18 results on '"Lamerz, A."'
Search Results
2. Leishmania UDP-sugar Pyrophosphorylase: THE MISSING LINK IN GALACTOSE SAL VAGE?
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Damerow, Sebastian, Lamerz, Anne-Christin, Haselhorst, Thomas, Führing, Jana, Zarnovican, Patricia, von Itzstein, Mark, and Routier, Françoise H.
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LEISHMANIA , *GLUCURONOSYLTRANSFERASE , *SUGARS , *GALACTOSE , *BIOSYNTHESIS , *BINDING sites - Abstract
The Leishmania parasite glycocalyx is rich in galactose-containing glycoconjugates that are synthesized by specific glycosyltransferases that use UDP-galactose as a glycosyl donor. UDP-galactose biosynthesis is thought to be predominantly a de novo process involving epimerization of the abundant nucleotide sugar UDP-glucose by the UDP-glucose 4-epimerase, although galactose salvage from the environment has been demonstrated for Leishmania major. Here, we present the characterization of an L. major UDP-sugar pyrophosphorylase able to reversibly activate galactose 1-phosphate into UDP-galactose thus proving the existence of the Isselbacher salvage pathway in this parasite. The ordered bisubstrate mechanism and high affinity of the enzyme for UTP seem to favor the synthesis of nucleotide sugar rather than their pyrophosphorolysis. Although L. major UDP-sugar pyrophosphorylase preferentially activates galactose 1-phosphate and glucose 1-phosphate, the enzyme is able to act on a variety of hexose 1-phosphates as well as pentose 1-phosphates but not hexosamine 1-phosphates and hence presents a broad in vitro specificity. The newly identified enzyme exhibits a low but significant homology with UDP-glucose pyrophosphorylases and conserved in particular is the pyrophosphorylase consensus sequence and residues involved in nucleotide and phosphate binding. Saturation transfer difference NMR spectroscopy experiments confirm the importance of these moieties for substrate binding. The described leishmanial enzyme is closely related to plant UDP-sugar pyrophosphorylases and presents a similar substrate specificity suggesting their common origin. [ABSTRACT FROM AUTHOR] more...
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- 2010
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Catalog
3. In vivo profiling of DPP4 inhibitors reveals alterations in collagen metabolism and accumulation of an amyloid peptide in rat plasma
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Jost, Marco M., Lamerz, Jens, Tammen, Harald, Menzel, Christoph, De Meester, Ingrid, Lambeir, Anne-Marie, Augustyns, Koen, Scharpé, Simon, Zucht, Hans Dieter, Rose, Horst, Jürgens, Michael, Schulz-Knappe, Peter, and Budde, Petra more...
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ENZYME inhibitors , *CD26 antigen , *COLLAGEN , *PEPTIDES , *BLOOD plasma , *ELECTROSPRAY ionization mass spectrometry , *LABORATORY rats - Abstract
Abstract: Dipeptidyl peptidase 4 (DPP4) inhibitors represent a novel class of oral anti-hyperglycemic agents. The complete pharmacological profile of these protease inhibitors remains unclear. In order to gain deeper insight into the in vivo effects caused by DPP4 inhibition, two different DPP4 inhibitors (vildagliptin and AB192) were analyzed using differential peptide display. Wistar rats were treated with the DPP4 inhibitors (0.3mgkg−1; 1mgkg−1 or 3mgkg−1 body weight) and DPP4 activity was measured before and at the end of the experiment. One hour after compound administration, blood plasma samples were collected to generate peptide displays and to subsequently identify differentially regulated peptides. A dose-dependent decrease in blood plasma DPP4 activity was measured for both inhibitors. DPP4 inhibition influenced collagen metabolism leading to depletion of collagen derived peptides (e.g. collagen alpha 1 (III) 521–554) and accumulation of related N-terminally extended collagen derived peptides (e.g. collagen alpha 1 (III) 519–554). Furthermore, the intact amyloid rat BRI (1–23) peptide was detected in plasma following in vivo DPP4 inhibition. DPP4 catalyzed cleavage kinetics of the BRI peptide were determined in vitro. The k cat and K m for cleavage by DPP4 were 5.2s−1 and 14μM, respectively, resulting in a specificity constant k cat/K m of 0.36×106 s−1 M−1. Our results demonstrate that differential peptide analysis can be applied to monitor action of DPP4 inhibition in blood plasma. For the first time effects on basal collagen metabolism following DPP4 inhibition in vivo were demonstrated and the BRI amyloid peptide was identified as a novel DPP4 substrate. [Copyright &y& Elsevier] more...
