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Search Results: 1 - 10 of 121683 matches for " Lars Dyrskj?t "
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Expression Profiling of Hereditary versus Sporadic Prostate Cancer Suggests CYR61, EGR3, KLF6 and SNF1LK as Differentially Expressed Genes  [PDF]
Diem Nguyen Bentzon, Martin M?rck Mortensen, Torben ?rntoft, Lars Dyrskjt, Michael Borre
Open Journal of Urology (OJU) , 2012, DOI: 10.4236/oju.2012.22010
Abstract: Background: Distinguishing between sub-clinical and aggressive forms of prostate cancer is difficult due to the heterogeneity of the disease. It is, however, important to identify aggressive forms to guide proper treatment. This study compared gene expression profiles in cancer cells from hereditary and sporadic prostate cancer cases and attempted to correlate differentially regulated genes with clinico-pathological characteristics and prognosis. Materials and methods: The study population comprised patients diagnosed with clinically localized prostate cancer undergoing prostatectomy. Patients were divided into hereditary and sporadic cancer cases based on their family history. Fresh frozen biopsies from prostatectomy specimens were laser-dissected for RNA-extraction. Affymetrix HG-U133 Plus GeneChips were used to measure gene expression loaded onto Cluster 3.0 and Ingenuity Pathway Analysis softwares to examine the relationship among genes between groups. Differentially expressed genes were selected for protein expression analysis using immunohistochemistry on histological sections and tissue microarrays. Results: No single genes were signifycantly differentially expressed between hereditary and sporadic cases after adjustment for multiple testing. Using cluster analysis, four transcripts were found to be upregulated in hereditary prostate cancer tissue: CYR61, EGR3, KLF6 and SNF1LK. The intensity of CYR61, EGR2, KLF6 and SNF1LK immunostainings, however, were not significantly different in a separate sample of hereditary and sporadic prostate cancers. Furthermore, no correlations between CYR61, EGR2, KLF6, and SNF1LK staining intensities and the clinico-pathological variables or disease-free survival were detected, except for EGR3 that was significantly associated with T stage (p = 0.04). Conclusion: Overall, no single transcript level was significantly associated with hereditary prostate cancer. Cluster analysis suggested that the expression of CYR61, EGR3, KLF6 and SNF1LK were upregulated in cancer tissue from hereditary cases, but we were not able to confirm this on the protein level, and levels of these proteins were not found to correlate with clinico-pathological characteristics or biochemical recurrence.
Diagnosis of Bladder Cancer Recurrence Based on Urinary Levels of EOMES, HOXA9, POU4F2, TWIST1, VIM, and ZNF154 Hypermethylation
Thomas Reinert, Michael Borre, Anders Christiansen, Gregers G. Hermann, Torben F. ?rntoft, Lars Dyrskjt
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0046297
Abstract: Background Non muscle invasive bladder cancer (NMIBC) has the highest recurrence rate of any malignancy and as many as 70% of patients experience relapse. Aberrant DNA methylation is present in all bladder tumors and can be detected in urine specimens. Previous studies have identified DNA methylation markers that showed significant diagnostic value. We evaluated the significance of the biomarkers for early detection of tumor recurrence in urine. Methodology/Principal Findings The methylation levels of EOMES, HOXA9, POU4F2, TWIST1, VIM, and ZNF154 in urine specimens were measured by real-time PCR (MethyLight). We analyzed 390 urine sediments from 184 patients diagnosed with NMIBC. Urine from 35 age-matched control individuals was used to determine the methylation baseline levels. Recurrence was diagnosed by cystoscopy and verified by histology. Initially, we compared urine from bladder cancer patients and healthy individuals and detected significant hypermethylation of all six markers (P<0.0001) achieving sensitivity in the range 82%–89% and specificity in the range 94%–100%. Following, we validated the urinary hypermethylation for use in recurrence surveillance and found sensitivities of 88–94% and specificities of 43–67%. EOMES, POU4F2, VIM and ZNF154 were more frequently methylated in urine from patients with higher grade tumors (P≤0.08). Univariate Cox regression analysis showed that five markers were significantly associated with disease recurrence; HOXA9 (HR = 7.8, P = 0.006), POU4F2 (HR = 8.5, P = 0.001), TWIST1 (HR = 12.0, P = 0.015), VIM (HR = 8.0, P = 0.001), and ZNF154 (HR = 13.9, P<0.001). Interestingly, for one group of patients (n = 15) we found that hypermethylation was consistently present in the urine samples despite the lack of tumor recurrences, indicating the presence of a field defect. Conclusion/Significance Methylation levels of EOMES, HOXA9, POU4F2, TWIST1, VIM, and ZNF154 in urine specimens are promising diagnostic biomarkers for bladder cancer recurrence surveillance.
