المؤلفون: Matthias Zeis, Adel L. Barsoum, Christoph Schulte, Klaus Heidorn, Joseph H. Coggin, Rudolph Reimer, Dieter Kabelitz, Birte Friedrichs, Sandra Siegel, Norbert Schmitz

المصدر: Leukemia Research. 35:721-729

مصطلحات موضوعية: Adult, Male, Ribosomal Proteins, Cancer Research, Chronic lymphocytic leukemia, Blotting, Western, Immunoglobulin Variable Region, CD38, Biology, Disease-Free Survival, Flow cytometry, Receptors, Laminin, Antigen, Predictive Value of Tests, medicine, Humans, Progression-free survival, Cells, Cultured, Aged, Aged, 80 and over, ZAP-70 Protein-Tyrosine Kinase, medicine.diagnostic_test, Hematology, Middle Aged, Flow Cytometry, Prognosis, medicine.disease, ADP-ribosyl Cyclase 1, Leukemia, Lymphocytic, Chronic, B-Cell, Tumor antigen, Oncology, Predictive value of tests, Multivariate Analysis, Mutation, Immunology, Cancer research, Immunoglobulin heavy chain, Female, Immunoglobulin Heavy Chains

الوصف: The immature laminin receptor (iLR) is a tumor-associated antigen. We analyzed the expression of iLR on malignant B cells of 134 unselected patient samples with CLL and hypothesized that iLR expression would have prognostic significance due to a differential expression pattern. High ILR expression (cutoff value 30) was correlated with mutated IGVH status (p < 0.0001). Patients with high iLR-expression had a significantly longer time to progression (p = 0.039). Combination of CD38, ZAP-70, and iLR by flow cytometry can be used to construct a diagnostic score identifying patients with a median progression free survival of 80 months, if no adverse marker is present. (C) 2010 Elsevier Ltd. All rights reserved.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::14a6df2f79ea6dc7bc0037d5d40303cdTest
https://doi.org/10.1016/j.leukres.2010.10.002Test

المؤلفون: Dieter Kabelitz, Christoph Schulte, James W. Rohrer, Ilja Jakob, Matthias Zeis, Birte Friedrichs, Marita Kloess, Jörg Steinmann, Norbert Schmitz, Markus Tiemann, Joseph H. Coggin, Adel L. Barsoum, Sandra Siegel, Klaus Heidorn

المصدر: The Journal of Immunology. 180:6374-6384

مصطلحات موضوعية: Adult, Male, Ribosomal Proteins, Antibodies, Neoplasm, Chronic lymphocytic leukemia, Immunology, Graft vs Leukemia Effect, Disease-Free Survival, Epitope, Subclass, Receptors, Laminin, Immune system, Antibody Specificity, Antigens, Neoplasm, immune system diseases, hemic and lymphatic diseases, medicine, Extracellular, Humans, Transplantation, Homologous, Immunology and Allergy, Aged, Aged, 80 and over, business.industry, Hematopoietic Stem Cell Transplantation, Middle Aged, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Survival Rate, Transplantation, Immunoglobulin G, Antibody Formation, Humoral immunity, Female, Stem cell, business

الوصف: Chronic lymphocytic leukemia (CLL) is characterized by a highly variable clinical course. The role of an autologous tumor-specific immune control contributing to the variable length of survival in CLL is poorly understood. We investigated whether humoral immunity specific for the CLL-associated Ag oncofetal Ag/immature laminin receptor (OFA/iLR) has a prognostic value in CLL. Among sera of 67 untreated patients with CLL, 23 (34.3%) had detectable OFA/iLR Abs that were reactive for at least one specific OFA/iLR epitope. Patients with humoral responses compared with patients with nonreactive sera had a longer progression-free survival (p = 0.029). IgG subclass analyses showed a predominant IgG1 and IgG3 response. OFA/iLR Abs were capable of recognizing and selectively killing OFA/iLR-expressing CLL cells in complement-mediated and Ab-dependent cellular cytotoxi cityassays. In the analysis of 11 CLL patients after allogeneic hematopoetic stem cell transplantation, 8 showed high values for OFA/iLR Abs that specifically recognized the extracellular domain of the protein, suggesting a potential role of anti-OFA/iLR-directed immune responses to the graft-vs-leukemia effect in CLL. Our data suggest that spontaneous tumor-specific humoral immune responses against OFA/iLR exist in a significant proportion of CLL patients and that superior progression-free survival in those patients could reflect autologous immune control.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::36074d862ae7d4deff2aee12585df9c8Test
https://doi.org/10.4049/jimmunol.180.9.6374Test