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- 2009
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4. Open and Closed Structures of the UDP-glucose Pyrophosphorylase from Leishmania major.
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Steiner, Thomas, Lamerz, Anne-Christin, Hess, Petra, Breithaupt, Constanze, Krapp, Stephan, Bourenkov, Gleb, Huber, Robert, Gerardy-Schahn, Rita, and Jacob, Uwe
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PHOSPHORYLASES , *GLUCOSE , *LEISHMANIA , *PARASITES , *INFECTIOUS disease transmission - Abstract
Uridine diphosphate-glucose pyrophosphorylase (UGPase) represents a ubiquitous enzyme, which catalyzes the formation of UDP-glucose, a key metabolite of the carbohydrate pathways of all organisms. In the protozoan parasite Leishmania major, which causes a broad spectrum of diseases and is transmitted to humans by sand fly vectors, UGPase represents a virulence factor because of its requirement for the synthesis of cell surface glycoconjugates. Here we present the crystal structures of the L. major UGPase in its uncomplexed apo form (open conformation) and in complex with UDP-glucose (closed conformation). The UGPase consists of three distinct domains. The N-terminal domain exhibits species-specific differences in length, which might permit distinct regulation mechanisms. The central catalytic domain resembles a Rossmann-fold and contains key residues that are conserved in many nucleotidyltransferases. The C-terminal domain forms a left-handed parallel β-helix (LβH), which represents a rarely observed structural element. The presented structures together with mutagenesis analyses provide a basis for a detailed analysis of the catalytic mechanism and for the design of species-specific UGPase inhibitors. [ABSTRACT FROM AUTHOR] more...
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- 2007
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5. Targeted Gene Deletion of Leishmania major UDP-galactopyranose Mutase Leads to Attenuated Virulence.
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Kleczka, Barbara, Lamerz, Anne-Christin, Van Zandbergen, Ger, Wenzel, Alexander, Gerardy-Schahn, Rita, Wiese, Martin, and Routier, Françoise H.
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LEISHMANIA , *ENZYMES , *MONOSACCHARIDES , *METABOLISM , *MICROBIAL virulence - Abstract
Considering the high incidence of galactofuranose (Galf) in pathogens and its absence from higher eukaryotes, the enzymes involved in the biosynthesis of this unusual monosaccharide appear as attractive drug targets. However, although the importance of Galf in bacterial survival or pathogenesis is established, its role in eukaryotic pathogens is still undefined. Recently, we reported the identification and characterization of the first eukaryotic UDP-galactopyranose mutases. This enzyme holds a central role in Gale metabolism by providing UDP-Galf to all galactofuranosyltransferases. In this work, the therapeutical potential of Galf metabolism in Leishmania major was hence evaluated by targeted replacement of the GLF gene encoding UDP-galactopyranose mutase. In L. major, Galf is present in the membrane anchor of the lipophosphoglycan (LPG) and in glycoinositolphospholipids. Accordingly, the generated glf- mutant is deficient in LPG backbone and expresses truncated glycoinositolphospholipids. These structural changes do not influence the in vitro growth of the parasite but lead to an attenuation of virulence comparable with that observed with a mutant exclusively deficient in LPG. [ABSTRACT FROM AUTHOR] more...
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- 2007
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6. Molecular Cloning of the Leishmania major UDP-glucose Pyrophosphorylase, Functional Characterization, and Ligand Binding Analyses Using NMR Spectroscopy.
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Lamerz, Anne-Christin, Haseihorst, Thomas, Bergfeld, Anne K., Von Itzstein, Mark, and Gerardy-Schahn, Rita
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MOLECULAR cloning , *CLONING , *MOLECULAR genetics , *LEISHMANIA , *TRYPANOSOMATIDAE - Abstract
The dense glycocalyx surrounding the protozoan parasite Leishmania is an essential virulence factor. It protects the parasite from hostile environments in the sandfly vector and mammalian host and supports steps of development and invasion. Therefore, new therapeutic concepts concentrate on disturbing glycocalyx biosynthesis. Deletion of genes involved in the metabolism of galactose and mannose have been shown to drastically reduce Leishmania virulence. Here we report the identification of Leishmania major UDP-glucose pyrophosphorylase (UGP). UGP catalyzes the formation of UDP-glucose from glucose 1-phosphate and UTP. This activation step enables glucose to enter metabolic pathways and is crucial for the activation of galactose. UDP-galactose is made from UDP-glucose by nucleotide-donor transfer to galactose 1-phosphate or by epimerization of the glucose moiety. Isolated in a complementation cloning approach, the activity of L. major UGP was proven in vitro. Moreover, purified protein was used to investigate enzyme kinetics, quaternary organization, and binding of ligands. Whereas sequestration by oligomerization is a known regulatory mechanism for eukaryotic UGPs, the recombinant as well as native L. major UGP migrated as monomer in size exclusion chromatography and in accord with this showed simple Michaelis-Menten kinetics toward all substrates. In saturation transfer difference (STD)-NMR studies, we clearly demonstrated that the molecular geometry at position 4 of glucose is responsible for substrate specificity. Furthermore, the γ-phosphate group of UTP is essential for binding and for induction of the open conformation, which then allows entry of glucose 1-phosphate. Our data provide the first direct proof for the ordered bi-bi mechanism suggested in earlier studies. [ABSTRACT FROM AUTHOR] more...
