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Search Results: 1 - 10 of 10580 matches for " Andreas Rosenwald "
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Single Nucleotide Polymorphism Array Profiling of Adrenocortical Tumors - Evidence for an Adenoma Carcinoma Sequence?
Cristina L. Ronchi, Silviu Sbiera, Ellen Leich, Katharina Henzel, Andreas Rosenwald, Bruno Allolio, Martin Fassnacht
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0073959
Abstract: Adrenocortical tumors consist of benign adenomas and highly malignant carcinomas with a still incompletely understood pathogenesis. A total of 46 adrenocortical tumors (24 adenomas and 22 carcinomas) were investigated aiming to identify novel genes involved in adrenocortical tumorigenesis. High-resolution single nucleotide polymorphism arrays (Affymetrix) were used to detect copy number alterations (CNAs) and copy neutral losses of heterozygosity (cnLOH). Genomic clustering showed good separation between adenomas and carcinomas, with best partition including only chromosome 5, which was highly amplified in 17/22 malignant tumors. The malignant tumors had more relevant genomic aberrations than benign tumors, such as a higher median number of recurrent CNA (2631 vs 94), CNAs >100 Kb (62.5 vs 7) and CN losses (72.5 vs 5.5), and a higher percentage of samples with cnLOH (91% vs 29%). Within the carcinoma cohort, a precise genetic pattern (i.e. large gains at chr 5, 7, 12, and 19, and losses at chr 1, 2, 13, 17, and 22) was associated with a better prognosis (overall survival: 72.2 vs 35.4 months, P=0.063). Interestingly, >70% of gains frequent in beningn were also present in malignant tumors. Notch signaling was the most frequently involved pathway in both tumor entities. Finally, a CN gain at imprinted “IGF2” locus chr 11p15.5 appeared to be an early alteration in a multi-step tumor progression, followed by the loss of one or two alleles, associated with increased IGF2 expression, only in carcinomas. Our study serves as database for the identification of genes and pathways, such as Notch signaling, which could be involved in the pathogenesis of adrenocortical tumors. Using these data, we postulate an adenoma-carcinoma sequence for these tumors.
Non-Invasive Bioluminescence Imaging to Monitor the Immunological Control of a Plasmablastic Lymphoma-Like B Cell Neoplasia after Hematopoietic Cell Transplantation
Martin Chopra, Sabrina Kraus, Stefanie Schwinn, Miriam Ritz, Katharina Mattenheimer, Anja Mottok, Andreas Rosenwald, Hermann Einsele, Andreas Beilhack
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0081320
Abstract: To promote cancer research and to develop innovative therapies, refined pre-clinical mouse tumor models that mimic the actual disease in humans are of dire need. A number of neoplasms along the B cell lineage are commonly initiated by a translocation recombining c-myc with the immunoglobulin heavy-chain gene locus. The translocation is modeled in the C.129S1-Ighatm1(Myc)Janz/J mouse which has been previously engineered to express c-myc under the control of the endogenous IgH promoter. This transgenic mouse exhibits B cell hyperplasia and develops diverse B cell tumors. We have isolated tumor cells from the spleen of a C.129S1-Ighatm1(Myc)Janz/J mouse that spontaneously developed a plasmablastic lymphoma-like disease. These cells were cultured, transduced to express eGFP and firefly luciferase, and gave rise to a highly aggressive, transplantable B cell lymphoma cell line, termed IM380. This model bears several advantages over other models as it is genetically induced and mimics the translocation that is detectable in a number of human B cell lymphomas. The growth of the tumor cells, their dissemination, and response to treatment within immunocompetent hosts can be imaged non-invasively in vivo due to their expression of firefly luciferase. IM380 cells are radioresistant in vivo and mice with established tumors can be allogeneically transplanted to analyze graft-versus-tumor effects of transplanted T cells. Allogeneic hematopoietic stem cell transplantation of tumor-bearing mice results in prolonged survival. These traits make the IM380 model very valuable for the study of B cell lymphoma pathophysiology and for the development of innovative cancer therapies.
