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  • 1.
    Farnebo, Lovisa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
    Jedlinski, Adam
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Ansell, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery . Linköping University, Faculty of Health Sciences.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Thunell, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Grenman, Reidar
    University of Turku.
    Johansson, Ann-Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
    Proteins and single nucleotide polymorphisms involved in apoptosis, growth control, and DNA repair predict cisplatin sensitivity in head and neck cancer cell lines2009In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 24, no 4, p. 549-556Article in journal (Refereed)
    Abstract [en]

    The present study was undertaken to evaluate the possibility of using a panel of proteins and single nucleotide polymorphisms (SNPs) involved in apoptosis, growth control, and DNA repair as predictive markers for cisplatin sensitivity. For this purpose the intrinsic cisplatin sensitivity (ICS) was determined in 39 cell lines derived from squamous cell carcinomas of the head and neck using a colony-forming assay. In these cell lines and in normal oral keratinocytes (NOK), the expression of epidermal growth factor receptor (EGFR), Hsp70, Bax, Bcl-2, Bcl-XL, survivin, and COX-2 was determined. Moreover, the p53, MDM2, FGFR4, XPC, XPD, XRCC1, and XRCC3 genes were analyzed for the presence of specific single nucleotide polymorphisms (SNPs). Pearsons correlation test showed that EGFR was the only protein that was significantly correlated to the ICS (r=0.388, p=0.015). The combination of EGFR, Hsp70, Bax, and Bcl-2 gave the strongest correlation (r=0.566, p andlt;= 0.001), whereas Bax alone had the second highest influence on the ICS. Furthermore, all four SNPs within genes involved in DNA repair, i.e. XPC, XPD, XRCC1, and XRCC3, tended to influence the ICS. In order to find the combination of factors, on both protein and gene levels, with the highest correlation to ICS, a multivariate statistical calculation was performed. Our results indicate that SNPs in DNA repair genes (XRCC3(241) and XPD751) influence the ICS and together with the expression of EGFR, Hsp70, Bax, and Bcl-2, they could predict the cisplatin sensitivity of head and neck cancer cell lines (r=0.614, p andlt;= 0.001).

  • 2.
    Farnebo, Lovisa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
    Jerhammar, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
    Ceder, Rebecca
    Institute of Environmental Medicine, Division of Biochemical Toxicology and Experimental Cancer Research, Karolinska Institute, Stockholm, Sweden.
    Grafström, Roland C
    Institute of Environmental Medicine, Division of Biochemical Toxicology and Experimental Cancer Research, Karolinska Institute, Stockholm, Sweden.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
    Thunell, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Grénman, Reidar
    Medical Biochemistry, University of Turku, Finland.
    Johansson, Ann-Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
    Combining factors on protein and gene level to predict radioresponse in head and neck cancer cell lines2011In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 40, no 10, p. 739-746Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Radiotherapy is the main therapy for head and neck squamous cell carcinoma (HNSCC); however, treatment resistance and local recurrence are significant problems, highlighting the need for predictive markers. In this study, we evaluated selected proteins, mutations, and single nucleotide polymorphisms (SNPs) involved in apoptosis, cell proliferation, and DNA repair alone or combined as predictive markers for radioresponse in 42 HNSCC cell lines.

    METHODS: The expression of epidermal growth factor receptor, survivin, Bax, Bcl-2, Bcl-XL, cyclooxygenase-2, and heat shock protein 70 was analyzed by ELISA. Furthermore, mutations and SNPs in the p53 gene as well as SNPs in the MDM2, XRCC1, and XRCC3 genes were analyzed for their relation to radioresponse. To enable the evaluation of the predictive value of several factors combined, each cell line was allocated points based on the number of negative points (NNP) system, and the NNP sum was correlated with radioresponse.

    RESULTS: Survivin was the only factor that alone was significantly correlated with the intrinsic radiosensitivity (r=0.36, p=0.02). The combination of survivin, Bax, Bcl-2, Bcl-XL, cyclooxygenase-2, and the p53 Arg72Pro polymorphism was found to most strongly correlate with radioresponse (r=0.553, p<0.001).

