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  • 1. Bernsen, Monique R
    et al.
    Smetsers, Toon
    van der Westerlo, Els
    Ruiter, Dirk
    Håkansson, Leif
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    van Kuppevelt, Toin
    Krysander, Lennart
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Hand och plastikkirurgi. Östergötlands Läns Landsting, Rekonstruktionscentrum, Hand- och plastikkirurgiska kliniken US.
    Rettrup, Björn
    Håkansson, Annika
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Heparan sulphate epitope-expression is associated with the inflammatory response in metastatic malignant melanoma2003Inngår i: Cancer Immunology and Immunotherapy, ISSN 0340-7004, E-ISSN 1432-0851, Vol. 52, nr 12, s. 780-783Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 2. Bernsen, MR
    et al.
    Håkansson, Leif
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Krysander, Lennart
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Hand och plastikkirurgi. Östergötlands Läns Landsting, Rekonstruktionscentrum, Hand- och plastikkirurgiska kliniken US.
    Rettrup, B
    Ruiter, D
    Håkansson, Annika
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    On the biological relevance of MHC class II and B7 expression by tumour cells in melanoma metastases2003Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 88, nr 3, s. 424-431Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 3.
    Clinchy, Birgitta
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi.
    Fransson, Annelie
    Druvefors, Pelle
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för kirurgi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Hellsten, Anna
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi.
    Håkansson, Annika
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Sjödahl, Rune
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för kirurgi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Håkansson, Leif
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Preoperative interleukin-6 production by mononuclear blood cells predicts survival after radical surgery for colorectal carcinoma2007Inngår i: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 109, nr 9, s. 1742-1749Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 4.
    Dahlfors, Gunilla
    et al.
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Chen, Yun
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Gustafsson, Bertil
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik. Linköpings universitet, Hälsouniversitetet.
    Arnqvist, Hans
    Linköpings universitet, Institutionen för medicin och vård, Internmedicin. Östergötlands Läns Landsting, MKC-2, GE: endomed. Linköpings universitet, Hälsouniversitetet.
    Inhibitory effect of diabetes on proliferation of vascular smooth muscle after balloon injury in rat aorta2000Inngår i: Experimental Diabetes Research, ISSN 1687-5214, E-ISSN 1687-5303, Vol. 1, nr 2, s. 101-109Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 5.
    Diffner, Eva
    et al.
    Lund University.
    Gauffin, Fredrika
    Karolinska University Hospital.
    Anagnostaki, Lola
    Malmö University Hospital .
    Nordgren, Ann
    Karolinska Institutet.
    Gustafsson, Bertil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Sander, Birgitta
    Karolinska University Hospital.
    Gustafsson, Britt
    Karolinska Institutet.
    Liao Persson, Jenny
    Lund University.
    Expression of VEGF and VEGF Receptors in Childhood Precursor B-cell Acute Lymphoblastic Leukemia Evaluated by Immunohistochemistry2009Inngår i: Journal of pediatric hematology/oncology (Print), ISSN 1077-4114, E-ISSN 1536-3678, Vol. 31, nr 9, s. 696-701Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 6.
    Farnebäck, Malin
    et al.
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Håkansson, Annika
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Håkansson, Leif
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Gustafsson, Bertil
    Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och cytologi. Linköpings universitet, Hälsouniversitetet.
    Kågedal, Bertil
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Expression of tumor associated transcripts in malignant melanoma metastases: with methodological aspectsManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Several antigens expressed in malignant melanoma are involved in the immunological surveillance of the tumor. The mRNAs of these antigens, especially tyrosinase, have also been used in the detection of minimal residual disease in the blood of melanoma patients. We have therefore analyzed the expression of tyrosinase, TRP-1, TRP-2, MART-1/Melan-A, MAGE-A3, MAGE-A12, S-100 and GD2 synthase by real-time PCR in snap frozen sections from 28 regional and systemic metastases. Treatment with cisplatinum, dacarbazine and interferon-α2b was given to 15 patients before surgery. The transcript concentrations varied widely between individual metastases. However, in general the pigment-related transcripts and that of S-100 were found at higher levels than those of MAGE-A3, MAGE-A12 and GD2 synthase. Significant correlations (p<0.001) were found between tyrosinase and MART-1/Melan-A and between MAGE-A3 and MAGE-A12. TRP-2 and GD2 synthase were both influenced by the treatment, TRP-2 expression was increased in the metastases from treated patients, whereas GD2 synthase expression was decreased. Furthermore, a decrease in tyrosinase expression was found in metastases without tumor-infiltrating lymphocytes. ln this work normalization by the section area contra normalization by housekeeping genes was also evaluated and similar results were obtained with both methods.

