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  • 1.
    Adell, Gunnar
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Boeryd, B.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Frånlund, B.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Sjödahl, Rune
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Håkansson, L.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Occurrence and prognostic importance of micrometastases in regional lymph nodes in Dukes' B colorectal carcinoma: an immunohistochemical study1996In: European Journal of Surgery, ISSN 1102-4151, E-ISSN 1741-9271, Vol. 162, no 8, p. 637-642Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate the incidence and prognostic importance of micrometastatic disease in regional lymph nodes from Dukes' B colorectal carcinomas.

    DESIGN: Retrospective study.

    SETTING: University hospital, Sweden.

    SUBJECTS: 100 patients operated on for primary colorectal carcinoma, classified as Dukes' B lesions.

    INTERVENTIONS: The regional lymph nodes were re-examined immunohistochemically using monoclonal antibodies against cytokeratin.

    OUTCOME MEASURES: Incidence and prognostic importance of micrometastases.

    RESULTS: Micrometastases were found in 39% (39/100) of the patients. The number of positive cells in the lymph nodes examined varied from 1 to over 100. They appeared as single cells or small clusters of cells located within the capsule or in the peripheral sinus of the lymph node. At least three sections from each of three lymph nodes had to be examined to identify 95% of the patients with lymph node micrometastases. The outcome of the patients with micrometastases was not significantly different from that of patients with no epithelial cells in the lymph nodes.

    CONCLUSION: Micrometastases in regional lymph nodes are a interesting phenomenon but clinically seem to be of only weak prognostic value.

  • 2.
    Agholme, Lotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in the East of Östergötland, Department of Geriatrics.
    Lindström, Tobias
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Kågedal, Katarina
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    An In Vitro Model for Neuroscience: Differentiation of SH-SY5Y Cells into Cells with Morphological and Biochemical Characteristics of Mature Neurons2010In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 20, no 4, p. 1069-1082Article in journal (Refereed)
    Abstract [en]

    Neuroscience, including research on Alzheimers disease, is hampered by the lack of suitable in vitro models to study the human nervous system. To counteract this, many attempts to differentiate cell lines into more neuron-like cells have been performed, resulting in partial expression of neuronal features. Furthermore, it has been reported that neuroblastoma cell lines lack mature isoforms of tau. Our aim was to develop an improved in vitro model, generating sustainable cells with morphology and biochemistry of human, mature neurons. To obtain cells with neuronal differentiation and function, we investigated the effect of combining three-dimensional culturing of SH-SY5Y cells in extracellular matrix (ECM) gel with several factors reported to have neuro-differentiating effects. This resulted in cells with apparent neuronal morphology with long, extensively branched neurites. Further investigation revealed expression of several neurospecific markers including synapse protein Sv2 and nuclear marker NeuN, as well as the presence of synapses and axonal vesicle transport. In addition, these cells expressed mature tau isoforms, and tau protein expression was significantly increased compared to undifferentiated cells, reaching levels found in adult human brain. In conclusion, we found that pre-treatment with retinoic acid followed by ECM gel culturing in combination with brain derived neurotrophic factor, neuregulin beta(1), nerve growth factor, and vitamin D-3 treatment generated sustainable cells with unambiguous resemblance to adult neurons. These cells also expresses adult splicing forms of tau with neuronal localization, making this cellular in vitro model useful in many areas of neuroscience research, particularly the Alzheimers disease field.

  • 3.
    Agrup, Måns
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Stål, Olle
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Olsen, Karen
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine. Linköping University, Faculty of Health Sciences.
    Wingren, Sten
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    C-erbB-2 overexpression and survival in early onset breast cancer2000In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 63, no 1, p. 23-29Article in journal (Refereed)
    Abstract [en]

    Young breast cancer patients have a decreased survival rate and it has been demonstrated that young age is an independent predictor of adverse prognosis. Overexpression of c-erbB-2 protein (also known as HER-2/neu) has been shown to be a prognostic indicator in breast cancer in general and especially among patients with axillary nodal metastases. The present study was initiated to determine the prognostic significance of c-erbB-2 protein overexpression in early onset breast cancer.

    A population consisting of 110 young breast cancer patients, ≤ 36-year-old at diagnosis, was analyzed with immunohistochemical staining for c-erbB-2 protein.

    Thirty patients (27%) were found to overexpress the c-erbB-2 protein. C-erbB-2 positivity was significantly associated with poor survival when all patients were included in the analysis (P = 0.002) and for patients with axillary nodal metastases (P = 0.0007). No such association was found for node-negative patients. Furthermore, the difference in prognosis in relation to c-erbB-2 among node-positive patients was maintained, when these were stratified in groups treated or not treated with adjuvant chemotherapy.

    The study indicates that overexpression of c-erbB-2 protein is a strong prognostic factor in young breast cancer patients with axillary nodal metastases. Moreover, the adverse prognosis associated with c-erbB-2 overexpression in node-positive patients was observed whether or not the patients had received adjuvant chemotherapy.

  • 4.
    Almroth, Gabriel
    et al.
    Linköping University, Department of Medicine and Care, Nephrology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Nephrology.
    Eneström, S.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Hed, J.
    Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Transfusion Medicine and Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Samuelsson, I.
    Section of Nephrology, Department of Internal Medicine. Örebro Medical Centre, Örebro, Sweden.
    Sjöström, P.
    Section of Nephrology, Department of Internal Medicine. Örebro Medical Centre, Örebro, Sweden.
    Autoantibodies to leucocyte antigens in hydralazine-associated nephritis1992In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 231, no 1, p. 37-42Article in journal (Refereed)
    Abstract [en]

    Clinical and laboratory findings and drug history were studied in 17 patients with suspected hydralazine-associated nephritis, five of whom only had renal disease, while twelve also had extrarenal manifestations. Renal biopsies revealed extracapillary proliferative or focal segmental proliferative glomerulonephritis in 10 patients, and tubulo-interstitial nephritis in five patients. Antinuclear antibody (ANA) was found in 16 patients, but none of the 14 patients tested had antibodies to DNA. Tests for antibodies to myeloperoxidase (anti-MPO) and antibodies to neutrophil cytoplasm antigen (ANCA) were performed by ELISA. Twelve of the 14 patients tested had anti-MPO; five of these 14 patients had ANCA, while one had borderline levels. These findings suggest that hydralazine facilitates the induction of a systemic disease with multiple autoantibody production.

  • 5.
    Andersson, Thomas
    et al.
    Linköping University, Department of Biomedicine and Surgery, Dermatology. Linköping University, Faculty of Health Sciences.
    Johansson, Anders G.
    Kliniskt Mikrobiologiska Laboratoriet, Akademiska Sjukhuset, Uppsala.
    Westermark, Per
    Avdelningen för Genetik och Patologi, Enheten för Patologi, Akademiska Sjukhuset, Uppsala.
    Lundmark, Katarzyna
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Vanlig svamp gav ovanlig hudinfektion: Fallbeskrivning1999In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, no 45, p. 4926-4927Article in journal (Other (popular science, discussion, etc.))
    Abstract [sv]

    Vid opportunistisk svampinfektion i huden är diagnosen sällan självklar. Ett samarbete mellan dermatolog, patolog och mykolog kan behövas, som i detta fall av kutan alternarios. Denna typ av svampinfektion innefattas i begreppet feohyfomykos.

  • 6. Antunes, Fernando
    et al.
    Cadenas, Enrique
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Apoptosis, induced by exposure to a low and steady-state concentration of H2O2, is a consequence of lysosomal rupture2001In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 356, p. 549-555Article in journal (Refereed)
  • 7.
    Appelqvist, Hanna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Nilsson, Cathrine
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Garner, Brett
    University of Wollongong.
    Brown, Andrew J
    University of New South Wales.
    Kågedal, Katarina
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Attenuation of the Lysosomal Death Pathway by Lysosomal Cholesterol Accumulation2011In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 178, no 2, p. 629-639Article in journal (Refereed)
    Abstract [en]

    In the past decade, lysosomal membrane permeabilization (LMP) has emerged as a significant component of cell death signaling. The mechanisms by which lysosomal stability is regulated are not yet fully understood, but changes in the lysosomal membrane lipid composition have been suggested to be involved. Our aim was to investigate the importance of cholesterol in the regulation of lysosomal membrane permeability and its potential impact on apoptosis. Treatment of normal human fibroblasts with U18666A, an amphiphilic drug that inhibits cholesterol transport and causes accumulation of cholesterol in lysosomes, rescued cells from lysosome-dependent cell death induced by the lysosomotropic detergent 0-methyl-serine dodecylamide hydrochloride (MSDH), staurosporine (STS), or cisplatin. LMP was decreased by pretreating cells with U18666A, and there was a linear relationship between the cholesterol content of lysosomes and their resistance to permeabilization induced by MSDH. U18666A did not induce changes in expression or localization of 70-kDa heat shock proteins (Hsp70) or antiapoptotic Bcl-2 proteins known to protect the lysosomal membrane. Induction of autophagy also was excluded as a contributor to the protective mechanism. By using Chinese hamster ovary (CHO) cells with lysosomal cholesterol overload due to a mutation in the cholesterol transporting protein Niemann-Pick type C1 (NPC1), the relationship between lysosomal cholesterol accumulation and protection from lysosome-dependent cell death was confirmed. Cholesterol accumulation in lysosomes attenuates apoptosis by increasing lysosomal membrane stability.