    CONCLUSION: These data indicate that the intrinsic radiosensitivity of 42 HNSCC cell lines can be predicted by a panel of factors on both the protein and gene levels. Moreover, among the investigated factors, survivin was the most promising biomarker of radioresponse.

  • 3.
    Farnebo, Lovisa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
    Jerhammar, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Grénman, Reidar
    Department of Otorhinolaryngology, Head and Neck Surgery, Central Hospital and University of Turku and Medical Biochemistry, University of Turku, Finland.
    Norberg-Spaak, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
    Number of negative points: a novel method for predicting radiosensitivity in head and neck tumor cell lines.2008In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 20, no 2, p. 453-461Article in journal (Refereed)
    Abstract [en]

    The present study was aimed at establishing a method that combines multiple factors of protein and genetic changes that enables prediction of radiosensitivity in the head and neck squamous cell carcinoma (HNSCC) cell lines. In nine HNSCC cell lines, the quantity of protein expression and the type of genetic alterations were translated into a point system, called the Number of Negative Points. The expression of 14 proteins involved in growth control and/or apoptosis was quantified using a densitometric assessment of Western blots. The blots were adjusted to actin and standardised to normal oral keratinocytes classifying them into four groups depending on the amount of protein expressed (0-3 points). Mutations of the p53 gene were classified into three groups and each mutation was given one point. Since the cell lines each had a known intrinsic radiosensitivity, a multivariate statistical calculation could then be performed to select for the combination of factors having the strongest correlation to radiosensitivity. The strongest correlation of the investigated factors was the combination of epidermal growth factor receptor, survivin and splice site/missense p53 mutations (R=0.990 and P<0.0001). No single factor had a significant correlation to the intrinsic radiosensitivity. Since a significant correlation to the intrinsic radiosensitivity was achieved only when two or more factors were combined, we conclude that a method such as the Number of Negative Points is necessary for prediction of treatment response. We present a novel method to combine factors which enables the prediction of radiosensitivity of HNSCC cell lines.

  • 4.
    Persson, H L
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Respiratory Medicine UHL.
    Vainikka, Linda K
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lysosomal iron in pulmonary alveolar proteinosis: a case report.2009In: The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology, ISSN 1399-3003, Vol. 33, no 3, p. 673-679Article in journal (Refereed)
    Abstract [en]

    Pulmonary alveolar proteinosis is characterised by accumulation of surfactant-like material in the distal air spaces. Since lysosomes play a crucial role for degradation of large biomolecules taken up from the cell's environment, it was hypothesised that oxidant-induced lysosomal disruption and ensuing cell death might play a role in disease development. In the present study, alveolar macrophages, harvested by whole-lung lavage from a patient diagnosed with pulmonary alveolar proteinosis, are shown to contain large amounts of undigested material within lysosomes, and the same organelle exhibits increased amounts of haemosiderin-bound iron. Compared with murine macrophage-like J774 cells (iron exposed or not), the status of human macrophages was pro-oxidative, i.e. macrophages exhibited a low level of the antioxidant glutathione and large amounts of iron available for Fenton-type chemistry. As a consequence, macrophageal lysosomes were particularly fragile when exposed to physiological concentrations of hydrogen peroxide (generated by glucose oxidase in culture medium). Such lysosomal disruption resulted in extensive cell death by both necrosis and apoptosis independent of caspase-3 activation. Considering the potential role of iron-catalysed oxidant-induced lysosomal rupture and ensuing cell killing for pulmonary alveolar proteinosis pathology and disease progression, whole-lung lavage might be considered early in those cases in which cytochemical staining reveals great numbers of haemosiderin-laden alveolar macrophages.

