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Berlin Brandenburg

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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 07 January 2014, Vol.111(1), pp.409-14
    Description: A hypoxic microenvironment induces resistance to alkylating agents by activating targets in the mammalian target of rapamycin (mTOR) pathway. The molecular mechanisms involved in this mTOR-mediated hypoxia-induced chemoresistance, however, are unclear. Here we identify the mTOR target N-myc downstream regulated gene 1 (NDRG1) as a key determinant of resistance toward alkylating chemotherapy, driven by hypoxia but also by therapeutic measures such as irradiation, corticosteroids, and chronic exposure to alkylating agents via distinct molecular routes involving hypoxia-inducible factor (HIF)-1alpha, p53, and the mTOR complex 2 (mTORC2)/serum glucocorticoid-induced protein kinase 1 (SGK1) pathway. Resistance toward alkylating chemotherapy but not radiotherapy was dependent on NDRG1 expression and activity. In posttreatment tumor tissue of patients with malignant gliomas, NDRG1 was induced and predictive of poor response to alkylating chemotherapy. On a molecular level, NDRG1 bound and stabilized methyltransferases, chiefly O(6)-methylguanine-DNA methyltransferase (MGMT), a key enzyme for resistance to alkylating agents in glioblastoma patients. In patients with glioblastoma, MGMT promoter methylation in tumor tissue was not more predictive for response to alkylating chemotherapy in patients who received concomitant corticosteroids.
    Keywords: Drug Resistance, Neoplasm ; Gene Expression Regulation, Neoplastic ; Antineoplastic Agents, Alkylating -- Pharmacology ; Brain Neoplasms -- Drug Therapy ; Cell Cycle Proteins -- Metabolism ; Glioblastoma -- Drug Therapy ; Glioma -- Drug Therapy ; Intracellular Signaling Peptides and Proteins -- Metabolism ; O(6)-Methylguanine-DNA Methyltransferase -- Pharmacology ; Tor Serine-Threonine Kinases -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    In: Nature, 2014, Vol.509(7501), p.465
    Description: Cell competition is an emerging principle underlying selection for cellular fitness during development and disease. Competition may be relevant for cancer, but an experimental link between defects in competition and tumorigenesis is elusive. In the thymus, T lymphocytes develop from precursors that are constantly replaced by bone-marrow-derived progenitors. Here we show that in mice this turnover is regulated by natural cell competition between 'young' bone- marrow-derived and 'old' thymus-resident progenitors that, although genetically identical, execute differential gene expression programs. Disruption of cell competition leads to progenitor self-renewal, upregulation of Hmga1, transformation, and T-cell acute lymphoblastic leukaemia (T-ALL) resembling the human disease in pathology, genomic lesions, leukaemia-associated transcripts, and activating mutations in Notch1. Hence, cell competition is a tumour suppressor mechanism in the thymus. Failure to select fit progenitors through cell competition may explain leukaemia in X-linked severe combined immune deficiency patients who showed thymus-autonomous T-cell development after therapy with gene-corrected autologous progenitors.
    Keywords: Tumor Suppressor Genes -- Research ; Thymus Gland -- Physiological Aspects ; Cell Interactions -- Research ; Genetic Research;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 3
    Language: English
    In: Cancer, 15 May 2011, Vol.117(10), pp.2136-44
    Description: In the era of novel agents such as lenalidomide and bortezomib, risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches in patients with multiple myeloma (MM). The authors analyzed the prognostic value of deletion del(13q14), del(17p13), +1q21, translocation t(4;14), t(11;14), and t(14;16) by fluorescence in situ hybridization (FISH) in a series of 92 patients with recurrent MM who were treated with lenalidomide and dexamethasone (len/dex) at the study center. Patients carrying del(13q14) or t(14;16) were found to have a shorter median time to disease progression (TTP) of 5.1 months (vs 14.4 months; P = .009) and 2.0 months (vs 10.5 months; P 〈.001), respectively. However, no effect on TTP was observed in patients harboring del(13q14) as an exclusive chromosomal aberration without the concomitant presence of t(4;14) or del(17p13). The median overall survival (OS) for patients with del(17p13) or +1q21 was 6.7 months (P = .002) and 8.3 months (P 〈 .001), respectively, whereas the median OS for patients carrying none of these abnormalities was not reached. Multivariate analysis revealed that the effects of del(17p13) and +1q21 on OS were independent of patient age as well as the type and number of regimens administered before len/dex. The results of the current study suggest that the prognostic significance of t(4;14) may be ameliorated or eliminated in patients treated with len/dex, whereas the presence of del(17p13) or +1q21 is still associated with a dismal OS. The presence of t(11;14) and del(13q14) as exclusive chromosomal aberrations indicates no impact on outcome. Because of its rarity in MM, a confirmation of the prognostic role of the t(14;16) aberration is still pending.