Chromosomal imbalance in the progression of high-risk non-muscle invasive bladder cancer
Karsten Zieger, Carsten Wiuf, Klaus Jensen, Torben ?rntoft, Lars Dyrskjt
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-149
Abstract: To investigate the relationship between CI and subsequent disease progression, we performed a case-control-study of 125 patients with "high-risk" non-muscle invasive bladder neoplasms, 67 with later disease progression, and 58 with no progression. Selection criteria were conservative (non-radical) resections and full prospective clinical follow-up (> 5 years). We investigated primary lesions in 59, and recurrent lesions in 66 cases.We used Affymetrix GeneChip? Mapping 10 K and 50 K SNP microarrays to evaluate genome wide chromosomal imbalance (loss-of-heterozygosity and DNA copy number changes) in 48 representative tumors. DNA copy number changes of 15 key instability regions were further investigated using QPCR in 101 tumors (including 25 tumors also analysed on 50 K SNP microarrays).Chromosomal instability did not predict any higher risk of subsequent progression. Stage T1 and high-grade tumors had generally more unstable genomes than tumors of lower stage and grade (mostly non-primary tumors following a "high-risk" tumor). However, about 25% of the "high-risk" tumors had very few alterations. This was independent of subsequent progression. Recurrent lesions represent underlying field disease. A separate analysis of these lesions did neither reflect any difference in the risk of progression. Of specific chromosomal alterations, a possible association between loss of chromosome 8p11 and the risk of progression was found. However, the predictive value was limited by the heterogeneity of the changes.Chromosomal instability (CI) was associated with "high risk" tumors (stage T1 or high-grade), but did not predict subsequent progression. Recurrences after "high-risk" tumors had fewer chromosomal alterations, but there was no association with the risk of progression in this group either. Thus, the prediction of progression of "high risk" non-muscle invasive bladder tumors using chromosomal changes is difficult. Loss of chromosome 8p11 may play a role in the progression p
Bioinformatic identification of FGF, p38-MAPK, and calcium signalling pathways associated with carcinoma in situ in the urinary bladder
Malene Herbsleb, Ole F Christensen, Thomas Thykjaer, Carsten Wiuf, Michael Borre, Torben F ?rntoft, Lars Dyrskjt
BMC Cancer , 2008, DOI: 10.1186/1471-2407-8-37
Abstract: We developed a pathway based classifier approach to predict presence or absence of CIS in patients suffering from non muscle invasive bladder cancer. From Ingenuity Pathway Analysis we considered four canonical signalling pathways (p38 MAPK, FGF, Calcium, and cAMP pathways) with most coherent expression of transcription factors (TFs) across samples in a set of twenty-eight non muscle invasive bladder carcinomas. These pathways contained twelve TFs in total. We used the expression of the TFs to predict presence or absence of CIS in a Leave-One-Out Cross Validation classification.We showed that TF expression levels in three pathways (FGF, p38 MAPK, and calcium signalling) or the expression of the twelve TFs together could be used to predict presence or absence of concomitant CIS. A cluster analysis based on expression of the twelve TFs separated the samples in two main clusters: one branch contained 11 of the 15 patients without concomitant CIS and with the majority of the genes being down regulated; the other branch contained 10 of 13 patients with concomitant CIS, and here genes were mostly up regulated. The expression in the CIS group was comparable to the expression of twenty-three patients suffering from muscle-invasive bladder carcinoma. Finally, we validated our results in an independent test set and found that prediction of CIS status was possible using TF expression of the p38 MAPK pathway.We conclude that it is possible to use pathway analysis for molecular classification of bladder tumors.Carcinoma in situ (CIS) is characterized by flat, non-papillary, disordered proliferation and differentiation of urothelial cells. The tumor cells are per definition high grade and are usually associated with significant architectural disorder like loss of polarity and maturation [1]. The cells are highly dysplastic and only weakly adherent. Though CIS is a non-invasive condition progression to the invasive stage is seen in about 50% of the cases [2].It is believed that bl
High frequency of tumor cells with nuclear Egr-1 protein expression in human bladder cancer is associated with disease progression
