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Gustafsson, Bertil
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Kurz, T., Gustafsson, B. & Brunk, U. (2011). Cell sensitivity to oxidative stress is influenced by ferritin autophagy. FREE RADICAL BIOLOGY AND MEDICINE, 50(11), 1647-1658
Öppna denna publikation i ny flik eller fönster >>Cell sensitivity to oxidative stress is influenced by ferritin autophagy
2011 (Engelska)Ingår i: FREE RADICAL BIOLOGY AND MEDICINE, ISSN 0891-5849, Vol. 50, nr 11, s. 1647-1658Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

To test the consequences of lysosomal degradation of differently iron-loaded ferritin molecules and to mimic ferritin autophagy under iron-overload and normal conditions, J774 cells were allowed to endocytose heavily iron loaded ferritin, probably with some adventitious iron (Fe-Ft), or iron-free apo-ferritin (apo-Ft). When cells subsequently were exposed to a bolus dose of hydrogen peroxide, apo-Ft prevented lysosomal membrane permeabilization (LMP), whereas Fe-Ft enhanced LMP. A 4-h pulse of Fe-Ft initially increased oxidative stress-mediated LMP that was reversed after another 3 h under standard culture conditions, suggesting that lysosomal iron is rapidly exported from lysosomes, with resulting upregulation of apo-ferritin that supposedly is autophagocytosed, thereby preventing LMP by binding intralysosomal redox-active iron. The obtained data suggest that upregulation of the stress protein ferritin is a rapid adaptive mechanism that counteracts LMP and ensuing apoptosis during oxidative stress. In addition, prolonged iron starvation was found to induce apoptotic cell death that, interestingly, was preceded by LMP, suggesting that LMP is a more general phenomenon in apoptosis than so far recognized. The findings provide new insights into aging and neurodegenerative diseases that are associated with enhanced amounts of cellular iron and show that lysosomal iron loading sensitizes to oxidative stress.

Ort, förlag, år, upplaga, sidor
Elsevier Science B.V., Amsterdam., 2011
Nyckelord
Apoptosis, Autophagy, Ferritin, Lysosomes, Oxidative stress, Redox-active iron, Free radicals
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-68690 (URN)10.1016/j.freeradbiomed.2011.03.014 (DOI)000290603700021 ()
Anmärkning
Original Publication: Tino Kurz, Bertil Gustafsson and Ulf Brunk, Cell sensitivity to oxidative stress is influenced by ferritin autophagy, 2011, FREE RADICAL BIOLOGY AND MEDICINE, (50), 11, 1647-1658. http://dx.doi.org/10.1016/j.freeradbiomed.2011.03.014 Copyright: Elsevier Science B.V., Amsterdam. http://www.elsevier.com/Tillgänglig från: 2011-05-27 Skapad: 2011-05-27 Senast uppdaterad: 2012-03-23
Koch, A., Gustafsson, B., Fohlin, H. & Sörenson, S. (2011). Cyclooxygenase-2 expression in lung cancer cells evaluated by immunocytochemistry. Diagnostic Cytopathology, 39(3), 188-193
Öppna denna publikation i ny flik eller fönster >>Cyclooxygenase-2 expression in lung cancer cells evaluated by immunocytochemistry
2011 (Engelska)Ingår i: Diagnostic Cytopathology, ISSN 8755-1039, E-ISSN 1097-0339, Vol. 39, nr 3, s. 188-193Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Cyclooxygenase-2 (COX-2) expression may be a prognostic factor in lung cancer. In previous studies, COX-2 expression has almost exclusively been evaluated with immunohistochemical methods performed on histology sections of tissue biopsies. However, in clinical practice, lung cancer is often diagnosed with cytological techniques only. We present methodology and results from analysis of COX-2 expression with immunochemistry on cytological material in 53 patients with lung cancer. Preparation and staining with the method established at our laboratory were easy to perform and resulted in good quality slides. The percentage COX-2-stained cells and the intensity of staining varied widely between and within the different cases. The proportion of positively stained tumor cells was as follows: <1% in 20 patients, 1-10% in 7 patients, 11-50% in 17 patients, and more than 50% in 9 patients. In 17 cases, groups of cells with different intensity of COX-2 staining were found in the same slide. In conclusion, immunocytochemical analysis of COX-2 expression is technically easy to perform with routine diagnostic procedures. There is a great variation in the proportion of COX-2-positive cells among patients and in the intensity of staining among individual cells in many single cases. Diagn. Cytopathol.2011;39:188-193. © 2010 Wiley-Liss, Inc.