    Keywords: Chromosome Aberrations ; Antineoplastic Combined Chemotherapy Protocols -- Therapeutic Use ; Dexamethasone -- Administration & Dosage ; Multiple Myeloma -- Drug Therapy ; Thalidomide -- Analogs & Derivatives
    ISSN: 0008-543X
    E-ISSN: 10970142
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  • 4
    Language: English
    In: Kidney International, January 2016, Vol.89(1), pp.82-94
    Description: Renal dendritic cells are a major component of the renal mononuclear phagocytic system. In the renal interstitium, these cells are exposed to an osmotic gradient, mainly sodium, whose concentration progressively increases towards inner medulla. Renal allograft rejection affects predominantly the cortex, suggesting a protective role of the renal medullary micromilieu. Whether osmolar variations can modulate the function of renal dendritic cells is currently undefined. Considering the central role of dendritic cells in promoting allorejection, we tested whether the biophysical micromilieu, particularly the interstitial osmotic gradient, influences their alloreactivity. There was a progressive depletion of leukocytes towards the medulla of homeostatic kidney. Only macrophages opposed this tendency. Flow cytometry of homeostatic and post-transplant medullary dendritic cells revealed a switch towards a macrophage-like phenotype. Similarly, bone marrow–derived dendritic cells developed in sodium chloride–enriched medium acquired a M2-like signature. Microarray analysis of allotransplant dendritic cells posed a medullary downregulation of genes mainly involved in alloantigen recognition. Gene expression profiles of both medullary dendritic cells and bone marrow–derived dendritic cells matured in hyperosmolar medium had an overlap with the macrophage M2 signature. Thus, the medullary environment inhibits an alloimmune response by modulating the phenotype and function of dendritic cells.
    Keywords: Acute Rejection ; Inflammation ; Renal Pathology ; Medicine
    ISSN: 0085-2538
    E-ISSN: 1523-1755
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  • 5
    In: International Journal of Cancer, 01 February 2014, Vol.134(3), pp.703-716
    Description: Based on extensive pre‐clinical studies, the oncolytic parvovirus H‐1 (H‐1PV) is currently applied to patients with recurrent glioblastoma in a phase I/IIa clinical trial (ParvOryx01, NCT01301430). Cure rates of about 40% in pediatric high‐risk medulloblastoma (MB) patients also indicate the need of new therapeutic approaches. In order to prepare a future application of oncolytic parvovirotherapy to MB, the present study preclinically evaluates the cytotoxic efficacy of H‐1PV on MB cells and characterizes cellular target genes involved in this effect. Six MB cell lines were analyzed by whole genome oligonucleotide microarrays after treatment and the results were matched to known molecular and cytogenetic risk factors. In contrast to non‐transformed infant astrocytes and neurons, in five out of six MB cell lines lytic H‐1PV infection and efficient viral replication could be demonstrated. The cytotoxic effects induced by H‐1PV were observed at LD50s below 0.05 p. f. u. per cell indicating high susceptibility. Gene expression patterns in the responsive MB cell lines allowed the identification of candidate target genes mediating the cytotoxic effects of H‐1PV. H‐1PV induced down‐regulation of key regulators of early neurogenesis shown to confer poor prognosis in MB such as ZIC1, FOXG1B, MYC, and NFIA. In MB cell lines with genomic amplification of MYC, expression of MYC was the single gene most significantly repressed after H‐1PV infection. H‐1PV virotherapy may be a promising treatment approach for MB since it targets genes of functional relevance and induces cell death at very low titers of input virus. What's new? Medulloblastoma, the most frequent pediatric brain cancer, causes death in about 60 percent of high‐risk patients, and so there is a major need for novel, highly effective therapies. One therapy of interest is parvovirus H‐1 (H‐1PV), which was found in this study to produce marked cytotoxic effects in six medulloblastoma cell lines. Gene expression profiling revealed that H‐1PV infection causes down‐regulation of key regulatory genes involved in early neurogenesis, with significant repression of . The master regulators affected may represent putative direct or indirect H‐1PV target genes.
    Keywords: Medulloblastoma ; Oncolytic Virus ; Parvovirus H‐1pv ; Cellular Targets ; Myc ; Master Regulators Of Neurogenesis
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 6
    Language: English
    In: Cancer Research, 04/15/2013, Vol.73(8 Supplement), pp.2-2
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 7
    In: International Journal of Cancer, 15 November 2014, Vol.135(10), pp.2380-2386
    Description: The aim of our study was to assess in which way different infiltration patterns of monoclonal plasma cell diseases in whole‐body (wb) magnetic resonance imaging (MRI) are associated with clinical stages, plasma cell content in bone marrow samples and established serum markers of disease activity. Institutional review board approval was obtained. We performed wb‐MRI in 547 consecutive, unselected and untreated patients with monoclonal gammopathy of undetermined significance (MGUS,  = 138), smoldering myeloma (SMM,  = 157) and multiple myeloma (MM,  = 252) on two 1.5 T MRI‐scanners with body array coils. The studies were evaluated in consensus by two experienced radiologists blinded to the diagnosis. We observed focal lesions in 23.9% (MGUS), 34.4% (SMM) and 81.3% (MM), respectively. A diffuse infiltration pattern was detected in 38.4%, 45.9% and 71%, respectively. The differences between all infiltration patterns were significant ( 〈 0.0001). The presence of focal lesions and the presence of a diffuse bone marrow infiltration was associated with an increased plasma cell percentage in bone marrow samples (median 22% . 14%, 26% . 10%, both  〈 0.0001) and monoclonal protein concentration (median 18 g/dl . 13 g/dl,  = 0.003, 20 g/dl . 11 g/dl,  〈 0.0001). Further categorization of the diffuse infiltration patterns in wb‐MRI into “salt‐and‐pepper,” moderate and severe identified significant associations with M‐protein (median g/dl for S+P/moderate/severe 23/18/25,  = 0.04), plasma cell percentage in the bone marrow (median 25%/24%/40%,  = 0.02), and age (median years 67/60/57,  〈 0.0001). Bone marrow infiltration in wb‐MRI is significantly different between the various stages of plasma cell disease and correlates well with established markers of disease activity. What's new? Plasma‐cell disorders such as multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) may produce different cellular patterns in the bone marrow. This study used whole‐body magnetic resonance imaging (wb‐MRI) to assess how these different infiltration patterns relate to clinical stages. The authors found that the number of focal lesions, as well as the presence and type of diffuse bone marrow infiltration, correlated with disease stage, as did serum markers of disease activity. Thus, wb‐MRI is promising, non‐invasive technique for more precisely staging and evaluating prognosis in MM and its asymptomatic precursors.