  • 5.
    Persson, Hans Lennart
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Increased lysosomal membrane permeabilization in oxidant-exposed macrophages of human fibrotic lungs2013In: Journal of Cell Death, ISSN 1179-0660, Vol. 6, no 1, p. 69-74Article in journal (Refereed)
    Abstract [en]

    A disrupted balance of reduced glutathione (GSH) and iron (Fe) and subsequent enhanced susceptibility of lysosomes of lung macrophages (LMs) to oxidants may play a role in lung fibrogenesis. We assessed cellular Fe/GSH, lysosomal membrane permeabilization (LMP), and cell death in cultures of oxidant exposed LMs. LMs from 7 lung fibrosis patients and healthy subjects were exposed to a physiologic concentration of H2O2 for 1 h. LMP was assessed with acridine orange green fluorescence, apoptosis/necrosis were estimated by apoptotic DNA and typical morphology, Fe was assessed with Prussian blue staining/atomic absorption spectrophotometry, and GSH was evaluated using a GSH assay kit. Oxidant-induced LMP and cell death were more pronounced in cultures of LMs from patients with lung fibrosis, and these cells contained less GSH and more cytochemically stained Fe. These observations indicate that LMP may be involved in fibrosis development, possibly through activation of the inflammasome complex. Further studies are warranted for a detailed understanding.

  • 6.
    Persson, Hans Lennart
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Eriksson, Ida
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Wennerstrom, Urban
    Hospital Vastervik, Sweden .
    TNF-alpha-stimulated macrophages protect A549 lung cells against iron and oxidation2013In: Experimental and Toxicological Pathology, ISSN 0940-2993, E-ISSN 1618-1433, Vol. 65, no 1-2, p. 81-89Article in journal (Refereed)
    Abstract [en]

    Previously, we have shown that TNF-alpha protects iron-exposed J774 macrophages against iron-catalyzed oxidative lysosomal disruption and cell death by increasing reduced glutathione and H-ferritin in cells. Because J774 cells are able to harbor large amounts of iron, which is potentially harmful in a redox-active state, we hypothesized that TNF-alpha-stimulated J774 macrophages will prevent iron-driven oxidative killing of alveolar epithelial A549 cells in co-culture. In the present study, iron trichloride (which is endocytosed by cells as hydrated iron-phosphate complexes) was mainly deposited inside the lysosomes of J774 macrophages, while A549 cells, equally iron exposed, accumulated much less iron. When challenged by oxidants, however, reactive lysosomal iron in A549 cells promoted lysosomal disruption and cell death, particularly in the presence of TNF-alpha. This effect resulted from an elevation in ROS generation by TNF-alpha, while a compensatory upregulation of protective molecules (H-ferritin and/or reduced glutathione) by TNF-alpha was absent. A549 cell death was particularly pronounced when iron and TNF-alpha were present in the conditioned medium during oxidant challenge; thus, iron-driven oxidative reactions in the culture medium were a much greater hazard to A549 cells than those taking place inside their lysosomes. Consequently, the iron chelator, deferoxamine, efficiently prevented A549 cell death when added to the culture medium during an oxidant challenge. In co-cultures of TNF-alpha-stimulated lung cells, J774 macrophages sequestered iron inside their lysosomes and protected A549 cells from oxidative reactions and cell death. Thus, the collective effect of TNF-alpha on co-cultured lung cells was mainly cytoprotective.

  • 7.
    Persson, Lennart
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pulmonary Medicine . Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Respiratory Medicine.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    TNF-alpha preserves lysosomal stability in macrophages: A potential defense against oxidative lung injury2010In: TOXICOLOGY LETTERS, ISSN 0378-4274, Vol. 192, no 2, p. 261-267Article in journal (Refereed)
    Abstract [en]

