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Hammarsten, Peter
Publications (10 of 27) Show all publications
Hammarsten, P., Josefsson, A., Thysell, E., Lundholm, M., Hägglöf, C., Iglesias-Gato, D., . . . Bergh, A. (2019). Immunoreactivity for prostate specific antigen and Ki67 differentiates subgroups of prostate cancer related to outcome. Modern Pathology, 32(9), 1310-1319
Open this publication in new window or tab >>Immunoreactivity for prostate specific antigen and Ki67 differentiates subgroups of prostate cancer related to outcome
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2019 (English)In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 32, no 9, p. 1310-1319Article in journal (Refereed) Published
Abstract [en]

Based on gene-expression profiles, prostate tumors can be subdivided into subtypes with different aggressiveness and response to treatment. We investigated if similar clinically relevant subgroups can be identified simply by the combination of two immunohistochemistry markers: one for tumor cell differentiation (prostate specific antigen, PSA) and one for proliferation (Ki67). This was analyzed in men with prostate cancer diagnosed at transurethral resection of the prostate 1975-1991 (n = 331) where the majority was managed by watchful waiting. Ki67 and PSA immunoreactivity was related to outcome and to tumor characteristics previously associated with prognosis. Increased Ki67 and decreased PSA were associated with poor outcome, and they provided independent prognostic information from Gleason score. A combinatory score for PSA and Ki67 immunoreactivity was produced using the median PSA and Ki67 levels as cut-off (for Ki67 the upper quartile was also evaluated) for differentiation into subgroups. Patients with PSA low/Ki67 high tumors showed higher Gleason score, more advanced tumor stage, and higher risk of prostate cancer death compared to other patients. Their tumor epithelial cells were often ERG positive and expressed higher levels of ErbB2, phosphorylated epidermal growth factor receptor (pEGF-R) and protein kinase B (pAkt), and their tumor stroma showed a reactive response with type 2 macrophage infiltration, high density of blood vessels and hyaluronic acid, and with reduced levels of caveolin-1, androgen receptors, and mast cells. In contrast, men with PSA high/Ki67 low tumors were characterized by low Gleason score, and the most favorable outcome amongst PSA/Ki67-defined subgroups. Men with PSA low/Ki67 low tumors showed clinical and tumor characteristics intermediate of the two groups above. A combinatory PSA/Ki67 immunoreactivity score identifies subgroups of prostate cancers with different epithelial and stroma phenotypes and highly different outcome but the clinical usefulness of this approach needs to be validated in other cohorts.

National Category
Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-163898 (URN)10.1038/s41379-019-0260-6 (DOI)000484437000009 ()30980038 (PubMedID)2-s2.0-85064215051 (Scopus ID)
Available from: 2019-10-07 Created: 2019-10-07 Last updated: 2019-11-14Bibliographically approved
Adamo, H. H., Hammarsten, P., Hägglöf, C., Scherdin, T. D., Egevad, L., Stattin, P., . . . Bergh, A. (2019). Prostate cancer induces C/EBP expression in surrounding epithelial cells which relates to tumor aggressiveness and patient outcome. The Prostate, 79(5)
Open this publication in new window or tab >>Prostate cancer induces C/EBP expression in surrounding epithelial cells which relates to tumor aggressiveness and patient outcome
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2019 (English)In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 79, no 5Article in journal (Refereed) Published
Abstract [en]

Background: Implantation of rat prostate cancer cells into the normal rat prostate results in tumor-stimulating adaptations in the tumor-bearing organ. Similar changes are seen in prostate cancer patients and they are related to outcome. One gene previously found to be upregulated in the non-malignant part of tumor-bearing prostate lobe in rats was the transcription factor CCAAT/enhancer-binding protein- (C/EBP).