  • 7.
    Gauffin, Fredrika
    et al.
    Karolinska University Hospital.
    Diffner, Eva
    Malmö University Hospital.
    Gustafsson, Bertil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Nordgren, Ann
    Karolinska Institute.
    Gjorloff Wingren, Anette
    Malmö University Hospital.
    Sander, Birgitta
    Karolinska Institute.
    Liao Persson, Jenny
    Lund University.
    Gustafsson, Britt
    Karolinska Institute.
    Expresson of PTEN and SHP1, Ivestigated from Tissue Microarrays in Pediatric Acute Lymphoblastic, Leukemia2009Inngår i: Pediatric Hematology & Oncology, ISSN 0888-0018, E-ISSN 1521-0669, Vol. 26, nr 1, s. 48-56Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 8.
    Gustafsson, Bertil
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Hjalmar, V.
    Winiarski, J
    Gustafsson, B.
    Christensson, B.
    Cellular expression of MDM2 and p53 in childhood leukemias with poor prognosis2000Inngår i: Medical and Pediatric Oncology, ISSN 0098-1532, E-ISSN 1096-911X, Vol. 34, nr 2, s. 117-124Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 9. Gustafsson, Britt
    et al.
    Axelsson, Birgitta
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Christensson, Birger
    Winiarski, Jacek
    MDM2 and p53 in childhood acute lymphoblastic leukemia: Higher expression in childhood leukemias with poor prognosis compared to long-term survivors2001Inngår i: Pediatric Hematology & Oncology, ISSN 0888-0018, E-ISSN 1521-0669, Vol. 18, s. 497-508Artikkel i tidsskrift (Fagfellevurdert)
  • 10.
    Håkansson, Annika
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Abdiu, Avni
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Hand och plastikkirurgi. Östergötlands Läns Landsting, Rekonstruktionscentrum, Hand- och plastikkirurgiska kliniken US.
    Krysander, Lennart
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Hand och plastikkirurgi. Östergötlands Läns Landsting, Rekonstruktionscentrum, Hand- och plastikkirurgiska kliniken US.
    Håkansson, Leif
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Bcl-2 expression in metastatic malignant melanoma. Importance for the therapeutic efficacy of biochemotherapy2003Inngår i: Cancer Immunology and Immunotherapy, ISSN 0340-7004, E-ISSN 1432-0851, Vol. 52, nr 4, s. 249-254Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    For the majority of patients with metastatic malignant melanoma the prognosis is poor. Immunotherapy and biochemotherapy have shown promise with a subset of durable responses, but there is still a great need for a better understanding of the mechanisms of action during treatment to optimize future treatment schedules. In the present study Bcl-2 expression was studied in biopsies from ten patients with metastatic malignant melanoma (five with regional disease and five with systemic disease) treated with biochemotherapy, (cisplatinum 30 mg/m2 days 1-3, DTIC 250 mg/m2 days 1-3 i.v. and Interferon-a2b 10 MIU s.c. 3 days a week, on a 28-day cycle). The expression of Bcl-2 by the tumour cells was separately recorded in areas of histopathological regressive changes and in areas of unaffected tumour growth. Comparisons were made with biopsies from 14 untreated patients. In 10 of 10 treated patients a high expression of Bcl-2 by the tumour cells was found in areas of unaffected tumour growth. In contrast, only in 5 of 13 untreated patients was a high expression of Bcl-2 by the tumour cells found in these areas (P = 0.008). A significant difference was also found in the expression of Bcl-2 by the tumour cells between areas of unaffected tumour growth and areas of histopathological regressive changes (P=0.03). The significantly higher expression of Bcl-2 by the tumour cells in areas of unaffected tumour growth in treated patients compared to untreated patients indicates that clones with a high expression of Bcl-2 may be present after therapy, preventing apoptosis and eventually in many patients resulting in progressive disease. Supporting this concept, a difference was also found between the expression of Bcl-2 in areas of unaffected tumour growth, i.e. in areas of treatment failure, and the expression in areas of histopathological regressive changes. Thus immunohistochemical analysis of tumour biopsies shortly after therapy seems to be a good surrogate endpoint that allows a detailed analysis of Bcl-2 expression. The high expression of Bcl-2 shown in unaffected tumour areas after therapy suggests the need for additional treatment, e.g. Bcl-2 antisense therapy.