  • 8.
    Appelqvist, Hanna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Sandin, Linnea
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Björnström, Karin
    Linköping University, Department of Medical and Health Sciences, Anesthesiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Intensive Care.
    Saftig, Paul
    Biochemical Institute, Christian-Albrechts-University Kiel, Kiel, Germany.
    Garner, Brett
    Illawarra Health and Medical Research Institute, University of Wollongong, Australia.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Kågedal, Katarina
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Sensitivity to Lysosome-Dependent Cell Death is Directly Regulated by Lysosomal Cholesterol Content2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 11Article in journal (Refereed)
    Abstract [en]

    Alterations in lipid homeostasis are implicated in several neurodegenerative diseases, although the mechanisms responsible are poorly understood. We evaluated the impact of cholesterol accumulation, induced by U18666A, quinacrine or mutations in the cholesterol transporting Niemann-Pick disease type C1 (NPC1) protein, on lysosomal stability and sensitivity to lysosome-mediated cell death. We found that neurons with lysosomal cholesterol accumulation were protected from oxidative stress-induced apoptosis. In addition, human fibroblasts with cholesterol-loaded lysosomes showed higher lysosomal membrane stability than controls. Previous studies have shown that cholesterol accumulation is accompanied by the storage of lipids such as sphingomyelin, glycosphingolipids and sphingosine and an up regulation of lysosomal associated membrane protein-2 (LAMP-2), which may also influence lysosomal stability. However, in this study the use of myriocin and LAMP deficient fibroblasts excluded these factors as responsible for the rescuing effect and instead suggested that primarily lysosomal cholesterol content determined the cellular sensitivity to toxic insults. Further strengthening this concept, depletion of cholesterol using methyl-β-cyclodextrin or 25-hydroxycholesterol decreased the stability of lysosomes and cells became more prone to undergo apoptosis. In conclusion, cholesterol content regulated lysosomal membrane permeabilization and thereby influenced cell death sensitivity. Our data suggests that lysosomal cholesterol modulation might be used as a therapeutic strategy for conditions associated with accelerated or repressed apoptosis.

  • 9.
    Babic, Ankica
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Medical Informatics.
    Bodemar, Göran
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Mathiesen, Ulrik
    Oskarshamns sjukhus .
    Åhlfeldt, Hans
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Medical Informatics.
    Franzén, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Wigertz, Ove
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Medical Informatics.
    Machine learning to support diagnostics in the domain of asymptomatic liver disease1995In: MEDINFO95,1995, Edmonton: HC & CC , 1995, p. 809-Conference paper (Refereed)
  • 10.
    Babic, Ankica
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Medical Informatics.
    Hedin, Kristina
    Linköping University, Department of Molecular and Clinical Medicine.
    Mathiesen, Ulrik
    Oskarshamns sjukhus .
    Franzén, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Frydén, Aril
    Linköping University, Department of Molecular and Clinical Medicine.
    Bodemar, Göran
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Wigertz, Ove
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Medical Informatics.
    Decision support for monitoring of chronic Hepatitis C: can blood laboratory tests help?1996In: Medical Informatics Europe 96,1996, Amsterdam: IOS Press , 1996, p. 551-Conference paper (Refereed)
  • 11. Bernsen, Monique R
    et al.
    Smetsers, Toon
    van der Westerlo, Els
    Ruiter, Dirk
    Håkansson, Leif
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Gustafsson, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    van Kuppevelt, Toin
    Krysander, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Plastic Surgery, Hand Surgery and Burns. Östergötlands Läns Landsting, Reconstruction Centre, Department of Plastic Surgery, Hand surgery UHL.
    Rettrup, Björn
    Håkansson, Annika
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Heparan sulphate epitope-expression is associated with the inflammatory response in metastatic malignant melanoma2003In: Cancer Immunology and Immunotherapy, ISSN 0340-7004, E-ISSN 1432-0851, Vol. 52, no 12, p. 780-783Article in journal (Refereed)
    Abstract [en]

    Heparan sulphate (HS) represents a heterogeneous class of molecules on cell membranes and extracellular matrices. These molecules are involved in a variety of biological processes, including immune responses, through their binding and functional modulation of proteins. Recently a panel of HS-epitope-specific, human single chain antibodies have been generated by phage display, facilitating analysis of the structural heterogeneity of HS in relation to pathological conditions. In a pilot study a heterogeneous staining pattern in melanoma metastases was observed with one of the clones (EW4G1). Using a double-staining technique, the expression of this epitope was studied in 12 metastatic melanoma lesions in relation to the presence of a CD3 + cell infiltrate. Different staining patterns with EW4G1 were observed in the different lesions. The different staining patterns were associated with the presence and pattern of inflammation with CD3+ cells. A pronounced staining pattern of blood vessels with EW4G1 was associated with a more or less brisk presence of CD3+ cells, while a pronounced staining of tumour cells or tumour cell matrix or absence of staining with EW4G1 was associated with absence of CD3+ cells. These results suggest a dualistic role for HS in the recruitment and intratumoural migration of CD3+ cells, depending on the location of expression of its epitope recognized by EW4G1. Further characterization of the structural diversity of HS and its function in T-cell recruitment and migration is therefore warranted, since detailed understanding of this relation may provide new targets for therapeutic intervention, such that better homing and migration of T cells (in)to tumours might be achieved in immunologically based treatment strategies.

  • 12. Bernsen, MR
    et al.
    Håkansson, Leif
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Gustafsson, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Krysander, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Plastic Surgery, Hand Surgery and Burns. Östergötlands Läns Landsting, Reconstruction Centre, Department of Plastic Surgery, Hand surgery UHL.
    Rettrup, B
    Ruiter, D
    Håkansson, Annika
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    On the biological relevance of MHC class II and B7 expression by tumour cells in melanoma metastases2003In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 88, no 3, p. 424-431Article in journal (Refereed)
    Abstract [en]

    A large number of studies have indicated that specific immune reactivity plays a crucial role in the control of malignant melanoma. In this context, expression of MHC I, MHC II and B7 molecules by melanoma cells is seen as relevant for the immune response against the tumour. For a better understanding of the biological relevance of MHC II and B7 expression by tumour cells in metastatic melanoma, we studied the expression of these molecules in melanoma metastases in relation to the inflammatory response, regression of the tumour and survival from 27 patients treated with biochemotherapy (30 mg m-2 Cisplatin and 250 mg m-2 decarbazine (dimethyl-triazene-imidazole-carboxamide, DTIC) on days 1-3 i.v., and 107 IU IFN-a2b 3 days a week s.c., q. 28d). In 19 out of 27 lesions studied, we found expression of MHC II by the tumour cells, while only in one out of II tumour biopsies obtained from untreated metastatic melanoma patients, MHC II expression was detected. Expression of B7.1 and B7.2 by tumour cells was found in nine out of 24 and 19 out of 24 lesions, respectively. In all cases where B7.1 expression was found, expression of B7.2 by the tumour cells was also seen. In general, no or only few inflammatory cells positive for B7 were found. Expression of MHC II by tumour cells was positively correlated with the presence of tumour-infiltrating lymphocytes, regression of the lesion, and with time to progression (TTP) and overall survival (OS) of the patient. However, no significant correlation between B7.1 or B7.2 expression and regression of the tumour, TTP or OS was found. In light of other recent findings, these data altogether do support a role as biomarker for MHC II expression by tumour cells, however, its exact immunological pathomechanism(s) remain to be established. ⌐ 2003 Cancer Research UK.

