140 results on '"Wurdinger, Thomas"'
Search Results
102. Functional Drug Screening Assay Reveals Potential Glioma Therapeutics
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Badr, Christian E., primary, Wurdinger, Thomas, additional, and Tannous, Bakhos A., additional
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- 2011
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103. Human Glioma Growth Is Controlled by MicroRNA-10b
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Gabriely, Galina, primary, Yi, Ming, additional, Narayan, Ravi S., additional, Niers, Johanna M., additional, Wurdinger, Thomas, additional, Imitola, Jaime, additional, Ligon, Keith L., additional, Kesari, Santosh, additional, Esau, Christine, additional, Stephens, Robert M., additional, Tannous, Bakhos A., additional, and Krichevsky, Anna M., additional
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- 2011
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104. In vivo tomographic imaging of red-shifted fluorescent proteins
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Deliolanis, Nikolaos C., primary, Wurdinger, Thomas, additional, Pike, Lisa, additional, Tannous, Bakhos A., additional, Breakefield, Xandra O., additional, Weissleder, Ralph, additional, and Ntziachristos, Vasilis, additional
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- 2011
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105. Monitoring of Tumor Growth and Post‐Irradiation Recurrence in a Diffuse Intrinsic Pontine Glioma Mouse Model
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Caretti, Viola, primary, Zondervan, Ilse, additional, Meijer, Dimphna H., additional, Idema, Sander, additional, Vos, Wim, additional, Hamans, Bob, additional, Bugiani, Marianna, additional, Hulleman, Esther, additional, Wesseling, Pieter, additional, Vandertop, W. Peter, additional, Noske, David P., additional, Kaspers, Gertjan, additional, Molthoff, Carla F.M., additional, and Wurdinger, Thomas, additional
- Published
- 2010
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106. Abstract B30: Regulation of angiogenesis by the VEGF/miR-101/EZH2 axis
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Smits, Michiel, primary, Mir, Shahryar E., additional, Nilsson, Jonas, additional, van der Stoop, Petra, additional, Niers, Anneke, additional, Marquez, Victor, additional, Cloos, Jacqueline, additional, Breakefield, Xandra, additional, Krichevsky, Anna, additional, Noske, David, additional, Tannous, Bakhos, additional, and Wurdinger, Thomas, additional
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- 2010
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107. Fluorescence Tomography of Red-shifted Fluorescent Proteins
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Deliolanis, Nikolaos C., primary, Wurdinger, Thomas, additional, Tannous, Bakhos, additional, and Ntziachristos, Vasilis, additional
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- 2010
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108. Microfluidic isolation and transcriptome analysis of serum microvesicles
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Chen, Chihchen, primary, Skog, Johan, additional, Hsu, Chia-Hsien, additional, Lessard, Ryan T., additional, Balaj, Leonora, additional, Wurdinger, Thomas, additional, Carter, Bob S., additional, Breakefield, Xandra O., additional, Toner, Mehmet, additional, and Irimia, Daniel, additional
- Published
- 2010
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109. Comparative Protein Profiling Reveals Minichromosome Maintenance (MCM) Proteins As Novel Potential Tumor Markers for Meningiomas
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Saydam, Okay, primary, Senol, Ozlem, additional, Schaaij-Visser, Tieneke B. M., additional, Pham, Thang V., additional, Piersma, Sander R., additional, Stemmer-Rachamimov, Anat O., additional, Wurdinger, Thomas, additional, Peerdeman, Saskia M., additional, and Jimenez, Connie R., additional
- Published
- 2009
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110. Real-Time Monitoring of Nuclear Factor κB Activity in Cultured Cells and in Animal Models
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Badr, Christian E., primary, Niers, Johanna M., additional, Tjon-Kon-Fat, Lee-Ann, additional, Noske, David P., additional, Wurdinger, Thomas, additional, and Tannous, Bakhos A., additional
- Published
- 2009
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111. Mutant Sodium Channel for Tumor Therapy
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Tannous, Bakhos A, primary, Christensen, Adam P, additional, Pike, Lisa, additional, Wurdinger, Thomas, additional, Perry, Katherine F, additional, Saydam, Okay, additional, Jacobs, Andreas H, additional, García-Añoveros, Jaime, additional, Weissleder, Ralph, additional, Sena-Esteves, Miguel, additional, Corey, David P, additional, and Breakefield, Xandra O, additional
- Published
- 2009
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112. In-vivo imaging of murine tumors using complete-angle projection fluorescence molecular tomography
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Deliolanis, Nikolaos C., primary, Dunham, Joshua, additional, Wurdinger, Thomas, additional, Figueiredo, Jose-Luiz, additional, Bakhos, Tannous, additional, and Ntziachristos, Vasilis, additional
- Published
- 2009
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113. MicroRNA 21 Promotes Glioma Invasion by Targeting Matrix Metalloproteinase Regulators
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Gabriely, Galina, primary, Wurdinger, Thomas, additional, Kesari, Santosh, additional, Esau, Christine C., additional, Burchard, Julja, additional, Linsley, Peter S., additional, and Krichevsky, Anna M., additional
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- 2008
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114. Gaussia luciferase blood level as an index of cell growth and proliferation
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Wurdinger, Thomas, additional, Badr, Christian, additional, and Tannous, Bakhos, additional
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- 2008
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115. A secreted luciferase for ex vivo monitoring of in vivo processes