  • 11.
    Håkansson, Annika
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Krysander, Lennart
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Hand och plastikkirurgi. Östergötlands Läns Landsting, Rekonstruktionscentrum, Hand- och plastikkirurgiska kliniken US.
    Hjelmqvist, B
    Rettrup, B
    Håkansson, L
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Biochemotherapy of metastatic malignant melanoma. Predictive value of tumour-infiltrating lymphocytes2001Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 85, nr 12, s. 1871-1877Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The therapeutic efficacy of biochemotherapy in metastatic malignant melanoma still carries a low remission rate, but with some durable responses. It would therefore be of considerable importance if patients with a high probability of responding could be identified using predictive tests. The response to interferon-alpha (IFN-a) correlates with the occurrence of CD4+ lymphocytes identified by fine-needle aspirates from melanoma metastases (Hσkansson et al, 1996). The present investigation studies a possible correlation between tumour-infiltrating CD4+ lymphocytes in malignant melanoma metastases and the therapeutic effect of biochemotherapy. A total of 25 patients with systemic and 16 with regional metastatic melanoma were analysed before initiation of biochemotherapy (cis-platinum 30 mg/m2 d.1-3, DTIC 250 mg/m2 d.1-3 i.v. and IFN-a2b 10 million IU s.c. 3 days a week, q. 28d.). A monoclonal antibody, anti-CD4, was used to identify tumour-infiltrating lymphocytes in fine-needle aspirates before start of treatment. The presence of these lymphocytes was correlated to response, time to progression and overall survival. A statistically significant correlation (P = 0.01) was found between the occurrence of CD4+ lymphocytes and tumour regression during biochemotherapy in patients with systemic disease. Out of 14 patients with moderate to high numbers of infiltrating CD4+ lymphocytes, 12 achieved tumour regression. In contrast, among patients with low numbers of these cells in metastatic lesions, 8 out of 11 had progressive disease. We also found a significantly longer time to progression (P < 0.003) and overall survival (P < 0.01) among patients with moderate to high numbers of these cells compared to patients with low numbers of these cells before initiation of biochemotherapy. Furthermore, in patients with regional disease, we found a significantly longer time to progression (P = 0.01) and a trend toward a longer overall survival time (P = 0.09). Based on these results and as previously shown with IFN-a therapy alone, there seems to be a need for CD4+ lymphocytes infiltrating the tumours before the start of biochemotherapy to make the treatment successful. Determination of these cells in fine-needle aspirates seems to be a method to predict responders to biochemotherapy, thus increasing the cost-benefit of this treatment strategy considerably, both in terms of patient adverse reactions and health care costs. ⌐ 2001 Cancer Research Campaign.