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- 2006
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7. Analysis of promoter methylation in stool: A novel method for the detection of colorectal cancer.
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Lenhard, Konstanze, Bommer, Guido T., Asutay, Silke, Schauer, Rolf, Brabletz, Thomas, Göke, Burkhard, Lamerz, Rolf, and Kolligs, Frank T.
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CANCER patients ,METHYLATION ,STATISTICAL hypothesis testing ,BLOOD testing - Abstract
Background & Aims: Detection of tumor-derived DNA alterations in stool is an intriguing new approach with high potential for the noninvasive detection of colorectal cancer (CRC). Because of heterogeneity of tumors, usually multiple markers distributed throughout the human genome need to be analyzed. This is labor intensive and does not allow for high through-put screening. Therefore, markers with high sensitivity and good specificity are needed. We explored the potential of a single epigenetic marker in comparison with fecal occult blood testing (FOBT) for the discrimination of patients with CRCs and adenomas from those without. Methods: Methylation-specific polymerase chain reaction (PCR) was performed to analyze hypermethylated in cancer 1 (HIC1) promoter methylation status in a blinded fashion in stool samples from 26 patients with CRC, 13 with adenoma ≥1 cm, 9 with hyperplastic polyps, 9 with chronic inflammatory bowel disease, and 32 with endoscopically normal colon. Results: Ninety-seven percent of the stool samples contained amplifiable DNA. Forty-two percent of the samples from patients with CRC and 31% of the samples from patients with colorectal adenoma ≥1 cm were positive for HIC1 promoter methylation. No methylated HIC1 promoter DNA was detected in the fecal DNA from patients with endoscopically normal colon or hyperplastic polyps. Conclusions: The epigenetic marker HIC1 promoter methylation carries high potential for the remote detection of CRCs. We postulate that a panel of merely a few genetic and epigenetic markers will be required for the highly sensitive and specific detection of CRCs and adenomas in fecal samples from affected patients. [Copyright &y& Elsevier] more...
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- 2005
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8. 997 RETROSPECTIVE ANALYSIS OF 191 PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA TREATED WITH TRANSARTERIAL CHEMOEMBOLISATION (TACE): VALIDATION OF THE ESTABLISHED AND CONSTRUCTION OF AN IMPROVED HCC-STAGING-SYSTEM
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op den Winkel, M., Nagel, D., op den Winkel, P., Sappl, J., Straub, G., Lamerz, R., Zech, C., Stieber, P., and Kolligs, F.T.
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- 2011
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9. 68 Chemical proteomics profiling of erlotinib in NSCLC cell lines suggests novel mode of action.
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Augustin, A., Lamerz, J., Golling, S., Meistermann, H., Tzouros, M., Burtscher, H., Spleiss, O., Essioux, L., Langen, H., and Klughammer, B.
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- 2010
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10. Predictive value of serum procollagen-III-peptide for the survival of patients with cirrhosis
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Bayerdörffer, Ekkehard, Lamerz, Rolf, Fliege, Robert, Köpcke, Wolfgang, and Mannes, Gerd A.
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- 1991
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11. Immunological comparison of ovarian and colonic CEA
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Burtin, P., Lamerz, R., Gendron, M.C., Maunoury, M.Th., and Schnabel, G.
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- 1982
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12. Tumor markers in pancreatic cancer: a European Group on Tumor Markers (EGTM) status report.
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Duffy, M. J., Sturgeon, C., Lamerz, R., Haglund, C., Holubec, V. L., Klapdor, R., Nicolini, A., Topolcan, O., and Heinemann, V.