Methods: To explore this further, we examined C/EBP expression by quantitative RT-PCR, immunohistochemistry, and Western blot in normal rat prostate tissue surrounding slow-growing non-metastatic Dunning G, rapidly growing poorly metastatic (AT-1), and rapidly growing highly metastatic (MatLyLu) rat prostate tumors?and also by immunohistochemistry in a tissue microarray (TMA) from prostate cancer patients managed by watchful waiting.

Results: In rats, C/EBP mRNA expression was upregulated in the surrounding tumor-bearing prostate lobe. In tumors and in the surrounding non-malignant prostate tissue, C/EBP was detected by immunohistochemistry in some epithelial cells and in infiltrating macrophages. The magnitude of glandular epithelial C/EBP expression in the tumor-bearing prostates was associated with tumor size, distance to the tumor, and metastatic capacity. In prostate cancer patients, high expression of C/EBP in glandular epithelial cells in the surrounding tumor-bearing tissue was associated with accumulation of M1 macrophages (iNOS+) and favorable outcome. High expression of C/EBP in tumor epithelial cells was associated with high Gleason score, high tumor cell proliferation, metastases, and poor outcome.

Conclusions: This study suggest that the expression of C/EBP-beta, a transcription factor mediating multiple biological effects, is differentially expressed both in the benign parts of the tumor-bearing prostate and in prostate tumors, and that alterations in this may be related to patient outcome.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
biomarkers, C, EBP, prostate cancer, tumors instruct adjacent tissues
National Category
Cancer and Oncology Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-157947 (URN)10.1002/pros.23749 (DOI)000461573200001 ()30536410 (PubMedID)
Available from: 2019-04-17 Created: 2019-04-17 Last updated: 2019-04-17Bibliographically approved
Hammarsten, P., Scherdin, T. D., Hagglöf, C., Andersson, P., Wikström, P., Stattin, P., . . . Bergh, A. (2016). High Caveolin-1 Expression in Tumor Stroma Is Associated with a Favourable Outcome in Prostate Cancer Patients Managed by Watchful Waiting. PLoS ONE, 11(10), Article ID e0164016.
Open this publication in new window or tab >>High Caveolin-1 Expression in Tumor Stroma Is Associated with a Favourable Outcome in Prostate Cancer Patients Managed by Watchful Waiting
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id e0164016Article in journal (Refereed) Published
Abstract [en]

In the present study we have investigated whether Caveolin-1 expression in non-malignant and malignant prostate tissue is a potential prognostic marker for outcome in prostate cancer patients managed by watchful waiting. Caveolin-1 was measured in prostate tissues obtained through transurethral resection of the prostate from 395 patients diagnosed with prostate cancer. The majority of the patients (n = 298) were followed by watchful waiting after diagnosis. Tissue microarrays constructed from malignant and non-malignant prostate tissue were stained with an antibody against Caveolin-1. The staining pattern was scored and related to clinicopathologic parameters and outcome. Microdissection and qRT-PCR analysis of Cav-1 was done of the prostate stroma from non-malignant tissue and stroma from Gleason 3 and 4 tumors. Cav-1 RNA expression was highest in non-malignant tissue and decreased during cancer progression. High expression of Caveolin-1 in tumor stroma was associated with significantly longer cancer specific survival in prostate cancer patients. This association remained significant when Gleason score and local tumor stage were combined with Caveolin-1 in a Cox regression model. High stromal Caveolin-1 immunoreactivity in prostate tumors is associated with a favourable prognosis in prostate cancer patients managed by watchful waiting. Caveolin-1 could possibly become a useful prognostic marker for prostate cancer patients that are potential candidates for active surveillance.