  • 12.
    Håkansson, Annika
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Krysander, Lennart
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Hand och plastikkirurgi. Östergötlands Läns Landsting, Rekonstruktionscentrum, Hand- och plastikkirurgiska kliniken US.
    Hjelmqvist, B.
    Rettrup, B.
    Håkansson, L.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Expression of ICAM-1 during IFN-alpha-based treatment of metastatic malignant melanoma: relation to tumour infiltrating mononuclear cells and regressive tumour changes.1999Inngår i: Journal of Interferon and Cytokine Research, ISSN 1079-9907, E-ISSN 1557-7465, Vol. 19, s. 171-177Artikkel i tidsskrift (Fagfellevurdert)
  • 13.
    Håkansson, Annika
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Krysander, Lennart
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Hand och plastikkirurgi. Östergötlands Läns Landsting, Rekonstruktionscentrum, Hand- och plastikkirurgiska kliniken US.
    Hjelmqvist, Bengt
    Rettrup, Björn
    Håkansson, Leif
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    On down-regulation of the immune response to metastatic malignant melanoma.1999Inngår i: Cancer Immunology and Immunotherapy, ISSN 0340-7004, E-ISSN 1432-0851, Vol. 48, s. 253-262Artikkel i tidsskrift (Fagfellevurdert)
  • 14.
    Håkansson, Annika
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Håkansson, Leif
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Krysander, Lennart
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Hand och plastikkirurgi. Östergötlands Läns Landsting, Rekonstruktionscentrum, Hand- och plastikkirurgiska kliniken US.
    Rettrup, Björn
    Ruiter, Dirk
    Bernsen, Monique
    Biochemotherapy of metastatic malignant melanoma. On down-regulation of CD282002Inngår i: Cancer Immunology and Immunotherapy, ISSN 0340-7004, E-ISSN 1432-0851, Vol. 51, nr 9, s. 499-504Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Immunotherapy and combination treatments such as biochemotherapy have shown promise, with higher response rates and a subset of durable responses, however, as the majority of responses are still of short duration, they do not provide any survival benefit. There is therefore a great need to better understand the mechanisms whereby tumours escape immune surveillance. The present study examines the expression of CD28 in patients with untreated and treated melanoma metastases. Twenty-eight patients with metastatic malignant melanoma were treated by biochemotherapy (cisplatinum 30 mg/m2 days 1-3, DTIC 250 mg/m2 days1-3 i.v., and IFN-a2b 10 million IU s.c. three days a week for 28 days treatment cycle). Tumours were resected post-biochemotherapy and analysed for the expression of CD28 in CD4+ and CD8+ lymphocytes in areas where histopathological regressive changes had occurred, and close to tumour cells in areas of unaffected tumour growth using a double-staining technique. A high percentage of the lymphocytes in areas with regressive changes were found to be CD4+ CD28-. In contrast, the vast majority of CD4+ lymphocytes migrating close to the tumour cells were found to be CD28+ (P<0.001). A similar difference in the expression of CD28 was also found for the CD8+ subset (P=0.004). A difference in down-regulation of the expression of CD28 was found between CD4+ and CD8+ lymphocytes both in the areas of regressive changes and in the unaffected tumour areas. The present study demonstrates that extensive down-regulation of the co-stimulatory factor CD28 is found in metastases following biochemotherapy. These results indicate that parameters of importance for the immune function have already undergone modification after one or two treatment cycles and that this down-regulation occurs in particular in areas with regressive tumour changes.

  • 15.
    Håkansson, Annika
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Håkansson, Leif
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Krysander, Lennart
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Hand och plastikkirurgi. Östergötlands Läns Landsting, Rekonstruktionscentrum, Hand- och plastikkirurgiska kliniken US.
    Rettrup, Björn
    Ruiter, Dirk
    Bernsen, Monique R
    On the effect of biochemotherapy in metastatic malignant melanoma: An immunopathological evaluation2003Inngår i: Melanoma research, ISSN 0960-8931, E-ISSN 1473-5636, Vol. 13, nr 4, s. 401-407Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Although immunotherapy and biochemotherapy have shown promise, producing a subset of durable responses, for the majority of patients with metastatic melanoma the prognosis is still poor. Therefore there is a great need for predictive tests to identify patients with a high probability of responding. Furthermore, there is also a need for a better understanding of the mechanisms of action during treatment in order to be able to monitor the relevant antitumour reactivity during treatment and to optimize the efficacy of future immunotherapy and biochemotherapy. In the present study histopathological regression criteria were used to study the efficacy of biochemotherapy. Thirty-two patients with metastatic malignant melanoma (18 with regional disease and 14 with systemic disease) were treated with biochemotherapy (cisplatin 30 mg/m2 intravenously on days 1-3, dacarbazine 250 mg/m2 intravenously on days 1-3 and interferon-a2b 10 million IU subcutaneously 3 days a week, every 28 days). Pre-treatment fine needle aspirates were obtained from metastases to analyse the number of tumour-infiltrating CD4+ lymphocytes. Therapeutic efficacy was evaluated in metastases resected after treatment using histopathological criteria of tumour regression. Comparisons were also made with metastases from 17 untreated patients, all with regional disease. Regressive changes of 25% or more (of the section area) were found in two of the 17 untreated patients with regional disease compared with 13 of the 18 patients with regional disease and 10 of the 14 patients with systemic disease after biochemotherapy. Fifty per cent of the patients with regional disease showed a high degree of regressive changes (75-100% of the section area) after biochemotherapy. These results demonstrate the occurrence of an antitumour reactivity in the majority of patients. Patients with extensive regressive changes in 75-100% of the analysed biopsies were also found to have a longer overall survival (P = 0.019). In patients with regional disease there was a close correlation between a larger number of CD4+ lymphocytes pre-treatment and a higher degree of regressive changes post-treatment (P < 0.05). Thus, immunohistochemical analysis of tumour biopsies shortly after treatment seems to be a good surrogate endpoint This technique also allows detailed analysis of antitumour reactivity and escape mechanisms. ⌐ 2003 Lippincott Williams & Wilkins.