Frederikke Egerod, Annette Bartels, Niels Fristrup, Michael Borre, Torben F ?rntoft, Martin B Oleksiewicz, Nils Brünner, Lars Dyrskjt
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-385
Abstract: Expression of Egr-1 protein in human bladder cancer was examined by immunohistochemistry, on a tissue microarray constructed from tumors from 289 patients with non-muscle invasive urothelial bladder cancer.The frequency of tumor cells with nuclear Egr-1 immunolabelling correlated to bladder cancer stage, grade and to later progression to muscle-invasive bladder cancer (T2-4). Stage T1 tumors exhibited significantly higher frequencies of tumor cells with nuclear Egr-1 immunolabelling than Ta tumors (P = 0.001). Furthermore, Kaplan-Meier survival analysis showed that a high frequency of tumor cells with nuclear Egr-1 immunolabelling was significantly associated with a higher risk of progression to stage T2-4 (log-rank test, P = 0.035). Tumor cells with nuclear Egr-1 immunolabelling were found to localize at the tumor front in some of the tumor biopsies.The results from this study support a potential involvement of Egr-1 in the progression from non-muscle invasive bladder cancers to muscle invasive bladder cancer.Human bladder cancer is the forth most common malignancy in men, and the tenth most common in women [1]. The majority of malignant bladder tumors are urothelial cell carcinomas evolved from the epithelial lining of the bladder wall (urothelium). These tumors can be further divided into papillary, solid and carcinoma in situ (CIS) lesions. Papillary tumors are the most common type, they tend to grow slowly. Solid tumors are less frequent and more aggressive and infiltrate the muscular layer of the bladder wall. CIS is a lesion involving only the inner lining of the bladder. Bladder tumors are classified according to the depth of invasion: non-invasive Ta, and lamina-propria invasive but not muscle-invasive T1 tumors, and muscle-invasive T2-4 tumors. More than 60% of the Ta tumors recur, which makes this tumor type mainly responsible for the high prevalence rate. About 40% of the patients experience multiple recurrences, which has a significant impact on the qua
Evaluation of two commercial global miRNA expression profiling platforms for detection of less abundant miRNAs
Steffen G Jensen, Philippe Lamy, Mads H Rasmussen, Marie S Ostenfeld, Lars Dyrskjt, Torben F ?rntoft, Claus L Andersen
BMC Genomics , 2011, DOI: 10.1186/1471-2164-12-435
Abstract: Using synthetic miRNA samples and plasma RNA samples spiked with different ratios of 174 synthetic miRNAs we assessed the performance characteristics reproducibility, recovery, specificity, sensitivity and linearity. It was found that while the qRT-PCR based platforms were sufficiently sensitive to reproducibly detect miRNAs at the abundance levels found in human plasma, the array based platform was not. At high miRNA levels both qRT-PCR based platforms performed well in terms of specificity, reproducibility and recovery. At low miRNA levels, as in plasma, the miRCURY platform showed better sensitivity and linearity than the TaqMan platform.For profiling clinical samples with low miRNA abundance, such as plasma samples, the miRCURY platform with its better sensitivity and linearity would probably be superior.microRNAs (miRNAs) are short 20-23 nucleotide long non-coding RNAs that are widely distributed in almost all eukaryotic organisms. They have multiple functions however the main function is believed to be post transcriptional regulation of protein levels [1,2]. While miRNAs are often abundant in tissues, the amount found circulating in body fluids such as plasma and serum is often limited. It has been reported that the total RNA level in plasma is in the range 6-300 ng/ml [3,4] and that the miRNA fraction constitutes only a few percent of this [5]. The mechanisms regulating secretion of miRNA into circulation is still unclear. Reports have shown that while endogenous miRNAs appear stable in plasma/serum exogenous miRNAs are not, and as a result of this it has been suggested that endogenous circulating miRNAs are either encapsulated in microvesicles or bound to RNA-binding proteins in complexes, e.g. Ago2 and NPM1, protecting them from degradation [6-8]. Detailed knowledge of the biological function of circulating miRNA does not exist, however it has been shown that vesicular miRNAs can be transferred from cell to cell and influence the behavior of the recipient c
Prediction and diagnosis of bladder cancer recurrence based on urinary content of hTERT, SENP1, PPP1CA, and MCM5 transcripts