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Wurdinger, Thomas, primary, Badr, Christian, additional, Pike, Lisa, additional, de Kleine, Ruben, additional, Weissleder, Ralph, additional, Breakefield, Xandra O, additional, and Tannous, Bakhos A, additional
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- 2008
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116. Comparison of the Fluorescent Protein Performance in Deep-Tissue Small-Animal Imaging Applications
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Deliolanis, Nikolaos, primary, Wurdinger, Thomas, additional, Tannous, Bakhos A., additional, Shah, Khalid, additional, Ntziachristos, Vasilis, additional, and Weissleder, Ralph, additional
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- 2008
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117. Performance of the red-shifted fluorescent proteins in deep-tissue molecular imaging applications
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Deliolanis, Nikolaos C., primary, Kasmieh, Randa, additional, Wurdinger, Thomas, additional, Tannous, Bakhos A., additional, Shah, Khalid, additional, and Ntziachristos, Vasilis, additional
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- 2008
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118. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions
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Nahrendorf, Matthias, primary, Swirski, Filip K., additional, Aikawa, Elena, additional, Stangenberg, Lars, additional, Wurdinger, Thomas, additional, Figueiredo, Jose-Luiz, additional, Libby, Peter, additional, Weissleder, Ralph, additional, and Pittet, Mikael J., additional
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- 2007
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119. Development of bioluminescent chick chorioallantoic membrane (CAM) models for primary pancreatic cancer cells: a platform for drug testing
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Rovithi, Maria, Avan, Amir, Funel, Niccola, Leon, Leticia G., Gomez, Valentina E., Wurdinger, Thomas, Griffioen, Arjan W., Verheul, Henk M. W., and Giovannetti, Elisa
- Abstract
The aim of the present study was to develop chick-embryo chorioallantoic membrane (CAM) bioluminescent tumor models employing low passage cell cultures obtained from primary pancreatic ductal adenocarcinoma (PDAC) cells. Primary PDAC cells transduced with lentivirus expressing Firefly-luciferase (Fluc) were established and inoculated onto the CAM membrane, with >80% engraftment. Fluc signal reliably correlated with tumor growth. Tumor features were evaluated by immunohistochemistry and genetic analyses, including analysis of mutations and mRNA expression of PDAC pivotal genes, as well as microRNA (miRNA) profiling. These studies showed that CAM tumors had histopathological and genetic characteristic comparable to the original tumors. We subsequently tested the modulation of key miRNAs and the activity of gemcitabine and crizotinib on CAM tumors, showing that combination treatment resulted in 63% inhibition of tumor growth as compared to control (p < 0.01). These results were associated with reduced expression of miR-21 and increased expression of miR-155. Our study provides the first evidence that transduced primary PDAC cells can form tumors on the CAM, retaining several histopathological and (epi)genetic characteristics of original tumors. Moreover, our results support the use of these models for drug testing, providing insights on molecular mechanisms underlying antitumor activity of new drugs/combinations.
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- 2017
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120. Rearranged EML4-ALK fusion transcripts sequester in circulating blood platelets and enable blood-based crizotinib response monitoring in non-small-cell lung cancer
- Author
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Nilsson, R. Jonas A., Karachaliou, Niki, Berenguer, Jordi, Gimenez-Capitan, Ana, Schellen, Pepijn, Teixido, Cristina, Tannous, Jihane, Kuiper, Justine L., Drees, Esther, Grabowska, Magda, van Keulen, Marte, Heideman, Danielle A.M., Thunnissen, Erik, Dingemans, Anne-Marie C., Viteri, Santiago, Tannous, Bakhos A., Drozdowskyj, Ana, Rosell, Rafael, Smit, Egbert F., and Wurdinger, Thomas
- Subjects
diagnostics ,NSCLC ,liquid biopsies ,platelets ,EML4-ALK - Abstract
Purpose: Non-small-cell lung cancers harboring EML4-ALK rearrangements are sensitive to crizotinib. However, despite initial response, most patients will eventually relapse, and monitoring EML4-ALK rearrangements over the course of treatment may help identify these patients. However, challenges associated with serial tumor biopsies have highlighted the need for blood-based assays for the monitoring of biomarkers. Platelets can sequester RNA released by tumor cells and are thus an attractive source for the non-invasive assessment of biomarkers. Methods: EML4-ALK rearrangements were analyzed by RT-PCR in platelets and plasma isolated from blood obtained from 77 patients with non-small-cell lung cancer, 38 of whom had EML4-ALK-rearranged tumors. In a subset of 29 patients with EML4-ALK-rearranged tumors who were treated with crizotinib, EML4-ALK rearrangements in platelets were correlated with progression-free and overall survival. Results: RT-PCR demonstrated 65% sensitivity and 100% specificity for the detection of EML4-ALK rearrangements in platelets. In the subset of 29 patients treated with crizotinib, progression-free survival was 3.7 months for patients with EML4-ALK+ platelets and 16 months for those with EML4-ALK− platelets (hazard ratio, 3.5; P = 0.02). Monitoring of EML4-ALK rearrangements in the platelets of one patient over a period of 30 months revealed crizotinib resistance two months prior to radiographic disease progression. Conclusions: Platelets are a valuable source for the non-invasive detection of EML4-ALK rearrangements and may prove useful for predicting and monitoring outcome to crizotinib, thereby improving clinical decisions based on radiographic imaging alone.
- Published
- 2016
121. Functional delivery of viral miRNAs via exosomes.
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PegteI, D. Michiel, Cosmopoulos, Katherine, ThorIey-Lawson, David A., Van Eijndhoven, Monique A. J., Hopmans, Erik S., Lindenberg, Jelle L., de Gruijl, Tanja D., Wurdinger, Thomas, and Middeldorp, Jaap M.