  • 16.
    Håkansson, Annika
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Håkansson, Leif
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Kågedal, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för klinisk kemi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk kemi.
    Bcl-2 monitoring in malignant melanoma2004Inngår i: Hospital Pharmacy, ISSN 0018-5787, E-ISSN 1945-1253, s. 46-47Artikkel i tidsskrift (Annet vitenskapelig)
  • 17.
    Koch, Andrea
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Internmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Allergicentrum US.
    Gustafsson, Bertil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Fohlin, Helena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Sörenson, Sverre
    Linköpings universitet, Institutionen för medicin och hälsa, Lungmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Lungmedicinska kliniken US.
    Cyclooxygenase-2 expression in lung cancer cells evaluated by immunocytochemistry2011Inngår i: Diagnostic Cytopathology, ISSN 8755-1039, E-ISSN 1097-0339, Vol. 39, nr 3, s. 188-193Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 18.
    Kurz, Tino
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi.
    Brunk, Ulf
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Cell sensitivity to oxidative stress is influenced by ferritin autophagy2011Inngår i: FREE RADICAL BIOLOGY AND MEDICINE, ISSN 0891-5849, Vol. 50, nr 11, s. 1647-1658Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 19.
    Kurz, Tino
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Intralysosomal iron chelation protects against oxidative stress-induced cellular damage2006Inngår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 273, nr 13, s. 3106-3117Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Oxidant-induced cell damage may be initiated by peroxidative injury to lysosomal membranes, catalyzed by intralysosomal low mass iron that appears to comprise a major part of cellular redox-active iron. Resulting relocation of lytic enzymes and low mass iron would result in secondary harm to various cellular constituents. In an effort to further clarify this still controversial issue, we tested the protective effects of two potent iron chelators - the hydrophilic desferrioxamine (dfo) and the lipophilic salicylaldehyde isonicotinoyl hydrazone (sih), using cultured lysosome-rich macrophage-like J774 cells as targets. dfo slowly enters cells via endocytosis, while the lipophilic sih rapidly distributes throughout the cell. Following dfo treatment, long-term survival of cells cannot be investigated because dfo by itself, by remaining inside the lysosomal compartment, induces apoptosis that probably is due to iron starvation, while sih has no lasting toxic effects if the exposure time is limited. Following preincubation with 1 mm dfo for 3 h or 10 μm sih for a few minutes, both agents provided strong protection against an ensuing ∼LD50 oxidant challenge by preventing lysosomal rupture, ensuing loss of mitochondrial membrane potential, and apoptotic/necrotic cell death. It appears that once significant lysosomal rupture has occurred, the cell is irreversibly committed to death. The results lend strength to the concept that lysosomal membranes, normally exposed to redox-active iron in high concentrations, are initial targets of oxidant damage and support the idea that chelators selectively targeted to the lysosomal compartment may have therapeutic utility in diminishing oxidant-mediated cell injury. © 2006 The Authors.

