesper
    Reg Jonkoping Cty, Sweden.
    Arenas, Alex
    Univ Rovira and Virgili, Spain.
    Asking, Bengt
    Reg Jonkoping Cty, Sweden.
    Bengner, Malin
    Reg Jonkoping Cty, Sweden.
    Bjorkander, Janne
    Reg Jonkoping Cty, Sweden.
    Biggs, Sophie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Ernerudh, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Hjortswang, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Karlsson, Jan-Erik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Reg Jonkoping Cty, Sweden.
    Köpsén, Mattias
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Jung Lee, Eun Jung
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Yonsei Univ, South Korea.
    Lentini, Antonio
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Li, Xinxiu
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Magnusson, Mattias
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Martinez, David
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Matussek, Andreas
    Reg Jonkoping Cty, Sweden; Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Nestor, Colm
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Schafer, Samuel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Seifert, Oliver
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Reg Jonkoping Cty, Sweden.
    Sonmez, Ceylan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Stjernman, Henrik
    Reg Jonkoping Cty, Sweden.
    Tjärnberg, Andreas
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Wu, Simon
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Åkesson, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Reg Jonkoping Cty, Sweden.
    Shalek, Alex K.
    MIT, MA 02139 USA; Broad Inst MIT and Harvard, MA 02142 USA; Ragon Inst MGH MIT and Harvard, MA USA.
    Stenmarker, Margaretha
    Reg Jonkoping Cty, Sweden; Inst Clin Sci, Sweden.
    Zhang, Huan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Gustafsson, Mika
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus Linköping/Motala.
    A validated single-cell-based strategy to identify diagnostic and therapeutic targets in complex diseases2019Inngår i: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 11, artikkel-id 47Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Genomic medicine has paved the way for identifying biomarkers and therapeutically actionable targets for complex diseases, but is complicated by the involvement of thousands of variably expressed genes across multiple cell types. Single-cell RNA-sequencing study (scRNA-seq) allows the characterization of such complex changes in whole organs.

    Methods

    The study is based on applying network tools to organize and analyze scRNA-seq data from a mouse model of arthritis and human rheumatoid arthritis, in order to find diagnostic biomarkers and therapeutic targets. Diagnostic validation studies were performed using expression profiling data and potential protein biomarkers from prospective clinical studies of 13 diseases. A candidate drug was examined by a treatment study of a mouse model of arthritis, using phenotypic, immunohistochemical, and cellular analyses as read-outs.

    Results

    We performed the first systematic analysis of pathways, potential biomarkers, and drug targets in scRNA-seq data from a complex disease, starting with inflamed joints and lymph nodes from a mouse model of arthritis. We found the involvement of hundreds of pathways, biomarkers, and drug targets that differed greatly between cell types. Analyses of scRNA-seq and GWAS data from human rheumatoid arthritis (RA) supported a similar dispersion of pathogenic mechanisms in different cell types. Thus, systems-level approaches to prioritize biomarkers and drugs are needed. Here, we present a prioritization strategy that is based on constructing network models of disease-associated cell types and interactions using scRNA-seq data from our mouse model of arthritis, as well as human RA, which we term multicellular disease models (MCDMs). We find that the network centrality of MCDM cell types correlates with the enrichment of genes harboring genetic variants associated with RA and thus could potentially be used to prioritize cell types and genes for diagnostics and therapeutics. We validated this hypothesis in a large-scale study of patients with 13 different autoimmune, allergic, infectious, malignant, endocrine, metabolic, and cardiovascular diseases, as well as a therapeutic study of the mouse arthritis model.

    Conclusions

    Overall, our results support that our strategy has the potential to help prioritize diagnostic and therapeutic targets in human disease.

  • 174.
    Gawria, Ghassaan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Tillmar, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Landberg, Eva
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    A comparison of stability of chemical analytes in plasma from the BD Vacutainer (R) Barricor (TM) tube with mechanical separator versus tubes containing gel separator2019Inngår i: Journal of clinical laboratory analysis (Print), ISSN 0887-8013, E-ISSN 1098-2825, artikkel-id e23060Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: There is a need of prolonged stability of certain chemical analytes in lithium heparin tubes with separators. A new tube with a mechanical separator has recently been launched (Barricor (TM)), which according to the manufacturer may have these benefits. The aim of this study was to evaluate stability performance of this tube in comparison with plasma gel tubes under clinically realistic circumstances. Methods: Blood was collected in tubes containing lithium heparin with different separators; gel separator (Vacutainer (R) PST (TM), Becton Dickinson and Vacuette (R), Greiner bio-one) and mechanical separator (Vacutainer (R) Barricor (TM), Becton Dickinson). All tubes had an aspiration volume of 3 mL and were centrifuged at similar time and force. Tubes were transported manually or by car. Seven analytes from 122 patients were analyzed after 3 to 80 hours by Cobas c701 (Roche). Results The Barricor (TM) tube showed increased stability of phosphate and potassium and similar stability of aspartate aminotransferase, glucose, homocysteine, lactate dehydrogenase, and magnesium compared with gel tubes. Maximal allowable bias for phosphate was exceeded after 68 hours for Barricor (TM) tubes compared with 29 or 35 hours for gel tubes and for potassium after 40 hours for Barricor (TM) tubes vs 9 or 12 hours for gel tubes. Transportation did not affect stability. Hemolysis index was slightly lower in Barricor tubes than in gel tubes (P = .01). Conclusion Implementing the new Barricor (TM) tube will improve stability of potassium and phosphate in plasma. Blood sampling facilities far from the laboratory may benefit from using these tubes, thus diminishing preanalytical errors.