- Subjects
NON-coding RNA ,GENE expression ,EPSTEIN-Barr virus ,CELL communication ,MESSENGER RNA ,GENE therapy - Abstract
Noncoding regulatory microRNAs (miRNAs) of cellular and viral origin control gene expression by repressing the translation of mRNAs into protein. Interestingly, miRNAs are secreted actively through small vesicles called "exosomes" that protect them from degradation by RNases, suggesting that these miRNAs may function outside the cell in which they were produced. Here we demonstrate that miRNAs secreted by EBV-infected cells are transferred to and act in uninfected recipient cells. Using a quantitative RT-PCR approach, we demonstrate that mature EBV-encoded miRNAs are secreted by EBV-infected B cells through exosomes. These EBV-miRNAs are functional because internalization of exosomes by M0DC results in a dose-dependent, miRNAmediated repression of confirmed EBVtargetgenes, including CXCLI 1/ ITAC, an immunoregulatory gene down-regulated in primary EBVassociated lymphomas. We demonstrate that throughout coculture of EBV-infected B cells EBV-miRNAs accumulate in noninfected neighboring M0DC and show that this accumulation is mediated by transfer of exosomes. Thus, the exogenous EBV-miRNAs transferred through exosomes are delivered to subcellular sites of gene repression in recipient cells. Finally, we show in peripheral blood mononuclear cells from patients with increased EBV load that, although EBV DNA is restricted to the circulating B-cell population, EBV BART miRNAs are present in both B-cell and non-B-cell fractions, suggestive of miRNA transfer. Taken together our findings are consistent with miRNA-mediated gene silencing as a potential mechanism of intercellular communication between cells of the immune system that may be exploited by the persistent human γ-herpesvirus EBV. [ABSTRACT FROM AUTHOR]
- Published
- 2010
122. EFEMP1 induces γ-secretase/Notch-mediated temozolomide resistance in glioblastoma
- Author
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Hiddingh, Lotte, Tannous, Bakhos A., Teng, Jian, Tops, Bas, Jeuken, Judith, Hulleman, Esther, Boots-Sprenger, Sandra H., Vandertop, W. Peter, Noske, David P., Kaspers, Gertjan J.L., Wesseling, Pieter, and Wurdinger, Thomas
- Subjects
Temozolomide resistance ,glioblastoma ,EFEMP1 ,γ-secretase ,Notch ,GSI - Abstract
Glioblastoma is the most common malignant primary brain tumor. Temozolomide (TMZ) is the standard chemotherapeutic agent for this disease. However, intrinsic and acquired TMZ-resistance represents a major obstacle for this therapy. In order to identify factors involved in TMZ-resistance, we engineered different TMZ-resistant glioblastoma cell lines. Gene expression analysis demonstrated that EFEMP1, an extracellular matrix protein, is associated with TMZ-resistant phenotype. Silencing of EFEMP1 in glioblastoma cells resulted in decreased cell survival following TMZ treatment, whereas overexpression caused TMZ-resistance. EFEMP1 acts via multiple signaling pathways, including γ-secretase-mediated activation of the Notch pathway. We show that inhibition of γ-secretase by RO4929097 causes at least partial sensitization of glioblastoma cells to temozolomide in vitro and in vivo. In addition, we show that EFEMP1 expression levels correlate with survival in TMZ-treated glioblastoma patients. Altogether our results suggest EFEMP1 as a potential therapeutic target to overcome TMZ-resistance in glioblastoma.
- Published
- 2014
123. Regulation of Monocyte Functional Heterogeneity by miR-146aand Relb
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Etzrodt, Martin, Cortez-Retamozo, Virna, Newton, Andita, Zhao, Jimmy, Ng, Aylwin, Wildgruber, Moritz, Romero, Pedro, Wurdinger, Thomas, Xavier, Ramnik, Geissmann, Frederic, Meylan, Etienne, Nahrendorf, Matthias, Swirski, Filip K., Baltimore, David, Weissleder, Ralph, and Pittet, Mikael J.
- Abstract
Monocytes serve as a central defense system against infection and injury but can also promote pathological inflammatory responses. Considering the evidence that monocytes exist in at least two subsets committed to divergent functions, we investigated whether distinct factors regulate the balance between monocyte subset responses in vivo. We identified a microRNA (miRNA), miR-146a, which is differentially regulated both in mouse (Ly-6Chi/Ly-6Clo) and human (CD14hi/CD14loCD16+) monocyte subsets. The single miRNA controlled the amplitude of the Ly-6Chimonocyte response during inflammatory challenge whereas it did not affect Ly-6Clocells. miR-146a-mediated regulation was cell-intrinsic and depended on Relb, a member of the noncanonical NF-κB/Rel family, which we identified as a direct miR-146atarget. These observations not only provide mechanistic insights into the molecular events that regulate responses mediated by committed monocyte precursor populations but also identify targets for manipulating Ly-6Chimonocyte responses while sparing Ly-6Clomonocyte activity.
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- 2012
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124. Omics Analysis of Educated Platelets in Cancer and Benign Disease of the Pancreas.
