Finsen Laboratory

Copenhagen, Denmark

Finsen Laboratory

Copenhagen, Denmark
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Troelsen L.N.,Copenhagen University | Troelsen L.N.,Rigshospitalet | Garred P.,Rigshospitalet | Christiansen B.,Gentofte University Hospital | And 4 more authors.
Molecular Immunology | Year: 2010

Background: Patients with rheumatoid arthritis (RA) have increased risk of atherosclerosis and cardiovascular disease (CVD) that cannot be explained by excess of traditional risk factors. Several studies indicate that mannose-binding lectin (MBL) may modify the development of atherosclerosis; both high and low serum levels of MBL are reported to be associated with CVD. Intima-media thickness of the common carotid artery (ccIMT) is a validated non-invasive anatomic measure of subclinical CVD. We examined the relation between ccIMT and MBL in 114 RA patients. Methods: In a cross-sectional study MBL2 genotypes and serum concentrations of MBL were assessed; ccIMT was determined by means of ultrasonography; traditional and RA related cardiovascular risk modifiers were measured. Results: The median ccIMT was 0.67 mm. The investigated MBL2 genotypes were not significantly associated with ccIMT. Using a general linear model, ccIMT was not linearly associated with serum MBL but was highly associated with the quadratic term of serum MBL (MBL2) (P = 0.001) reflecting a U-shaped relation. MBL2 was also significantly associated with ccIMT in a multivariable analysis adjusting for traditional and RA related cardiovascular risk modifiers (P = 0.025). Conclusion: In RA patients, a quadratic U-shaped relation between serum MBL and ccIMT was observed independently of the effects of traditional and RA related risk factors for CVD. These results provide further support to the notion that both high and low levels of MBL may be associated with CVD. © 2010 Elsevier Ltd. All rights reserved.


Gao S.,University of Aarhus | Nielsen B.S.,Finsen Laboratory | Krogdahl A.,University of Southern Denmark | Sorensen J.A.,University of Southern Denmark | And 4 more authors.
Genes Chromosomes and Cancer | Year: 2010

A high level of plasminogen activator inhibitor-1 (PAI-1 or SERPINE1) in tumor extracts is a marker of a poor prognosis in human cancers, including oral carcinomas. However, the mechanisms responsible for the upregulation of PAI-1 in cancers remain unclear. Investigating specific PAI-1 expressing cells in oral carcinomas by immunohistochemistry, we found that PAI-1 was expressed in 18 of the 20 patients, mainly by cancer cells. Two showed PAI-1 positive stromal cells surrounding the tumor areas and five showed PAI-1 positive cells in tumor-adjacent normal epithelium. By real-time RT-PCR analysis, 17 of 20 patients with oral carcinoma were found to have between 2.5- and 50-fold increased tumor PAI-1 mRNA level, as compared with the matched tumor-adjacent normal tissues. The PAI-1 mRNA level in connective tissues from 15 healthy volunteers was similar to the level in tumor-adjacent normal tissues, but the level in epithelium was 5- to 10-fold lower. Analyzing DNA methylation of 25 CpG sites within 960 bp around the transcription initiation site of the SERPINE1 gene by bisulfite sequencing, we did the surprising observation that both tumors and tumor-adjacent normal tissue had a significant level of methylation, whereas there was very little methylation in tissue from healthy volunteers, suggesting that tumor-adjacent normal tissue already contains transformation-associated epigenetic changes. However, there was no general inverse correlation between PAI-1 mRNA levels and SERPINE1 gene methylation in all tissues, showing that CpG methylation is not the main determinant of the PAI-1 expression level in oral tissue. © 2010 Wiley-Liss, Inc.