National Category
Urology and Nephrology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-127714 (URN)10.1371/journal.pone.0164016 (DOI)000386204500015 ()27764093 (PubMedID)
Available from: 2016-12-15 Created: 2016-11-18 Last updated: 2018-06-09Bibliographically approved
Nilsson, M., Hägglöf, C., Hammarsten, P., Thysell, E., Stattin, P., Egevad, L., . . . Bergh, A. (2015). High Lysyl Oxidase (LOX) in the Non-Malignant Prostate Epithelium Predicts a Poor Outcome in Prostate Cancer Patient Managed by Watchful Waiting. PLoS ONE, 10(10), Article ID e0140985.
Open this publication in new window or tab >>High Lysyl Oxidase (LOX) in the Non-Malignant Prostate Epithelium Predicts a Poor Outcome in Prostate Cancer Patient Managed by Watchful Waiting
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 10, article id e0140985Article in journal (Refereed) Published
Abstract [en]

Lysyl oxidase (LOX) has been shown to both promote and suppress tumor progression, but its role in prostate cancer is largely unknown. LOX immunoreactivity was scored in prostate tumor epithelium, tumor stroma and in the tumor-adjacent non-malignant prostate epithelium and stroma. LOX scores in tumor and non-malignant prostate tissues were then examined for possible associations with clinical characteristics and survival in a historical cohort of men that were diagnosed with prostate cancer at transurethral resection and followed by watchful waiting. Men with a low LOX score in the non-malignant prostate epithelium had significantly longer cancer specific survival than men with a high score. Furthermore, LOX score in non-malignant prostate epithelium remained prognostic in a multivariable analysis including Gleason score. LOX score in prostate tumor epithelium positively correlated to Gleason score and metastases but was not associated with cancer survival. LOX score in tumor and non-malignant prostate stroma appeared unrelated to these tumor characteristics. In radical prostatectomy specimens, LOX immune-staining corresponded to LOX in-situ hybridization and LOX mRNA levels were found to be similar between tumor and adjacent non-malignant areas, but significantly increased in bone metastases samples. LOX levels both in tumors and in the surrounding tumor-bearing organ are apparently related to prostate cancer aggressiveness.

Place, publisher, year, edition, pages
Public library science, 2015
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-112009 (URN)10.1371/journal.pone.0140985 (DOI)000363799900020 ()26501565 (PubMedID)
Available from: 2015-11-30 Created: 2015-11-30 Last updated: 2018-06-07Bibliographically approved
Werner, M., Van De Water, T. R., Hammarsten, P., Arnoldsson, G. & Berggren, D. (2015). Morphological and morphometric characterization of direct transdifferentiation of support cells into hair cells in ototoxin-exposed neonatal utricular explants. Hearing Research, 321, 1-11
Open this publication in new window or tab >>Morphological and morphometric characterization of direct transdifferentiation of support cells into hair cells in ototoxin-exposed neonatal utricular explants
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2015 (English)In: Hearing Research, ISSN 0378-5955, E-ISSN 1878-5891, Vol. 321, p. 1-11Article in journal (Refereed) Published
Abstract [en]

We have studied aminoglycoside-induced vestibular hair-cell renewal using long-term culture of utricular macula explants from 4-day-old rats. Explanted utricles were exposed to 1 mM of gentamicin for 48 h, during 2nd and 3rd days in vitro (DIV), and then recovering in unsupplemented medium. Utricles were harvested at specified time points from the 2nd through the 28th DIV. The cellular events that occurred within hair cell epithelia during the culture period were documented from serial sectioned specimens. Vestibular hair cells (HCs) and supporting cells (SCs) were systematically counted using light microscopy (LM) with the assistance of morphometric software. Ultrastructural observations were made from selected specimens with transmission electron microscopy (TEM). After 7 DIV, i.e. four days after gentamicin exposure, the density of HCs was 11% of the number of HCs observed in non-gentamicin-exposed control explants. At 28 DIV the HC density was 61% of the number of HCs observed in the control group explant specimens. Simultaneously with this increase in HCs there was a corresponding decline in the number of SCs within the epithelium. The proportion of HCs in relation to SCs increased significantly in the gentamicin-exposed explant group during the 5th to the 28th DIV period of culture. There were no significant differences in the volume estimations of the gentamicin-exposed and the control group explants during the observed period of culture. Morphological observations showed that gentamicin exposure induced extensive loss of HCs within the epithelial layer, which retained their intact apical and basal linings. At 7 to 14 DIV (i.e. 3-11 days after gentamicin exposure) a pseudostratified epithelium with multiple layers of disorganized cells was observed. At 21 DIV new HCs were observed that also possessed features resembling SCs. After 28 DIV a new luminal layer of HCs with several layers of SCs located more basally characterized the gentamicin-exposed epithelium. No mitoses were observed within the epithelial layer of any explants. Our conclusion is that direct transdifferentiation of SCs into HCs was the only process contributing to the renewal of HCs after gentamicin exposure in these explants of vestibular inner ear epithelia obtained from the labyrinths of 4-day-old rats.