المؤلفون: Jörn Bullerdiek, Klaus Heidorn, André Fehr, Cora Hallas, Thomas Löning, Kerstin Röser

المصدر: Genes, Chromosomes and Cancer. 47:203-206

مصطلحات موضوعية: Cancer Research, Oncogene Proteins, Fusion, Oncogene Proteins, Sequence analysis, Chimeric gene, Biology, CREB, Fusion gene, Mucoepidermoid carcinoma, Genetics, Carcinoma, medicine, Humans, Gene, Reverse Transcriptase Polymerase Chain Reaction, Nuclear Proteins, Sequence Analysis, DNA, medicine.disease, DNA-Binding Proteins, stomatognathic diseases, Trans-Activators, biology.protein, Cancer research, Carcinoma, Mucoepidermoid, Sequence Alignment, Transcription Factors

الوصف: The present study reports for the first time a CRTC3-MAML2 fusion gene in a mucoepidermoid carcinoma, as determined by RT-PCR and sequencing. We screened a total of 67 formalin-fixed, paraffin-embedded mucoepidermoid carcinomas for the presence of chimeric genes. In one of these samples, a CRTC3-MAML2 fusion gene was detected. Thus, this report demonstrates the existence of a fusion of MAML2 with CREB regulated transcriptional coactivator CRTC3 additional to the already known fusion of MAML2 and CRTC1. Both gene fusions seem to result in an identical tumor phenotype and the fusion genes CRTC1-MAML2 and CRTC3-MAML2 may play a similar role in the development of mucoepidermoid carcinomas.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6aa767d576d7d36b2ef01065ebda45a3Test
https://doi.org/10.1002/gcc.20522Test

المؤلفون: Jochen A. Werner, Steffen Maune, Burkard M. Lippert, Markus Hoffmann, Stefan Gottschlich, Klaus Heidorn, Jens E. Meyer, Heinrich Rudert, Tibor Görögh

المصدر: Journal of Cancer Research and Clinical Oncology. 127:166-172

مصطلحات موضوعية: Keratinocytes, Cancer Research, Transcription, Genetic, Molecular Sequence Data, Biology, Transfection, Gene product, Gene expression, Tumor Cells, Cultured, Humans, Gene silencing, RNA, Messenger, RNA, Neoplasm, Laryngeal Neoplasms, Reporter gene, Differential display, Base Sequence, Reverse Transcriptase Polymerase Chain Reaction, Nucleic Acid Hybridization, General Medicine, Blotting, Northern, Molecular biology, Fibronectins, Gene Expression Regulation, Neoplastic, Oncology, Epidermoid carcinoma, Cell culture, Carcinoma, Squamous Cell

الوصف: Purpose: The aim of the experiments was to analyze the mRNA expression pattern and verify the repression of FN gene expression in laryngeal squamous cell carcinoma (SCC) cells in comparison with benign mucosal keratinocytes. Methods: Messenger RNA from SCC cells and benign keratinocytes was reverse transcribed and subjected to PCR following differential display (DD) analysis of the amplicons. Northern hybridization was carried out to confirm the reduction of the FN-mRNA expression in both laryngeal SCC cells and larynx carcinoma biopsies, in contrast to adjacent normal mucosa. Quantitation of protein synthesis was performed with homogenates of fresh tumor biopsies and their normal phenotypes, as well as of benign keratinocytes and laryngeal SCC cell lines, respectively, using ELISA. In the liposome-mediated transient transfection assay, FN promoter activity was analyzed by linking the FN promoter sequence to the chloramphenicol acetyltransferase (CAT) reporter gene. Transfection efficacy was monitored by co-transfection with pGL3 control vector. Results: A 191 bp mRNA fragment revealing a 99% homology with the human FN-mRNA was detected, the expression of which was repressed 20 times as much in SCC cells as compared to benign phenotypes. Northern hybridization confirmed the distinctly reduced expression of FN-mRNA in both laryngeal SCC cells and larynx carcinoma biopsies, in contrast to adjacent normal mucosa. The quantitation experiments showed a correlation between the range of FN synthesis and the expression of FN-mRNA in cell lines and the biopsies which were used. The 1.28 kb FN gene promoter drove expression of the CAT reporter gene, which was similar to the FN-mRNA expression showed by DD and Northern hybridization. Conclusions: The mechanisms leading to the low level of FN in many tumors have not yet been sufficiently investigated. Our findings suggest that the decrease of FN in laryngeal SCC cells is transcriptionally regulated.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::68c23faf28995017240f6ef366bf44c5Test
https://doi.org/10.1007/s004320000198Test