Case report: a unique pediatric case of a primary CD8 expressing ALK-1 positive anaplastic large cell lymphoma of skeletal muscle
Timo Gaiser, Eva Geissinger, Torsten Schattenberg, Hanns-Peter Scharf, Matthias Dürken, Dietmar Dinter, Andreas Rosenwald, Alexander Marx
Diagnostic Pathology , 2012, DOI: 10.1186/1746-1596-7-38
Abstract: Anaplastic large cell lymphoma (ALCL) was discovered by Stein et al. and characterized by strong expression of the Ki-1 (CD30) antigen [1]. In 1988, ALCL was included in the revised Kiel classification and is nowadays classified as a Non-Hodgkin lymphoma of T-cell origin by the World Health Organization [2,3]. The key moment in understanding the primary biological driver behind ALCL was the discovery of the recurrent t(2;5)(p23;q35) translocation in this lymphoma type [4]. This finding was further elucidated by Morris and colleagues who identified the two genes involved in this translocation: the anaplastic lymphoma kinase (ALK-1) on chromosome 2 and nucleophosmin (NPM1) on chromosome 5 [5]. Subsequently, the NPM-ALK fusion protein was proven to have oncogenic capacity [6]. Among the four main types of pediatric non-Hodgkin lymphoma (Burkitt lymphoma, diffuse large B-cell lymphoma, anaplastic large cell lymphoma and lymphoblastic lymphoma) ALCL has the best prognosis: event-free and overall survival rates were 72% and 88%, respectively, even in advanced-stage diseases [7].Here, we report a case of a 10-year old boy diagnosed with an ALK-1 positive anaplastic large cell lymphoma of the skeletal muscle. Primary involvement of skeletal muscle by ALCL is extremely rare and so far only four pediatric cases have been reported in the literature [8-11].A 10-year old boy presented with a painful swelling in the dorsal aspect of the left distal thigh without history of trauma. Pain started 3 weeks before, increased with time and resulted in difficulties in walking at time of presentation. No fever, night sweats or weight loss was reported. Physical examination revealed a 9 × 4 cm palpable firm mass in the biceps femoris muscle. Magnetic resonance imaging (MRI) demonstrated a 4 × 3 × 9 cm ill-defining tumor within the long head of the biceps femoris muscle with vivid uptake of contrast medium (Figure 1). Also, enlarged lymph nodes up to a diameter of 2 cm were detected poplite
Natalizumab Exerts Direct Signaling Capacity and Supports a Pro-Inflammatory Phenotype in Some Patients with Multiple Sclerosis
Thomas F. Benkert, Lena Dietz, Elena M. Hartmann, Ellen Leich, Andreas Rosenwald, Edgar Serfling, Mathias Buttmann, Friederike Berberich-Siebelt
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0052208
Abstract: Natalizumab is a recombinant monoclonal antibody raised against integrin alpha-4 (CD49d). It is approved for the treatment of patients with multiple sclerosis (MS), a chronic inflammatory autoimmune disease of the CNS. While having shown high therapeutic efficacy, treatment by natalizumab has been linked to progressive multifocal leukoencephalopathy (PML) as a serious adverse effect. Furthermore, drug cessation sometimes induces rebound disease activity of unknown etiology. Here we investigated whether binding of this adhesion-blocking antibody to T lymphocytes could modulate their phenotype by direct induction of intracellular signaling events. Primary CD4+ T lymphocytes either from healthy donors and treated with natalizumab in vitro or from MS patients receiving their very first dose of natalizumab were analyzed. Natalizumab induced a mild upregulation of IL-2, IFN-γ and IL-17 expression in activated primary human CD4+ T cells propagated ex vivo from healthy donors, consistent with a pro-inflammatory costimulatory effect on lymphokine expression. Along with this, natalizumab binding triggered rapid MAPK/ERK phosphorylation. Furthermore, it decreased CD49d surface expression on effector cells within a few hours. Sustained CD49d downregulation could be attributed to integrin internalization and degradation. Importantly, also CD4+ T cells from some MS patients receiving their very first dose of natalizumab produced more IL-2, IFN-γ and IL-17 already 24 h after infusion. Together these data indicate that in addition to its adhesion-blocking mode of action natalizumab possesses mild direct signaling capacities, which can support a pro-inflammatory phenotype of peripheral blood T lymphocytes. This might explain why a rebound of disease activity or IRIS is observed in some MS patients after natalizumab cessation.