Ort, förlag, år, upplaga, sidor
John Wiley and Sons, 2011
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-66083 (URN)10.1002/dc.21366 (DOI)000288035400006 ()21319320 (PubMedID)
Tillgänglig från: 2011-03-04 Skapad: 2011-03-02 Senast uppdaterad: 2017-12-11Bibliografiskt granskad
Diffner, E., Gauffin, F., Anagnostaki, L., Nordgren, A., Gustafsson, B., Sander, B., . . . Liao Persson, J. (2009). Expression of VEGF and VEGF Receptors in Childhood Precursor B-cell Acute Lymphoblastic Leukemia Evaluated by Immunohistochemistry. Journal of pediatric hematology/oncology (Print), 31(9), 696-701
Öppna denna publikation i ny flik eller fönster >>Expression of VEGF and VEGF Receptors in Childhood Precursor B-cell Acute Lymphoblastic Leukemia Evaluated by Immunohistochemistry
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2009 (Engelska)Ingår i: Journal of pediatric hematology/oncology (Print), ISSN 1077-4114, E-ISSN 1536-3678, Vol. 31, nr 9, s. 696-701Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Perturbation in the expression and signaling pathways of vascular endothelial growth factor (VEGF) has been linked to pathogenesis of hematologic malignancies. We investigated the expression and clinical importance of VEGF and two of its receptors, VEGFR-1 and VEGFR-2, in childhood precursor B-cell acute lymphoblastic leukemia (pre-B ALL) by using immunohistochemistry. These angiogenic proteins were expressed in the majority of leukemic bone marrow samples. Notably, pre-B ALL patients had significantly increased expression of VEGFR-1 compared with no expression in the nonmalignant group, indicating a link between VEGFR-1 protein expression and pre-B ALL. These novel findings suggest that VEGFR-1 may have clinical importance in childhood pre-B ALL.

Nyckelord
VEGF; VEGFR-1; VEGFR-2; childhood pre-B ALL; immunohistochemistry
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-53853 (URN)10.1097/MPH.0b013e3181b258df (DOI)000269701800018 ()
Tillgänglig från: 2010-02-06 Skapad: 2010-02-06 Senast uppdaterad: 2017-12-12
Gauffin, F., Diffner, E., Gustafsson, B., Nordgren, A., Gjorloff Wingren, A., Sander, B., . . . Gustafsson, B. (2009). Expresson of PTEN and SHP1, Ivestigated from Tissue Microarrays in Pediatric Acute Lymphoblastic, Leukemia. Pediatric Hematology & Oncology, 26(1), 48-56
Öppna denna publikation i ny flik eller fönster >>Expresson of PTEN and SHP1, Ivestigated from Tissue Microarrays in Pediatric Acute Lymphoblastic, Leukemia
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2009 (Engelska)Ingår i: Pediatric Hematology & Oncology, ISSN 0888-0018, E-ISSN 1521-0669, Vol. 26, nr 1, s. 48-56Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

PTEN and SHP1 are tumor suppressor genes involved in the regulation of cell cycle control and apoptosis. The authors investigated the protein expression of PTEN and SHP1, by immunohistochemistry in tissue microarrays from bone marrow samples in children, diagnosed with acute lymphoblastic leukaemia and nonmalignant controls. PTEN was overexpressed in diagnostic ALL samples, while SHP1 showed a low expression. Both proteins showed a significant difference in expression compared to nonmalignant controls. The roles of PTEN and SHP1 are not well investigated in pediatric leukemia and could in the future play a role as prognostic factors.