  • 175.
    Ge, Yue
    et al.
    National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency.
    Wang, Da-Zhi
    State Key Laboratory of Marine Environmental Science, College of the Environment and Ecology, Xiamen University, China .
    Chiu, Jen-Fu
    University of Hong Kong and Shantou University College of Medicine, China.
    Cristobal, Susana
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Sheehan, David
    Department of Biochemistry, University College Cork, Ireland.
    Silvestre, Frédéric
    Research Unit in Environmental and Evolutionary Biology, University of Namur, Belgium.
    Peng, Xianxuan
    Center for Proteomics, State Key Laboratory of Bio-Control, School of Life Sciences, Sun Yat-Sen University, China.
    Li, Hui
    Center for Proteomics, State Key Laboratory of Bio-Control, School of Life Sciences, Sun Yat-Sen University, China.
    Gong, Zhiyuan
    Department of Biological Sciences, National University of Singapore, Singapore.
    Lam, Siew Hong
    Department of Biological Sciences, National University of Singapore, Singapore.
    Wentao, Hu
    Department of Biochemistry, University College Cork, Ireland.
    Iwahashi, Hitoshi
    Department of Applied Biological Sciences, Gifu University, Japan.
    Liu, Jianjun
    Shenzhen Center for Disease Control and Prevention, China.
    Mei, Nan
    National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
    Shi, Leming
    National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
    Bruno, Maribel
    National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency.
    Foth, Heidi
    Institute for Environmental Toxicology, Martin Luther University, Halle/Saale, Germany.
    Teichman, Kevin
    Office of Research and Development, U.S. Environmental Protection Agency, Washington D.C., USA.
    Environmental OMICS: Current Status and Future Directions2013Inngår i: JOURNAL OF INTEGRATED OMICS, ISSN 2182-0287, Vol. 3, nr 2, s. 75-87Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Applications of OMICS to high throughput studies of changes of genes, RNAs, proteins, metabolites, and their associated functionsin cells or organisms exposed to environmental chemicals has led to the emergence of a very active research field: environmental OMICS.This developing field holds an important key for improving the scientific basis for understanding the potential impacts of environmentalchemicals on both health and the environment. Here we describe the state of environmental OMICS with an emphasis on its recent accomplishmentsand its problems and potential solutions to facilitate the incorporation of OMICS into mainstream environmental and healthresearch.Data sources: We reviewed relevant and recently published studies on the applicability and usefulness of OMICS technologies to the identificationof toxicity pathways, mechanisms, and biomarkers of environmental chemicals for environmental and health risk monitoring andassessment, including recent presentations and discussions on these issues at The First International Conference on Environmental OMICS(ICEO), held in Guangzhou, China during November 8-12, 2011. This paper summarizes our review.Synthesis: Environmental OMICS aims to take advantage of powerful genomics, transcriptomics, proteomics, and metabolomics tools toidentify novel toxicity pathways/signatures/biomarkers so as to better understand toxicity mechanisms/modes of action, to identify/categorize/prioritize/screen environmental chemicals, and to monitor and predict the risks associated with exposure to environmental chemicalson human health and the environment. To improve the field, some lessons learned from previous studies need to be summarized, aresearch agenda and guidelines for future studies need to be established, and a focus for the field needs to be developed.Conclusions: OMICS technologies for identification of RNA, protein, and metabolic profiles and endpoints have already significantly improvedour understanding of how environmental chemicals affect our ecosystem and human health. OMICS breakthroughs are empoweringthe fields of environmental toxicology, chemical toxicity characterization, and health risk assessment. However, environmental OMICS is stillin the data generation and collection stage. Important data gaps in linking and/or integrating toxicity data with OMICS endpoints/profilesneed to be filled to enable understanding of the potential impacts of chemicals on human health and the environment. It is expected thatfuture environmental OMICS will focus more on real environmental issues and challenges such as the characterization of chemical mixturetoxicity, the identification of environmental and health biomarkers, and the development of innovative environmental OMICS approachesand assays. These innovative approaches and assays will inform chemical toxicity testing and prediction, ecological and health risk monitoringand assessment, and natural resource utilization in ways that maintain human health and protects the environment in a sustainable manner.

  • 176.
    Gelmi, Amy
    et al.
    Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Imperial Coll London, England.
    Cieslar-Pobuda, Artur
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Silesian Technical University, Poland.
    de Muinck, Ebo
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Kardiologiska kliniken US. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Los, Marek Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Pomeranian Medical University, Poland.
    Rafat, Mehrdad
    Linköpings universitet, Institutionen för medicinsk teknik, Biomedicinsk instrumentteknik. Linköpings universitet, Tekniska fakulteten.
    Jager, Edwin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska fakulteten.
    Direct Mechanical Stimulation of Stem Cells: A Beating Electromechanically Active Scaffold for Cardiac Tissue Engineering2016Inngår i: Advanced Healthcare Materials, ISSN 2192-2640, E-ISSN 2192-2659, Vol. 5, nr 12, s. 1471-1480Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The combination of stem cell therapy with a supportive scaffold is a promising approach to improving cardiac tissue engineering. Stem cell therapy can be used to repair nonfunctioning heart tissue and achieve myocardial regeneration, and scaffold materials can be utilized in order to successfully deliver and support stem cells in vivo. Current research describes passive scaffold materials; here an electroactive scaffold that provides electrical, mechanical, and topographical cues to induced human pluripotent stem cells (iPS) is presented. The poly(lactic-co-glycolic acid) fiber scaffold coated with conductive polymer polypyrrole (PPy) is capable of delivering direct electrical and mechanical stimulation to the iPS. The electroactive scaffolds demonstrate no cytotoxic effects on the iPS as well as an increased expression of cardiac markers for both stimulated and unstimulated protocols. This study demonstrates the first application of PPy as a supportive electroactive material for iPS and the first development of a fiber scaffold capable of dynamic mechanical actuation.

  • 177.
    Gelmi, Amy
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska fakulteten.
    Kozak Ljunggren, Monika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Rafat, Mehrdad
    Linköpings universitet, Institutionen för medicinsk teknik, Biomedicinsk instrumentteknik. Linköpings universitet, Medicinska fakulteten.
    Jager, Edwin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska fakulteten.
    Bioelectronic nanofibre scaffolds for tissue engineering and whole-cell biosensors2014Konferansepaper (Fagfellevurdert)
  • 178.
    Gelmi, Amy
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska högskolan.
    Kozak Ljunggren, Monika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Rafat, Mehrdad
    Linköpings universitet, Institutionen för medicinsk teknik. Linköpings universitet, Hälsouniversitetet.
    Jager, Edwin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska högskolan.
    Influence of conductive polymer doping on the viability of cardiac progenitor cells2014Inngår i: Journal of materials chemistry. B, ISSN 2050-750X, E-ISSN 2050-7518, Vol. 2, nr 24, s. 3860-3867Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cardiac tissue engineering via the use of stem cells is the future for repairing impaired heart function that results from a myocardial infarction. Developing an optimised platform to support the stem cells is vital to realising this, and through utilising new smart materials such as conductive polymers we can provide a multi-pronged approach to supporting and stimulating the stem cells via engineered surface properties, electrical, and electromechanical stimulation. Here we present a fundamental study on the viability of cardiac progenitor cells on conductive polymer surfaces, focusing on the impact of surface properties such as roughness, surface energy, and surface chemistry with variation of the polymer dopant molecules. The conductive polymer materials were shown to provide a viable support for both endothelial and cardiac progenitor cells, while the surface energy and roughness were observed to influence viability for both progenitor cell types. Characterising the interaction between the cardiac progenitor cells and the conductive polymer surface is a critical step towards optimising these materials for cardiac tissue regeneration, and this study will advance the limited knowledge on biomaterial surface interactions with cardiac cells.