Lawaetz A.J.,Copenhagen University | Bro R.,Copenhagen University | Kamstrup-Nielsen M.,Copenhagen University | Christensen I.J.,Finsen Laboratory | And 2 more authors.
Metabolomics | Year: 2012

Fluorescence spectroscopy Excitation Emission Matrix (EEM) measurements were applied on human blood plasma samples from a case control study on colorectal cancer. Samples were collected before large bowel endoscopy and included patients with colorectal cancer or with adenomas, and from individuals with other non malignant findings or no findings (N = 308). The objective of the study was to explore the possibilities for applying fluorescence spectroscopy as a tool for detection of colorectal cancer. Parallel Factor Analysis (PARAFAC) was applied to decompose the fluorescence EEMs into estimates of the underlying fluorophores in the sample. Both the pooled score matrix from PARAFAC, holding the relative concentrations of the derived components, and the raw unfolded spectra were used as basis for discrimination models between cancer and the various controls. Both methods gave test set validated sensitivity and specificity values around 0. 75 between cancer and controls, and poor discriminations between the various controls. The PARAFAC solution gave better options for analyzing the chemical mechanisms behind the discrimination, and revealed a blue shift in tryptophan emission in the cancer patients, a result that supports previous findings. The present findings show how fluorescence spectroscopy and chemometrics can help in cancer diagnostics, and with PARAFAC fluorescence spectroscopy can be a potential metabonomic tool. © 2011 Springer Science+Business Media, LLC.


Hasselbalch B.,Copenhagen University | Eriksen J.G.,Aarhus University Hospital | Broholm H.,Copenhagen University | Christensen I.J.,Finsen Laboratory | And 5 more authors.
APMIS | Year: 2010

Several recent studies have demonstrated a beneficial effect of anti-angiogenic treatment with the vascular endothelial growth factor-neutralizing antibody bevacizumab in recurrent high-grade glioma. In the current study, immunohistochemical evaluation of biomarkers involved in angiogenesis, hypoxia and mediators of the epidermal growth factor receptor (EGFR) pathway were investigated. Tumor tissue was obtained from a previous phase II study, treating recurrent primary glioblastoma multiforme (GBM) patients with the EGFR inhibitor cetuximab in combination with bevacizumab and irinotecan. Of the 37 patients with available tumor tissue, 29 were evaluable for response. We concurrently performed immunohistochemical stainings on tumor tissue from 21 GBM patients treated with bevacizumab and irinotecan. We found a tendency of correlation between the hypoxia-related markers, indicating that they share the same regulatory mechanisms. None of the EGFR-related biomarkers showed any significant correlations with each other. None of the biomarkers tested alone or in combination could identify a patient population likely to benefit from bevacizumab and irinotecan, with or without the addition of cetuximab. There is still an urgent need for one or more reliable and reproducible biomarkers able to predict the efficacy of anti-angiogenic therapy. © 2010 APMIS.


Sugiyama N.,Haartman Institute | Sugiyama N.,University of Helsinki | Varjosalo M.,University of Helsinki | Meller P.,Haartman Institute | And 13 more authors.
Cancer Research | Year: 2010

Aberrant expression and polymorphism of fibroblast growth factor receptor 4 (FGFR4) has been linked to tumor progression and anticancer drug resistance. We describe here a novel mechanism of tumor progression by matrix degradation involving epithelial-to-mesenchymal transition in response to membrane-type 1 matrix metalloproteinase (MT1-MMP, MMP-14) induction at the edge of tumors expressing the FGFR4-R388 risk variant. Both FGFR4 and MT1-MMP were upregulated in tissue biopsies from several human cancer types including breast adenocarcinomas, where they were partially coexpressed at the tumor/stroma border and tumor invasion front. The strongest overall coexpression was found in prostate carcinoma. Studies with cultured prostate carcinoma cell lines showed that the FGFR4-R388 variant, which has previously been associated with poor cancer prognosis, increased MT1-MMP-dependent collagen invasion. In this experimental model, knockdown of FGFR4-R388 or MT1-MMP by RNA interference blocked tumor cell invasion and growth in collagen. This was coupled with impaired phosphorylation of FGFR substrate 2 and Src, upregulation of E-cadherin, and suppression of cadherin-11 and N-cadherin. These in vitro results were substantiated by reduced MT1-MMP content and in vivo growth of prostate carcinoma cells after the FGFR4-R388 gene silencing. In contrast, knockdown of the alternative FGFR4-G388 allele enhanced MT1-MMP and invasive tumor cell growth in vivo and within three-dimensional collagen. These results will help to explain the reported association of the FGFR4-R388 variant with the progression and poor prognosis of certain types of tumors. ©2010 AACR.