  • 13. Birringer, M
    et al.
    EyTina, J H
    Salvatore, B A
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Vitamin E analogues as inducers of apoptosis: Structure-function relation2003In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 88, no 12, p. 1948-1955Article in journal (Refereed)
    Abstract [en]

    Recent results show that a-tocopheryl succinate (a-TOS) is a proapoptotic agent with antineoplastic activity. As modifications of the vitamin E (VE) molecule may affect its apoptogenic activity, we tested a number of newly synthesised VE analogues using malignant cell lines. Analogues of a-TOS with lower number of methyl substitutions on the aromatic ring were less active than a-TOS. Replacement of the succinyl group with a maleyl group greatly enhanced the activity, while it was lower for the glutaryl esters. Methylation of the free succinyl carboxyl group on a-TOS and d-TOS completely prevented the apoptogenic activity of the parent compounds. Both Trolox and its succinylated derivative were inactive. a-tocotrienol (a-T3 H) failed to induce apoptosis, while ?-T3 H was apoptogenic, and more so when succinylated. Shortening the aliphatic side chain of ?-T3 by one isoprenyl unit increased its activity. Neither phytyl nor oleyl succinate caused apoptosis. These findings show that modifications of different functional moieties of the VE molecule can enhance apoptogenic activity. It is hoped that these observations will lead to the synthesis of analogues with even higher apoptogenic and, consequently, antineoplastic efficacy.

  • 14.
    Brehmer, M
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Svensson, Irene
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Heat-induced apoptosis in human prostatic stromal cells2000In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 85, no 4, p. 535-541Article in journal (Refereed)
    Abstract [en]

    Objective. To determine whether heat, used in transurethral microwave thermotherapy (TUMT) for benign prostatic hyperplasia and which causes necrotic lesions within the adenoma, induces apoptosis in benign human prostatic stromal cells. Materials and methods. Prostatic stromal cells were cultured from benign human prostatic tissue. The origin of the cells was identified by immunohistochemical staining and transmission electron microscopy. Cell cultures were exposed to moderate hyperthermia (47░C) for 1 h and any apoptosis detected by light microscopy, transmission electron microscopy and the measurement of induced caspase-3-like activity. Results. The cultures contained a mixed population of smooth muscle cells and myofibroblasts. Twenty-four hours after heat exposure, 76% of the cells were apoptotic and the caspase activity had increased, whereas only 14% of the cells were necrotic. Conclusion. Moderate hyperthermia induces apoptosis in cultured human prostatic stromal cells.

  • 15. Brigelius-Flohé, R
    et al.
    Kelly, FJ
    Salonen, JT
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Zing, JM
    Azzi, A
    The European perspective on vitamin E: Current knowledge and future research2002In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 76, no 4, p. 703-716Article in journal (Refereed)
    Abstract [en]

    Vitamin E is indispensible for reproduction in female rats. In humans, vitamin E deficiency primarily causes neurologic dysfunctions, but the underlying molecular mechanisms are unclear. Because of its antioxidative properties, vitamin E is believed to help prevent diseases associated with oxidative stress, such as cardiovascular disease, cancer, chronic inflammation, and neurologic disorders. However, recent clinical trials undertaken to prove this hypothesis failed to verify a consistent benefit. Given these findings, a group of European scientists met to analyze the most recent knowledge of vitamin E function and metabolism. An overview of their discussions is presented in this article, which includes considerations of the mechanisms of absorption, distribution, and metabolism of different forms of vitamin E, including the a-tocopherol transfer protein and a-tocopherol-associated proteins, the mechanism of tocopherol side-chain degradation and its putative interaction with drug metabolism, the usefulness of tocopherol metabolites as biomarkers, and the novel mechanisms of the antiatherosclerotic and anticarcinogenic properties of vitamin E, which involve modulation of cellular signaling, transcriptional regulation, and induction of apoptosis. Clinical trials were analyzed on the basis of the selection of subjects, the stage of disease, and the mode of intake, dosage, and chemical form of vitamin E. In addition, the scarce knowledge on the role of vitamin E in reproduction was summarized. In conclusion, the scientists agreed that the functions of vitamin E were underestimated if one considered only its antioxidative properties. Future research on this essential vitamin should focus on what makes it essential for humans, why the body apparently utilizes a-tocopherol preferentially, and what functions other forms of vitamin E have.

  • 16.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Book review "Lysosomal pathways of protein degradation"2001In: Experimental Gerontology, ISSN 0531-5565, E-ISSN 1873-6815, Vol. 36, p. 1419-1420Article in journal (Refereed)
  • 17.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Lysosomotropic detergents induce time- and dose- dependent apoptosis/necrosis in cultured cells.2000In: Redox report, ISSN 1351-0002, E-ISSN 1743-2928, Vol. 5, p. 87-88Article in journal (Refereed)
  • 18.
    Brunk, Ulf
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Svensson, Irene
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Oxidative stress, growth-factor starvation, and CD-95-activation may all cause apoptosis through lysosomal leak.1999In: Redox report, ISSN 1351-0002, E-ISSN 1743-2928, Vol. 4Article in journal (Refereed)
  • 19.
    Brunk, Ulf
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Lipofuscin: Mechanisms of age-related accumulation and influence on cell function2002In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 33, no 5, p. 611-619Article in journal (Refereed)
    Abstract [en]

    The accumulation of lipofuscin within postmitotic cells is a recognized hallmark of aging occuring with a rate inversely related to longevity. Lipofuscin is an intralysosomal, polymeric substance, primarily composed of cross-linked protein residues, formed due to iron-catalyzed oxidative processes. Because it is undegradable and cannot be removed via exocytosis, lipofuscin accumulation in postmitotic cells is inevitable, whereas proliferative cells efficiently dilute it during division. The rate of lipofuscin formation can be experimentally manipulated. In cell culture models, oxidative stress (e.g., exposure to 40% ambient oxygen or low molecular weight iron) promotes lipofuscin accumulation, whereas growth at 8% oxygen and treatment with antioxidants or iron-chelators diminish it. Lipofuscin is a fluorochrome and may sensitize lysosomes to visible light, a process potentially important for the pathogenesis of age-related macular degeneration. Lipofuscin-associated iron sensitizes lysosomes to oxidative stress, jeopardizing lysosomal stability and causing apoptosis due to release of lysosomal contents. Lipofuscin accumulation may also diminish autophagocytotic capacity by acting as a sink for newly produced lysosomal enzymes and, therefore, interfere with recycling of cellular components. Lipofuscin, thus, may be much more directly related to cellular degeneration at old age than was hitherto believed.

  • 20.
    Brunk, Ulf
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    The mitochondrial-lysosomal axis theory of aging: Accumulation of damaged mitochondria as a result of imperfect autophagocytosis2002In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 269, no 8, p. 1996-2002Article in journal (Refereed)
    Abstract [en]

    Cellular manifestations of aging are most pronounced in postmitotic cells, such as neurons and cardiac myocytes. Alterations of these cells, which are responsible for essential functions of brain and heart, are particularly important contributors to the overall aging process. Mitochondria and lysosomes of postmitotic cells suffer the most remarkable age-related alterations of all cellular organelles. Many mitochondria undergo enlargement and structural disorganization, while lysosomes, which are normally responsible for mitochondrial turnover, gradually accumulate an undegradable, polymeric, autofluorescent material called lipofuscin, or age pigment. We believe that these changes occur not only due to continuous oxidative stress (causing oxidation of mitochondrial constituents and autophagocytosed material), but also because of the inherent inability of cells to completely remove oxidatively damaged structures (biological 'garbage'). A possible factor limiting the effectiveness of mitochondial turnover is the enlargement of mitochondria which may reflect their impaired fission. Non-autophagocytosed mitochondria undergo further oxidative damage, resulting in decreasing energy production and increasing generation of reactive oxygen species. Damaged, enlarged and functionally disabled mitochondria gradually displace normal ones, which cannot replicate indefinitely because of limited cell volume. Although lipofuscin-loaded lysosomes continue to receive newly synthesized lysosomal enzymes, the pigment is undegradable. Therefore, advanced lipofuscin accumulation may greatly diminish lysosomal degradative capacity by preventing lysosomal enzymes from targeting to functional autophagosomes, further limiting mitochondrial recycling. This interrelated mitochondrial and lysosomal damage irreversibly leads to functional decay and death of postmitotic cells.