المؤلفون: Iwona Michalska, Guido Krupp, Sontka Tamm, Axel Hauschild, Pierre Rudolph, Stephania Jablonska, Christoph Schubert, Slavomir Majewski, Reza Parwaresch, Klaus Heidorn

المصدر: The American Journal of Pathology. 156:1425-1432

مصطلحات موضوعية: Telomerase, Pathology, medicine.medical_specialty, Melanoma, Cell cycle, Melanocytic nevus, Biology, medicine.disease, Pathology and Forensic Medicine, Malignant transformation, Metastasis, Dysplastic nevus syndrome, Cancer research, medicine, Immunohistochemistry, neoplasms

الوصف: Telomerase activation, being a cardinal requirement for immortalization, is a crucial step in the development of malignancy. With a view toward diagnostic and biological aspects in melanocytic neoplasia, we investigated the relative levels of telomerase activity in 72 nevi and 16 malignant melanomas by means of a modified telomeric repeat amplification protocol (TRAP) assay, including an internal amplification standard. We further compared telomerase activity with the expression of two different proliferation-specific proteins, Ki-67 and repp86, a protein expressed exclusively in the cell cycle phases S, G2, and M. Telomerase activity was associated with the overall growth fraction (Ki-67) but showed a closer correlation with the expression of repp86. Both telomerase activity and proliferation indices discriminated clearly between malignant melanomas and nevi, but not between common and dysplastic nevi. Nonetheless, a portion of nevi exhibited markedly elevated telomerase activity levels without proportionally increased proliferation. This was independent of discernible morphological changes. Clinicopathological correlations showed an association between high telomerase activity and early metastatic spread in melanomas, linking telomerase to tumor biology. Our results provide arguments in favor of an occasional progression from nevi to melanomas and imply that proliferation measurements in combination with telomerase assays may help to elicit early malignant transformation that is undetectable by conventional morphology.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::1b122b19d148174767c12a8ad3fa2078Test
https://doi.org/10.1016/s0002-9440Test(10)65011-0

المؤلفون: Sven Olaf Frahm, Klaus Heidorn, D Körbächer, J. Felgner, Reza Parwaresch

المصدر: Leukemia. 13:530-534

مصطلحات موضوعية: Cancer Research, Transcription, Genetic, Cellular differentiation, Biology, Leukemia, Myelomonocytic, Acute, Monocytes, Cell Line, Growth Factor Receptor Gene, Cell surface receptor, Macrophages, Alveolar, Gene expression, Tumor Cells, Cultured, Humans, Cell Lineage, Lymphocytes, Receptor, Cell Line, Transformed, Gene Expression Regulation, Leukemic, Macrophages, Gene Expression Regulation, Developmental, Cell Differentiation, Promoter, U937 Cells, Hematology, Methylation, DNA Methylation, Hematopoiesis, Neoplasm Proteins, Oncology, Receptors, Granulocyte Colony-Stimulating Factor, DNA methylation, Leukocytes, Mononuclear, Macrophages, Peritoneal, Neoplastic Stem Cells, Cancer research, K562 Cells, Polymorphism, Restriction Fragment Length