Nielsen H.J.,Copenhagen University | Jakobsen K.V.,Copenhagen University | Christensen I.J.,Finsen Laboratory | Brunner N.,Copenhagen University
Scandinavian Journal of Gastroenterology | Year: 2011

Emerging results indicate that screening improves survival of patients with colorectal cancer. Therefore, screening programs are already implemented or are being considered for implementation in Asia, Europe and North America. At present, a great variety of screening methods are available including colono- and sigmoidoscopy, CT- and MR-colonography, capsule endoscopy, DNA and occult blood in feces, and so on. The pros and cons of the various tests, including economic issues, are debated. Although a plethora of evaluated and validated tests even with high specificities and reasonable sensitivities are available, an international consensus on screening procedures is still not established. The rather limited compliance in present screening procedures is a significant drawback. Furthermore, some of the procedures are costly and, therefore, selection methods for these procedures are needed. Current research into improvements of screening for colorectal cancer includes blood-based biological markers, such as proteins, DNA and RNA in combination with various demographically and clinically parameters into a "risk assessment evaluation" (RAE) test. It is assumed that such a test may lead to higher acceptance among the screening populations, and thereby improve the compliances. Furthermore, the involvement of the media, including social media, may add even more individuals to the screening programs. Implementation of validated RAE and progressively improved screening methods may reform the cost/benefit of screening procedures for colorectal cancer. Therefore, results of present research, validating RAE tests, are awaited with interest. © 2011 Informa Healthcare.


Sonne-Hansen K.,Danish Cancer Society | Norrie I.C.,Danish Cancer Society | Emdal K.B.,Danish Cancer Society | Benjaminsen R.V.,Danish Cancer Society | And 4 more authors.
Breast Cancer Research and Treatment | Year: 2010

The majority of breast cancers are estrogen responsive, but upon progression of disease other growth promoting pathways are activated, e.g., the ErbB receptor system. The present study focuses on resistance to the pure estrogen antagonist fulvestrant and strategies to treat resistant cells or even circumvent development of resistance. Limited effects were observed when targeting EGFR and ErbB2 with the monoclonal antibodies cetuximab, trastuzumab, and pertuzumab, whereas the pan-ErbB inhibitor CI-1033 selectively inhibited growth of fulvestrant resistant cell lines. CI-1033 inhibited Erk but not Akt signaling, which as well as Erk is important for antiestrogen resistant cell growth. Accordingly, combination therapy with CI-1033 and the Akt inhibitor SH-6 or the Protein Kinase C inhibitor RO-32-0432 was applied and found superior to single agent treatment. Further, the resistant cell lines were more sensitive to CI-1033 treatment when grown in the presence of fulvestrant, as withdrawal of fulvestrant restored signaling through the estrogen receptor α (ERα), partly overcoming the growth inhibitory effects of CI-1033. Thus, the resistant cells could switch between ERα and ErbB signaling for growth promotion. Although parental MCF-7 cell growth primarily depends on ERα signaling, a heregulin-1 β induced switch to ErbB signaling rescued MCF-7 cells from the growth inhibition exerted by fulvestrant-mediated blockade of ERα signaling. This interplay between ERα and ErbB signaling could be abrogated by combined therapy targeting both receptor systems. Thus, the present study indicates that upon development of antiestrogen resistance, antiestrogen treatment should be continued in combination with signal transduction inhibitors. Further, upfront combination of endocrine therapy with pan-ErbB inhibition may postpone or even prevent development of treatment resistance. © Springer Science+Business Media, LLC. 2009.