  • 21.
    Buciuto, Robert
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics. Linköping University, Faculty of Health Sciences.
    Hammer, Richard
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics. Linköping University, Faculty of Health Sciences.
    Herder, Anders
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Spontaneous Subcapital Femoral Neck Fracture After Healed Trochanteric Fracture1997In: Clinical Orthopaedics and Related Research, ISSN 0009-921X, E-ISSN 1528-1132, Vol. 352, p. 156-163Article in journal (Refereed)
    Abstract [en]

    Two hundred thirty-three patients with an unstable trochanteric hip fracture were randomized prospectively for stabilization with a fixed angle blade plate or a compression hip screw. Twenty patients had the implant removed after the fracture was healed (average, 20.5 months; range, 12-42 months). In seven of these 20 patients, a spontaneous fracture of the femoral neck occurred at an average of 19 days after implant removal. Four of the these seven patients had been treated with the fixed angle blade plate and three with the sliding screw plate. The histologic examination of three specimens was inconclusive. The authors have not observed subcapital fracture among patients whose implants were not removed. The mechanism behind this complication is unknown.

  • 22. Buss, Joan L
    et al.
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Gellert, Nina
    Weber, Christian
    Ponka, Prem
    Pyridoxal isonicotinoyl hydrazone analogs induce apoptosis in hematopoietic cells due to their iron-chelating properties2003In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 65, no 2, p. 161-172Article in journal (Refereed)
    Abstract [en]

    Analogs of pyridoxal isonicotinoyl hydrazone (PIH) are of interest as iron chelators for the treatment of secondary iron overload and cancer. PIH, salicylaldehyde isonicotinoyl hydrazone (SIH), and 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (NIH), the toxicity of which vary over two orders of magnitude, were selected for a study of their mechanisms of toxicity. PIH analogs and their iron complexes caused concentration- and time-dependent apoptosis in Jurkat T lymphocytes and K562 cells. Bcl-2 overexpression was partially anti-apoptotic, suggesting mitochondrial mediation of apoptosis. Since the pan-caspase inhibitor zVAD-fmk did not reduce lysosomal and mitochondrial destabilization, these events occur upstream of caspase activation. In contrast, phosphatidylserine externalization and the development of apoptotic morphology were inhibited significantly, indicating the role of caspases in mediating these later events. Since overexpression of CrmA had no effect on apoptosis, caspase-8 is not likely involved. Fe3+ complexes of SIH and NIH, which accumulated in 59Fe-labeled mouse reticulocytes during incubation with the chelators, also caused apoptosis. BSA, which promotes release of the complexes from cells, reduced the toxicity of SIH and NIH, suggesting that the induction of apoptosis by PIH analogs involves toxic effects mediated by their Fe3+ complexes. Moreover, analogs of these agents lacking the iron-chelating moiety were non-toxic. ⌐ 2002 Published by Elsevier Science Inc.

  • 23. Buss, Joan L
    et al.
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Ponka, Prem
    Oxidative stress mediates toxicity of pyridoxal isonicotinoyl hydrazone analogs2004In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 421, no 1Article in journal (Refereed)
    Abstract [en]

    Pyridoxal isonicotinoyl hydrazone (PIH) and many of its analogs are effective iron chelators in vivo and in vitro, and are of interest for the treatment of secondary iron overload. Because previous work has implicated the Fe3+-chelator complexes as a determinant of toxicity, the role of iron-based oxidative stress in the toxicity of PIH analogs was assessed. The Fe3+ complexes of PIH analogs were reduced by K562 cells and the physiological reductant, ascorbate. Depletion of the antioxidant, glutathione, sensitized Jurkat T lymphocytes to the toxicity of PIH analogs and their Fe 3+ complexes, and toxicity of the chelators increased with oxygen tension. Fe3+ complexes of pyridoxal benzoyl hydrazone (PBH) and salicyloyl isonicotinoyl hydrazone (SIH) caused lipid peroxidation and toxicity in K562 cells loaded with eicosapentenoic acid (EPA), a readily oxidized fatty acid, whereas Fe(PIH)2 did not. The lipophilic antioxidant, vitamin E, completely prevented both the toxicity and lipid peroxidation caused by Fe(PBH)2 in EPA-loaded cells, indicating a causal relationship between oxidative stress and toxicity. PBH also caused concomitant lipid peroxidation and toxicity in EPA-loaded cells, both of which were reversed as its concentration increased. In contrast, PIH was inactive, while SIH was equally toxic toward control and EPA-loaded cells, without causing lipid peroxidation, indicating a much smaller contribution of oxidative stress to the mechanism of toxicity of these analogs. In summary, PIH analogs and their Fe3+ complexes are redox active in the intracellular environment. The contribution of oxidative stress to the overall mechanism of toxicity varies across the series. © 2003 Elsevier Inc. All rights reserved.

  • 24.
    Cederbrant, Karin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Marcusson, Jan A.
    Department of Dermatology, Huddinge Hospital, Huddinge.
    Tibbling, Lita
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
    In vitro Lymphocyte Proliferation as Compared to Patch Test Using Gold, Palladium and Nickel1997In: International Archives of Allergy and Immunology, ISSN 1018-2438, E-ISSN 1423-0097, Vol. 112, no 3, p. 212-217Article in journal (Refereed)
    Abstract [en]

    Background: A conventional lymphocyte transformation test (LTT) was compared to the commercially available MELISA® (memory lymphocyte immuno-stimulation assay), a lymphoproliferative assay that has been suggested to be a valuable instrument for the diagnosis of metal allergy. Sensitivity and specificity of the two assays were calculated using a patch test as a reference method.

    Methods: 34 patients were patch-tested for gold sodium thiosulfate, palladium chloride and nickel sulfate, and the lymphocyte proliferation to these metals was tested in vitro using mononuclear cells from peripheral blood.

    Results: No significant differences regarding sensitivity and specificity were found between MELISA and conventional LTT. The sensitivity varied between 55 and 95% and the specificity between 17 and 79%.

    Conclusions: The low specificity of the two in vitro assays suggests that they are not useful for diagnosis of contact allergy to the metals gold, palladium and nickel, since a large number of false-positive results will be obtained.

  • 25.
    Chowdhury, Shamsul
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Medical Informatics.
    Mathiesen, Ulrik
    Oskarshamns sjukhus .
    Krusinska, Ewa
    Technical University of Wroclaw, Poland .
    Franzén, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Wigertz, Ove
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Medical Informatics.
    Bodemar, Göran
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Design and delivery of information resources and knowledge bases for the diagnosis and managementof liver disorders1994In: ANZIIS-94,1994, Brisbane: IEEE , 1994Conference paper (Refereed)
  • 26.
    Clinchy, Birgitta
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery.
    Fransson, Annelie
    Druvefors, Pelle
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Hellsten, Anna
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery.
    Håkansson, Annika
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Gustafsson, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Sjödahl, Rune
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Håkansson, Leif
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Preoperative interleukin-6 production by mononuclear blood cells predicts survival after radical surgery for colorectal carcinoma2007In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 109, no 9, p. 1742-1749Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. Colorectal cancer is one of the most common forms of cancer in the Western world. Staging based on histopathology is currently the most accurate predictor of outcome after surgery. Colorectal cancer is curable if treated at an early stage (stage I-III). However, for tumors in stages II and III there is a great need for tests giving more accurate prognostic information defining the patient population in need of closer follow-up and/or adjuvant therapy. Furthermore, tests that provide prognostic information preoperatively could provide a guide both for preoperative oncologic treatment and the surgical procedure. METHODS. Peripheral blood mononuclear cells (PBMCs) were isolated preoperatively, within a week before primary surgery, from 39 patients undergoing surgery for colorectal cancer. The PBMCs were cultured in vitro for 24 hours in the presence of autologous serum and lipopolysaccharide (LPS). Interleukin-6 (IL-6) production was measured with enzyme-linked immunosorbent assay (ELISA). Staging based on histopathology was performed in all patients. Patients were followed for at least 54 months. RESULTS. A production of >5000 pg/mL of IL-6 identified colorectal cancer patients with a poor prognosis. Eight out of 13 patients with >5000 pg/mL IL-6 died from cancer within the follow-up period, whereas no cancer-related deaths were recorded among 21 patients with 5000 pg/mL IL-6 or less. A multivariate Cox regression analysis, stratified for T- and N-stage, identified IL-6 production as an independent prognostic factor. CONCLUSIONS. IL-6 production in vitro by PBMC can predict survival after radical surgery for colorectal cancer. © 2007 American Cancer Society.