الوصف: In hematopoiesis the evolution of specialized cell lineages from a common stem cell is mediated by lineage-specific growth factors. The role of DNA methylation in the multilevel regulation of the differential gene expression, especially in the case of growth factor receptor genes, has remained elusive. In earlier studies we showed a lineage-specific methylation pattern of the M-CSF receptor gene c-fms in blood monocytes and tissue macrophages. Here, we provide evidence that a lineage- specific hypomethylation exists for the G-CSF receptor gene for myelomonocytic cells but not in lymphocytes without any interindividual differences. Constant differences were found between alveolar and peritoneal macrophages with a lesser degree of methylation in peritoneal macrophages. Acute myelomonocytic leukemias showed an increased methylation as compared with normal granulocytes and monocytes. All permanent cell lines analyzed revealed hypermethylation of the G-CSF receptor gene. Lymphocytes of B-CLL showed a strong hypermethylation of this gene. Increased methylation has been shown to be inversely correlated with transcriptional gene activities. We conclude that the methylation pattern of growth factor receptor genes may be one of the regulatory mechanisms in multi-lineage differentiation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::737be11ff47b9c70b6cf2189700c205fTest
https://doi.org/10.1038/sj.leu.2401386Test

المؤلفون: Klaus Heidorn, Guido Krupp, Wolfram Klapper, Kumud K. Singh, Reza Parwaresch

المصدر: Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1442:120-126

مصطلحات موضوعية: Telomerase, Somatic cell, Molecular Sequence Data, Biophysics, Biology, medicine.disease_cause, Polymerase Chain Reaction, Biochemistry, Culture Media, Serum-Free, Gene Expression Regulation, Enzymologic, Structural Biology, Tumor Cells, Cultured, Genetics, medicine, Humans, Telomerase reverse transcriptase, Cell Line, Transformed, DNA Primers, Repetitive Sequences, Nucleic Acid, Base Sequence, Cell growth, U937 Cells, Telomere, Hodgkin Disease, Molecular biology, Gene Expression Regulation, Neoplastic, Kinetics, Cell culture, Carcinogenesis, Immortalised cell line, Cell Division

الوصف: Telomerase is a key enzyme in carcinogenesis; telomerase activity has been found in more than 90% of human tumors. Understanding the regulation of this enzyme will improve our knowledge of tumor biology and may lead to novel strategies in cancer therapy. We examined effects of growth arrest on telomerase activity in the human immortalized cell lines U 937 (lymphoma) and L 428 (Hodgkin's disease). Cells were starved by serum depletion for 4 days. After readdition of serum, a recovery phase followed. Cell proliferation was monitored with the monoclonal antibody Ki-S5. In the absence of serum, telomerase levels declined fivefold. After serum readdition, recovery to threefold increased level was observed. Furthermore, the prevalence of telomerase-positive cells in normal tissues is an important issue for understanding tumorigenesis. Our TRAP assay is robust against false positives and in mixed cell samples, we found a rather limited sensitivity of the telomere repeat amplification protocol (TRAP) assay. This means that adequate screenings for telomerase-positive somatic cells have to include enrichment steps.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8b26e0cb9696a9ff88233bbcb5bcc4f2Test
https://doi.org/10.1016/s0167-4781Test(98)00155-9

المؤلفون: Reza Parwaresch, Guido Krupp, Klaus Heidorn, Wolfram Klapper, Karen Kühne

المصدر: FEBS Letters. 434:409-412

مصطلحات موضوعية: Senescence, Telomerase, Somatic cell, Biophysics, DNA replication, Cell Biology, Biology, Biochemistry, Molecular biology, Telomere, Telomerase RNA component, Structural Biology, Genetics, Telomerase reverse transcriptase, Stem cell, Molecular Biology

الوصف: Eukaryotic chromosome termini consist of telomeres, short sequence repeats. According to the telomere hypothesis, DNA replication leads to telomere shortening, resulting in a cellular mitotic clock. Telomerase resets it by telomere synthesis. In mammals with a limited growth phase, telomerase activity in somatic tissues is restricted to stem cell derivatives with high proliferation potential. But other animals, like some fish, grow throughout their life with little senescence. All somatic cells require a high proliferation capacity and telomerase should be active in all cells, irrespective of fish age. Indeed, we detected high telomerase activities in all analyzed organs of rainbow trout (Oncorhynchus mykiss).