Anne Brems-Eskildsen, Karsten Zieger, Helle Toldbod, Cherie Holcomb, Russell Higuchi, Francisco Mansilla, Pia P Munksgaard, Michael Borre, Torben F ?rntoft, Lars Dyrskjt
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-646
Abstract: We analyzed 123 prospectively cross-sectional collected urine samples from 117 patients with bladder cancer (12 incident cancers and 111 control visits). We used biopsies from cystoscopies as diagnostic criteria for recurrence, and followed the patients for a median time of 28.5 months (range 0-44 months). We measured the levels of hTERT, SENP1, PPP1CA, and MCM5 mRNA in urine by q-RT- PCR.We found significant differences in urinary content of hTERT (p < 0.001), SENP1 (p < 0.001), MCM5 (p < 0.001), and PPP1CA (p < 0.001) transcripts, when comparing urine samples from patients with and without tumor present in the bladder. We obtained sensitivity and specificity values for hTERT: 63/73, SENP1: 56/78, MCM5: 63/66, and PPP1CA: 69/63, respectively. Including follow-up data resulted in sensitivity and specificity values for hTERT: 62/84, SENP1:53/84, MCM5: 61/73, and PPP1CA: 65/66. Interestingly, at non-tumor visits the urinary content of especially hTERT (p = 0.0001) and MCM5 (p = 0.02) were significantly associated with subsequent tumour recurrence. Combining the markers with cytology improved the detection. The best combination was hTERT and cytology with a sensitivity of 71% and a specificity of 86% after follow-up. Further prospective validation or registration studies needs to be carried out before clinical use.We could use the urinary content of hTERT, SENP1, PPP1CA, and MCM5 to detect bladder cancer recurrence. All markers showed a higher sensitivity than cytology. The detection rate improved when including cytology results, but also the combination of hTERT and MCM5 increased the detection rate. Furthermore, hTERT and MCM5 levels predicted subsequent tumor recurrences.Non-muscle invasive bladder cancer is characterized by frequent tumor recurrences. Today the standard follow-up consists of cystoscopy combined with cytological examination at an interval of 3 to 6 months depending on tumor malignancy and previous recurrence rate. Cystoscopic examinations are unplea
Increased expression of transcription factor TFAP2α correlates with chemosensitivity in advanced bladder cancer
Iver Nordentoft, Lars Dyrskjt, Julie S B?dker, Peter J Wild, Arndt Hartmann, Simone Bertz, Jan Lehmann, Torben F ?rntoft, Karin Birkenkamp-Demtroder
BMC Cancer , 2011, DOI: 10.1186/1471-2407-11-135
Abstract: TFAP2α expression and localization was assessed by immunohistochemistry using a tissue microarray (TMA) containing 282 bladder cancer tumors from patients with locally advanced (pT2-T4b and N1-3) or metastatic (M1) disease. All patients had received cisplatin containing chemotherapy. Furthermore, QPCR analysis of three TFAP2α isoforms was performed on tumor specimens of advanced muscle invasive bladder cancers (T2-4). Using the bladder cell lines T24 and SW780 the relation of TFAP2α and cisplatin and gemcitabine sensitivity as well as cell proliferation was examined using siRNA directed TFAP2α knockdown.TFAP2α protein expression was analyzed on a TMA with cores from 282 advanced bladder cancer tumors from patients treated with cisplatin based combinational chemotherapy. TFAP2α was identified as a strong independent predictive marker for a good response and survival after cisplatin-containing chemotherapy in patients with advanced bladder cancer. Strong TFAP2α nuclear and cytoplasmic staining predicted good response to chemotherapy in patients with lymph node metastasis, whereas weak TFAP2α nuclear staining predicted good response in patients without lymph node metastasis. In vitro studies showed that siRNA mediated knockdown of TFAP2α increased the proliferation of SW780 cells and rendered the cells less sensitive to cisplatin and gemcitabine. In contrast to that T24 bladder cells with mutated p53 showed to be more drug sensitive upon TFAP2α depletion.High levels of nuclear and cytoplasmic TFAP2α protein were a predictor of increased overall survival and progression free survival in patients with advanced bladder cancer treated with cisplatin based chemotherapy. TFAP2α knockdown increased the proliferation of the SW780 bladder cells and reduced cisplatin and gemcitabine induced cell death. The inverse effect was observed in the TP53 mutated T24 cell line where TFAP2α silencing augmented cisplatin and gemcitabine sensitivity and did not stimulate proliferation.Bladde
Increased cell motility and invasion upon knockdown of lipolysis stimulated lipoprotein receptor (LSR) in SW780 bladder cancer cells