  • 27.
    Dabrosin, Charlotta
    Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Effects of sex steroids on normal human breast: studies in vivo using microdialysis and in vitro in cell culture1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Prolonged exposure to sex steroids may constitute a risk factor for the development of breast cancer. The biological mechanisms involved in breast carcinogenesis are not well understood.

    Basic knowledge of sex steroid effects on the normal human breast is still limited, one reason being the lack of an available in vivo technique for investigations of breast tissue metabolism.

    In this study, the microdialysis technique was developed and evaluated as a method for measurements of tissue-specific concentrations of amino acids, lactate, pyruvate and glutathione in normal human breast tissue during the menstrual cycle. The technique was successfully applied to breast tissue and it was observed that the concentrations of several amino acids as well as glutathione changed during the menstrual cycle. Oxidative damage to cells is one of the mechanisms which may be involved in the development of breast cancer. Normal aerobic metabolism generates potentially dangerous oxidants which are controlled by a variety of antioxidant systems. The exact regulatory mechanisms of these systems are not yet fully understood. We studied the effects of estradiol and progesterone on antioxidative activity in normal human breast tissue, in vivo with the microdialysis technique, and in vitro using normal human breast epithelial cells in culture. The in vivo levels of the antioxidant glutathione were measured early and late in the menstrual cycle in breast tissue and subcutaneous fat. The glutathione levels were higher late in the menstrual cycle in both tissues, when the serum levels of estradiol and progesterone were high. In vitro, breast epithelium exposed to estradiol and progesterone exhibited decreased activity of the antioxidative enzymes catalase and glutathione reductase, whereas the activity of glutathione peroxidase tended to increase compared with cells grown in medium without added sex hormones. The vulnerability to oxidative stress, induced by hydrogen peroxide, increased in cells grown with estradiol and progesterone present in the media. α-Tocopherol, and α-tocopherol in combination with ascorbic acid, but not ascorbic acid alone, protected from cell death induced by hydrogen peroxide. This effect was not dependent on estradiol and progesterone exposure.

    In conclusion, the data suggest an effect of estradiol and progesterone on antioxidative activity in normal human breast tissue both in vivo and in vitro.

    Microdialysis will be a useful tool in future research of these and other aspects concerning human breast tissue.

  • 28.
    Dabrosin, Charlotta
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Johansson, Ann-Charlotte
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Öllinger, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Decreased secretion of Cathepsin D in breast cancer in vivo by tamoxifen: Mediated by the mannose-6-phosphate/IGF-II receptor?2004In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 85, no 3, p. 229-238Article in journal (Refereed)
    Abstract [en]

    The lysosomal protease Catliepsin D (Cath D) is associated with increased invasiveness and metastasis in breast cancer. Both estrogen and tamoxifen have been reported to increase Cath D, which seems to contradict the efficacy of tamoxifen as an adjuvant for estrogen dependent breast cancer. Cath D is bioactive in the extracellular space but very little is known about hormonal regulation of secreted Cath D in vivo. In this study we used microdialysis to sample the extracellular fluid in estrogen receptor positive MCF-7 tumors in nude mice. We show that tamoxifen in combination with estradiol decreased secreted Cath D compared with estradiol treatment only in solid tumors in situ. Cell culture of MCF-7 cells revealed that estradiol and tamoxifen increased intracellular proteolytic activity of Cath D in a similar fashion whereas secretion of Cath D was increased by estradiol and inhibited by tamoxifen. Immunofluorescence showed that estradiol located Cath D to the cell surface, while tamoxifen accumulated Cath D to dense lysosomes in perinuclear regions. Moreover, tamoxifen increased the intracellular transporter of Cath D, the mannose 6-phosphate/IGF-II receptor (M6P/IGF2R). In contrast, estradiol decreased the levels of this receptor. Thus, secretion of Cath D is hormone dependent and may be mediated by altered expression of the M6P/IGF2R. Our results highlight the importance of measurements of proteins in all compartments where they are biological active and show that microdialysis is a viable technique for sampling of Cath D in vivo.

  • 29.
    Dabrosin, Charlotta
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Öllinger, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Variability of glutathione during the menstrual cycle - Due to estrogen effects on hepatocytes?2004In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 36, no 2, p. 145-151Article in journal (Refereed)
    Abstract [en]

    Oxidative stress and alterations in the antioxidative defense system may be involved in carcinogenesis. We have previously shown that the levels of glutathione (GSH) in vivo in both breast tissue and subcutaneous fat were higher in the luteal phase compared with the follicular phase, suggesting an overall increase in GSH. This result was confirmed in the present study. Moreover, we exposed normal breast tissue in vivo, breast epithelial cells in vitro, and hepatocytes in culture to ovarian hormones. We found that local perfusion with estradiol, using microdialysis, in normal human breast tissue did not alter the local GSH levels in vivo. In vitro, treatment with estradiol and progesterone of normal human breast epithelial cells did not alter GSH levels. However, levels of GSH in hepatocytes were after 8 h estradiol exposure initially decreased, 76.6 ± 5% of control cells, p < .05, whereas 20 h exposure more than doubled GSH, 209 ± 26% compared with control cells, p < .01. Progesterone had no additional effect. Exposure of hepatocytes to estradiol increased the cellular content of γ-glutamylcysteine synthetase, the rate-limiting enzyme in GSH synthesis. In conclusion we suggest that estradiol affects the GSH homeostasis mainly by effects on hepatocytes, whereas local production in the breast is unaffected by estradiol.

  • 30.
    Dahlfors, Gunilla
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Chen, Yun
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Gustafsson, Bertil
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, MKC-2, GE: endomed. Linköping University, Faculty of Health Sciences.
    Inhibitory effect of diabetes on proliferation of vascular smooth muscle after balloon injury in rat aorta2000In: Experimental Diabetes Research, ISSN 1687-5214, E-ISSN 1687-5303, Vol. 1, no 2, p. 101-109Article in journal (Refereed)
    Abstract [en]

    The effect of streptozotocin-induced diabetes on cell proliferation in rat aortic intima-media, as well as on local gene expression of transforming growth factor-β1 (TGF-β1) was studied. TGF-β1 mRNA was measured by solution hybridization and TGF-β1 protein by ELISA. Proliferation was measured by bromodeoxyuridine incorporation into DNA two days after balloon injury. All BrdU-labelled cells observed were smooth muscle cells. After a diabetes duration of 2 and 4 weeks, labelled cells were significantly fewer compared with controls. Circulating levels of total TGF-β1 were lowered in rats with 2 weeks diabetes. Although the balloon injury procedure by itself stimulated the gene expression of TGF-β1, no significant difference in TGF-β1 mRNA content between diabetic and control rats after injury was found. In conclusion: vascular smooth muscle proliferation in vivo is inhibited by the diabetic state in this model of insulin deficient diabetes and this inhibition is not related to an impaired local expression of TGF-β1.

  • 31.
    Dalen, Helge
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    a-tocopheryl succinate sensitises a T lymphoma cell line to TRAIL-induced apoptosis by suppressing NF-?B activation2003In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 88, no 1, p. 153-158Article in journal (Refereed)
    Abstract [en]

    Activation of nuclear factor-?B (NF-?B) can interfere with induction of apoptosis triggered by the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL, Apo2L). Therefore, agents that suppress NF-?B activation may sensitise cells to TRAIL-dependent apoptosis. Exposure of Jurkat cells to TRAIL resulted in massive and saturable apoptosis induction, following an initial lag time. This lag was abolished by pretreatment of the cells with subapoptotic doses of a-tocopheryl succinate (a-TOS) or the proteasome inhibitor MGI32. Exposure of the cells to TRAIL led to a rapid, transient activation of NF-?B, a process that was suppressed by cell pretreatment with a-TOS or MGI32. Activation of NF-?B by TNF-a prior to TRAIL exposure increased resistance of the cells to TRAIL-mediated apoptosis. We conclude that a-TOS sensitises cells to TRAIL killing, at least in some cases, through inhibition of NF-?B activation. This further supports the possibility that this semisynthetic analogue of vitamin E is a potential adjuvant in cancer treatment, such as in the case of TRAIL-mediated inhibition of cancer.