    Iron-catalyzed oxidative damage on the respiratory epithelium is prevented by alveolar macrophages depositing iron inside their lysosomes. Bound in an un-reactive state to various metalloproteins, e.g. ferritin, most lysosomal iron is kept separated from reactive oxygen species (ROS) by intracellular anti-oxidative enzyme systems. Some ROS may, however, escape this protective shield of antioxidants, react with small amounts of free redox-active iron within lysosomes, thereby causing peroxidative damage on lysosomes and possibly also ensuing cell death. Since macrophages, containing large amounts of lysosomal iron, are very resistant to TNF-alpha, we hypothesized that this cell type has developed specific defense mechanisms against TNF-alpha-induced ROS generation. Murine macrophages were exposed (or not) to non-toxic concentrations of TNF-alpha and/or iron and were then challenged with H2O2. Iron-exposed oxidatively stressed cells exhibited extensive lysosomal disruption resulting in pronounced cell death. In contrast, TNF-alpha stabilized lysosomes and protected cells, particularly those iron-exposed, by reducing cellular iron and increasing H-ferritin. Intracellular generation of H2O2 under oxidative stress was kept unchanged by TNF-alpha and/or iron. However, TNF-alpha increased basal levels of glutathione by up-regulating the synthesis of gamma-glutamylcystein synthetase, thereby strengthening the anti-oxidative capacity. TNF-alpha inhibitors would block this novel anti-oxidative defense system, possibly explaining their adverse effects on the lung.

  • 8.
    Persson, Lennart
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine UHL.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Eriksson, Hanna
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology.
    Wennerstrom, Urban
    Hospital Vastervik.
    Lane-Hamilton Syndrome Ferritin Protects Lung Macrophages Against Iron and Oxidation2011In: CHEST, ISSN 0012-3692, Vol. 139, no 2, p. 361-367Article in journal (Refereed)
    Abstract [en]

    Background: Lysosomal disruption and consequent apoptosis have been implicated in lung diseases characterized by iron overload. Free reactive iron in lysosomes sensitizes cells to oxidative stress. Apoptosis is prevented by heavy-chain (H)-ferritin, which can incorporate lysosomal iron into ferritin molecules. Tumor necrosis factor (TNF)-alpha stimulates the synthesis of H-ferritin. Idiopathic pulmonary hemosiderosis presents with the accumulation of iron and the upregulation of ferritin synthesis. We therefore analyzed the lysosomal response to oxidants and the role of H-ferritin synthesis in lung macrophages (LMs) harvested from the first Swedish case, to our knowledge, of Lane-Hamilton syndrome. Methods: Iron-exposed murine macrophages were used as a reference. Both cell types were stimulated with TNF-alpha (or not), then iron was assessed cytochemically and by atomic absorption spectrophotometry. H-ferritin expression was analyzed by Western blot and reduced glutathione (GSH) by spectrofluorometry. Following exposure to hydrogen peroxide, lysosomal membrane integrity and DNA degradation were analyzed by flow cytometry, whereas morphologic signs of apoptosis and necrosis were assessed by light microscopy. Results: GSH levels were approximately equal in LMs and murine macrophages. Although LMs contained much more iron than murine macrophages, lysosomal iron was bound in a harmless unreactive state by ample amounts of ferritin and hemosiderin, its lysosomal degradation product. Therefore, lysosomes of LMs were more oxidant resistant, and these cells were more adept at surviving oxidative stress. In both cell types, TNF-alpha prevented oxidant-induced lysosomal damage and cell death by upregulating synthesis of H-ferritin and GSH. Conclusions: Iron-overloaded LMs are equipped with an efficient armor of antioxidative mechanisms of which H-ferritin and hemosiderin seem to be particularly important.

  • 9.
    Persson, Lennart
    et al.
    Linköping University, Department of Medical and Health Sciences, Pulmonary Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Sege, Maria
    Linköping University, Department of Medical and Health Sciences, Pulmonary Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Wennerström, Urban
    Division of Medicine, Hospital of Västervik, Västervik, Sweden.
    Dam-Larsen, Sören
    Division of Medicine, Hospital of Eksjö, Eksjö, Sweden.
    Persson, Jenny
    Division of Pulmonary Medicine, Ryhov Hospital, Jönköping, Sweden.
    Leaky lysosomes in lung transplant macrophages: azithromycin prevents oxidative damage2012In: Respiratory research (Online), ISSN 1465-9921, E-ISSN 1465-993X, Vol. 13, no 83Article in journal (Refereed)
    Abstract [en]