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Mantini, Giulia, Meijer, Laura L., Glogovitis, Ilias, In 't Veld, Sjors G. J. G., Paleckyte, Rosita, Capula, Mjriam, Le Large, Tessa Y. S., Morelli, Luca, Pham, Thang V., Piersma, Sander R., Frampton, Adam E., Jimenez, Connie R., Kazemier, Geert, Koppers-Lalic, Danijela, Wurdinger, Thomas, and Giovannetti, Elisa
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PANCREATIC tumors ,BLOOD proteins ,BLOOD platelets ,MICRORNA ,RNA ,SIGNAL peptides ,PANCREATIC diseases ,DUCTAL carcinoma ,GENE expression ,NUCLEOTIDES ,MESSENGER RNA ,GENOMICS ,BODY fluid examination ,STATISTICAL correlation - Abstract
Simple Summary: Tumor cells are known to produce and secrete pro-coagulants that recruit blood particles such as platelets, inducing hypercoagulability. However, platelets can also influence tumor carcinogenesis and metastasis, creating a reciprocal, vicious loop with the tumors. Confrontation of platelets with tumor cells via transfer of tumor-associated biomolecules or influencing platelets biology ("education") is an emerging concept, that has been recently proposed to create innovative platforms for biomarkers within blood-based "liquid biopsies". In this study, we explore the intrinsic regulation and the potential "education" of platelets using -omics profiling in pancreatic cancer patients. Our results showed: (i) a high activity on RNA splicing that can lead to subsequent platelets education; (ii) enrichment of specific modified forms (isomiRs) of canonical miRNAs; and (iii) inhibition of SPARC transcription by specific class of isomiRs. Moreover, we created an interactive tool to visualize expected correlations, to facilitate further investigations on additional potential biomarkers and therapeutic tools. Pancreatic ductal adenocarcinoma (PDAC) is traditionally associated with thrombocytosis/hypercoagulation and novel insights on platelet-PDAC "dangerous liaisons" are warranted. Here we performed an integrative omics study investigating the biological processes of mRNAs and expressed miRNAs, as well as proteins in PDAC blood platelets, using benign disease as a reference for inflammatory noise. Gene ontology mining revealed enrichment of RNA splicing, mRNA processing and translation initiation in miRNAs and proteins but depletion in RNA transcripts. Remarkably, correlation analyses revealed a negative regulation on SPARC transcription by isomiRs involved in cancer signaling, suggesting a specific "education" in PDAC platelets. Platelets of benign patients were enriched for non-templated additions of G nucleotides (#ntaG) miRNAs, while PDAC presented length variation on 3′ (lv3p) as the most frequent modification on miRNAs. Additionally, we provided an actionable repertoire of PDAC and benign platelet-ome to be exploited for future studies. In conclusion, our data show that platelets change their biological repertoire in patients with PDAC, through dysregulation of miRNAs and splicing factors, supporting the presence of de novo protein machinery that can "educate" the platelet. These novel findings could be further exploited for innovative liquid biopsies platforms as well as possible therapeutic targets. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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125. HUMAN DIPG CELLS INJECTED IN THE MURINE PONS GIVE RISE TO MURINE TUMORS WITH PONTINE PRECURSOR-LIKE CELL MARKERS
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Caretti, Viola, Schellen, Pepijn, Lagerweij, Tonny, Bugiani, Marianna, Navis, Anneke, P. Wesseling, Vandertop, W. Peter, Noske, David P., Kaspers, Gertjan, and Wurdinger, Thomas
126. A NATIONWIDE DIPG AUTOPSY PROTOCOL IN THE NETHERLANDS AND DEVELOPMENT OF A DIPG CELL LINE
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Caretti, Viola, Jansen, Marc H., Vuurden, Dannis G., Hulleman, Esther, Lagerweij, Tonny, Bugiani, Marianna, Noske, David P., Vandertop, Peter W., P. Wesseling, Wurdinger, Thomas, and Kaspers, Gertjan J.
127. HISTOPATHOLOGICAL HETEROGENEITY IN DIFFUSE INTRINSIC PONTINE GLIOMA
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Caretti, Viola, Bugiani, Marianna, Boor, Ilja, Schellen, Pepijn, Vandertop, W. Peter, Noske, David P., Gertjan Kaspers, Wurdinger, Thomas, and Wesseling, Pieter
128. Development of vector-based strategies against glioblastoma
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Crommentuijn, M.H.W., Wurdinger, Thomas, Noske, D.P., and Tannous, B.A.
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vectors ,platelets ,glioblastoma ,adeno-associated virus ,extracellular vesicles ,gene therapy - Published
- 2017
129. Full-length tRNAs lacking a functional CCA tail are selectively sorted into the lumen of extracellular vesicles.
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Scheepbouwer C, Aparicio-Puerta E, Gómez-Martin C, van Eijndhoven MAJ, Drees EEE, Bosch L, de Jong D, Wurdinger T, Zijlstra JM, Hackenberg M, Gerber A, and Pegtel DM
- Abstract
Small extracellular vesicles (sEVs) are heterogenous lipid membrane particles typically less than 200 nm in size and secreted by most cell types either constitutively or upon activation signals. sEVs isolated from biofluids contain RNAs, including small non-coding RNAs (ncRNAs), that can be either encapsulated within the EV lumen or bound to the EV surface. EV-associated microRNAs (miRNAs) are, despite a relatively low abundance, extensively investigated for their selective incorporation and their role in cell-cell communication. In contrast, the sorting of highly-structured ncRNA species is understudied, mainly due to technical limitations of traditional small RNA sequencing protocols. Here, we adapted ALL-tRNAseq to profile the relative abundance of highly structured and potentially methylated small ncRNA species, including transfer RNAs (tRNAs), small nucleolar RNAs (snoRNAs), and Y RNAs in bulk EV preparations. We determined that full-length tRNAs, typically 75 to 90 nucleotides in length, were the dominant small ncRNA species (>60% of all reads in the 18-120 nucleotides size-range) in all cell culture-derived EVs, as well as in human plasma-derived EV samples, vastly outnumbering 21 nucleotides-long miRNAs. Nearly all EV-associated tRNAs were protected from external RNAse treatment, indicating a location within the EV lumen. Strikingly, the vast majority of luminal-sorted, full-length, nucleobase modification-containing EV-tRNA sequences, harbored a dysfunctional 3' CCA tail, 1 to 3 nucleotides truncated, rendering them incompetent for amino acid loading. In contrast, in non-EV associated extracellular particle fractions (NVEPs), tRNAs appeared almost exclusively fragmented or 'nicked' into tRNA-derived small RNAs (tsRNAs) with lengths between 18 to 35 nucleotides. We propose that in mammalian cells, tRNAs that lack a functional 3' CCA tail are selectively sorted into EVs and shuttled out of the producing cell, offering a new perspective into the physiological role of secreted EVs and luminal cargo-selection.