  • 179.
    Gelmi, Amy
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska fakulteten.
    Kozak Ljunggren, Monika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Rafat, Mehrdad
    Linköpings universitet, Institutionen för medicinsk teknik, Biomedicinsk instrumentteknik. Linköpings universitet, Medicinska fakulteten.
    Jager, Edwin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska fakulteten.
    Smart Electroactive Scaffolds for Cardiac Tissue Regeneration2014Konferansepaper (Fagfellevurdert)
  • 180.
    Gelmi, Amy
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska högskolan.
    Ljunggren, Monika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Rafat, Mehrdad
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Jager, Edwin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska högskolan.
    Electroactive scaffolds for cardiac tissue regeneration2013Konferansepaper (Annet vitenskapelig)
    Abstract [en]

    Myocardial Infarction (MI), commonly known as a heart attack, is the interruption of blood supply to a part of the heart, causing heart cells to die. In order to restore function by-pass surgery or ultimately heart transplantation is needed. However, due to the shortage of organ donors and complications associated with immune suppressive treatments, development of new strategies to help regenerate the injured heart is necessary. Stem cell therapy can be used to repair necrotic heart tissue and achieve myocardial regeneration. This research is focused on developing implantable electroactive fiber scaffolds that will increase the differentiation ratio of mesenchymal stem cells into cardiomyocytes and thus increase the formation of novel cardiac tissue to repair or replace the damaged cardiac tissue after MI. Composite nanofibrous scaffold of poly(dl-lactide-co-glycolide) (PLGA) have been coated with biodoped polypyrrole to create an electroactive fiber scaffold, with controllable fiber dimensions and alignment. The electrical properties of the polymers are an integral factor in creating these 'intelligent' 3-D materials; not only does the inherent conductivity provide a platform for electrical stimulation, but the ionic actuation of the polymer can also provide mechanical stimulation to the seeded cells. The biocompatibility of the polymer, PLGA scaffolds, and coated PLGA scaffolds has been investigated using primary cardiovascular progenitor cells.

  • 181.
    Gelmi, Amy
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska fakulteten.
    Zhang, Jiabin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska fakulteten.
    Cieslar-Pobuda, Artur
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Ljunggren, Monika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Los, Marek
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Rafat, Mehrdad
    Linköpings universitet, Institutionen för medicinsk teknik, Biomedicinsk instrumentteknik. Linköpings universitet, Medicinska fakulteten.
    Jager, Edwin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska fakulteten.
    Electroactive polymer scaffolds for cardiac tissue engineering2015Inngår i: Proc. SPIE 9430, Electroactive Polymer Actuators and Devices (EAPAD) 2015 / [ed] Bar-Cohen, SPIE - International Society for Optical Engineering, 2015, Vol. 9430, s. 94301T-1-94301T-7Konferansepaper (Fagfellevurdert)
    Abstract [en]

    By-pass surgery and heart transplantation are traditionally used to restore the heart’s functionality after a myocardial Infarction (MI or heart attack) that results in scar tissue formation and impaired cardiac function. However, both procedures are associated with serious post-surgical complications. Therefore, new strategies to help re-establish heart functionality are necessary. Tissue engineering and stem cell therapy are the promising approaches that are being explored for the treatment of MI. The stem cell niche is extremely important for the proliferation and differentiation of stem cells and tissue regeneration. For the introduction of stem cells into the host tissue an artificial carrier such as a scaffold is preferred as direct injection of stem cells has resulted in fast stem cell death. Such scaffold will provide the proper microenvironment that can be altered electronically to provide temporal stimulation to the cells. We have developed an electroactive polymer (EAP) scaffold for cardiac tissue engineering. The EAP scaffold mimics the extracellular matrix and provides a 3D microenvironment that can be easily tuned during fabrication, such as controllable fibre dimensions, alignment, and coating. In addition, the scaffold can provide electrical and electromechanical stimulation to the stem cells which are important external stimuli to stem cell differentiation. We tested the initial biocompatibility of these scaffolds using cardiac progenitor cells (CPCs), and continued onto more sensitive induced pluripotent stem cells (iPS). We present the fabrication and characterisation of these electroactive fibres as well as the response of increasingly sensitive cell types to the scaffolds.

  • 182.
    Ghafouri, Bijar
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Smärt och rehabiliteringscentrum.
    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.
    Microdialysis in Profiling Cytokines and Other Macromolecules in the Skin in Health and Disease: A Comment to Falcone et al.2017Inngår i: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 97, nr 10, s. 1269-1269Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    n/a

  • 183.
    Ghafouri, Nazdar
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Smärt och rehabiliteringscentrum. Umeå University, Umeå, Sweden.
    Ghafouri, Bijar
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Smärt och rehabiliteringscentrum. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Arbets- och miljömedicin.
    Fowler, Christopher J.
    Umeå University, Sweden.
    Larsson, Britt
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Smärt och rehabiliteringscentrum.
    Turkina, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Karlsson, Linn
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Smärt och rehabiliteringscentrum.
    Gerdle, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Smärt och rehabiliteringscentrum.
    Effects of Two Different Specific Neck Exercise Interventions on Palmitoylethanolamide and Stearoylethanolamide Concentrations in the Interstitium of the Trapezius Muscle in Women with Chronic Neck Shoulder Pain2014Inngår i: Pain medicine (Malden, Mass.), ISSN 1526-2375, E-ISSN 1526-4637, Vol. 15, nr 8, s. 1379-1389Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose. Chronic neck/shoulder pain (CNSP) is one of the most common pain conditions. The understanding of mechanisms, including the peripheral balance between nociceptive and antinociceptive processes, is incomplete. N-acylethanolamines (NAEs) are a class of endogenous compounds that regulate inflammation and pain. The aim of this study was to investigate the levels of two NAEs: the peroxisome proliferator-activated receptor type-a ligand palmitoylethanolamide (PEA) and stearoylethanolamide (SEA) in the muscle interstitium of the trapezius muscle in women with CNSP randomized to two different neck specific training programs and in a healthy pain-free control group (CON). Materials and Methods. Fifty-seven women with CNSP were randomized to strength + stretch or stretch alone exercise programs. Twenty-nine subjects underwent microdialysis procedure before and after 4-6 months of exercise. Twenty-four CON subjects underwent microdialysis procedure before and after 4-6 months without any intervention in between. Microdialysate samples were collected from the trapezius muscle and analyzed by mass spectrometry for PEA and SEA levels. Results. PEA and SEA levels were significantly higher in CNSP patients compared with CON. PEA was significantly higher in CNSP than in CON after both training programs. SEA was significantly higher in CNSP than in CON after stretch alone but not after strength + stretch training. A significant positive correlation was found between changes in pain intensity and in SEA levels in the strength + stretch group, but not in the stretch alone group. Conclusion. Our results indicate that exercise interventions differentially affect the levels of the bioactive lipids PEA and SEA in the interstitium of the trapezius muscle in women with CNSP.