Nyckelord
pediatric leukemia, PTEN, SHP1, tissue microarray
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-16959 (URN)10.1080/08880010802625530 (DOI)
Tillgänglig från: 2009-02-28 Skapad: 2009-02-27 Senast uppdaterad: 2017-12-13
Kurz, T., Terman, A., Gustafsson, B. & Brunk, U. (2008). Lysosomes and oxidative stress in aging and apoptosis. Biochimica et Biophysica Acta - General Subjects, 1780(11), 1291-1303
Öppna denna publikation i ny flik eller fönster >>Lysosomes and oxidative stress in aging and apoptosis
2008 (Engelska)Ingår i: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1780, nr 11, s. 1291-1303Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The lysosomal compartment consists of numerous acidic vesicles (pH ~ 4-5) that constantly fuse and divide. It receives a large number of hydrolases from the trans-Golgi network, while their substrates arrive from both the cell's outside (heterophagy) and inside (autophagy). Many macromolecules under degradation inside lysosomes contain iron that, when released in labile form, makes lysosomes sensitive to oxidative stress. The magnitude of generated lysosomal destabilization determines if reparative autophagy, apoptosis, or necrosis will follow. Apart from being an essential turnover process, autophagy is also a mechanism for cells to repair inflicted damage, and to survive temporary starvation. The inevitable diffusion of hydrogen peroxide into iron-rich lysosomes causes the slow oxidative formation of lipofuscin in long-lived postmitotic cells, where it finally occupies a substantial part of the volume of the lysosomal compartment. This seems to result in a misdirection of lysosomal enzymes away from autophagosomes, resulting in depressed autophagy and the accumulation of malfunctioning mitochondria and proteins with consequent cellular dysfunction. This scenario might put aging into the category of autophagy disorders. © 2008 Elsevier B.V. All rights reserved.

Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-43541 (URN)10.1016/j.bbagen.2008.01.009 (DOI)74137 (Lokalt ID)74137 (Arkivnummer)74137 (OAI)
Tillgänglig från: 2009-10-10 Skapad: 2009-10-10 Senast uppdaterad: 2017-12-13
Kurz, T., Terman, A., Gustafsson, B. & Brunk, U. T. (2008). Lysosomes In Iron Metabolism, Ageing And Apoptosis. Histochemistry and Cell Biology, 129(4), 389-406
Öppna denna publikation i ny flik eller fönster >>Lysosomes In Iron Metabolism, Ageing And Apoptosis
2008 (Engelska)Ingår i: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 129, nr 4, s. 389-406Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The lysosomal compartment is essential for a variety of cellular functions, including the normal turnover of most long-lived proteins and all organelles. The compartment consists of numerous acidic vesicles (pH ~4-5) that constantly fuse and divide. It receives a large number of hydrolases (~50) from the trans-Golgi network, and substrates from both the cells’ outside (heterophagy) and inside (autophagy). Many macromolecules contain iron that gives rise to an iron-rich environment in lysosomes that recently have degraded such macromolecules. Iron-rich lysosomes are sensitive to oxidative stress, while ‘resting’ lysosomes, which have not recently participated in autophagic events, are not. The magnitude of oxidative stress determines the degree of lysosomal destabilization and, consequently, whether arrested growth, reparative autophagy, apoptosis, or necrosis will follow. Heterophagy is the first step in the process by which immunocompetent cells modify antigens and produce antibodies, while exocytosis of lysosomal enzymes may promote tumor invasion, angiogenesis, and metastasis. Apart from being an essential turnover process, autophagy is also a mechanism by which cells will be able to sustain temporary starvation and rid themselves of intracellular organisms that have invaded, although some pathogens have evolved mechanisms to prevent their destruction. Mutated lysosomal enzymes are the underlying cause of a number of lysosomal storage diseases involving the accumulation of materials that would be the substrate for the corresponding hydrolases, were they not defective. The normal, low-level diffusion of hydrogen peroxide into iron-rich lysosomes causes the slow formation of lipofuscin in long-lived postmitotic cells, where it occupies a substantial part of the lysosomal compartment at the end of the life span. This seems to result in the diversion of newly produced lysosomal enzymes away from autophagosomes, leading to the accumulation of malfunctioning mitochondria and proteins with consequent cellular dysfunction. If autophagy were a perfect turnover process, postmitotic ageing and several age-related neurodegenerative diseases would, perhaps, not take place.