- Published
- 2024
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130. Blood platelet RNA profiles do not enable for nivolumab response prediction at baseline in patients with non-small cell lung cancer.
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Muller M, Best MG, van der Noort V, Hiltermann TJN, Niemeijer AN, Post E, Sol N, In 't Veld SGJG, Nogarede T, Visser L, Schouten RD, van den Broek D, Hummelink K, Monkhorst K, de Langen AJ, Schuuring E, Smit EF, Groen HJM, Wurdinger T, and van den Heuvel MM
- Subjects
- Humans, Nivolumab therapeutic use, Blood Platelets pathology, RNA genetics, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology
- Abstract
Background: Anti-PD-(L)1 immunotherapy has emerged as a promising treatment approach for non-small cell lung cancer (NSCLC), though the response rates remain low. Pre-treatment response prediction may improve patient allocation for immunotherapy. Blood platelets act as active immune-like cells, thereby constraining T-cell activity, propagating cancer metastasis, and adjusting their spliced mRNA content., Objective: We investigated whether platelet RNA profiles before start of nivolumab anti-PD1 immunotherapy may predict treatment responses., Methods: We performed RNA-sequencing of platelet RNA samples isolated from stage III-IV NSCLC patients before treatment with nivolumab. Treatment response was scored by the RECIST-criteria. Data were analyzed using a predefined thromboSeq analysis including a particle-swarm-enhanced support vector machine (PSO/SVM) classification algorithm., Results: We collected and processed a 286-samples cohort, separated into a training/evaluation and validation series and subjected those to training of the PSO/SVM-classification algorithm. We observed only low classification accuracy in the 107-samples validation series (area under the curve (AUC) training series: 0.73 (95% -CI: 0.63-0.84, n = 88 samples), AUC evaluation series: 0.64 (95% -CI: 0.51-0.76, n = 91 samples), AUC validation series: 0.58 (95% -CI: 0.45-0.70, n = 107 samples)), employing a five-RNAs biomarker panel., Conclusions: We concluded that platelet RNA may have minimally discriminative capacity for anti-PD1 nivolumab response prediction, with which the current methodology is insufficient for diagnostic application.
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- 2024
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131. Tumor-educated platelet blood tests for Non-Small Cell Lung Cancer detection and management.
- Author
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Antunes-Ferreira M, D'Ambrosi S, Arkani M, Post E, In 't Veld SGJG, Ramaker J, Zwaan K, Kucukguzel ED, Wedekind LE, Griffioen AW, Oude Egbrink M, Kuijpers MJE, van den Broek D, Noske DP, Hartemink KJ, Sabrkhany S, Bahce I, Sol N, Bogaard HJ, Koppers-Lalic D, Best MG, and Wurdinger T
- Subjects
- Humans, Biomarkers, Tumor genetics, Algorithms, RNA metabolism, Blood Platelets metabolism, Hematologic Tests, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms genetics
- Abstract
Liquid biopsy approaches offer a promising technology for early and minimally invasive cancer detection. Tumor-educated platelets (TEPs) have emerged as a promising liquid biopsy biosource for the detection of various cancer types. In this study, we processed and analyzed the TEPs collected from 466 Non-small Cell Lung Carcinoma (NSCLC) patients and 410 asymptomatic individuals (controls) using the previously established thromboSeq protocol. We developed a novel particle-swarm optimization machine learning algorithm which enabled the selection of an 881 RNA biomarker panel (AUC 0.88). Herein we propose and validate in an independent cohort of samples (n = 558) two approaches for blood samples testing: one with high sensitivity (95% NSCLC detected) and another with high specificity (94% controls detected). Our data explain how TEP-derived spliced RNAs may serve as a biomarker for minimally-invasive clinical blood tests, complement existing imaging tests, and assist the detection and management of lung cancer patients., (© 2023. The Author(s).)
- Published
- 2023
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132. Platelet RNA enables accurate detection of ovarian cancer: an intercontinental, biomarker identification study.