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ADENOCARCINOMA , *TUMOR markers , *JAUNDICE , *CANCER patients , *BIOMARKERS - Abstract
Pancreatic ductal adenocarcinoma is one of the most difficult malignancies to diagnose and treat. The aim of this article is to review how tumor markers can aid the diagnosis and management of patients with this malignancy. The most widely used and best validated marker for pancreatic cancer is CA 19-9. Inadequate sensitivity and specificity limit the use of CA 19-9 in the early diagnosis of pancreatic cancer. In non-jaundiced patients, however, CA 19-9 may complement other diagnostic procedures. In patients with resectable pancreatic cancer, presurgical and postresection CA 19-9 levels correlate with overall survival. In advanced disease, elevated pretreatment levels of CA 19-9 are associated with adverse patient outcome and thus may be combined with other factors for risk stratification. Most, but not all, reports indicate that serial levels of CA 19-9 correlate with response to systemic therapy. Use of CA 19-9 kinetics in conjunction with imaging is therefore recommended in monitoring therapy. Although several potential serum and tissue markers for pancreatic cancer are currently undergoing evaluation, none are sufficiently validated for routine clinical use. CA 19-9 thus remains the serum pancreatic cancer marker against which new markers for this malignancy should be judged. [ABSTRACT FROM PUBLISHER] more...
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- 2010
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13. Symmetric signal transduction and negative allosteric modulation of heterodimeric mGlu1/5 receptors.
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Werthmann, Ruth C., Tzouros, Manuel, Lamerz, Jens, Augustin, Angélique, Fritzius, Thorsten, Trovò, Luca, Stawarski, Michal, Raveh, Adi, Diener, Catherine, Fischer, Christophe, Gassmann, Martin, Lindemann, Lothar, and Bettler, Bernhard more...
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CELLULAR signal transduction , *G protein coupled receptors , *HETERODIMERS , *HOMODIMERS , *G proteins - Abstract
For a long time metabotropic glutamate receptors (mGluRs) were thought to regulate neuronal functions as obligatory homodimers. Recent reports, however, indicate the existence of heterodimers between group-II and –III mGluRs in the brain, which differ from the homodimers in their signal transduction and sensitivity to negative allosteric modulators (NAMs). Whether the group-I mGluRs, mGlu1 and mGlu5, form functional heterodimers in the brain is still a matter of debate. We now show that mGlu1 and mGlu5 co-purify from brain membranes and hippocampal tissue and co-localize in cultured hippocampal neurons. Complementation assays with mutants deficient in agonist-binding or G protein-coupling reveal that mGlu1/5 heterodimers are functional in heterologous cells and transfected cultured hippocampal neurons. In contrast to heterodimers between group-II and –III mGluRs, mGlu1/5 receptors exhibit a symmetric signal transduction, with both protomers activating G proteins to a similar extent. NAMs of either protomer in mGlu1/5 receptors partially inhibit signaling, showing that both protomers need to be able to reach an active conformation for full receptor activity. Complete heterodimer inhibition is observed when both protomers are locked in their inactive state by a NAM. In summary, our data show that mGlu1/5 heterodimers exhibit a symmetric signal transduction and thus intermediate signaling efficacy and kinetic properties. Our data support the existence of mGlu1/5 heterodimers in neurons and highlight differences in the signaling transduction of heterodimeric mGluRs that influence allosteric modulation. [Display omitted] • Transfected mGlu1/5 receptors are functional in heterologous cells and hippocampal neurons. • MGlu1/5 receptors signal symmetrically through both protomers. • MGlu1/5 receptors are partially antagonized by selective mGlu1 or mGlu5 NAMs. • MGlu1/5 receptors are completely blocked in the presence of NAMs for both protomers. • MGluR heterodimers differ in their signal transduction and allosteric modulation. [ABSTRACT FROM AUTHOR] more...
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- 2021
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14. Impact of non-ionizable lipids and phase mixing methods on structural properties of lipid nanoparticle formulations.
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Pratsinis, Anna, Fan, Yuchen, Portmann, Michaela, Hammel, Michal, Kou, Ponien, Sarode, Apoorva, Ringler, Philippe, Kovacik, Lubomir, Lauer, Matthias E., Lamerz, Jens, Hura, Greg L., Yen, Chun-Wan, and Keller, Michael more...