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::cf332e652587432b18cdc92732a3a226Test
https://doi.org/10.1016/s0014-5793Test(98)01020-5

المؤلفون: Susann Andreasa, Gabriele Bonatz, Sven Olaf Frahm, Reza Parwaresch, Walter Jonat, Klaus Heidorn

المصدر: American Journal of Obstetrics and Gynecology. 179:591-596

مصطلحات موضوعية: Adult, medicine.medical_specialty, Pathology, X Chromosome, Genetic Linkage, Uterus, Benign tumor, Glycerol Kinase, Internal medicine, medicine, Humans, neoplasms, Uterine Neoplasm, Alleles, Aged, Aged, 80 and over, Polymorphism, Genetic, Uterine leiomyoma, Leiomyoma, business.industry, Myometrium, Obstetrics and Gynecology, Myoma, Middle Aged, Telomere, musculoskeletal system, medicine.disease, female genital diseases and pregnancy complications, Endocrinology, medicine.anatomical_structure, Uterine Neoplasms, Female, business

الوصف: To gain a better understanding of proliferation control mechanisms in a common benign tumor, we investigated the mean telomere length and the clonality of uterine leiomyomas.Deoxyribonucleic acid from uterine leiomyomas and from the adjacent normal myometrium of 51 patients (total number of uterine leiomyomas 107; 28 patients with single leiomyoma, 23 patients with multiple leiomyomas ranging from 2 to 8 myoma nodules per case) was hybridized to a telomeric oligonucleotide probe by Southern blot and chemiluminescent detection. The mean telomere length was evaluated by densitometry. Clonality was assessed with use of the phosphoglycerokinase gene polymorphism.The mean telomere length was significantly shorter in uterine leiomyomas (median 7950 bp, interquartile range 7261 to 8372 bp) than in normal myometrium (median 9688 bp, interquartile range 8528 to 10535 bp) (P.001). There was no correlation between tumor size and telomere attrition. Multiple uterine leiomyomas were found to have an independent clonal origin.Telomere attrition in uterine leiomyomas reflects enhanced proliferation activity in the course of tumor evolution. The basic telomere lengths differ in the myocytes from which the uterine leiomyomas originate, probably explaining the lack of correlation between telomere attrition and tumor size.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bab7aa8573429008d3999e80316f53f7Test
https://doi.org/10.1016/s0002-9378Test(98)70050-x

المؤلفون: Tibor Görögh, Burkard M. Lippert, E. Henze, Jochen A. Werner, S. Saffran, Klaus Heidorn, E. Sprenger, G. Bergmann

المصدر: Journal of Cancer Research and Clinical Oncology. 123:39-44

مصطلحات موضوعية: Cancer Research, Biology, Flow cytometry, chemistry.chemical_compound, Methionine, Tumor Cells, Cultured, medicine, Humans, Mitosis, medicine.diagnostic_test, Cell growth, DNA, Neoplasm, General Medicine, Aneuploidy, Flow Cytometry, Molecular biology, Neoplasm Proteins, Nuclear DNA, stomatognathic diseases, Oncology, chemistry, Epidermoid carcinoma, Head and Neck Neoplasms, Cell culture, Carcinoma, Squamous Cell, Ploidy, Cell Division, DNA

الوصف: Aneuploidy, as abnormal nuclear DNA content, is considered almost positive evidence of malignancy. In this study three diploid and three aneuploid squamous cell carcinoma (SCC) cell lines were examined for DNA content by flow cytometry. The DNA indices of the SCC cell lines were found to range from 1.0 to 2.1. The mitotic activity of the diploid cell lines was 1.6 times higher and the cells were smaller than aneuploid cells. To find a molecular basis for these differences, the pattern of the de-novo synthesized proteins was analyzed by means of [35S]methionine incorporation, electrophoresis, and autoradiography. In all aneuploid SCC cell lines tested in this experiment, the increase of nuclear DNA content is associated with the synthesis of a novel protein with a molecular mass of approximate 55 kDa as well as with altered synthesis rates of two preexisting proteins (50 kDa and 100 kDa). For determination of the amino acid uptake in diploid and aneuploid cells, the accumulation of [35S]methionine was measured as a function of time by liquid scintillation counting. No significant difference was found in the uptake rate between diploid and aneuploid cells with the same protein content. However, discrepancies were revealed when equal numbers of cells with different DNA index were used, suggesting, that protein turnover is different in diploid and aneuploid SCC cells.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c222204d30f212717e003005aad7f137Test
https://doi.org/10.1007/bf01212613Test