National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:umu:diva-102465 (URN)10.1016/j.heares.2014.12.011 (DOI)000350933600001 ()25576788 (PubMedID)
Available from: 2015-05-19 Created: 2015-04-26 Last updated: 2018-06-07Bibliographically approved
Hammarsten, P., Winther, J., Rudolfsson, S. H., Häggström, J., Karalija, A., Egevad, L., . . . Fowler, C. (2014). ErbB2 Receptor Immunoreactivity in Prostate Cancer: Relationship to the Androgen Receptor, Disease Severity at Diagnosis and Disease Outcome. PLoS ONE, 9(9), Article ID e105063.
Open this publication in new window or tab >>ErbB2 Receptor Immunoreactivity in Prostate Cancer: Relationship to the Androgen Receptor, Disease Severity at Diagnosis and Disease Outcome
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, article id e105063Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: ErbB2 is a member of the epidermal growth factor family of tyrosine kinases that is centrally involved in the pathogenesis of prostate cancer and several studies have reported that a high expression of this protein has prognostic value. In the present study, we have investigated whether tumour ErbB2 immunoreactivity (ErbB2-IR) has clinically useful prognostic value, i.e. that it provides additional prognostic information to that provided by routine clinical tests (Gleason score, tumour stage).

METHODOLOGY/PRINCIPAL FINDINGS: ErbB2-IR was measured in a well-characterised tissue microarray of tumour and non-malignant samples obtained at diagnosis. Additionally, mRNA levels of ErbB2-IR in the prostate were determined in the rat following manipulation of circulating androgen levels. Tumour ErbB2-IR was significantly associated with the downstream signalling molecule phosphorylated-Akt and with the cell proliferation marker Ki-67. The significant association of tumour ErbB2-IR with the Gleason score at diagnosis was lost when controlled for the association of both parameters with Ki-67. In the rat prostate, mRNA for ErbB2 was inversely associated with circulating androgen levels. There was no association between ErbB2-IR and the androgen receptor (AR)-IR in the tumours, but an interaction between the two parameters was seen with respect to their association with the tumour stage. Tumour ErbB2-IR was confirmed to be a prognostic marker for disease-specific survival, but it did not provide significant additive information to the Gleason score or to Ki-67.

CONCLUSIONS/SIGNIFICANCE: It is concluded that tumour ErbB2-IR is of limited clinical value as a prognostic marker to aid treatment decisions, but could be of pathophysiological importance in prostate cancer.

Place, publisher, year, edition, pages
Public Library Science, 2014
National Category
Immunology in the medical area Other Basic Medicine
Identifiers
urn:nbn:se:umu:diva-93295 (URN)10.1371/journal.pone.0105063 (DOI)000341774300001 ()25215939 (PubMedID)
Available from: 2014-09-16 Created: 2014-09-16 Last updated: 2018-06-07Bibliographically approved
Tidehag, V., Hammarsten, P., Egevad, L., Grantors, T., Stattin, P., Leanderson, T., . . . Bergh, A. (2014). High density of S100A9 positive inflammatory cells in prostate cancer stroma is associated with poor outcome. European Journal of Cancer, 50(10), 1829-1835
Open this publication in new window or tab >>High density of S100A9 positive inflammatory cells in prostate cancer stroma is associated with poor outcome
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2014 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 50, no 10, p. 1829-1835Article in journal (Refereed) Published
Abstract [en]