Ort, förlag, år, upplaga, sidor
Institutionen för medicin och hälsa, 2008
Nyckelord
Ageing, Autophagy, Lipofuscin, Lysosomes, Mitochondria, Oxidative stress
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-11216 (URN)10.1007/s00418-008-0394-y (DOI)
Anmärkning

Original publication: Tino Kurz, Alexei Terman, Bertil Gustafsson, and Ulf T. Brunk, Lysosomes In Iron Metabolism, Ageing And Apoptosis, 2008, Histochemistry and Cell Biology. http://dx.doi.org/10.1007/s00418-008-0394-y. Copyright: The original publication is available at www.springerlink.com

Tillgänglig från: 2009-02-09 Skapad: 2008-04-15 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
Terman, A., Kurz, T., Gustafsson, B. & Brunk, U. (2008). The involvement of lysosomes in myocardial aging and disease. Current Cardiology Reviews, 4(2), 107-115
Öppna denna publikation i ny flik eller fönster >>The involvement of lysosomes in myocardial aging and disease
2008 (Engelska)Ingår i: Current Cardiology Reviews, ISSN 1573-403X, Vol. 4, nr 2, s. 107-115Artikel, forskningsöversikt (Refereegranskat) Published
Abstract [en]

The myocardium is mainly composed of long-lived postmitotic cells with, if there is any at all, a very low rate of replacement through the division and differentiation of stem cells. As a consequence, cardiac myocytes gradually undergo pronounced age-related alterations which, furthermore, occur at a rate that inversely correlates with the longevity of species. Basically, these alterations represent the accumulation of structures that have been damaged by oxidation and that are useless and often harmful. These structures (so-called 'waste' materials), include defective mitochondria, aberrant cytosolic proteins, often in aggregated form, and lipofuscin, which is an intralysosomal undegradable polymeric substance. The accumulation of 'waste' reflects the insufficient capacity for autophagy of the lysosomal compartment, as well, as the less than perfect functioning of proteasomes, calpains and other cellular digestive systems. Senescent mitochondria are usually enlarged, show reduced potential over their inner membrane, are deficient in ATP production, and often produce increased amounts of reactive oxygen species. The turnover of damaged cellular structures is hindered by an increased lipofuscin loading of the lysosomal compartment. This particularly restricts the autophagic turnover of enlarged, defective mitochondria, by diverting the flow of lysosomal hydrolases from autophagic vacuoles to lipofuscin-loaded lysosomes where the enzymes are lost, since lipofuscin is not degradable by lysosomal hydrolases. As a consequence, aged lipofuscin-rich cardiac myocytes become overloaded with damaged mitochondria, leading to increased oxidative stress, apoptotic cell death, and the gradual development of heart failure. Defective lysosomal function also underlies myocardial degeneration in various lysosomal storage diseases, while other forms of cardiomyopathies develop due to mitochondrial DNA mutations, resulting in an accumulation of abnormal mitochondria that are not properly eliminated by autophagy. The degradation of iron-saturated ferritin in lysosomes mediates myocardial injury in hemochromatosis, an acquired or hereditary disease associated with iron overload. Lysosomes then become sensitized to oxidative stress by the overload of low mass, redox-active iron that accumulates when iron-saturated ferritin is degraded following autophagy. Lysosomal destabilization is of importance in the induction and/or execution of programmed cell death (either classical apoptotic or autophagic), which is a common manifestation of myocardial aging and a variety of cardiac pathologies. © 2008 Bentham Science Publishers Ltd.

Ort, förlag, år, upplaga, sidor
Bussum, Netherlands: Bentham Science Publishers Ltd., 2008
Nyckelord
Aging, Apoptosis, Autophagy, Cardiac myocytes, Mitochondria, Oxidative stress
Nationell ämneskategori
Cellbiologi
Identifikatorer
urn:nbn:se:liu:diva-46333 (URN)10.2174/157340308784245801 (DOI)19936285 (PubMedID)2-s2.0-41049090468 (Scopus ID)
Tillgänglig från: 2009-10-11 Skapad: 2009-10-11 Senast uppdaterad: 2015-11-19Bibliografiskt granskad
Terman, A., Gustafsson, B. & Brunk, U. (2007). Autophagy, organelles and ageing. Journal of Pathology, 211(2), 134-143
Öppna denna publikation i ny flik eller fönster >>Autophagy, organelles and ageing
2007 (Engelska)Ingår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 211, nr 2, s. 134-143Artikel, forskningsöversikt (Refereegranskat) Published
Abstract [en]