Malene Herbsleb, Karin Birkenkamp-Demtroder, Thomas Thykjaer, Carsten Wiuf, Anne-Mette K Hein, Torben F ?rntoft, Lars Dyrskjt
BMC Medical Genomics , 2008, DOI: 10.1186/1755-8794-1-31
Abstract: A time course siRNA knock down experiment was performed to investigate the functional role of LSR in SW780 bladder cancer cells. Since LSR was previously shown to be regulated by P53, siRNA against TP53 was included in the experimental setup. We used Affymetrix GeneChips for measuring gene expression changes and we used Ingenuity Pathway Analysis to investigate the relationship among differentially expressed genes upon siRNA knockdown.By Ingenuity Pathway analysis of the microarray data from the different timepoints we identified six gene networks containing genes mainly related to the functional categories "cancer", "cell death", and "cellular movement". We determined that genes annotated to the functional category "cellular movement" including "invasion" and "cell motility" were highly significantly overrepresented. A matrigel assay showed that 24 h after transfection the invasion capacity was significantly increased 3-fold (p < 0.02) in LSR-siRNA transfected cells, and 2.7-fold (p < 0.02) in TP53-siRNA transfected cells compared to controls. After 48 h the motility capacity was significantly increased 3.5-fold (p < 0.004) in LSR-siRNA transfected cells, and 4.7-fold (p < 0.002) in TP53-siRNA transfected cells compared to controls.We conclude that LSR may impair bladder cancer cells from gaining invasive properties.Completion of the human genome project [1,2] together with development of microarray techniques have made it possible to investigate global changes in expression patterns that occur during bladder cancer development. Gene expression profiles associated with disease stage [3-7], disease progression [4,7,8], recurrence pattern [4], survival [6,9], and treatment response [10] have been delineated by several groups. Other studies have focused on the impact of single genes on tumorigenesis like the oncogenes HRAS, FGFR3, ERBB2, CCND1, and MDM2, and the tumor suppressors CDKN2A, PTEN, TSC1, and DBC1 (recently reviewed in [11]). Thus, knowledge on molecular al
Tumor-specific usage of alternative transcription start sites in colorectal cancer identified by genome-wide exon array analysis
Kasper Thorsen, Troels Schepeler, Bodil ?ster, Mads H Rasmussen, S?ren Vang, Kai Wang, Kristian Q Hansen, Philippe Lamy, Jakob Pedersen, Asger Eller, Francisco Mansilla, Kirsti Laurila, Carsten Wiuf, S?ren Laurberg, Lars Dyrskjt, Torben F ?rntoft, Claus L Andersen
BMC Genomics , 2011, DOI: 10.1186/1471-2164-12-505
Abstract: By profiling 108 colorectal samples using exon arrays, we identified nine genes (TCF12, OSBPL1A, TRAK1, ANK3, CHEK1, UGP2, LMO7, ACSL5, and SCIN) showing tumor-specific alternative TSS usage in both adenoma and cancer samples relative to normal mucosa. Analysis of independent exon array data sets corroborated these findings. Additionally, we confirmed the observed patterns for selected mRNAs using quantitative real-time reverse-transcription PCR. Interestingly, for some of the genes, the tumor-specific TSS usage was not restricted to colorectal cancer. A comprehensive survey of the nine genes in lung, bladder, liver, prostate, gastric, and brain cancer revealed significantly altered mRNA isoform ratios for CHEK1, OSBPL1A, and TCF12 in a subset of these cancer types.To identify the mechanism responsible for the shift in alternative TSS usage, we antagonized the Wnt-signaling pathway in DLD1 and Ls174T colorectal cancer cell lines, which remarkably led to a shift in the preferred TSS for both OSBPL1A and TRAK1. This indicated a regulatory role of the Wnt pathway in selecting TSS, possibly also involving TP53 and SOX9, as their transcription binding sites were enriched in the promoters of the tumor preferred isoforms together with their mRNA levels being increased in tumor samples.Finally, to evaluate the prognostic impact of the altered TSS usage, immunohistochemistry was used to show deregulation of the total protein levels of both TCF12 and OSBPL1A, corresponding to the mRNA levels observed. Furthermore, the level of nuclear TCF12 had a significant correlation to progression free survival in a cohort of 248 stage II colorectal cancer samples.Alternative TSS usage in colorectal adenoma and cancer samples has been shown for nine genes, and OSBPL1A and TRAK1 were found to be regulated in vitro by Wnt signaling. TCF12 protein expression was upregulated in cancer samples and correlated with progression free survival.Colorectal cancer (CRC) is a leading cause of cancer mo
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