Purpose: To elucidate if the density of inflammatory cells expressing S100A9 in malignant and surrounding non-malignant prostate tissues is a prognostic marker for outcome in prostate cancer patients. Experimental design: Tissue was obtained from 358 men diagnosed with prostate cancer at transurethral resection of the prostate due to obstructive voiding problems, of which 260 were then followed with watchful waiting. Tissue microarrays of both malignant and non-malignant tissues were stained with an antibody against S100A9. The number of stained inflammatory cells was scored and related to clinical outcome and histopathological parameters of known prognostic value. Results: A high number of inflammatory cells expressing S100A9 in both malignant and surrounding non-malignant tissues were associated with significantly shorter cancer-specific survival. This association remained significant when Gleason score and local tumour stage were analysed together with S100A9 in a Cox regression model. Low number of S100A9 positive cells in non-malignant stroma was correlated to significantly longer cancer-specific survival also in patients with Gleason score 8-10 tumours. S100A9 positive cells in tumour stroma were correlated with Gleason score, hyaluronan, platelet-derived growth factor receptor beta (PDGFR-beta), and androgen receptor (inverse correlation) in tumour stroma. S100A9 positive cells in non-malignant stroma correlated with androgen receptor in this tissue compartment (inverse correlation). Conclusions: A high number of S100A9 positive inflammatory cells in tumour stroma and in non-malignant stroma were associated with shorter cancer-specific survival in prostate cancer patients.

Keywords
Prostate cancer, S100A9, Prognostic marker, Watchful waiting
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-91261 (URN)10.1016/j.ejca.2014.03.278 (DOI)000337875800016 ()
Available from: 2014-07-30 Created: 2014-07-28 Last updated: 2018-06-07Bibliographically approved
Bruzzese, F., Hägglöf, C., Leone, A., Sjöberg, E., Roca, M. S., Kiflemariam, S., . . . Augsten, M. (2014). Local and systemic protumorigenic effects of cancer-associated fibroblast-derived GDF15. Cancer Research, 74(13), 3408-3417
Open this publication in new window or tab >>Local and systemic protumorigenic effects of cancer-associated fibroblast-derived GDF15
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2014 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 13, p. 3408-3417Article in journal (Refereed) Published
Abstract [en]

The tumor stroma is vital to tumor development, progression, and metastasis. Cancer-associated fibroblasts (CAF) are among the abundant cell types in the tumor stroma, but the range of their contributions to cancer pathogenicity has yet to be fully understood. Here, we report a critical role for upregulation of the TGF beta/BMP family member GDF15 (MIC-1) in tumor stroma. GDF15 was found upregulated in situ and in primary cultures of CAF from prostate cancer. Ectopic expression of GDF15 in fibroblasts produced prominent paracrine effects on prostate cancer cell migration, invasion, and tumor growth. Notably, GDF15-expressing fibroblasts exerted systemic in vivo effects on the outgrowth of distant and otherwise indolent prostate cancer cells. Our findings identify tumor stromal cells as a novel source of GDF15 in human prostate cancer and illustrate a systemic mechanism of cancer progression driven by the tumor microenvironment. Further, they provide a functional basis to understand GDF15 as a biomarker of poor prognosis and a candidate therapeutic target in prostate cancer. (C)2014 AACR.