  • 20.
    Kurz, Tino
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Terman, Alexei
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Geriatrik.
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi.
    Lysosomes and oxidative stress in aging and apoptosis2008Inngår i: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1780, nr 11, s. 1291-1303Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 21.
    Kurz, Tino
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Terman, Alexei
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Geriatrik. Linköpings universitet, Hälsouniversitetet.
    Gustafsson, Bertil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Brunk, Ulf T.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lysosomes In Iron Metabolism, Ageing And Apoptosis2008Inngår i: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 129, nr 4, s. 389-406Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 22.
    Kågedal, Bertil
    et al.
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Farnebäck, Malin
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Håkansson, Annika
    Department of Oncology, University Hospital MAS and Lund University, Malmö, Sweden.
    Gustafsson, Bertil
    Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och cytologi. Linköpings universitet, Hälsouniversitetet.
    Håkansson, Leif
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    How useful are housekeeping genes?: variable expression in melanoma metastases2007Inngår i: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 45, nr 11, s. 1481-1487Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 23. Schüle, Jana
    et al.
    Bergkvist, Leif
    Håkansson, Leif
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Håkansson, Annika
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Down-regulation of the CD3-? chain in sentinel node biopsies from breast cancer patients2002Inngår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 74, nr 1, s. 33-40Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. In several neoplastic diseases, immunosuppression has been shown to correlate with disease stage, progression, and outcome. As the prognosis for metastatic breast cancer is still pessimistic, additional strategies are being sought to improve survival. Local immunosuppression in sentinel node biopsies from 24 evaluable breast cancer patients was studied as a possible way of selecting patients for immunotherapy. Method. Sentinel node biopsy was performed in 24 out of 25 women operated on for primary breast cancer (one was not evaluable). Specimens were snap-frozen and double-stained for the ?-chain of the T-cell receptor. The degree of down-regulation of the ?-chain was evaluated in three different lymph-node areas: primary follicles, secondary follicles, and paracortex. Results. Down-regulation of varying degrees was noted in all 24 sentinel node biopsies. A high degree of down-regulation (more than 50% of T-cells not expressing ?-chain) was seen in the primary follicles in six patients (25%), in the secondary follicles in 13 patients (72%), and in the paracortex in 19 patients (79%). Conclusion. Local down-regulation of an immune function parameter was seen in sentinel node biopsies from breast cancer patients. In addition to possible prognostic implications, the sentinel node might be an appropriate location for detecting early-stage immunological down-regulation, which might open a possibility of selecting patients who could benefit from immunotherapy.

  • 24. Schüle, Jana M
    et al.
    Bergkvist, Leif
    Håkansson, Leif
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Håkansson, Annika
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    CD28 expression in sentinel node biopsies from breast cancer patients in comparison with CD3-ζ chain expression2004Inngår i: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 2Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Immunosuppression is documented in several malignant diseases, including breast cancer. Subsequently, future therapeutic concepts might include immunological approaches. However, detailed knowledge about tumor immunogenicity and host immunoreactivity, and how to assess these adequately, is still limited. We studied CD28 and CD3-ζ expression in sentinel node biopsies (SNB) from breast cancer patients to analyze tumor-related changes in T cell activity. Method: 25 women underwent surgery for primary breast cancer, including SNB. Frozen sections from 21 sentinel nodes could be analyzed with a double-staining technique. CD28 expression was studied in CD4+ and CD8+ T-lymphocyte subsets and compared with CD3-ζ expression in three specified nodal regions. Results: The degree of CD28 expression varied between the different lymph node areas. The lowest degree of CD28 expression was observed in CD4+ T-lymphocytes in the paracortex and germinal centers. Here, a good agreement with CD3-ζ expression was found. A higher CD28 expression was noted in CD4+ T-cells in the primary follicles, where concordance with CD3-ζ expression was weaker. The CD8+ T-lymphocyte subset displayed generally a higher degree of CD28 expression than the CD4+ subset. Conclusion: Sentinel lymph nodes from breast cancer patients displayed local immunosuppression of varying extent. In the areas with the lowest degree of CD28 expression an accordingly low CD3-ζ expression was found. The SNB might prove an important diagnostic tool for the evaluation of interactions between tumor and the host immune system, helping to select patients who might benefit from adjuvant immunotherapy.

  • 25.
    Terman, Alexei
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Geriatrik.
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi.
    Autophagy, organelles and ageing2007Inngår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 211, nr 2, s. 134-143Artikkel, forskningsoversikt (Fagfellevurdert)
    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.

  • 26.
    Terman, Alexei
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Geriatrik.
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Mitochondrial damage and intralysosomal degradation in cellular aging2006Inngår i: Molecular Aspects of Medicine, ISSN 0098-2997, E-ISSN 1872-9452, Vol. 27, nr 5-6, s. 471-482Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Normal mitochondrial respiration is associated with a continuous production of superoxide and hydrogen peroxide, inevitably resulting in minor macromolecular damage. Damaged cellular components are not completely turned over by autophagy and other cellular repair systems, leading to a progressive age-related accumulation of biological "garbage" material, such as defective mitochondria, cytoplasmic protein aggregates and an intralysosomal undegradable material, lipofuscin. These changes primarily affect neurons, cardiac myocytes and other long-lived postmitotic cells that neither dilute this "garbage" by mitotic activity, nor are replaced by newly differentiated cells. Defective mitochondria are insufficient in ATP production and often generate increased amounts of reactive oxygen species, further enhancing oxidative stress. Lipofuscin-loaded lysosomes, in turn, poorly turn over mitochondria that gradually leads to the overload of long-lived postmitotic cells with "garbage" material, decreased adaptability and eventual cell death. © 2006 Elsevier Ltd. All rights reserved.