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NANOPARTICLES , *SMALL-angle scattering , *NANOPARTICLE size , *LIPIDS , *OLIGONUCLEOTIDES , *NUCLEIC acids , *HIGH throughput screening (Drug development) - Abstract
[Display omitted] Lipid nanoparticles (LNPs) have been widely investigated for nucleic acid therapeutic delivery, and demonstrated their potential in enabling new mRNA vaccines. LNPs are usually formulated with multi-lipid components and the composition variables may impact their structural properties. Here, we investigated the impact of helper lipids on physicochemical properties of LNPs using a Design of Experiments (DoE) definitive screening design. Phospholipid head group, degree of unsaturation, ratio to cholesterol as well as PEG-lipid content were varied and a series of 14 LNPs were prepared by microfluidic- and solvent-injection mixing. Solvent-injection mixing by a robotic liquid handler yielded 50–225 nm nanoparticles with highly ordered, ∼5 nm inter-lamellar spacing as measured by small angle X-ray scattering (SAXS) and confirmed by cryo-transmission electron microscopy (cryo-EM). In contrast, microfluidic mixing resulted in less ordered, notably smaller (50–75 nm) and more homogenous nanoparticles. Significant impacts of the stealth-lipid DSPE-PEG2000 on nanoparticle size, polydispersity and encapsulation efficiency of an oligonucleotide cargo were observed in LNPs produced by both methods, while varying the phospholipid type and content had only marginal effect on these physicochemical properties. These findings suggest that from a physicochemical perspective, the design space for combinations of helper lipids in LNPs may be considerably larger than anticipated based on the conservative formulation composition of the currently FDA-approved LNPs, thereby opening opportunities for screening and optimization of novel LNP formulations. [ABSTRACT FROM AUTHOR] more...
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- 2023
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15. Tumour markers in colorectal cancer: European Group on Tumour Markers (EGTM) guidelines for clinical use
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Duffy, M.J., van Dalen, A., Haglund, C., Hansson, L., Holinski-Feder, E., Klapdor, R., Lamerz, R., Peltomaki, P., Sturgeon, C., and Topolcan, O.
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COLON cancer , *CANCER treatment , *MICROSATELLITE repeats , *TUMOR markers - Abstract
Abstract: The aim of this article is to present updated guidelines for the use of serum, tissue and faecal markers in colorectal cancer (CRC). Lack of specificity and sensitivity preclude the use of all existing serum markers for the early detection of CRC. For patients with stage II or stage III CRC who may be candidates for either liver resection or systemic treatment should recurrence develop, CEA should be measured every 2–3 months for at least 3 years after diagnosis. Insufficient evidence exists to recommend routine use of tissue factors such as thymidylate synthase, microsatellite instability (MSI), p53, K-ras and deleted in colon cancer (DCC) for either determining prognosis or predicting response to therapy in patients with CRC. Microsatellite instability, however, may be used as a pre-screen for patients with suspected hereditary non-polyposis colorectal cancer. Faecal occult blood testing but not faecal DNA markers may be used to screen asymptomatic subjects 50 years or older for early CRC. [Copyright &y& Elsevier] more...
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- 2007
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16. Clinical utility of biochemical markers in colorectal cancer: European Group on Tumour Markers (EGTM) guidelines
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Duffy, M.J., van Dalen, A., Haglund, C., Hansson, L., Klapdor, R., Lamerz, R., Nilsson, O., Sturgeon, C., and Topolcan, O.
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COLON cancer , *TUMOR markers - Abstract
In recent years, numerous serum and cell/tissue-based markers have been described for colorectal cancer (CRC). The aim of this article was to provide guidelines for the routine clinical use of some of these markers. Lack of sensitivity and specificity preclude the use of any available serum markers such as carcinoembryonic antigen (CEA), CA 19-9, CA 242, CA 72-4, tissue polypeptide antigen (TPA) or tissue polypeptide-specific antigen (TPS) for the early detection of CRC. However, preoperative measurement of CEA is desirable as this may give independent prognostic information, help with surgical management and provide a baseline level for subsequent determinations. For patients with stage 2 (Dukes’ B) and 3 (Dukes’ C) disease who may be candidates for liver resection, CEA levels should be measured every 2-3 months for at least 3 years after diagnosis. For monitoring treatment of advanced disease, CEA should also be tested every 2-3 months. Insufficient evidence is presently available to recommend the routine use of other serum markers for monitoring purposes. Similarly, the new cell and tissue-based markers (e.g, ras, P53) cannot yet be recommended for routine clinical use. [Copyright &y& Elsevier] more...
- Published
- 2003
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17. Epidermal growth factor-receptor (EGF-R) characteristics in 2 cases of polyposis intestini as compared to normal mucosa and colorectal carcinomas
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Pfeiffer, A., Rothbauer, E., Borlinghaus, P., Wiebecke, B., Lamerz, R., Pratschke, E., Kremling, H.J., and Mann, K.
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- 1987
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18. Tumor markers in breast cancer – european group on tumor markers (EGTM) recommendations
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Molina, Rafael, Barak, Vivian, van Dalen, Arie, Duffy, Michael J., Einarsson, Roland, Gion, Massimo, Goike, Helena, Lamerz, Rolf, Nap, Marius, Sölétormos, György, and Stieber, Petra
- Published
- 2008
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