Place, publisher, year, edition, pages
American Association for Cancer Research, 2014
Keywords
macrophage-inhibitory cytokine-1; prostate-cancer; growth-factor; tumor-growth; colorectal-cancer; h6d polymorphism; autocrine factor; stromal cells; expression; beta
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-91752 (URN)10.1158/0008-5472.CAN-13-2259 (DOI)000338341700005 ()
Available from: 2014-08-19 Created: 2014-08-15 Last updated: 2018-06-07Bibliographically approved
Häggström, J., Cipriano, M., Plym Forshell, L., Persson, E., Hammarsten, P., Stella, N. & Fowler, C. J. (2014). Potential upstream regulators of cannabinoid receptor 1 signaling in prostate cancer: A Bayesian network analysis of data from a tissue microarray. The Prostate, 74(11), 1107-1117
Open this publication in new window or tab >>Potential upstream regulators of cannabinoid receptor 1 signaling in prostate cancer: A Bayesian network analysis of data from a tissue microarray
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2014 (English)In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 74, no 11, p. 1107-1117Article in journal (Refereed) Published
Abstract [en]

BACKGROUND The endocannabinoid system regulates cancer cell proliferation, and in prostate cancer a high cannabinoid CB1 receptor expression is associated with a poor prognosis. Down-stream mediators of CB1 receptor signaling in prostate cancer are known, but information on potential upstream regulators is lacking. RESULTS Data from a well-characterized tumor tissue microarray were used for a Bayesian network analysis using the max-min hill-climbing method. In non-malignant tissue samples, a directionality of pEGFR (the phosphorylated form of the epidermal growth factor receptor) CB1 receptors were found regardless as to whether the endocannabinoid metabolizing enzyme fatty acid amide hydrolase (FAAH) was included as a parameter. A similar result was found in the tumor tissue, but only when FAAH was included in the analysis. A second regulatory pathway, from the growth factor receptor ErbB2 FAAH was also identified in the tumor samples. Transfection of AT1 prostate cancer cells with CB1 receptors induced a sensitivity to the growth-inhibiting effects of the CB receptor agonist CP55,940. The sensitivity was not dependent upon the level of receptor expression. Thus a high CB1 receptor expression alone does not drive the cells towards a survival phenotype in the presence of a CB receptor agonist. CONCLUSIONS The data identify two potential regulators of the endocannabinoid system in prostate cancer and allow the construction of a model of a dysregulated endocannabinoid signaling network in this tumor. Further studies should be designed to test the veracity of the predictions of the network analysis in prostate cancer and other solid tumors.

Keywords
prostate cancer, epidermal growth factor, cannabinoid receptor, fatty acid amide hydrolase, directed acyclic graph
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-91251 (URN)10.1002/pros.22827 (DOI)000338039700004 ()
Available from: 2014-07-31 Created: 2014-07-28 Last updated: 2019-11-25Bibliographically approved
Hägglöf, C., Hammarsten, P., Strömvall, K., Egevad, L., Josefsson, A., Stattin, P., . . . Bergh, A. (2014). TMPRSS2-ERG Expression Predicts Prostate Cancer Survival and Associates with Stromal Biomarkers. PLoS ONE, 9(2), e86824
Open this publication in new window or tab >>TMPRSS2-ERG Expression Predicts Prostate Cancer Survival and Associates with Stromal Biomarkers
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2, p. e86824-Article in journal (Refereed) Published
Abstract [en]

The TMPRSS2-ERG gene fusion is found in approximately half of all prostate cancers. The functional and prognostic significance of TMPRSS2-ERG is, however, not fully understood. Based on a historical watchful waiting cohort, an association between TMPRSS2-ERG, evaluated as positive immune staining, and shorter survival of prostate cancer patients was identified. Expression of ERG was also associated with clinical markers such as advanced tumor stage, high Gleason score, presence of metastasis and prognostic tumor cell markers such as high Ki67, pEGFR and pAkt. Novel associations between TMPRSS2-ERG and alterations in the tumor stroma, for example, increased vascular density, hyaluronan and PDGFR beta and decreased Caveolin-1, all known to be associated with an aggressive disease, were found. The present study suggests that the TMPRSS2-ERG fusion gene is associated with a more aggressive prostate cancer phenotype, supported by changes in the tumor stroma.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-87026 (URN)10.1371/journal.pone.0086824 (DOI)000330829200028 ()
Available from: 2014-04-07 Created: 2014-03-18 Last updated: 2018-06-08Bibliographically approved
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