- Author
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Gao Y, Liu CJ, Li HY, Xiong XM, Li GL, In 't Veld SGJG, Cai GY, Xie GY, Zeng SQ, Wu Y, Chi JH, Liu JH, Zhang Q, Jiao XF, Shi LL, Lu WR, Lv WG, Yang XS, Piek JMJ, de Kroon CD, Lok CAR, Supernat A, Łapińska-Szumczyk S, Łojkowska A, Żaczek AJ, Jassem J, Tannous BA, Sol N, Post E, Best MG, Kong BH, Xie X, Ma D, Wurdinger T, Guo AY, and Gao QL
- Subjects
- Humans, Female, Biomarkers, Tumor genetics, China, Blood Platelets pathology, Ovarian Neoplasms diagnosis, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology
- Abstract
Platelets are reprogrammed by cancer via a process called education, which favors cancer development. The transcriptional profile of tumor-educated platelets (TEPs) is skewed and therefore practicable for cancer detection. This intercontinental, hospital-based, diagnostic study included 761 treatment-naïve inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers (China, n = 3; Netherlands, n = 5; Poland, n = 1) between September 2016 and May 2019. The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese (VC1 and VC2) and the European (VC3) validation cohorts collectively and independently. Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets. The AUCs for TEPs in the combined validation cohort, VC1, VC2, and VC3 were 0.918 (95% CI 0.889-0.948), 0.923 (0.855-0.990), 0.918 (0.872-0.963), and 0.887 (0.813-0.960), respectively. Combination of TEPs and CA125 demonstrated an AUC of 0.922 (0.889-0.955) in the combined validation cohort; 0.955 (0.912-0.997) in VC1; 0.939 (0.901-0.977) in VC2; 0.917 (0.824-1.000) in VC3. For subgroup analysis, TEPs exhibited an AUC of 0.858, 0.859, and 0.920 to detect early-stage, borderline, non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis. TEPs had robustness, compatibility, and universality for preoperative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities, heterogeneous histological subtypes, and early-stage ovarian cancer. However, these observations warrant prospective validations in a larger population before clinical utilities., (©The Author(s) 2022. Published by Oxford University Press on behalf of Higher Education Press.)
- Published
- 2023
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133. Platelet RNA as Pan-Tumor Biomarker for Cancer Detection.
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Wurdinger T, In 't Veld SGJG, and Best MG
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- Biomarkers, Tumor genetics, Biomarkers, Tumor isolation & purification, Humans, Liquid Biopsy, Mutation, Neoplasms blood, Neoplasms genetics, RNA genetics, RNA isolation & purification, RNA-Seq, Biomarkers, Tumor blood, Blood Platelets, Early Detection of Cancer methods, Neoplasms diagnosis, RNA blood
- Abstract
Blood-based liquid biopsies are considered a screening approach for early cancer detection. Sequencing technologies enable in-depth analyses of nucleic acids, including mutant cell-free (cf) DNA in the plasma. However, in the blood of patients with early-stage cancer the detection level of mutant cfDNA is relatively low, and complicated by the natural presence of noncancer cfDNA mutants attributed to aging-related processes. Consequently, analysis of methylated cfDNA patterns and alternative approaches such as tumor-educated platelets are gaining traction for the detection of early-stage tumors. Here, we dissect the use of platelet RNA as a potential biomarker for the development of early-stage, pan-cancer blood tests., (©2020 American Association for Cancer Research.)
- Published
- 2020
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134. Recycling drug screen repurposes hydroxyurea as a sensitizer of glioblastomas to temozolomide targeting de novo DNA synthesis, irrespective of molecular subtype.
- Author
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Teng J, Hejazi S, Hiddingh L, Carvalho L, de Gooijer MC, Wakimoto H, Barazas M, Tannous M, Chi AS, Noske DP, Wesseling P, Wurdinger T, Batchelor TT, and Tannous BA
- Subjects
- Animals, Antineoplastic Agents, Alkylating pharmacology, Apoptosis, Brain Neoplasms classification, Brain Neoplasms genetics, Brain Neoplasms pathology, Cell Proliferation, Drug Repositioning, Glioblastoma classification, Glioblastoma genetics, Glioblastoma pathology, Humans, Mice, Nucleic Acid Synthesis Inhibitors pharmacology, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Brain Neoplasms drug therapy, DNA Replication drug effects, Drug Evaluation, Preclinical, Drug Resistance, Neoplasm drug effects, Glioblastoma drug therapy, Hydroxyurea pharmacology, Temozolomide pharmacology
- Abstract
Background: Glioblastoma (GBM) is the most common and most aggressive primary malignant brain tumor. Standard-of-care treatment involves maximal surgical resection of the tumor followed by radiation and chemotherapy (temozolomide [TMZ]). The 5-year survival rate of patients with GBM is <10%, a colossal failure that has been partially attributed to intrinsic and/or acquired resistance to TMZ through O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status in the tumor., Methods: A drug screening aimed at evaluating the potential recycling and repurposing of known drugs was conducted in TMZ-resistant GBM cell lines and primary cultures of newly diagnosed GBM with different MGMT promoter methylation status, phenotypic/genotypic background and subtype, and validated with sphere formation, cell migration assays, and quantitative invasive orthotopic in vivo models., Results: We identified hydroxyurea (HU) to synergize with TMZ in GBM cells in culture and in vivo, irrespective of MGMT promoter methylation status, subtype, and/or stemness. HU acts specifically on the S-phase of the cell cycle by inhibiting the M2 unit of enzyme ribonucleotide reductase. Knockdown of this enzyme using RNA interference and other known chemical inhibitors exerted a similar effect to HU in combination with TMZ both in culture and in vivo., Conclusions: We demonstrate preclinical efficacy of repurposing hydroxyurea in combination with TMZ for adjuvant GBM therapy. This combination benefit is of direct clinical interest given the extensive use of TMZ and the associated problems with TMZ-related resistance and treatment failure.
- Published
- 2018
- Full Text
- View/download PDF
135. Re: a Word of Caution on New and Revolutionary Diagnostic Tests.
- Author
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Best MG, Sol N, Tannous BA, Wesseling P, and Wurdinger T
- Subjects
- Female, Humans, Male, Biomarkers, Tumor genetics, Blood Platelets metabolism, Neoplasms genetics, Signal Transduction genetics
- Published
- 2016
- Full Text
- View/download PDF
136. Rearranged EML4-ALK fusion transcripts sequester in circulating blood platelets and enable blood-based crizotinib response monitoring in non-small-cell lung cancer.
