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Search Results: 1 - 10 of 144769 matches for " Torben F ?rntoft "
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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 Dyrskj?t
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.
Clusterin expression can be modulated by changes in TCF1-mediated Wnt signaling
Troels Schepeler, Francisco Mansilla, Lise L Christensen, Torben Frntoft, Claus L Andersen
Journal of Molecular Signaling , 2007, DOI: 10.1186/1750-2187-2-6
Abstract: Over-expression of the cytoplasmic domain of E-cadherin tagged with GFP was used to abrogate Wnt signaling activity in LS174T and HCT116 colon carcinoma cells. This fusion construct sequestered signaling competent β-catenin whereby Wnt signaling was abrogated, and consequently cytoplasmic CLU protein levels increased as demonstrated by immunofluorescence. To determine which branch of the Wnt pathway was mediating the CLU response, we over-expressed dominant negative (dn) TCF1 and TCF4 transcription factors in stably transfected LS174T cells. We observed both intra- and extracellular levels of CLU protein to be induced by dnTCF1 but not dnTCF4. Subsequent analysis of the expression levels of three CLU mRNA variants by real time RT-PCR revealed only one CLU mRNA variant to be responsive to dnTCF1 over-expression. 5'-end RACE indicated that this CLU mRNA variant was shorter at the 5'-end than previously reported, and accordingly the translated protein was predicted to be shorter at the N-terminus and destined to the secretory pathway which fit our observations. Examination of the immediate expression kinetics of CLU after dnTCF1 over-expression using real time RT-PCR indicated that CLU might be a secondary Wnt target.In conclusion, we have demonstrated that the Wnt signaling pathway specifically regulates one out of three CLU mRNA variants via TCF1. This CLU transcript is shorter at the 5' end than reported by the RefSeq database, and produces the intracellular 60 kDa CLU protein isoform which is secreted as a ~80 kDa protein after post-translational processing.The clusterin (CLU) protein was first discovered more than 25 years ago in rat testis fluid because of its ability to facilitate clustering of a variety of cell types in culture[1]. Since then, homologues of the broadly expressed CLU gene have been identified in several species and CLU proteins have been found in most mammalian body fluids[2]. CLU is an enigmatic molecule, implicated in diverse biological proces
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 Frntoft, Lars Dyrskj?t
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
Construction and validation of the APOCHIP, a spotted oligo-microarray for the study of beta-cell apoptosis
Nils E Magnusson, Alessandra K Cardozo, Mogens Kruh?ffer, Decio L Eizirik, Torben Frntoft, Jens L Jensen
BMC Bioinformatics , 2005, DOI: 10.1186/1471-2105-6-311
Abstract: The APOCHIP was validated by a combination of approaches. First we performed an internal validation of the spotted probes based on a weighted linear regression model using dilution series experiments. Second we profiled expression measurements in ten dissimilar rat RNA samples for 515 genes that were represented on both the spotted oligonucleotide collection and on the in situ-synthesized 25-mer arrays (Affymetrix GeneChips). Internal validation showed that most of the spotted probes displayed a pattern of reaction close to that predicted by the model. By using simple rules for comparison of data between platforms we found strong correlations (rmedian= 0.84) between relative gene expression measurements made with spotted probes and in situ-synthesized 25-mer probe sets.In conclusion our data suggest that there is a high reproducibility of the APOCHIP in terms of technical replication and that relative gene expression measurements obtained with the APOCHIP compare well to the Affymetrix GeneChip. The APOCHIP is available to the scientific community and is a useful tool to study the molecular mechanisms regulating beta-cell apoptosis.Type 1 diabetes mellitus (T1DM) is an autoimmune disease caused by the selective destruction of the pancreatic beta-cells causing impaired insulin secretion. Beta-cell dysfunction and death in T1DM is the result of direct contact with activated macrophages and T-lymphocytes, and/or exposure to soluble mediators secreted by these cells, such as cytokines, oxygen free radicals and nitric oxide (NO) [1]. There is increasing evidence that apoptosis is the main cause of beta-cell death at the onset of T1DM [1-4] and after islet transplantation [1,5,6] Apoptosis is a regulated process, affected by expression of diverse pro- and anti-apoptotic genes [1,7,8] Cytokines play a role in the inflammatory destruction of islet grafts immediately after transplantation [9-11] a process that hampers the success of islet transplantation in patients with T1D
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 Frntoft, Martin B Oleksiewicz, Nils Brünner, Lars Dyrskj?t
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 Dyrskj?t, Torben Frntoft, 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
Identification of a Core Set of Genes That Signifies Pathways Underlying Cardiac Hypertrophy
Claes C. Str m,Mogens Kruh ffer,Steen Knudsen,Frank Stensgaard-Hansen,Thomas E. N. Jonassen,Torben F. rntoft,Stig Hauns ,S ren P. Sheikh
Comparative and Functional Genomics , 2004, DOI: 10.1002/cfg.428
Abstract: Although the molecular signals underlying cardiac hypertrophy have been the subject of intense investigation, the extent of common and distinct gene regulation between different forms of cardiac hypertrophy remains unclear. We hypothesized that a general and comparative analysis of hypertrophic gene expression, using microarray technology in multiple models of cardiac hypertrophy, including aortic banding, myocardial infarction, an arteriovenous shunt and pharmacologically induced hypertrophy, would uncover networks of conserved hypertrophy-specific genes and identify novel genes involved in hypertrophic signalling. From gene expression analyses (8740 probe sets, n = 46) of rat ventricular RNA, we identified a core set of 139 genes with consistent differential expression in all hypertrophy models as compared to their controls, including 78 genes not previously associated with hypertrophy and 61 genes whose altered expression had previously been reported. We identified a single common gene program underlying hypertrophic remodelling, regardless of how the hypertrophy was induced. These genes constitute the molecular basis for the existence of one main form of cardiac hypertrophy and may be useful for prediction of a common therapeutic approach. Supplementary material for this article can be found at: http://www.interscience.wiley.com/jpages/1531-6912/suppmat
Pressure Load: The Main Factor for Altered Gene Expression in Right Ventricular Hypertrophy in Chronic Hypoxic Rats
Jonas D. Baandrup,Lars H. Markvardsen,Christian D. Peters,Uffe K. Schou,Jens L. Jensen,Nils E. Magnusson,Torben F. ?rntoft,Mogens Kruh?ffer,Ulf Simonsen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015859
Abstract: The present study investigated whether changes in gene expression in the right ventricle following pulmonary hypertension can be attributed to hypoxia or pressure loading.
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 Frntoft, Lars Dyrskj?t
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 Dyrskj?t, Julie S B?dker, Peter J Wild, Arndt Hartmann, Simone Bertz, Jan Lehmann, Torben Frntoft, 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
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