  • 184.
    Ghani, Mozhdeh
    et al.
    Nanotechnology Institute, Amirkabir University of Technology, Tehran, Iran.
    Mak, Wing Cheung
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Sensor- och aktuatorsystem. Linköpings universitet, Tekniska fakulteten.
    Cheung, Kwan Yee
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Montazer, M.
    Nanotechnology Institute, Amirkabir University of Technology, Tehran, Iran.
    Rezaei, B.
    Nanotechnology Institute, Amirkabir University of Technology, Tehran, Iran.
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Cross-linked superfine electrospun tragacanth-based biomaterial as scaffolds for tissue engineering2016Inngår i: European Cells and Materials, ISSN 1473-2262, E-ISSN 1473-2262, Vol. 31, nr Suppl. 1, s. 204-204Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Natural polymer-based nanofibrous structures promote cell adhesion and proliferation due to their high surface area/volume ratio, high porosity, and similarity to native extracellular matrix in terms of both chemical composition and physical structure. Gum tragacanth (Tg) is a natural polysaccharides obtained from plants. It is a biocompatible, biodegradable and anionic polysaccharides that has been used extensively as an emulsifier in food and pharmaceutical industries. Despite, its good rheological properties and compatibility, the potential biomedical applications of Tg have not been fully investigated. The objective of the present study was to explore the feasibility of combining Tg with gelatin to fabricate a scaffold that serves as a simple collagen-glycosaminoglycans analog for tissue engineering applications, e.g. as a scaffold for human skin epithelial cells.

  • 185.
    Ghavami, Saeid
    et al.
    University of Manitoba, Canada.
    Sharma, Pawan
    University of Manitoba, Canada.
    Yeganeh, Behzad
    University of Manitoba, Canada.
    Ojo, Oluwaseun O.
    University of Manitoba, Canada.
    Jha, Aruni
    University of Manitoba, Canada.
    Mutawe, Mark M.
    University of Manitoba, Canada.
    Kashani, Hessam H.
    University of Manitoba, Canada.
    Los, Marek Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Klonisch, Thomas
    University of Manitoba, Canada .
    Unruh, Helmut
    University of Manitoba, Canada .
    Halayko, Andrew J.
    University of Manitoba, Canada.
    Airway mesenchymal cell death by mevalonate cascade inhibition: integration of autophagy, unfolded protein response and apoptosis focusing on Bcl2 family proteins2014Inngår i: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1843, nr 7, s. 1259-1271Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    HMG-CoA reductase, the proximal rate-limiting enzyme in the mevalonate pathway, is inhibited by statins. Beyond their cholesterol lowering impact, statins have pleiotropic effects and their use is linked to improved lung health. We have shown that mevalonate cascade inhibition induces apoptosis and autophagy in cultured human airway mesenchymal cells. Here, we show that simvastatin also induces endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in these cells. We tested whether coordination of ER stress, autophagy and apoptosis determines survival or demise of human lung mesenchymal cells exposed to statin. We observed that simvastatin exposure activates UPR (activated transcription factor 4, activated transcription factor 6 and IRE1 alpha) and caspase-4 in primary human airway fibroblasts and smooth muscle cells. Exogenous mevalonate inhibited apoptosis, autophagy and UPR, but exogenous cholesterol was without impact, indicating that sterol intermediates are involved with mechanisms mediating statin effects. Caspase-4 inhibition decreased simvastatin-induced apoptosis, whereas inhibition of autophagy by ATG7 or ATG3 knockdown significantly increased cell death. In BAX(-/-)/BAIC(-/) murine embryonic fibroblasts, simvastatin-triggered apoptotic and UPR events were abrogated, but autophagy flux was increased leading to cell death via necrosis. Our data indicate that mevalonate cascade inhibition, likely associated with depletion of sterol intermediates, can lead to cell death via coordinated apoptosis, autophagy, and ER stress. The interplay between these pathways appears to be principally regulated by autophagy and Bcl-2-family pro-apoptotic proteins. These findings uncover multiple mechanisms of action of statins that could contribute to refining the use of such agent in treatment of lung disease.

  • 186.
    Ghavami, Saeid
    et al.
    University of Manitoba.
    Shojaei, Shahla
    Shiraz University of Medical Sciences.
    Yeganeh, Behzad
    University of Manitoba.
    Ande, Sudharsana R.
    University of Manitoba.
    Jangamreddy, Jaganmohan R.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Mehrpour, Maryam
    Paris Descartes University Medical School.
    Christoffersson, Jonas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Chaabane, Wiem
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Moghadam, Adel Rezaei
    Islamic Azad University.
    Kashani, Hessam H.
    University of Manitoba.
    Hashemi, Mohammad
    Zahedan University of Medical Sciences.
    Owji, Ali A.
    Shiraz University of Medical Sciences.
    Łos, Marek J
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Autophagy and Apoptosis Dysfunction in Neurodegenerative Disorders2014Inngår i: Progress in Neurobiology, ISSN 0301-0082, E-ISSN 1873-5118, Vol. 112, s. 24-49Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Autophagy and apoptosis are basic physiologic processes contributing to the maintenance of cellular homeostasis. Autophagy encompasses pathways that target long-lived cytosolic proteins and damaged organelles. It involves a sequential set of events including double membrane formation, elongation, vesicle maturation and finally delivery of the targeted materials to the lysosome. Apoptotic cell death is best described through its morphology. It is characterized by cell rounding, membrane blebbing, cytoskeletal collapse, cytoplasmic condensation, and fragmentation, nuclear pyknosis, chromatin condensation/fragmentation, and formation of membrane-enveloped apoptotic bodies, that are rapidly phagocytosed by macrophages or neighboring cells. Neurodegenerative disorders are becoming increasingly prevalent, especially in the Western societies, with larger percentage of members living to an older age. They have to be seen not only as a health problem, but since they are care-intensive, they also carry a significant economic burden. Deregulation of autophagy plays a pivotal role in the etiology and/or progress of many of these diseases. Herein, we briefly review the latest findings that indicate the involvement of autophagy in neurodegenerative diseases. We provide a brief introduction to autophagy and apoptosis pathways focusing on the role of mitochondria and lysosomes. We then briefly highlight pathophysiology of common neurodegenerative disorders like Alzheimer's diseases, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Then, we describe functions of autophagy and apoptosis in brain homeostasis, especially in the context of the aforementioned disorders. Finally, we discuss different ways that autophagy and apoptosis modulation may be employed for therapeutic intervention during the maintenance of neurodegenerative disorders.