    Background: Lung allografts contain large amounts of iron (Fe), which inside lung macrophages may promote oxidative lysosomal membrane permeabilization (LMP), cell death and inflammation. The macrolide antibiotic azithromycin (AZM) accumulates 1000-fold inside the acidic lysosomes and may interfere with the lysosomal pool of Fe. Objective: Oxidative lysosomal leakage was assessed in lung macrophages from lung transplant recipients without or with AZM treatment and from healthy subjects. The efficiency of AZM to protect lysosomes and cells against oxidants was further assessed employing murine J774 macrophages. Methods: Macrophages harvested from 8 transplant recipients (5 without and 3 with ongoing AZM treatment) and 7 healthy subjects, and J774 cells pre-treated with AZM, a high-molecular-weight derivative of the Fe chelator desferrioxamine or ammonium chloride were oxidatively stressed. LMP, cell death, Fe, reduced glutathione (GSH) and H-ferritin were assessed. Results: Oxidant challenged macrophages from transplants recipients without AZM exhibited significantly more LMP and cell death than macrophages from healthy subjects. Those macrophages contained significantly more Fe, while GSH and H-ferritin did not differ significantly. Although macrophages from transplant recipients treated with AZM contained both significantly more Fe and less GSH, which would sensitize cells to oxidants, these macrophages resisted oxidant challenge well. The preventive effect of AZM on oxidative LMP and J774 cell death was 60 to 300 times greater than the other drugs tested. Conclusions: AZM makes lung transplant macrophages and their lysososomes more resistant to oxidant challenge. Possibly, prevention of obliterative bronchiolitis in lung transplants by AZM is partly due to this action.

  • 10.
    Samuelsson, Martin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Nordin, Conny
    Linköping University, Department of Clinical and Experimental Medicine. 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 Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Glutathione In Blood And Cerebrospinal Fluid2008Conference paper (Refereed)
  • 11.
    Samuelsson, Martin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. 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 Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Glutathione in the blood and cerebrospinal fluid: A study in healthy male volunteers2011In: Neuropeptides, ISSN 0143-4179, E-ISSN 1532-2785, Vol. 45, no 4, p. 287-292Article in journal (Refereed)
    Abstract [en]

    Glutathione (GSH) is an important regulator of intracellular redox homeostasis. In the brain, glutathione is considered a major antioxidant, which is also found at high concentrations in the extracellular environment. Altered GSH balance in plasma, blood and cerebrospinal fluid (CSF) has been observed in several disorders suggesting that an impaired antioxidant function is part of the pathophysiology. The aim of the present study was to investigate a possible relationship between glutathione in plasma and CSF. Blood samples were collected from 26 healthy male volunteers at 8 a.m., noon, 4 p.m. and 8 p.m. At 8 a.m. the following morning, blood was drawn and three 6-ml fractions of CSF were collected by lumbar puncture. In CSF, a disrupted gradient was found showing the highest glutathione concentration in the second compared to the first and third fraction (P andlt; 0.002). Moreover, correlation and regression analyses between glutathione in plasma and CSF revealed an association between the third fraction CSF and plasma glutathione 8 p.m. the day before lumbar puncture. Thus, if carefully standardised due to the disrupted gradient in CSF, it might be possible to estimate glutathione levels in CSF by analysing plasma in healthy males.

  • 12.
    Wegman (Palmebäck), Pia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Skoog, Lambert
    Division of Cytology, Karolinska Hospital, Stockholm, Sweden.
    Rutqvist, Lars-Erik
    Department of Oncology, Huddinge University Hospital, Stockholm, Sweden.
    Wingren, Sten
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients2005In: Breast Cancer Research, ISSN 1465-5411, Vol. 7, no 3, p. R284-R290Article in journal (Refereed)
    Abstract [en]

    Background

    Tamoxifen is widely used as endocrine therapy for oestrogen-receptor-positive breast cancer. However, many of these patients experience recurrence despite tamoxifen therapy by incompletely understood mechanisms. In the present report we propose that tamoxifen resistance may be due to differences in activity of metabolic enzymes as a result of genetic polymorphism. Cytochrome P450 2D6 (CYP2D6) and sulfotransferase 1A1 (SULT1A1) are polymorphic and are involved in the metabolism of tamoxifen. The CYP2D6*4 and SULT1A1*2 genotypes result in decreased enzyme activity. We therefore investigated the genotypes of CYP2D6 and SULT1A1 in 226 breast cancer patients participating in a trial of adjuvant tamoxifen treatment in order to validate the benefit from the therapy.