  • 32. Dare, E
    et al.
    Li, Wei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Zhivotovsky, B
    Yuan, Xi Ming
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Ceccatelli, S
    Methylmercury and H2O2 provoke lysosomal damage in human astrocytoma D384 cells followed by apoptosis2001In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 30, no 12, p. 1347-1356Article in journal (Refereed)
    Abstract [en]

    Methylmercury (MeHg) is a neurotoxic agent acting via diverse mechanisms, including oxidative stress. MeHg also induces astrocytic dysfunction, which can contribute to neuronal damage. The cellular effects of MeHg were investigated in human astrocytoma D384 cells, with special reference to the induction of oxidative-stress-related events. Lysosomal rupture was detected after short MeHg-exposure (1 ╡M, 1 h) in cells maintaining plasma membrane integrity. Disruption of lysosomes was also observed after hydrogen peroxide (H2O2) exposure (100 ╡M, 1 h), supporting the hypothesis that lysosomal membranes represent a possible target of agents causing oxidative stress. The lysosomal alterations induced by MeHg and H2O2 preceded a decrease of the mitochondrial potential. At later time points, both toxic agents caused the appearance of cells with apoptotic morphology, chromatin condensation, and regular DNA fragmentation. However, MeHg and H2O2 stimulated divergent pathways, with caspases being activated only by H2O2. The caspase inhibitor z-VAD-fmk did not prevent DNA fragmentation induced by H2O2, suggesting that the formation of high-molecular-weight DNA fragments was caspase independent with both MeHg and H2O2. The data point to the possibility that lysosomal hydrolytic enzymes act as executor factors in D384 cell death induced by oxidative stress. ⌐ 2001 Elsevier Science Inc.

  • 33. Davidsson, A.
    et al.
    Andersson, T.
    Hellquist, HB
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Apoptosis and phagocytosis of tissue-dwelling eosinophils in sinonasal polyps2000In: The Laryngoscope, ISSN 0023-852X, E-ISSN 1531-4995, Vol. 110, no 1, p. 111-116Article in journal (Refereed)
    Abstract [en]

    Objective: Sinonasal polyps contain numerous tissue-dwelling eosinophils, but the mechanisms causing their accumulation, functional activities, and resolution are largely unknown. Study Design: Nasal polyp tissue from 14 patients was evaluated for cellular expression of CD95, CD68, and Annexin-V, for the degree of apoptosis, and for phagocytosis of eosinophils. Material and Methods: Histological sections were immunostained as single stains for CD95, CD68, and Annexin-V, and as an immunostaining for CD68 combined with a modified Vital New Red staining. The latter staining is specific for eosinophils. Other sections were stained by terminal d-UTP nick end labeling (TUNEL) assay and routinely stained for H and E. Evaluation of the amount of stained cells was performed by counting the average number in 10 randomly chosen high-power fields. The TUNEL positivity was in all cases confirmed with apoptotic morphology. Results: The inflammatory infiltrate consisted of numerous eosinophils but also a considerable amount of lymphocytes, mast cells, and macrophage-like CD68+ cells. CD95 was frequently expressed on eosinophils, on numerous other inflammatory cells, and also on morphologically apoptotic cells. Annexin-V-positive eosinophils were not as frequent as CD95+ cells, but numerous Annexin-V-positive eosinophils were found. CD68+ cells approximately equalled the number of eosinophils. The number of cells phagocytosing eosinophils varied between polyps. Apoptosis of eosinophils (as evaluated by TUNEL combined with apoptotic morphology) was a common finding in six of the polyps. Conclusions: Previous in vitro and ex vivo findings of CD95 on eosinophils are now supported by demonstration of CD95 on eosinophils in this in vivo study. This investigation revealed a switch of the membrane-bound phosphatidylserine of apoptotic cells, which is a novel observation. The study has demonstrated apoptosis of tissue-dwelling eosinophils, and that CD68+ macrophage-like cells phagocytose eosinophils within the sinonasal polyps.

  • 34. D`Herde, Katharina
    et al.
    Mussche, Sylvie
    Roberg, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Morphological changes in dying cells2003In: Cell proliferation & apoptosis / [ed] D Hughes, FIMLS, H Mehmet;, Linköping: Linköpings universitet , 2003, p. 201-231Chapter in book (Other academic)
    Abstract [en]

    Cell Proliferation and Apoptosis provides a detailed and novel practical guide to cell proliferation and apoptosis detection methods.

  • 35. Doulias, Paschalis-Thomas
    et al.
    Christoforidis, Savas
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Galaris, Dimitrios
    Endosomal and lysosomal effects of desferrioxamine: Protection of HeLa cells from hydrogen peroxide-induced DNA damage and induction of cell-cycle arrest2003In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 35, no 7, p. 719-728Article in journal (Refereed)
    Abstract [en]

    The role of endosomal/lysosomal redox-active iron in H2O 2-induced nuclear DNA damage as well as in cell proliferation was examined using the iron chelator desferrioxamine (DFO). Transient transfections of HeLa cells with vectors encoding dominant proteins involved in the regulation of various routes of endocytosis (dynamin and Rab5) were used to show that DFO (a potent and rather specific iron chelator) enters cells by fluid-phase endocytosis and exerts its effects by chelating redox-active iron present in the endosomal/lysosomal compartment. Endocytosed DFO effectively protected cells against H2O2-induced DNA damage, indicating the importance of endosomal/lysosomal redox-active iron in these processes. Moreover, exposure of cells to DFO in a range of concentrations (0.1 to 100 ╡M) inhibited cell proliferation in a fluid-phase endocytosis- dependent manner. Flow cytometric analysis of cells exposed to 100 ╡M DFO for 24 h showed that the cell cycle was transiently interrupted at the G 2/M phase, while treatment for 48 h led to permanent cell arrest. Collectively, the above results clearly indicate that DFO has to be endocytosed by the fluid-phase pathway to protect cells against H2O 2-induced DNA damage. Moreover, chelation of iron in the endosomal/lysosomal cell compartment leads to cell cycle interruption, indicating that all cellular labile iron is propagated through this compartment before its anabolic use is possible.

  • 36.
    Eklund, Lena K.
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Lirvall, M.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Abnormal expression of proteins in Notch and Wnt pathways in human squamous cell carcinoma of the skinManuscript (preprint) (Other academic)
    Abstract [en]

    Background Members of the Notch pathway are involved in various differentiation processes. Signalling via the Wnt/ß-catenin-pathway controls transcription of genes involved in proliferation events. These two pathways are interconnected through the cytoplasmic protein Dishevelled (Dvl-1).

    Objectives To evaluate the expression patterns of Notch1, Dvl-1 and ß-catenin proteins in human squamous cell carcinomas of the skin.

    Methods 40 formalin-fixed paraffin-embedded SCCs were included in this study. Expression was detected with immunohistochemistry using avidin-biotin and DAB visualization.

    Results The majority of the normal epidermal cells lacked expression of Notch1, while the dysplastic and invasive tumour cells showed strong staining. Expression of Dvl-1 was observed in normal human epidermis, with a more intense staining indysplastic cells in 8 of 38 (21%) cases. Besides the expected cytoplasmic staining, 27 of 38 (71%) secs displayed nuclear staining and a potential nuclear localisation signal was identified. ß-catenin showed membranous and weak cytoplasmic staining in normal as well as tumour cells.

    Conclusions We have found enhanced expression of Notch1 in the majority of SCCs, indicating a disturbed differentiation process. We have also for the first time showed over-expression of Dvl-1 in dysplastic epidermal cells as well as normal staining of the nucleus. A classical nuclear localization signal is also identified in the Dvl-1 isoform A, whereas two other isoforms lack this recognition sequence.