  • 187.
    Ghofrani, Saeed
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Cellular and Molecular Research Center and Department of Neuroscience, School of Advanced Technology, Iran University of Medical Sciences, Tehran, Iran.
    Joghataei, Mohammad-Taghi
    Cellular and Molecular Research Center and Department of Neuroscience, School of Advanced Technology, Iran University of Medical Sciences, Tehran, Iran.
    Mohseni, Simin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Baluchnejadmojarad, Tourandokht
    Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
    Bagheri, Maryam
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Department of Physiology, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran.
    Khamse, Safoura
    Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
    Roghani, Mehrdad
    Neurophysiology Research Center, Shahed University, Tehran, Iran.
    Naringenin improves learning and memory in an Alzheimer's disease rat model: Insights into the underlying mechanisms2015Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 764, s. 195-201Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Alzheimer's disease (AD) is one of the prevalent neurological disorders of the central nervous system hallmarked by increased beta-amyloid (Aβ) deposition and ensuing learning and memory deficit. In the present study, the beneficial effect of naringenin on improvement of learning and memory was evaluated in an Alzheimer's disease rat model. The Aβ-injected rats showed a lower alternation score in Y-maze task, impairment of retention and recall capability in passive avoidance test, and lower correct choices and higher errors in radial arm maze (RAM) task as compared to sham group in addition to enhanced oxidative stress and apoptosis. Naringenin, but not a combination of naringenin and fulvestrant (an estrogenic receptor antagonist) significantly improved the performance of Aβ-injected rats in passive avoidance and RAM tasks. Naringenin pretreatment of Aβ-injected rats also lowered hippocampal malondialdehyde (MDA) with no significant effect on nitrite and superoxide dismutase (SOD) activity in addition to lowering apoptosis. These results suggest naringenin pretreatment attenuates Aβ-induced impairment of learning and memory through mitigation of lipid peroxidation and apoptosis and its beneficial effect is somewhat mediated via estrogenic pathway.

  • 188.
    Gouveia, Duarte
    et al.
    Laboratoire Innovations technologiques pour la Détection et le Diagnostic (Li2D), Service de Pharmacologie et Immunoanalyse (SPI), CEA, INRA, F-30207 Bagnols-sur-Cèze, France.
    Almunia, Christine
    Laboratoire Innovations technologiques pour la Détection et le Diagnostic (Li2D), Service de Pharmacologie et Immunoanalyse (SPI), CEA, INRA, F-30207 Bagnols-sur-Cèze, France.
    Cogne, Yannick
    Laboratoire Innovations technologiques pour la Détection et le Diagnostic (Li2D), Service de Pharmacologie et Immunoanalyse (SPI), CEA, INRA, F-30207 Bagnols-sur-Cèze, France.
    Pible, Olivier
    Laboratoire Innovations technologiques pour la Détection et le Diagnostic (Li2D), Service de Pharmacologie et Immunoanalyse (SPI), CEA, INRA, F-30207 Bagnols-sur-Cèze, France.
    Degli-Esposti, Davide
    Irstea, UR Riverly Laboratoire d'écotoxicologie, Centre de Lyon-Villeurbanne, F-69625 Villeurbanne, France.
    Salvador, Arnaud
    Université Claude Bernard Lyon 1, CNRS, ENS de Lyon, Institut des Sciences Analytiques, UMR 5280, 5 rue de la Doua, F-69100 Villeurbanne, France.
    Cristobal, Susana
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Department of Physiology, Ikerbasque, Faculty of Medicine and Dentistry, University of the Basque Country, Spain.
    Sheehan, David
    College of Arts and Sciences, Khalifa University of Science and Technology, PO Box 127788, Abu Dhabi, United Arab Emirates.
    Chaumot, Arnaud
    Irstea, UR Riverly Laboratoire d'écotoxicologie, Centre de Lyon-Villeurbanne, F-69625 Villeurbanne, France.
    Geffard, Olivier
    Irstea, UR Riverly Laboratoire d'écotoxicologie, Centre de Lyon-Villeurbanne, F-69625 Villeurbanne, France.
    Armengaud, Jean
    Laboratoire Innovations technologiques pour la Détection et le Diagnostic (Li2D), Service de Pharmacologie et Immunoanalyse (SPI), CEA, INRA, F-30207 Bagnols-sur-Cèze, France.
    Ecotoxicoproteomics: A decade of progress in our understanding of anthropogenic impact on the environment2019Inngår i: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 198, s. 66-77, artikkel-id S1874-3919(18)30423-8Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Anthropogenic pollutants are found worldwide. Their fate and effects on human and ecosystem health must be appropriately monitored. Today, ecotoxicology is focused on the development of new methods to assess the impact of pollutant toxicity on living organisms and ecosystems. In situ biomonitoring often uses sentinel animals for which, ideally, molecular biomarkers have been defined thanks to which environmental quality can be assessed. In this context, high-throughput proteomics methods offer an attractive approach to study the early molecular responses of organisms to environmental stressors. This approach can be used to identify toxicity pathways, to quantify more precisely novel biomarkers, and to draw the possible adverse outcome pathways. In this review, we discuss the major advances in ecotoxicoproteomics made over the last decade and present the current state of knowledge, emphasizing the technological and conceptual advancements that allowed major breakthroughs in this field, which aims to “make our planet great again”.

    Significance

    Ecotoxicoproteomics is a protein-centric methodology that is useful for ecotoxicology and could have future applications as part of chemical risk assessment and environmental monitoring. Ecotoxicology employing non-model sentinel organisms with highly divergent phylogenetic backgrounds aims to preserve the functioning of ecosystems and the overall range of biological species supporting them. The classical proteomics workflow involves protein identification, functional annotation, and extrapolation of toxicity across species. Thus, it is essential to develop multi-omics approaches in order to unravel molecular information and construct the most suitable databases for protein identification and pathway analysis in non-model species. Current instrumentation and available software allow relevant combined transcriptomic/proteomic studies to be performed for almost any species. This review summarizes these approaches and illustrates how they can be implemented in ecotoxicology for routine biomonitoring.