Aldulaymi B.,Hillerod Hospital | Christensen I.J.,Finsen Laboratory | Soletormos G.,Hillerod Hospital | Jess P.,Hillerod Hospital | And 3 more authors.
Anticancer Research | Year: 2010

Background: Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been suggested to be a valuable marker in colorectal cancer (CRC), but the effects of chemotherapy on TIMP-1 levels are unknown. The present study evaluated the effect of chemotherapy on TIMP-1 levels in comparison with carcinoembryonic antigen (CEA) levels in patients with stage III colon cancer. Patients and Methods: Thirty patients who had been curatively resected for stage III colon cancer were included. The patients received 10-12 cycles of modified FOLFOX6 regimen. Blood samples were collected before and after the first and the second cycle and three months later. Results: No significant change could be detected in CEA levels while TIMP-1 raised significantly after the second cycle but returned to normal 3 months later. Conclusion: Plasma CEA levels are stable during adjuvant chemotherapy while the plasma level of TIMP-1 might be directly affected by chemotherapy represented by a transient rise about 2 weeks following the initiation of treatment.


Bulow S.,Copenhagen University | Christensen I.J.,Finsen Laboratory | Hojen H.,Copenhagen University | Bjork J.,Karolinska University Hospital | And 5 more authors.
Colorectal Disease | Year: 2012

Aim Duodenal adenomatosis in familial adenomatous polyposis results in a cancer risk that increases with age. Endoscopic surveillance has been recommended, but the effect has not yet been documented. The aim of this study was to present the results of long-term duodenal surveillance and to evaluate the risk of cancer development. Method Follow up of patients in a previous study with gastroduodenoscopy in 1990-2010. Statistical analysis included the χ2 test, actuarial method and Kaplan-Meier analysis. Results Among 304 patients, 261 (86%) had more than one endoscopy. The median follow up was 14 (interquartile range, 9-17) years. The cumulative lifetime risk of duodenal adenomatosis was 88% (95% CI, 84-93), and of Spigelman stage IV was 35% (95% CI, 25-45). The Spigelman stage improved in 32 (12%) patients, remained unchanged in 88 (34%) and worsened in 116 (44%). Twenty (7%) patients had duodenal cancer at a median age of 56 (range, 44-82) years. The cumulative cancer incidence was 18% at 75years of age (95% CI, 8-28) and increased with increasing Spigelman stage at the index endoscopy to 33% in Spigelman stage IV (P<0.0001). The median overall survival was 6.4years (95% CI, 1.7 to not estimated): 8years after a screen-detected cancer vs 0.8years (95% CI, 0.03-1.7) after a symptomatic cancer (P<0.0001). The location of the mutation in the APC gene did not influence the risk of developing Spigelman stage IV (P=0.46) or duodenal cancer (P=0.83). Conclusion The risk of duodenal cancer in familial adenomatous polyposis is considerable, and regular surveillance and cancer prophylactic surgery result in a significantly improved prognosis. © 2011 The Authors. Colorectal Disease © 2011 The Association of Coloproctology of Great Britain and Ireland.


PubMed | Cornell University, University of California at Los Angeles and Finsen Laboratory
Type: | Journal: Journal of lipid research | Year: 2016

In mice lacking GPIHBP1, the lipoprotein lipase (LPL) secreted by adipocytes and myocytes remains bound to heparan sulfate proteoglycans (HSPGs) on all cells within tissues. That observation raises a perplexing issue: Why is the freshly secreted LPL in wild-type mice not captured by the same HSPGs, thereby preventing LPL from reaching GPIHBP1 on capillaries. We hypothesized that LPL-HSPG interactions are transient, allowing the LPL to detach and move to GPIHBP1 on capillaries. Indeed, we found that LPL detaches from HSPGs on cultured cells and moves to: (1) soluble GPIHBP1 in the cell culture medium; (2) GPIHBP1-coated agarose beads; and (3) nearby GPIHBP1-expressing cells. Movement of HSPG-bound LPL to GPIHBP1 did not occur when GPIHBP1 contained an Ly6 domain missense mutation (W109S) but was almost normal when the acidic domain of GPIHBP1 was mutated. To test the mobility of HSPG-bound LPL in vivo, we injected GPIHBP1-coated agarose beads into the brown adipose tissue of GPIHBP1-deficient mice. LPL moved quickly from HSPGs on adipocytes to GPIHBP1-coated beads, thereby depleting LPL stores on the surface of adipocytes. We conclude that HSPG-bound LPL in the interstitial spaces of tissues is mobile, allowing the LPL to move to GPIHBP1 on endothelial cells.

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