    Keywords: Monoclonal Plasma Cell Disease ; Magnetic Resonance Imaging ; Disease Activity ; Multiple Myeloma ; Correlation Analysis
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 8
    In: Biometrics, June 2011, Vol.67(2), pp.524-535
    Description: In clinical applications, the prediction error of survival models has to be taken into consideration to assess the practical suitability of conclusions drawn from these models. Different approaches to evaluate the predictive performance of survival models have been suggested in the literature. In this article, we analyze the properties of the estimator of prediction error developed by Schemper and Henderson (2000,  56, 249–255), which quantifies the absolute distance between predicted and observed survival functions. We provide a formal proof that the estimator proposed by Schemper and Henderson is not robust against misspecification of the survival model, that is, the estimator will only be meaningful if the model family used for deriving predictions has been specified correctly. To remedy this problem, we construct a new estimator of the absolute distance between predicted and observed survival functions. We show that this modified Schemper–Henderson estimator is robust against model misspecification, allowing its practical application to a wide class of survival models. The properties of the Schemper–Henderson estimator and its new modification are illustrated by means of a simulation study and the analysis of two clinical data sets.
    Keywords: Consistency ; Model Misspecification ; Prediction Error ; Prognostic Performance ; Survival Analysis
    ISSN: 0006-341X
    E-ISSN: 1541-0420
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  • 9
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(12), p.e83719
    Description: The glycome, i.e. the cellular repertoire of glycan structures, contributes to important functions such as adhesion and intercellular communication. Enzymes regulating cellular glycosylation processes are related to the pathogenesis of cancer including multiple myeloma. Here we analyze the transcriptional differences in the glycome of normal (n = 10) and two cohorts of 332 and 345 malignant plasma-cell samples, association with known multiple myeloma subentities as defined by presence of chromosomal aberrations, potential therapeutic targets, and its prognostic impact. We found i) malignant vs. normal plasma cells to show a characteristic glycome-signature. They can ii) be delineated by a lasso-based predictor from normal plasma cells based on this signature. iii) Cytogenetic aberrations lead to distinct glycan-gene expression patterns for t(11;14), t(4;14), hyperdiploidy, 1q21-gain and deletion of 13q14. iv) A 38-gene glycome-signature significantly delineates patients with adverse survival in two independent cohorts of 545 patients treated with high-dose melphalan and autologous stem cell transplantation. v) As single gene, expression of the phosphatidyl-inositol-glycan protein M as part of the targetable glycosyl-phosphatidyl-inositol-anchor-biosynthesis pathway is associated with adverse survival. The prognostically relevant glycome deviation in malignant cells invites novel strategies of therapy for multiple myeloma.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 10
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(1), p.e55261
    Description: We previously reported a rare germline variant (c.1-6531) that resulted in allele-specific expression (ASE) of death-associated protein kinase 1 (DAPK1) and predisposition to chronic lymphocytic leukemia (CLL). We investigated a cohort of CLL patients lacking this mutation for the presence of ASE of DAPK1. We developed a novel strategy that combines single-nucleotide primer extension (SNuPE) with MALDI-TOF mass spectrometry, and detected germline DAPK1 ASE in 17 out of 120 (14.2%) CLL patients associated with a trend towards younger age at diagnosis. ASE was absent in 63 healthy controls. Germline cells of CLL patients with ASE showed increased levels of DNA methylation in the promoter region, however, neither genetic nor further epigenetic aberrations could be identified in the DAPK1 5' upstream regulatory region, within distinct exons or in the 3'-UTR. We identified B-lymphoid malignancy related cell line models harboring allelic imbalance and found that allele-specific methylation in DAPK1 is associated with ASE. Our data indicate that ASE at the DAPK1 gene locus is a recurrent event, mediated by epigenetic mechanisms and potentially predisposing to CLL.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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