    Methods

    The patients were genotyped using PCR followed by cleavage with restriction enzymes.

    Results

    Carriers of the CYP2D6*4 allele demonstrated a decreased risk of recurrence when treated with tamoxifen (relative risk = 0.28, 95% confidence interval = 0.11–0.74, P = 0.0089). A similar pattern was seen among the SULT1A1*1 homozygotes (relative risk = 0.48, 95% confidence interval = 0.21–1.12, P = 0.074). The combination of CYP2D6*4 and/or SULT1A1*1/*1 genotypes comprised 60% of the patients and showed a 62% decreased risk of distant recurrence with tamoxifen (relative risk = 0.38, 95% confidence interval = 0.19–0.74, P = 0.0041).

    Conclusion

    The present study suggests that genotype of metabolic enzymes might be useful as a guide for adjuvant endocrine treatment of postmenopausal breast cancer patients. However, results are in contradiction to prior hypotheses and the present sample size is relatively small. Findings therefore need to be confirmed in a larger cohort.

  • 13.
    Wäster, Petra
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Eriksson, Ida
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Rosdahl, Inger
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Dermatology and Venerology.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Extracellular vesicles are transferred from melanocytes to keratinocytes after UVA irradiation2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, no 27890Article in journal (Refereed)
    Abstract [en]

    Ultraviolet (UV) irradiation induces skin pigmentation, which relies on the intercellular crosstalk of melanin between melanocytes to keratinocytes. However, studying the separate effects of UVA and UVB irradiation reveals differences in cellular response. Herein, we show an immediate shedding of extracellular vesicles (EVs) from the plasma membrane when exposing human melanocytes to UVA, but not UVB. The EV-shedding is preceded by UVA-induced plasma membrane damage, which is rapidly repaired by Ca2+-dependent lysosomal exocytosis. Using co-cultures of melanocytes and keratinocytes, we show that EVs are preferably endocytosed by keratinocytes. Importantly, EV-formation is prevented by the inhibition of exocytosis and increased lysosomal pH but is not affected by actin and microtubule inhibitors. Melanosome transfer from melanocytes to keratinocytes is equally stimulated by UVA and UVB and depends on a functional cytoskeleton. In conclusion, we show a novel cell response after UVA irradiation, resulting in transfer of lysosome-derived EVs from melanocytes to keratinocytes.

  • 14.
    Wäster, Petra
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Eriksson, Ida
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Sunbathing: What’ve lysosomes got to do with it?2014In: Communicative & Integrative Biology, ISSN 1942-0889, E-ISSN 1942-0889, Vol. 7, no 1, p. e28723-1-e28723-5Article in journal (Refereed)
    Abstract [en]

    Solar radiation is an important risk factor for skin cancer, the incidence of which is increasing, especially in the fair-skinned populations of the world. While the ultraviolet (UV)B component has direct DNA damaging ability, UVA-induced effects are currently mainly attributed to the production of reactive oxygen species. In our recent study, we compared the effects of UVA and UVB radiation on human keratinocytes and found that UVA-induced plasma membrane damage was rapidly repaired by lysosomal exocytosis, which was detected based on the expression of lysosomal membrane associated protein-1 (LAMP-1) on the plasma membrane of non-permeabilized cells. Later, the keratinocytes died through caspase-8 mediated apoptosis. In contrast, the plasma membranes of keratinocytes exposed to UVB showed no LAMP-1 expression, and, although the cells died by apoptosis, no initial caspase-8 activity was detected. We have also demonstrated the occurrence of UVA-induced lysosomal exocytosis in reconstructed skin and shown the relocation of lysosomes from the center of cells to the vicinity of the plasma membrane. Thus, we suggest that lysosomal exocytosis also occurs in keratinocytes covered by the stratum corneum following exposure to UVA. Our findings provide new insight into the mechanism of UVA-induced skin damage.

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