  • 37.
    Franzén, Lennart
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Ghassemifar, M.R.
    Salerud, Göran
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation.
    Tarpila, Erkki
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Reconstruction Centre, Department of Plastic Surgery, Hand surgery UHL.
    Actin fiber orientation in connective tissue contraction. A quantitative study using the perforated rat mesentery model.1996In: Wound Repair and Regeneration, ISSN 1067-1927, E-ISSN 1524-475X, Vol. 4, p. 454-460Article in journal (Refereed)
  • 38.
    Fälth-Magnusson, Karin
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Franzen, Lennart
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Jansson, Gunnar
    Department of Pediatrics, Motala, Sweden.
    Laurin, Pia
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Stenhammar, Lars
    Department of Pediatrics, Norrköping, Sweden.
    Infant feeding history shows distinct differences between Swedish celiac and reference children1996In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 7, no 1, p. 1-5Article in journal (Refereed)
    Abstract [en]

    Infant feeding history was investigated in 72 celiac and 288 age-matched reference children in a retrospective questionnaire study. The reply rate was 100% in celiac and 91. 6% in reference children. The celiac children were breast-fed for a significantly shorter time than reference children, and they were less often breast-fed at the introduction of gluten. The age of the children at gluten introduction was similar, but the cellac children were significantly more often introduced by a gluten-containing follow-up formula, while the reference children more often started on a gluten-containing porridge. The results can be interpreted in two ways. First, it could be argued that breast milk per se protects against symptoms of celiac disease in childhood. It could, however, also be claimed that breast-feeding merely modulates the gluten introduction, causing a less abrupt introduction of gluten in the baby diet and thereby fewer overt symptoms of the disease.

  • 39.
    Ganowiak, Katarzyna
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Engström, Ulla
    Ludwig Institute of Cancer Research, Uppsala Branch, Uppsala, Sweden.
    Gustavsson, Åsa
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Per
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Fibrils from Synthetic Amyloid-Related Peptides Enhance Development of Experimental AA-Amyloidosis in Mice1994In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 199, no 1, p. 306-312Article in journal (Refereed)
    Abstract [en]

    Amyloid enhancing factor is an incompletely characterized activity of extracts from many amyloid-containing tissues and which greatly shortens the preamyloidotic phase during experimental induction of AA-amyloidosis. In this communication we show that amyloid-like fibrils made in vitro from synthetic peptides, corresponding to segments of amyloid fibril proteins, have amyloid enhancing factor-like activity. Thus, there is a possibility that amyloid enhancing factor activity depends on small fibrils serving as nucleation centers for fibril elongation.

  • 40. Garner, B.
    et al.
    Roberg, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Qian, M.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Eaton, J W
    Truscott, RJW
    Redox availability of lens iron and copper: Implication for HO generation in cataract.1999In: Redox report, ISSN 1351-0002, E-ISSN 1743-2928, Vol. 4, p. 313-315Article in journal (Refereed)
  • 41. Garner, B
    et al.
    Roberg, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Qian, M
    Eaton, JW
    Truscott, RJW
    Distribution of ferritin and redox-active transition metals in normal and cataractous human lenses2000In: Experimental Eye Research, ISSN 0014-4835, E-ISSN 1096-0007, Vol. 71, no 6, p. 599-607Article in journal (Refereed)
    Abstract [en]

    Previous studies have shown that lenticular levels of Fe and Cu are elevated in age-related cataract. However, it is not known if these metals are present in a state that is permissive for redox reactions that may lead to the formation of free radicals. In addition, there is little data available concerning the concentration and lenticular distribution of ferritin, the major intracellular Fe-sequestering protein, in the lens. The aim of the present work was therefore to determine the distribution of ferritin and the redox-availability of Fe and Cu in healthy and cataractous lenses. Lens ferritin distribution was assessed by ELISA and immunohistochemistry. A modified ELISA detected ferritin in an 'insoluble' lens protein fraction. Ferritin levels were not significantly different in the cortex vs nucleus of healthy lenses. In contrast, ferritin levels in the cataractous lens nuclei appeared to be 70 % lower compared to the cortex. This was at least partially due to the presence of ferritin within an insoluble protein fraction of the homogenized lenses. In normal lenses, ferritin staining was most intense in the epithelium, with diffuse staining observed throughout the cortex and nucleus. The redox-availability of lenticular metals was determined using: (1) autometallography, (2) Ferene-S as a chromogenic Fe chelator, and (3) NO release from nitrosocysteine to probe for redox-active Cu. The antometallography studies showed that the cataractous lenses stained more heavily for redox-active metals in both the nucleus and cortex when compared to age-matched control lenses. Chelatable Fe was detected in homogenized control lenses after incubation with Ferene-S, with almost three-fold higher levels detected in the cataractous lenses on average. The Cu-catalysed liberation of NO from added nitrosocysteine was not demonstrated in any lens sample. When exogenous Cu (50 nM) was added to the lenses, it was rapidly chelated. The cataractous samples were approximately twice as effective at redox-inactivation of added Cu. These studies provide evidence that a chelatable pool of potentially redox-active Fe is present at increased concentrations in human cataractous lenses. In contrast, it seems that lenticular Cu may not be readily available for participation in redox reactions. (C) 2000 Academic Press.

  • 42.
    Garvin, Stina
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Öllinger, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Dabrosin, Charlotta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Resveratrol induces apoptosis and inhibits angiogenesis in human breast cancer xenografts in vivo2006In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 231, no 1, p. 113-122Article in journal (Refereed)
    Abstract [en]

    Resveratrol, a polyphenol found in grapes and wine, is considered a potential cancer chemopreventive agent. Resveratrol has been shown to induce transcription via both ERα and ERβ. We observed significantly lower tumor growth, decreased angiogenesis, and increased apoptotic index in ERα- ERβ+ MDA-MB-231 tumors in resveratrol-treated nude mice compared with controls. In vitro we found a significant increase in apoptosis in resveratrol-treated MDA-MB-231 cells in addition to significantly reduced extracellular levels of VEGF. This study supports the potential use of resveratrol as a chemotherapeutic agent in breast cancers. © 2005 Elsevier Ireland Ltd. All rights reserved.

  • 43.
    Gati, Istvan
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Neurology. Linköping University, Faculty of Health Sciences.
    Danielsson, Olof
    Linköping University, Department of Neuroscience and Locomotion, Neurology. Linköping University, Faculty of Health Sciences.
    Betmark, T
    Ernerudh, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Öllinger, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Dizdar Segrell, Nil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Neurology. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Effects of inhibitors of the arachidonic acid cascade on primary muscle culture from a Duchenne muscular dystrophy patient2007In: Prostaglandins, Leukotrienes and Essential Fatty Acids, ISSN 0952-3278, E-ISSN 1532-2823, Vol. 77, no 3-4, p. 217-223Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to elucidate the mechanisms of action for potential targets of therapeutic intervention related to the arachidonic acid cascade in muscular dystrophy. Primary cultures from a Duchenne patient were used to study the expression of dystrophin-1, utrophin, desmin, neonatal myosin heavy chain (MHCn) and Bcl-2 during inhibition of phospholipase A2 (PLA2), cyclooxygenase (COX) and lipoxygenase (LOX). Hypo-osmotic treatment was applied in order to trigger Ca2+ influx and PLA2 activity. Inhibition of PLA2 and LOX with prednisolone and nordihydroguaiaretic acid (NDGA) caused a semi-quantitative increase of utrophin and Bcl-2-, and a dose-dependent, quantitative increase of desmin expression, an effect that was augmented by hypo-osmotic treatment. Our results indicate that LOX inhibitors, similarly to corticosteroids, can be beneficial in the treatment of muscular dystrophies. © 2007 Elsevier Ltd. All rights reserved.

  • 44.
    Gentile, Massimiliano
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Bergman Jungeström, Malin
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Olsen, K. E.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Wingren, Sten
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    p53 and survival in early onset breast cancer: analysis of gene mutations, loss of heterozygosity and protein accumulation1999In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 35, no 8, p. 1202-1207Article in journal (Refereed)
    Abstract [en]

    The p53 protein has proven to be central in tumorigenesis by its cell cycle regulatory properties and both gene mutations and protein accumulation have been associated with poor prognosis in breast cancer. The present study was undertaken to investigate the prognostic significance of gene mutations, p53 protein accumulation and of loss of heterozygosity (LOH) at the TP53 locus in young (age <37 years) breast cancer patients. In total, gene mutations were found in 21 of the 123 patients (17%), LOH in 20 of the 47 informative cases (43%) and protein accumulation in 47 of the 102 available cases (46%). Log rank analysis revealed no significant association between survival and TP53 mutations (in general), p53 protein accumulation or LOH. However, missense mutations localised to the zinc binding domain were significantly (P=0.0007) associated with poorer prognosis. As indicated in this as well as other studies, p53 protein accumulation is frequently found in young breast cancer patients, but this protein overexpression appears to be of minor significance for survival. Nevertheless, the present report also suggests that specific mutations contribute substantially to tumour aggressiveness.