The Natural Human IgM Antibody PAT-SM6 Induces Apoptosis in Primary Human Multiple Myeloma Cells by Targeting Heat Shock Protein GRP78
Leo Rasche, Johannes Duell, Charlotte Morgner, Manik Chatterjee, Frank Hensel, Andreas Rosenwald, Hermann Einsele, Max S. Topp, Stephanie Br?ndlein
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063414
Abstract: In contrast to other haematological malignancies, targeted immunotherapy has not entered standard treatment regimens for de novo or relapsed multiple myeloma (MM) yet. While a number of IgG-formatted monoclonal antibodies are currently being evaluated in clinical trials in MM, our study aimed to investigate whether the fully human IgM monoclonal antibody PAT-SM6 that targets a tumour-specific variant of the heat shock protein GRP78 might be an attractive candidate for future immunotherapeutic approaches. We here show that GRP78 is stably and consistently expressed on the surface on tumour cells from patients with de novo, but also relapsed MM and that binding of PAT-SM6 to MM cells can specifically exert cytotoxic effects on malignant plasma cells, whereas non-malignant cells are not targeted. We demonstrate that the induction of apoptosis and, to a lesser extent, complement dependent cytotoxicity is the main mode of action of PAT-SM6, whereas antibody dependent cellular cytotoxicity does not appear to contribute to the cytotoxic properties of this antibody. Given the favourable safety profile of PAT-SM6 in monkeys, but also in a recent phase I trial in patients with malignant melanoma, our results form the basis for a planned phase I study in patients with relapsed MM.
Targeting Paraprotein Biosynthesis for Non-Invasive Characterization of Myeloma Biology
Katharina Lückerath, Constantin Lapa, Annika Spahmann, Gerhard J?rg, Samuel Samnick, Andreas Rosenwald, Herrmann Einsele, Stefan Knop, Andreas K. Buck
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0084840
Abstract: Purpose Multiple myeloma is a hematologic malignancy originating from clonal plasma cells. Despite effective therapies, outcomes are highly variable suggesting marked disease heterogeneity. The role of functional imaging for therapeutic management of myeloma, such as positron emission tomography with 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG-PET), remains to be determined. Although some studies already suggested a prognostic value of 18F-FDG-PET, more specific tracers addressing hallmarks of myeloma biology, e.g. paraprotein biosynthesis, are needed. This study evaluated the amino acid tracers L-methyl-[11C]-methionine (11C-MET) and [18F]-fluoroethyl-L-tyrosine (18F-Fet) for their potential to image myeloma and to characterize tumor heterogeneity. Experimental Design To study the utility of 11C-MET, 18F-Fet and 18F-FDG for myeloma imaging, time activity curves were compared in various human myeloma cell lines (INA-6, MM1.S, OPM-2) and correlated to cell-biological characteristics, such as marker gene expression and immunoglobulin levels. Likewise, patient-derived CD138+ plasma cells were characterized regarding uptake and biomedical features. Results Using myeloma cell lines and patient-derived CD138+ plasma cells, we found that the relative uptake of 11C-MET exceeds that of 18F-FDG 1.5- to 5-fold and that of 18F-Fet 7- to 20-fold. Importantly, 11C-MET uptake significantly differed between cell types associated with worse prognosis (e.g. t(4;14) in OPM-2 cells) and indolent ones and correlated with intracellular immunoglobulin light chain and cell surface CD138 and CXCR4 levels. Direct comparison of radiotracer uptake in primary samples further validated the superiority of 11C-MET. Conclusion These data suggest that 11C-MET might be a versatile biomarker for myeloma superior to routine functional imaging with 18F-FDG regarding diagnosis, risk stratification, prognosis and discrimination of tumor subtypes.
Delineation of Chondroid Lipoma: An Immunohistochemical and Molecular Biological Analysis
Ronald S. A. de Vreeze,Frits van Coevorden,Lucie Boerrigter,Petra M. Nederlof,Rick L. Haas,Johannes Bras,Andreas Rosenwald,Thomas Mentzel,Daphne de Jong
Sarcoma , 2011, DOI: 10.1155/2011/638403
Abstract: Aims. Chondroid lipoma (CL) is a benign tumor that mimics a variety of soft tissue tumors and is characterized by translocation (11;16). Here, we analyze CL and its histological mimics. Methods. CL (=4) was compared to a variety of histological mimics (=83) for morphological aspects and immunohistochemical features including cyclinD1(CCND1). Using FISH analysis, CCND1 and FUS were investigated as potential translocation partners. Results. All CLs were strongly positive for CCND1. One of 4 myoepitheliomas, CCND1, was positive. In well-differentiated lipomatous tumors and in chondrosarcomas, CCND1 was frequently expressed, but all myxoid liposarcomas were negative. FISH analysis did not give support for direct involvement of CCND1 and FUS as translocation partners. Conclusions. Chondroid lipoma is extremely rare and has several and more prevalent histological mimics. The differential diagnosis of chondroid lipomas can be unraveled using immunohistochemical and molecular support.