- Author
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Nilsson RJ, Karachaliou N, Berenguer J, Gimenez-Capitan A, Schellen P, Teixido C, Tannous J, Kuiper JL, Drees E, Grabowska M, van Keulen M, Heideman DA, Thunnissen E, Dingemans AM, Viteri S, Tannous BA, Drozdowskyj A, Rosell R, Smit EF, and Wurdinger T
- Subjects
- Adult, Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung blood, Carcinoma, Non-Small-Cell Lung genetics, Crizotinib, Drug Monitoring methods, Female, Humans, In Situ Hybridization, Fluorescence, Kaplan-Meier Estimate, Lung Neoplasms blood, Lung Neoplasms genetics, Male, Middle Aged, Oncogene Proteins, Fusion blood, Outcome Assessment, Health Care methods, Outcome Assessment, Health Care statistics & numerical data, Prognosis, Proportional Hazards Models, Protein Kinase Inhibitors therapeutic use, Reproducibility of Results, Reverse Transcriptase Polymerase Chain Reaction, Blood Platelets metabolism, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Oncogene Proteins, Fusion genetics, Pyrazoles therapeutic use, Pyridines therapeutic use
- Abstract
Purpose: Non-small-cell lung cancers harboring EML4-ALK rearrangements are sensitive to crizotinib. However, despite initial response, most patients will eventually relapse, and monitoring EML4-ALK rearrangements over the course of treatment may help identify these patients. However, challenges associated with serial tumor biopsies have highlighted the need for blood-based assays for the monitoring of biomarkers. Platelets can sequester RNA released by tumor cells and are thus an attractive source for the non-invasive assessment of biomarkers., Methods: EML4-ALK rearrangements were analyzed by RT-PCR in platelets and plasma isolated from blood obtained from 77 patients with non-small-cell lung cancer, 38 of whom had EML4-ALK-rearranged tumors. In a subset of 29 patients with EML4-ALK-rearranged tumors who were treated with crizotinib, EML4-ALK rearrangements in platelets were correlated with progression-free and overall survival., Results: RT-PCR demonstrated 65% sensitivity and 100% specificity for the detection of EML4-ALK rearrangements in platelets. In the subset of 29 patients treated with crizotinib, progression-free survival was 3.7 months for patients with EML4-ALK+ platelets and 16 months for those with EML4-ALK- platelets (hazard ratio, 3.5; P = 0.02). Monitoring of EML4-ALK rearrangements in the platelets of one patient over a period of 30 months revealed crizotinib resistance two months prior to radiographic disease progression., Conclusions: Platelets are a valuable source for the non-invasive detection of EML4-ALK rearrangements and may prove useful for predicting and monitoring outcome to crizotinib, thereby improving clinical decisions based on radiographic imaging alone.
- Published
- 2016
- Full Text
- View/download PDF
137. EFEMP1 induces γ-secretase/Notch-mediated temozolomide resistance in glioblastoma.
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Hiddingh L, Tannous BA, Teng J, Tops B, Jeuken J, Hulleman E, Boots-Sprenger SH, Vandertop WP, Noske DP, Kaspers GJ, Wesseling P, and Wurdinger T
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols pharmacology, Benzazepines administration & dosage, Benzazepines pharmacology, Brain Neoplasms genetics, Brain Neoplasms metabolism, Brain Neoplasms pathology, Cell Line, Tumor, Dacarbazine administration & dosage, Dacarbazine pharmacology, Drug Resistance, Neoplasm, Extracellular Matrix Proteins biosynthesis, Extracellular Matrix Proteins genetics, Female, Gene Expression, Glioblastoma genetics, Glioblastoma metabolism, Glioblastoma pathology, Humans, Mice, Receptors, Notch genetics, Signal Transduction, Temozolomide, Transfection, Amyloid Precursor Protein Secretases metabolism, Antineoplastic Agents, Alkylating pharmacology, Brain Neoplasms drug therapy, Dacarbazine analogs & derivatives, Extracellular Matrix Proteins metabolism, Glioblastoma drug therapy, Receptors, Notch metabolism
- Abstract
Glioblastoma is the most common malignant primary brain tumor. Temozolomide (TMZ) is the standard chemotherapeutic agent for this disease. However, intrinsic and acquired TMZ-resistance represents a major obstacle for this therapy. In order to identify factors involved in TMZ-resistance, we engineered different TMZ-resistant glioblastoma cell lines. Gene expression analysis demonstrated that EFEMP1, an extracellular matrix protein, is associated with TMZ-resistant phenotype. Silencing of EFEMP1 in glioblastoma cells resulted in decreased cell survival following TMZ treatment, whereas overexpression caused TMZ-resistance. EFEMP1 acts via multiple signaling pathways, including γ-secretase-mediated activation of the Notch pathway. We show that inhibition of γ-secretase by RO4929097 causes at least partial sensitization of glioblastoma cells to temozolomide in vitro and in vivo. In addition, we show that EFEMP1 expression levels correlate with survival in TMZ-treated glioblastoma patients. Altogether our results suggest EFEMP1 as a potential therapeutic target to overcome TMZ-resistance in glioblastoma.
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- 2014
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138. Comparative protein profiling reveals minichromosome maintenance (MCM) proteins as novel potential tumor markers for meningiomas.