  • 189.
    Granseth, Björn
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Andersson, Fredrik K
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Lindström, Sarah H
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    The initial stage of reversal learning is impaired in mice hemizygous for the vesicular glutamate transporter (VGluT1)2015Inngår i: Genes, Brain and Behavior, ISSN 1601-1848, E-ISSN 1601-183X, Vol. 14, nr 6, s. 477-485Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Behavioral flexibility is a complex cognitive function that is necessary for survival in changeable environments. Patients with schizophrenia or Parkinsons disease often suffer from cognitive rigidity, reducing their capacity to function in society. Patients and rodent models with focal lesions in the prefrontal cortex (PFC) show similar rigidity, owing to the loss of PFC regulation of subcortical reward circuits involved in behavioral flexibility. The vesicular glutamate transporter (VGluT1) is preferentially expressed at modulatory synapses, including PFC neurons that project to components of the reward circuit (such as the nucleus accumbens, NAc). VGluT1(+/-) mice display behavioral phenotypes matching many symptoms of schizophrenia, and VGluT1 expression is reduced in the PFC of patients with schizophrenia and Parkinsons disease. Thus, it appears likely that VGluT1-expressing synapses from PFC play a key role in behavioral flexibility. To examine this hypothesis, we studied behavioral flexibility in VGluT1(+/-) mice by testing reversal learning in a visual discrimination task. Here, we show that VGluT1(+/-) mice acquired the initial visual discrimination at the same rate as controls. However, they failed to suppress responses to the previously rewarded stimulus following reversal of reward contingencies. Thus, our genetic disruption of modulatory glutamatergic signaling, including that arising from PFC, appears to have impaired the first stage of reversal learning (extinguishing responses to previously rewarded stimuli). Our data show that this deficit stems from a preservative phenotype. These findings suggest that glutamatergic regulation from the cortex is important for behavioral flexibility and the disruption of this pathway may be relevant in diseases such as schizophrenia.

  • 190.
    Granseth, Björn
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Osaka University, Suita, Japan.
    Fukushima, Yuichi
    Osaka University, Suita, Japan.
    Sugo, Noriuki
    Osaka University, Suita, Japan.
    Lagnado, Leon
    Osaka University, Suita, Japan.
    Yamamoto, Nobuhiko
    Osaka University, Suita, Japan.
    Regulation of thalamocortical axon branching by BDNF and synaptic vesicle cycling2013Inngår i: Frontiers in Neural Circuits, ISSN 1662-5110, E-ISSN 1662-5110, Vol. 7, nr 202Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    During development, axons form branches in response to extracellular molecules. Little is known about the underlying molecular mechanisms. Here, we investigate how neurotrophin-induced axon branching is related to synaptic vesicle cycling for thalamocortical axons. The exogenous application of brain-derived neurotrophic factor (BDNF) markedly increased axon branching in thalamocortical co-cultures, while removal of endogenous BDNF reduced branching. Over-expression of a C-terminal fragment of AP180 that inhibits clathrin-mediated endocytosis affected the laminar distribution and the number of branch points. A dominant-negative synaptotagmin mutant that selectively targets synaptic vesicle cycling, strongly suppressed axon branching. Moreover, axons expressing the mutant synaptotagmin were resistant to the branch-promoting effect of BDNF. These results suggest that synaptic vesicle cycling might regulate BDNF induced branching during the development of the axonal arbor.

  • 191.
    Griffin, Paul
    et al.
    QIMR Berghofer Medical Research Institute, Australia; Q Pharm Pty Ltd, Australia; Mater Hospital and Mater Research, Australia; University of Queensland, Australia.
    Elliott, Suzanne
    Q Pharm Pty Ltd, Australia.
    Krauer, Kenia
    Q Pharm Pty Ltd, Australia.
    Davies, Cristyn
    University of Sydney, Australia; Childrens Hospital Westmead, Australia.
    Rachel Skinner, S.
    University of Sydney, Australia; Childrens Hospital Westmead, Australia.
    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.
    Forster, Angus
    Vaxxas Pty Ltd, Australia.
    Safety, acceptability and tolerability of uncoated and excipient-coated high density silicon micro-projection array patches in human subjects2017Inngår i: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 35, nr 48, s. 6676-6684Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Most vaccinations are performed by intramuscular injection with a needle and syringe. However, this method is not ideal due to limitations, such as the risk of needle-stick injury, the requirement for trained personnel to give injections and the need to reconstitute lyophilized vaccines. Therefore, we tested an alternative delivery technology that overcomes the problems with needle and syringe. The Nanopatch (TM) is an array of 10,000 silicon micro-projections per cm(2) that can be dry-coated with vaccine for skin delivery. The high number and density of micro-projections means that high velocity application is required to achieve consistent skin penetration. Before clinically testing a vaccine Nanopatch, this study tests the safety, tolerability and acceptability/utility of uncoated and excipient-coated Nanopatches in healthy adults. Nanopatches were applied to skin of the upper arm and volar forearm and left in contact with the skin for two minutes before removal. The application sites were assessed for local skin response over 28 days. Acceptability interviews were also performed. No unexpected adverse events directly related to the Nanopatch application were reported, All applications of the Nanopatch resulted in an expected erythema response which faded between days 3 and 7. In some subjects, some skin discolouration was visible for several days or up to 3 weeks after application. The majority (83%) of subjects reported a preference for the Nanopatch compared to the needle and syringe and found the application process to be simple and acceptable. On a pain scale from 0 to 10, 78% of applications were scored "0" (no pain) with the average scores for less than 1. The results from this study demonstrate the feasibility of the Nanopatch to improve vaccination by showing that application of the product without vaccine to human skin is safe, tolerable and preferred to needle and syringe administration. (C) 2017 The Authors. Published by Elsevier Ltd.

  • 192.
    Griffith, May
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Maisonneuve Rosemont Hospital, Canada.
    Alarcon, E. I.
    University of Ottawa, Canada.
    Brunette, I.
    Maisonneuve Rosemont Hospital, Canada; University of Montreal, Canada.
    Regenerative approaches for the cornea2016Inngår i: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 280, nr 3, s. 276-286Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The cornea is the transparent front part of the eye that transmits light to the back of the eye to generate vision. Loss of corneal transparency, if irreversible, leads to severe vision loss or blindness. For decades, corneal transplantation using human donor corneas has been the only option for treating corneal blindness. Despite recent improvement in surgical techniques, donor cornea transplantation remains plagued by risks of suboptimal optical results and visual acuity, immune rejection and eventually graft failure. Furthermore, the demand for suitable donor corneas is increasing faster than the number of donors, leaving thousands of curable patients untreated worldwide. Here, we critically review the state of the art of biomaterials for corneal regeneration. However, the lessons learned from the use of the cornea as a disease model will allow for extension of the biomaterials and techniques for regeneration of more complex organs such as the heart.

  • 193.
    Griffith, May
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Harkin, Damien G.
    Queensland University of Technology, and Queensland Eye Institute, South Brisbane, QLD, Australia.
    Recent advances in the design of artificial corneas2014Inngår i: Current Opinion in Ophthalmology, ISSN 1040-8738, E-ISSN 1531-7021, Vol. 25, nr 3, s. 240-247Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    PURPOSE OF REVIEW:

    Artificial corneas are being developed to meet a shortage of donor corneas and to address cases in which allografting is contraindicated. A range of artificial corneas has been developed. Here we review several newer designs and especially those inspired by naturally occurring biomaterials found with the human body and elsewhere.