Identification of Methylated Genes Associated with Aggressive Clinicopathological Features in Mantle Cell Lymphoma
Anna Enjuanes,Verònica Fernàndez,Luis Hernández,Alba Navarro,Sílvia Beà,Magda Pinyol,Armando López-Guillermo,Andreas Rosenwald,German Ott,Elías Campo,Pedro Jares
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019736
Abstract: Mantle cell lymphoma (MCL) is genetically characterized by the t(11;14)(q13;q32) translocation and a high number of secondary chromosomal alterations. The contribution of DNA methylation to MCL lymphomagenesis is not well known. We sought to identify epigenetically silenced genes in these tumours that might have clinical relevance.
Explorative data analysis of MCL reveals gene expression networks implicated in survival and prognosis supported by explorative CGH analysis
Steffen Blenk, Julia C Engelmann, Stefan Pinkert, Markus Weniger, J?rg Schultz, Andreas Rosenwald, Hans K Müller-Hermelink, Tobias Müller, Thomas Dandekar
BMC Cancer , 2008, DOI: 10.1186/1471-2407-8-106
Abstract: We compare patients over and below the median of survival. Exploratory principal component analysis of gene expression data showed that the second principal component correlates well with patient survival. Explorative analysis of CGH data shows the same correlation.On chromosome 7 and 9 specific genes and bands are delineated which improve prognosis prediction independent of the previously described proliferation signature. We identify a compact survival predictor of seven genes for MCL patients. After extensive re-annotation using GEPAT, we established protein networks correlating with prognosis. Well known genes (CDC2, CCND1) and further proliferation markers (WEE1, CDC25, aurora kinases, BUB1, PCNA, E2F1) form a tight interaction network, but also non-proliferative genes (SOCS1, TUBA1B CEBPB) are shown to be associated with prognosis. Furthermore we show that aggressive MCL implicates a gene network shift to higher expressed genes in late cell cycle states and refine the set of non-proliferative genes implicated with bad prognosis in MCL.The results from explorative data analysis of gene expression and CGH data are complementary to each other. Including further tests such as Wilcoxon rank test we point both to proliferative and non-proliferative gene networks implicated in inferior prognosis of MCL and identify suitable markers both in gene expression and CGH data.Mantle cell lymphomas (MCL) make up about 6% of all cases of non-Hodgkin's lymphomas. They occur at any age from the late 30s to old age, are more common in the over 50 years old population and three times more common in men than in women. Morphologically, MCL is characterized by a monomorphic lymphoid proliferation of cells that resemble centrocytes. MCL is associated with a poor prognosis and remains incurable with current chemotherapeutic approaches. Despite response rates of 50–70% with many regimens, the disease typically relapses and progresses after chemotherapy. The median survival time is appro
Epigenetic regulation of CD44 in Hodgkin and non-Hodgkin lymphoma
Sonja Eberth, Bj?rn Schneider, Andreas Rosenwald, Elena M Hartmann, Julia Romani, Margarete Zaborski, Reiner Siebert, Hans G Drexler, Hilmar Quentmeier
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-517
Abstract: We screened for TSG methylation using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in 40 lymphoma-derived cell lines representing anaplastic large cell lymphoma, Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Hodgkin lymphoma and mantle cell lymphoma (MCL) as well as in 50 primary lymphoma samples. The methylation status of differentially methylated CD44 was verified by methylation-specific PCR and bisulfite sequencing. Gene expression of CD44 and its reactivation by DNA demethylation was determined by quantitative real-time PCR and on the protein level by flow cytometry. Induction of apoptosis by anti-CD44 antibody was analyzed by annexin-V/PI staining and flow cytometry.On average 8 ± 2.8 of 24 TSG were methylated per lymphoma cell line and 2.4 ± 2 of 24 TSG in primary lymphomas, whereas 0/24 TSG were methylated in tonsils and blood mononuclear cells from healthy donors. Notably, we identified that CD44 was hypermethylated and transcriptionally silenced in all BL and most FL and DLBCL cell lines, but was usually unmethylated and expressed in MCL cell lines. Concordant results were obtained from primary lymphoma material: CD44 was not methylated in MCL patients (0/11) whereas CD44 was frequently hypermethylated in BL patients (18/29). In cell lines with CD44 hypermethylation, expression was re-inducible at mRNA and protein levels by treatment with the DNA demethylating agent 5-Aza-2'-deoxycytidine, confirming epigenetic regulation of CD44. CD44 ligation assays with a monoclonal anti-CD44 antibody showed that CD44 can mediate apoptosis in CD44+ lymphoma cells. CD44 hypermethylated, CD44- lymphoma cell lines were consistently resistant towards anti-CD44 induced apoptosis.Our data show that CD44 is epigenetically regulated in lymphoma and undergoes de novo methylation in distinct lymphoma subtypes like BL. Thus CD44 may be a promising new epigenetic marker for diagnosis and a potential therape
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