As a result of insufficient digestion of oxidatively damaged macromolecules and organelles by autophagy and other degradative systems, long-lived postmitotic cells, such as cardiac myocytes, neurons and retinal pigment epithelial cells, progressively accumulate biological 'garbage' ('waste' materials). The latter include lipofuscin (a non-degradable intralysosomal polymeric substance), defective mitochondria and other organelles, and aberrant proteins, often forming aggregates (aggresomes). An interaction between senescent lipofuscin-loaded lysosomes and mitochondria seems to play a pivotal role in the progress of cellular ageing. Lipofuscin deposition hampers autophagic mitochondrial turnover, promoting the accumulation of senescent mitochondria, which are deficient in ATP production but produce increased amounts of reactive oxygen species. Increased oxidative stress, in turn, further enhances damage to both mitochondria and lysosomes, thus diminishing adaptability, triggering mitochondrial and lysosomal pro-apoptotic pathways, and culminating in cell death. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Nyckelord
Ageing, Apoptosis, Autophagy, Lipofuscin, Lysosomes, Mitochondria, Oxidative stress, Reactive oxygen species
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-50022 (URN)10.1002/path.2094 (DOI)
Tillgänglig från: 2009-10-11 Skapad: 2009-10-11 Senast uppdaterad: 2017-12-12
Kågedal, B., Farnebäck, M., Håkansson, A., Gustafsson, B. & Håkansson, L. (2007). How useful are housekeeping genes?: variable expression in melanoma metastases. Clinical Chemistry and Laboratory Medicine, 45(11), 1481-1487
Öppna denna publikation i ny flik eller fönster >>How useful are housekeeping genes?: variable expression in melanoma metastases
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2007 (Engelska)Ingår i: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 45, nr 11, s. 1481-1487Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: There is a certain difference in opinion regarding the optimal choice of housekeeping genes used as normalization factors in gene expression analysis. We have therefore examined the suitability of three housekeeping genes, hypoxanthine phosphoribosyl transferase, β-glucuronidase and β2-micro-globulin, for normalization of expression data from melanoma metastases.

Methods: The expression of the three housekeeping genes was quantified by quantitative reverse transcription PCR in snap-frozen sections from 44 melanoma metastases, of which 19 were from patients treated with cisplatinum, dacarbazine and interferon-α2b.

Results: The expression of each housekeeping gene varied considerably between the different metastases. Histopathological examination of the tissue sections revealed variation in the amount of tumor cells in the tissue, necrosis, varying degrees of lymphocyte infiltration, and lymph node remnants. Based on this examination, 16 biopsies were omitted from further analysis because they had cracked, contained empty or necrotic areas, or were dominated by lymph node tissue. Even in sections with more than 90% tumor cells, a wide variation in the expression of the three housekeeping genes was found. The amount of lymphatic infiltrate in the tumors can have an effect on the expression of housekeeping genes in the meta-stases, whereas treatment did not seem to influence the expression.

Conclusions: We conclude that the choice of housekeeping genes can have great impact on the normalization of specific genes in melanoma metastases. Furthermore, in the analysis of mRNA expression in tumor tissue, microscopic examination is of great importance to evaluate the integrity and cellular composition of the biopsy.

Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-39472 (URN)10.1515/CCLM.2007.303 (DOI)48767 (Lokalt ID)48767 (Arkivnummer)48767 (OAI)
Tillgänglig från: 2009-10-10 Skapad: 2009-10-10 Senast uppdaterad: 2017-12-13
Clinchy, B., Fransson, A., Druvefors, P., Hellsten, A., Håkansson, A., Gustafsson, B., . . . Håkansson, L. (2007). Preoperative interleukin-6 production by mononuclear blood cells predicts survival after radical surgery for colorectal carcinoma. Cancer, 109(9), 1742-1749
Öppna denna publikation i ny flik eller fönster >>Preoperative interleukin-6 production by mononuclear blood cells predicts survival after radical surgery for colorectal carcinoma
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2007 (Engelska)Ingår i: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 109, nr 9, s. 1742-1749Artikel i tidskrift (Refereegranskat) Published
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.

Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-39824 (URN)10.1002/cncr.22623 (DOI)51413 (Lokalt ID)51413 (Arkivnummer)51413 (OAI)
Tillgänglig från: 2009-10-10 Skapad: 2009-10-10 Senast uppdaterad: 2017-12-13
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