  • 27.
    Terman, Alexei
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Geriatrik.
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    The lysosomal-mitochondrial axis theory of postmitotic aging and cell death2006Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 163, nr 1-2, s. 29-37Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aging (senescence) is characterized by a progressive accumulation of macromolecular damage, supposedly due to a continuous minor oxidative stress associated with mitochondrial respiration. Aging mainly affects long-lived postmitotic cells, such as neurons and cardiac myocytes, which neither divide and dilute damaged structures, nor are replaced by newly differentiated cells. Because of inherent imperfect lysosomal degradation (autophagy) and other self-repair mechanisms, damaged structures (biological "garbage") progressively accumulate within such cells, both extra- and intralysosomally. Defective mitochondria and aggregated proteins are the most typical forms of extralysosomal "garbage", while lipofuscin that forms due to iron-catalyzed oxidation of autophagocytosed or heterophagocytosed material, represents intralysosomal "garbage". Based on findings that autophagy is diminished in lipofuscin-loaded cells and that cellular lipofuscin content positively correlates with oxidative stress and mitochondrial damage, we have proposed the mitochondrial-lysosomal axis theory of aging, according to which mitochondrial turnover progressively declines with age, resulting in decreased ATP production and increased oxidative damage. Due to autophagy of ferruginous material, lysosomes contain a pool of redox-active iron, which makes these organelles particularly susceptible to oxidative damage. Oxidant-mediated destabilization of lysosomal membranes releases hydrolytic enzymes to the cytosol, eventuating in cell death (either apoptotic or necrotic depending on the magnitude of the insult), while chelation of the intralysosomal pool of redox-active iron prevents these effects. In relation to the onset of oxidant-induced apoptosis, but after the initiating lysosomal rupture, cytochrome c is released from mitochondria and caspases are activated. Mitochondrial damage follows the release of lysosomal hydrolases, which may act either directly or indirectly, through activation of phospholipases or pro-apoptotic proteins such as Bid. Additional lysosomal rupture seems to be a consequence of a transient oxidative stress of mitochondrial origin that follows the attack by lysosomal hydrolases and/or phospholipases, creating an amplifying loop system. © 2006 Elsevier Ireland Ltd. All rights reserved.

  • 28.
    Terman, Alexei
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Geriatrik.
    Kurz, Tino
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi.
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi.
    Lysosomal labilization2006Inngår i: IUBMB Life - A Journal of the International Union of Biochemistry and Molecular Biology, ISSN 1521-6543, E-ISSN 1521-6551, Vol. 58, nr 9, s. 531-539Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The lysosomal compartment is the place for cellular degradation of endocytosed and autophagocytosed material and a center for normal turnover of organelles as well as most long-lived proteins. Lysosomes were long considered stable structures that broke and released their many hydrolytic enzymes only following necrotic cell death. It is now realized that lysosomes instead are quite vulnerable, although in a heterogeneous way. Their exposure to a number of events, such as oxidative stress, lysosomotropic detergents and aldhydes, as well as overexpression of the p53 protein, causes time-and-dose-dependent lysosomal rupture that is followed by apoptosis or necrosis. Partial lysosomal rupture has often been found to be an early upstream event in apoptosis, while necrosis results from fulminant lysosomal rupture. Consequently, factors influencing the stability of lysosomes, for instance their content of labile and redox-active iron, seem to be essential for the survival of cells. © 2006 IUBMB.

  • 29.
    Terman, Alexei
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Geriatrik. Linköpings universitet, Hälsouniversitetet. Laboratory of Clinical Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Kurz, Tino
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Gustafsson, Bertil
    Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och cytologi. Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Brunk, Ulf
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    The involvement of lysosomes in myocardial aging and disease2008Inngår i: Current Cardiology Reviews, ISSN 1573-403X, Vol. 4, nr 2, s. 107-115Artikkel, forskningsoversikt (Fagfellevurdert)
    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.

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