  • 45.
    Gentile, Massimiliano
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Olsen, K.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine. Linköping University, Faculty of Health Sciences.
    Dufmats, Monika
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Wingren, Sten
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Frequent allelic losses at 11q24.1–q25 in young women with breast cancer: association with poor survival1999In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 80, no 5/6, p. 843-849Article in journal (Refereed)
    Abstract [en]

    Previous studies have demonstrated that the pathological features of breast cancer are more aggressive in younger women than in their older counterparts, and that young age may be an independent marker for adverse prognosis. These findings have raised the question whether these differences are also present at the molecular level. In order to characterize the genetic alterations associated with early-onset breast cancer, 102 cases selected for age under 37 at diagnosis were examined for loss of heterozygosity (LOH) at nine different loci on chromosomes 11, 13 and 17. Ninety cases (88%), exhibited LOH for at least one marker. The D17S855 marker, intragenic in the BRCA1 gene, showed a high proportion of LOH (63%), whereas the intragenic marker for the TP53 gene, HP53, exhibited LOH in 43% of the cases. On chromosome 11, frequencies of LOH peaked at the D11S969 and D11S387 markers, which expressed LOH in 53% and 48% of the informative cases, whereas D11S1818, which is proximate to the ATM gene, exhibited an LOH frequency of 24%. A statistically significant correlation was found between LOH at the D11S387 marker and poor survival (P = 0.028). No such correlation was found for the adjacent D11S969 marker, located approximately 500 kb centromeric to D11S387. We conclude that one or more as yet unidentified genes, situated in chromosome bands 11q24.1–q25, could be involved in the initiation and/or progression of breast cancer in younger women.

  • 46.
    Ghassemifar, M. Reza
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Connective tissue contraction in wound healing: An experimental study in vivo and in vitro1996Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Contraction of connective tissue is an important part of tissue repair that reduces the wound space and helps to decrease the formation of scar tissue, both of which are needed to restore tissue integrity. In the present study, certain cellular mechanisms that are active during connective tissue contraction were assessed and the influence of transforming growth factor-.131 on these mechanisms was evaluated in normal rat and protracted mouse contraction. A new double-embedding technique for sectioning of thin tissue membranes was developed and a multisequence template was constructed that allowed quantification of a number of target mRNAs [:rGF -.131, TGF -.13 type li receptor, alpha-SM actin and .13-actin) from 0.5-2 11g of total RNA. The fibroblast-populated collagen lattice model (FPCL) was used for studies of contraction in vitro, and, in vivo, the perforated mesentery models of rat and mouse were employed. Fourier transformation image analysis was used to assess the orientation of actin in mesenteric wound fibroblasts.

    Studies in vitro showed that rat, but not mouse, macrophage conditioned medium stimulated contraction of FPCL in serum free medium and that supplementation with serum impaired FPCL contraction. In vivo, rat wound fibroblasts expressed alpha-SM actin during closure of perforations, as shown by in situ hybridization. Using quantitative RT-PCR, it was shown that the expression of alphaSM actin was increased lOO-fold in wounded as compared to unwounded tissue, and that TGF -.131, while stimulating closure of perforations, also increased alpha-SM actin mRNA 4-5 fold inwounded tissue of both rat and mouse. However, the expression of alpha-SM actin was considerably higher in the wounded mesenteriesof rats than in those of mice. TGF -.131 was expressed by normal, unstimulated peritoneal macrophages and, for the first time, shown tobe downregulated in activated, wound macrophages in both rat and mouse. The orientation of actin bundles in wound fibroblasts wasderanged in impaired healing in zinc deficiency but unaffected by TGF -.131 in stimulated contrition.

    In conclusion, the results have shed further light on various cellular activities during connective tissue contraction. A number of differences were found between rats and mice that help to clarify the mechanism of protracted healing in the mouse. The complex interaction of these mechanisms await to be further elucidated.

  • 47. Ghassemifar, M.R.
    et al.
    Tarnuzzer, R.W.
    Salerud, Göran
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation.
    Schultz, G.S.
    Franzén, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Alpha-smooth muscle actin expression in rat and mouse mesenteric wounds after TGF-ß1 treatment1997In: Wound Repair and Regeneration, ISSN 1067-1927, E-ISSN 1524-475X, Vol. 5, p. 339-347Article in journal (Refereed)
  • 48.
    Gustafsson, Bertil
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Hjalmar, V.
    Winiarski, J
    Gustafsson, B.
    Christensson, B.
    Cellular expression of MDM2 and p53 in childhood leukemias with poor prognosis2000In: Medical and Pediatric Oncology, ISSN 0098-1532, E-ISSN 1096-911X, Vol. 34, no 2, p. 117-124Article in journal (Refereed)
    Abstract [en]

    Background. Previous studies have suggested that altered expression or dysfunction of the tumor suppressor gene p53 or the oncogene MDM2 could indicate disease progression in children with leukemia who would fail to achieve complete remission or who would relapse. While these studies mainly have described aberrations of MDM2 and p53 function at the DNA and mRNA- level, we have examined p53 and MDM2 expression at the protein level. Mutation of the p53 tumor suppressor gene may result in cellular accumulation of the p53 protein, due to prolonged half-life of the abnormal protein. The p53 protein can also be rendered nonfunctional by overexpression of proteins that bind to p53, such as MDM2. Both pathways have been proposed to disrupt cell cycle regulation in humans. Recent studies have shown that increased expressions of MDM2 as well as of p53 can be detected at the protein level in the absence of gene amplification. Procedure. Forty-three bone marrow samples were analyzed immunohistochemically for p53 and MDM2. Twenty-nine bone marrow samples were obtained in children with active, prognostically unfavorable leukemia and MDS. Fourteen bone marrow samples were from children with non- malignant hematological disorders. Results. p53 protein was expressed in 12 patients and MDM2 in 17 patients with leukemia. In the control group MDM2 expression was detected in one child, while p53 was not found in any of the samples. Conclusions. Our findings of p53 or MDM2 positive cells in a majority of children with unfavorable prognostic features suggests that dysfunction of the p53-dependent cell growth control have a role in the development of high risk leukemias.

  • 49. Gustafsson, Britt
    et al.
    Axelsson, Birgitta
    Gustafsson, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Christensson, Birger
    Winiarski, Jacek
    MDM2 and p53 in childhood acute lymphoblastic leukemia: Higher expression in childhood leukemias with poor prognosis compared to long-term survivors2001In: Pediatric Hematology & Oncology, ISSN 0888-0018, E-ISSN 1521-0669, Vol. 18, p. 497-508Article in journal (Refereed)
  • 50.
    Gustavsson, Åsa
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Transthyretin in senile systemic amyloidosis and familial amyloidotic polyneuropathy1994Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The amyloidoses comprise a heterogeneous group of disorders characterized by the deposition of fibrillar, proteinaceous amyloid deposits in various organs and tissues. To date, 17 different proteins of various sizes have been identified as amyloid proteins. Irrespective of the specific protein comprising the amyloid fibrils, the fibrils are all about 10 nm wide and of indefinite length.

    In the most common familial form of amyloidosis, familial amyloidotic polyneuropathy (FAP), the amyloid fibril protein is the plasma protein transthyretin (TTR). In FAP type I, which is the type found in Sweden, there is a mutation in the TTR gene leading to the substitution of a methionine for valine at position 30. This mutation leads to a form of amyloidosis characterized by polyneuropathy starting in the lower limbs and usually slowly progressing until death occurs. Another TTR-derived form of amyloidosis is senile systemic amyloidosis (SSA). This form of amyloidosis is present in about 25% of people 80 years of age or older. In SSA, amyloid is deposited mainly in the heart but deposits are also found in many other organs.

    In this study it is demonstrated that normal TTR can form fibrils in vitro. Fibril formation studies were also performed in vitro with synthetic peptides corresponding to parts of the TTR amino acid sequence. These results indicate that TTR peptides with 13-strand secondary structure are fibrillogenic in vitro and are likely important in in vivo amyloidogenesis.

    The TTR amino acid and DNA sequences in cases with SSA were determined and found to be normal, thus showing that no mutation is necessary for development of this form of amyloidosis. However, cleavage of TTR may be important in fibrillogenesis since TTR fragments lacking 45-51 N-terminal amino acid residues predominated in the amyloid.

    Antigenic epitopes exposed on normal TTR and TTR derived from amyloid deposits were also examined. The 13-strand H was found to be exposed in amyloid TTR and not in normal TTR, thus suggesting a changed structural conformation of TTR in amyloid fibrils.

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