    RECENT FINDINGS:

    Recent trends in the development of artificial corneas indicate a move towards the use of materials derived from native sources including decellularized corneal tissue and tissue substitutes synthesized by corneal cells in vitro when grown either on their own or in conjunction with novel protein-based scaffolds. Biologically inspired materials are also being considered for implantation on their own with the view to promoting endogenous corneal tissue.

    SUMMARY:

    More recent attempts at making artificial corneas have taken a more nature-based or nature-inspired approach. Several will in the near future be likely to be available clinically.

  • 194.
    Griffith, May
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Lee, Chyan-Jang
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Buznyk, Oleksiy
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Filatov Inst Eye Dis and Tissue Therapy, Ukraine.
    Artificial Corneas, and Reinforced Composite Implants for High Risk Donor Cornea Transplantation2017Inngår i: The Stem Cell Microenvironment and its Role in Regenerative Medicine and Cancer Pathogenesis, RIVER PUBLISHERS , 2017, Vol. 7, s. 93-102Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Here, we review examples of artificial corneas that have been developed as alternatives to donor cornea transplantation. These consist of artificial corneas developed as prostheses and regenerative scaffolds. Examples of reinforced and composite implants developed within our group are profiled.

  • 195.
    Griffith, May
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Rafat, Mehrdad
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Corneal stromal mesenchymal stem cells for corneal stroma reconstruction2011Inngår i: Acta Ophthalmologica; Special Issue: Abstracts from the 2011 European Association for Vision and Eye Research ConferenceVolume 89, Issue Supplement s248, page 0, September 2011, 2011Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Purpose

    To date, corneal epithelial reconstruction has been very successful. However, in a number of cases of injury or disease, the stromal layer is affected. Our goal is to develop biomaterials that will enable the regeneration of the corneal stroma. In this study, we compare endogenous vs exogenous stem cell courses for corneal stromal regeneration.

    Methods

    We have previously developed collagen-based corneal stromal extracellular matrix substitutes based on EDC crosslinked collagen, and have shown that they promote ingrowth of stromal cells from the host cornea (Merrett et al. 2009; Fagerholm et al. 2010). For cases where stromal progenitors are depleted, we developed a non-toxic collagen-based hydrogel system where a macromolecular photoinitiator (Dex-BBA)was used to form the hydrogel around cells. The feasibility of Dex-BBA as a photoinitiator to initiate the gelation of aminoethylmethacylate-modified collagen (Coll-AEMA) was examined with or without the presence of stroma cells.

    Results

    The Dex-BBA crosslinked hydrogels were weaker than the EDC crosslinked constructs. However, they were fairly robust and no apparent toxicity of the hydrogel system to mesenchymal stroma (or stem) cells (MSCs)were observed during the culture of 7 days, which indicated that Dex-BBA based macrophotoinitiator and our collagen-based hydrogel system may have potential in corneal stromal regeneration applications.

    Conclusions

    We show that corneal stromal regeneration can be achieved by endogenous stimulation of existing corneal progenitor cells. Where the host cells may be depleted, our results show that hydrogel encapsulated stem cells may be used in the future.

  • 196.
    Grosh, Karl
    et al.
    University of Michigan, MI 48109 USA.
    Ren, Tianying
    Oregon Health and Science University, OR 97201 USA.
    He, Wenxuan
    Oregon Health and Science University, OR 97201 USA.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    Li, Yizeng
    Johns Hopkins University, MD 21218 USA.
    Nankali, Amir
    University of Michigan, MI 48109 USA.
    Light-Induced Basilar Membrane Vibrations in the Sensitive Cochlea2015Inngår i: MECHANICS OF HEARING: PROTEIN TO PERCEPTION, AMER INST PHYSICS , 2015, Vol. 1703, nr 070005Konferansepaper (Fagfellevurdert)
    Abstract [en]

    The exceptional sensitivity of mammalian hearing organ is attributed to an outer hair cell-mediated active process, where forces produced by sensory cells boost sound-induced vibrations, making soft sounds audible. This process is thought to be local, with each section of the hearing organ capable of amplifying sound-evoked movement, and nearly instantaneous, since amplification can work for sounds at frequencies up to 100 kHz in some species. To test these precepts, we developed a method for focally stimulating the living hearing organ with light. Light pulses caused intense and highly damped mechanical responses followed by traveling waves that developed with considerable delay. The delayed response was identical to movements evoked by click-like sounds. A physiologically based mathematical model shows that such waves engage the active process, enhancing hearing sensitivity. The experiments and the theoretical analysis show that the active process is neither local nor instantaneous, but requires mechanical waves traveling from the cochlear base toward its apex.

  • 197.
    Grosso, Matthew J.
    et al.
    Hospital Special Surg, NY 10021 USA; Cleveland Clin, OH 44195 USA.
    Courtland, Hayden-William
    Hospital Special Surg, NY 10021 USA.
    Yang, Xu
    Hospital Special Surg, NY 10021 USA.
    Sutherland, James P.
    Hospital Special Surg, NY 10021 USA.
    Stoner, Kirsten
    Hospital Special Surg, NY 10021 USA.
    Nguyen, Joseph
    Hospital Special Surg, NY 10021 USA.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Hospital Special Surg, NY 10021 USA.
    Ross, F. Patrick
    Hospital Special Surg, NY 10021 USA.
    van der Meulen, Marjolein C. H.
    Hospital Special Surg, NY 10021 USA; Cornell University, NY 14853 USA.
    Bostrom, Mathias P.
    Hospital Special Surg, NY 10021 USA.
    Intermittent PTH Administration and Mechanical Loading Are Anabolic for Periprosthetic Cancellous Bone2015Inngår i: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 33, nr 2, s. 163-173Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The purpose of this study was to determine the individual and combined effects on periprosthetic cancellous bone of intermittent parathyroid hormone administration (iPTH) and mechanical loading at the cellular, molecular, and tissue levels. Porous titanium implants were inserted bilaterally on the cancellous bone of adult rabbits beneath a loading device attached to the distal lateral femur. The left femur received a sham loading device. The right femur was loaded daily, and half of the rabbits received daily PTH. Periprosthetic bone was evaluated up to 28 days for gene expression, histology, and mu CT analysis. Loading and iPTH increased bone mass by a combination of two mechanisms: (1) Altering cell populations in a pro-osteoblastic/anti-adipocytic direction, and (2) controlling bone turnover by modulating the RANKL-OPG ratio. At the tissue level, BV/TV increased with both loading (+53%, pless than0.05) and iPTH (+54%, pless than0.05). Combined treatment showed only small additional effects at the cellular and molecular levels that corresponded to a small additive effect on bone volume (+13% compared to iPTH alone, pgreater than0.05). This study suggests that iPTH and loading are potential therapies for enhancing periprosthetic bone formation. The elucidation of the cellular and molecular response may help further enhance the combined therapy and related targeted treatment strategies.