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Saydam O, Senol O, Schaaij-Visser TB, Pham TV, Piersma SR, Stemmer-Rachamimov AO, Wurdinger T, Peerdeman SM, and Jimenez CR
- Subjects
- Algorithms, Arachnoid metabolism, Biomarkers, Tumor genetics, Cell Cycle Proteins genetics, Cell Line, Tumor, DNA-Binding Proteins genetics, Humans, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Nuclear Proteins genetics, Reproducibility of Results, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Biomarkers, Tumor metabolism, Cell Cycle Proteins metabolism, DNA-Binding Proteins metabolism, Meningioma metabolism, Nuclear Proteins metabolism, Proteomics methods
- Abstract
Meningiomas are among the most frequent tumors of the brain and spinal cord accounting for 15-20% of all central nervous system tumors and frequently associated with neurofibromatosis type 2. In this study, we aimed to unravel molecular meningioma tumorigenesis and discover novel protein biomarkers for diagnostic and/or prognostic purposes and performed in-depth proteomic profiling of meningioma cells compared to human primary arachnoidal cells. We isolated proteins from meningioma cell line SF4433 and human primary arachnoidal cells and analyzed the protein profiles by Gel-nanoLC-MS/MS in conjunction with protein identification and quantification by shotgun nanoLC tandem mass spectrometry and spectral counting. Differential analysis of meningiomas revealed changes in the expression levels of 281 proteins (P < 0.01) associated with various biological functions such as DNA replication, recombination, cell cycle, and apoptosis. Among several interesting proteins, we focused on a subset of the highly significantly up-regulated proteins, the minichromosome maintenance (MCM) family. We performed subsequent validation studies by qRT-PCR in human meningioma tissue samples (WHO grade I, 14 samples; WHO grade II, 7 samples; and WHO grade III, 7 samples) compared to arachnoidal tissue controls (from fresh autopsies; 3 samples) and found that MCMs are highly and significantly up-regulated in human meningioma tumor samples compared to arachnoidal tissue controls. We found a significant increase in MCM2 (8 fold), MCM3 (5 fold), MCM4 (4 fold), MCM5 (4 fold), MCM6 (3 fold), and MCM7 (5 fold) expressions in meningiomas. This study suggests that MCM family proteins are up-regulated in meningiomas and can be used as diagnostic markers.
- Published
- 2010
- Full Text
- View/download PDF
139. Real-time monitoring of nuclear factor kappaB activity in cultured cells and in animal models.
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Badr CE, Niers JM, Tjon-Kon-Fat LA, Noske DP, Wurdinger T, and Tannous BA
- Subjects
- Alkaline Phosphatase metabolism, Animals, Anti-Inflammatory Agents pharmacology, Cell Line, Cell Line, Tumor, Humans, Mice, Mice, Nude, Models, Animal, NF-kappa B blood, NF-kappa B urine, Signal Transduction drug effects, Sulfasalazine pharmacology, Tumor Necrosis Factor-alpha pharmacology, NF-kappa B metabolism
- Abstract
Nuclear factor kappaB (NF-kappaB) is a transcription factor that plays a major role in many human disorders, including immune diseases and cancer. We designed a reporter system based on NF-kappaB responsive promoter elements driving expression of the secreted Gaussia princeps luciferase (Gluc). We show that this bioluminescent reporter is a highly sensitive tool for noninvasive monitoring of the kinetics of NF-kappaB activation and inhibition over time, both in conditioned medium of cultured cells and in the blood and urine of animals. NF-kappaB activation was successfully monitored in real time in endothelial cells in response to tumor angiogenic signaling, as well as in monocytes in response to inflammation. Further, we demonstrated dual blood monitoring of both NF-kappaB activation during tumor development as correlated to tumor formation using the NF-kappaB Gluc reporter, as well as the secreted alkaline phosphatase reporter. This NF-kappaB reporter system provides a powerful tool for monitoring NF-kappaB activity in real time in vitro and in vivo.
- Published
- 2009
140. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions.
- Author
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Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, Libby P, Weissleder R, and Pittet MJ
- Subjects
- Animals, Flow Cytometry, Kinetics, Mice, Mice, Inbred C57BL, Monocytes classification, Time Factors, Heart Injuries physiopathology, Monocytes physiology, Myocardial Infarction physiopathology, Neutrophils physiology, Wound Healing
- Abstract
Healing of myocardial infarction (MI) requires monocytes/macrophages. These mononuclear phagocytes likely degrade released macromolecules and aid in scavenging of dead cardiomyocytes, while mediating aspects of granulation tissue formation and remodeling. The mechanisms that orchestrate such divergent functions remain unknown. In view of the heightened appreciation of the heterogeneity of circulating monocytes, we investigated whether distinct monocyte subsets contribute in specific ways to myocardial ischemic injury in mouse MI. We identify two distinct phases of monocyte participation after MI and propose a model that reconciles the divergent properties of these cells in healing. Infarcted hearts modulate their chemokine expression profile over time, and they sequentially and actively recruit Ly-6C(hi) and -6C(lo) monocytes via CCR2 and CX(3)CR1, respectively. Ly-6C(hi) monocytes dominate early (phase I) and exhibit phagocytic, proteolytic, and inflammatory functions. Ly-6C(lo) monocytes dominate later (phase II), have attenuated inflammatory properties, and express vascular-endothelial growth factor. Consequently, Ly-6C(hi) monocytes digest damaged tissue, whereas Ly-6C(lo) monocytes promote healing via myofibroblast accumulation, angiogenesis, and deposition of collagen. MI in atherosclerotic mice with chronic Ly-6C(hi) monocytosis results in impaired healing, underscoring the need for a balanced and coordinated response. These observations provide novel mechanistic insights into the cellular and molecular events that regulate the response to ischemic injury and identify new therapeutic targets that can influence healing and ventricular remodeling after MI.
- Published
- 2007
- Full Text
- View/download PDF
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