  • 198.
    Gréen, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, Linkoping, Sweden; Royal Institute Technology, Sweden; Science for Life Laboratory,{ School of Biotechnology, Division of Gene Technology, Royal Institute of Technology, Stockholm, Sweden.
    Rehnberg, Malin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Svensson, Anneli
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Kardiologiska kliniken US.
    Gunnarsson, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Jonasson, Jon
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Assessment of HaloPlex Amplification for Sequence Capture and Massively Parallel Sequencing of Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Genes2015Inngår i: Journal of Molecular Diagnostics, ISSN 1525-1578, E-ISSN 1943-7811, Vol. 17, nr 1, s. 31-42Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The genetic basis of arrhythmogenic right ventricular cardiomyopathy (ARVC) is complex. Mutations in genes encoding components of the cardiac desmosomes have been implicated as being causally related to ARVC. Next-generation sequencing allows parallel sequencing and duplication/deletion analysis of many genes simultaneously, which is appropriate for screening of mutations in disorders with heterogeneous genetic backgrounds. We designed and validated a next-generation sequencing test panel for ARVC using HaloPlex. We used SureDesign to prepare a HaloPlex enrichment system for sequencing of DES, DSC2, DSG2, DSP, JUP, PKP2, RYR2, TGFB3, TMEM43, and TIN from patients with ARVC using a MiSeq instrument. Performance characteristics were determined by comparison with Sanger, as the gold standard, and TruSeq Custom Amplicon sequencing of DSC2, DSG2, DSP, JUP, and PKP2. All the samples were successfully sequenced after HaloPlex capture, with greater than99% of targeted nucleotides covered by greater than20x. The sequences were of high quality, although one problematic area due to a presumptive context-specific sequencing error causing motif Located in exon 1 of the DSP gene was detected. The mutations found by Sanger sequencing were also found using the HaloPlex technique. Depending on the bioinformatics pipeline, sensitivity varied from 99.3% to 100%, and specificity varied from 99.90/0 to 100%. Three variant positions found by Sanger and HaloPlex sequencing were missed by TruSeq Custom Amplicon owing to Loss of coverage.

  • 199.
    Gustafsson, Håkan
    et al.
    Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Hallbeck, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Norell, M.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    Lindgren, Mikael
    Norwegian University of Science and Technology, Trondheim, Norway.
    Engström, Maria
    Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Rosén, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Zachrisson, Helene
    Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Fysiologiska kliniken US.
    Fe(III) distribution varies substantially within and between atherosclerotic plaques2014Inngår i: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 2, nr 71, s. 885-892Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE:

    Vulnerable atherosclerotic plaques are structurally weak and prone to rupture, presumably due to local oxidative stress. Redox active iron is linked to oxidative stress and the aim of this study was to investigate the distribution of Fe(III) in carotid plaques and its relation to vulnerability for rupture.

    METHODS:

    Atherosclerotic plaques from 10 patients (three asymptomatic and seven symptomatic) were investigated. Plaque vulnerability was classified using ultrasound and immunohistochemistry and correlated to Fe(III) measured by electron paramagnetic resonance spectroscopy.

    RESULTS:

    Large intra-plaque Fe(III) variations were found. Plaques from symptomatic patients had a higher Fe(III) concentration as compared with asymptomatic plaques (0.36 ± 0.21 vs. 0.06 ± 0.04 nmol Fe(III)/mg tissue, P < 0.05, in sections adjoining narrowest part of the plaques). All but one plaque from symptomatic patients showed signs of cap rupture. No plaque from asymptomatic patients showed signs of cap rupture. There was a significant increase in cap macrophages in plaques from symptomatic patients compared with asymptomatic patients (31 ± 11% vs. 2.3 ± 2.3%, P < 0.01).

    CONCLUSION:

    Fe(III) distribution varies substantially within atherosclerotic plaques. Plaques from symptomatic patients had significantly higher concentrations of Fe(III), signs of cap rupture and increased cap macrophage activity.

  • 200.
    Gustafsson, Håkan
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Röntgenkliniken i Norrköping/Finspång. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Kale, Ajay
    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.
    Dasu, Alexandru
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. The Skandion Clinic, Uppsala, Sweden.
    Lund, Anders
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemisk Fysik. Linköpings universitet, Tekniska fakulteten.
    Edqvist, Per-Henrik
    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.
    EPR oximetry of cetuximab-treated head-and-neck tumours in a mouse model2017Inngår i: Cell Biochemistry and Biophysics, ISSN 1085-9195, E-ISSN 1559-0283, Vol. 75, nr 3-4, s. 299-309Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Head and neck squamous cell carcinoma (HNSCC) tumours are associated with high mortality despite advances in therapy. The monoclonal antibody cetuximab (Erbitux®) has been approved for the treatment of advanced HNSCC. However, only a subset of HNSC patients receiving cetuximab actually responds to treatment, underlining the need for a means to tailor treatments of individual patients. The aim of the present study was to investigate the effect of cetuximab treatment on tumour growth, on tumour partial oxygen pressure as measured by LiPc electron paramagnetic resonance oximetry and on the expression of proteins involved in tumour growth, metabolism and hypoxia. Two HNSCC cell lines, UT-SCC-2 and UT-SCC-14, were used to generate xenografts on female BALB/c (nu/nu) nude mice. Mice with xenografts were given three injections of intraperitoneal cetuximab or phosphate-buffered saline, and the tumour volume was recorded continuously. After treatment the tumour partial oxygen pressure was measured by LiPc electron paramagnetic resonance oximetry and the expression of epidermal growth factor receptor (EGFR), phosphorylated EGFR, Ki-67, MCT1, MCT4, GLUT1, CAIX and HIF-1α were investigated by immunohistochemistry. In xenografts from both cell lines (UT-SCC-2 and UT-SCC-14) cetuximab had effect on the tumour volume but the effect was more pronounced on UT-SCC-14 xenografts. A higher tumour oxygenation was measured in cetuximab-treated tumours from both cell lines compared to untreated controls. Immunocytochemical staining after cetuximab treatment shows a significantly decreased expression of EGFR, pEGFR, Ki67, CAIX and nuclear HIF-1α in UT-SCC-14 tumours compared to untreated controls. MCT1 and GLUT1 were significantly decreased in tumours from both cell lines but more pronounced in UT-SCC-14 tumours. Taken together, our results show that cetuximab treatment decreases the tumour growth and increases the tumour partial oxygen pressure of HNSCC xenografts. Furthermore we found a potential connection between the partial oxygen pressure of the tumours and the expression of proteins involved in tumour growth, metabolism and hypoxia.

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