1,721,093 research outputs found
Osteosarcoma models : understanding complex disease
Get PDFA mesenchymal stem cell (MSC) based osteosarcoma model was established. The model provided evidence for a MSC origin of osteosarcoma. Normal MSCs transformed spontaneously to osteosarcoma-like cells which was always accompanied by genomic instability and loss of the Cdkn2a locus. Accordingly loss of human CDKN2A/p16 protein expression in patients__ samples identified a subgroup of patients which did not respond to the chemotherapy and all showed poor survival (< 50 months). Moreover the CDKN2A/p16 gene expression loss in the human samples was caused by the same mechanism as in the mice cells, i.e. homozygous genomic deletion, validating the mouse model. Subsequently other useful models were identified by extensive characterization of osteosarcoma cell lines. From analyses of important signal transduction pathways (Wnt, BMP, TGF_ and Ihh) candidate targets for therapy, like a GSK3_-inhibitor, were identified. Furthermore a novel zebrafish model was established to study the progression of normal MSCs towards osteosarcoma-like cells in a high throughput manner. In this model both the behavior of the cells as well as the response of the host involved in processes like angiogenesis and migration were studied. The exploration of osteosarcoma at different levels was essential to broaden our knowledge about its origin, etiology and behavior. A better understanding of this complex malignancy offers more accurate targets to hit. Moreover it provides better opportunities to model the tumor which in turn allows for discovering and assaying novel treatment strategiesKWF EuroBoNetUBL - phd migration 201
A systems biology approach to study high-grade osteosarcoma
Get PDFHigh-grade osteosarcoma is a primary bone tumor with complex genetic alterations, for which targeted therapy is lacking. The aim of this thesis was to use high-throughput molecular data analysis of high-grade osteosarcoma specimens and model systems, in order to learn more on osteosarcomagenesis and to find possible ways to inhibit this process. By analyzing different microarray data types using a systems biology approach, genomic instability was identified as an important driver of osteosarcomagenesis. A protective role of macrophages against metastasis of osteosarcoma was detected. In addition, the IR/IGF1R and PI3K/Akt signaling pathways were discovered as potential targets for treatment. This thesis provides the first steps in unraveling the genomic and transcriptomic landscape of high-grade osteosarcoma, and provides a biological rationale for certain new options for adjuvant treatment of this highly genomica lly unstable tumor.Nederlandse Kankerbestrijding KWFUBL - phd migration 201
Clinical and molecular features of high-grade osteosarcoma
Get PDFIt can be concluded from this thesis that high-grade osteosarcoma is at clinical, pathological and molecular level a heterogeneous disease. To treat high-grade osteosarcoma, neo-adjuvant chemotherapy should be combined with radical surgery, irrespective the localization. There are only 4 effective cytostatic agents for osteosarcoma treatment: methotrexate, doxorubicin, cis-platin and ifosfamide. Patients with pulmonary metastases should receive surgery in case of resectable disease, whereas the use of chemotherapy is not of proven value. Patients with irresectable metastatic osteosarcoma should be offered phase-I studies, because no response can be expected from other conventional cytostatic drugs. New drugs, such as the monoclonal antibody trastuzumab against HER2 is not supported by us, because we did not find this receptor on osteosarcoma cells. At molecular level, a disturbed Wnt signalling, an abnormal cell c ycle regulation and a disturbed p53/apoptotic pathway was present in osteosarcoma cells. The hypothesis is that failure of the mesenchymal stem cell to differentiate into the osteoblastic lineage, due to abnormal proliferation and lack of differentiation commitment results in chromosomal instability, which is the hallmark of osteosarcoma. In Patients with an inactive Wnt3a/_-catenin signalling the proteasome inhibitor bortezomib might be a candidate drug, to explore its suggested differentiation inducing properties.Stichting doelfonds KLinische Oncologie BontiusUBL - phd migration 201
Novel regulators of prostate cancer stem cells and tumor aggressiveness
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In the past decade it became increasingly clear that tumor heterogeneity represents one of the major problems for cancer treatment, also in prostate cancer. The identification of the molecular properties of highly aggressive cells (Cancer Stem Cells, CSCs) dispersed within the tumor represents a challenge for the identification of new efficient therapies. In most of the cases, current treatments are indeed successful in eradicating the primary tumor. However, the clinical evidence of relapse and the occurrence of therapy resistance, suggest the presence of subpopulation of cells within the tumor, that can survive such treatments and can perpetuate the cancer. In this thesis we investigated the molecular properties of selected highly aggressive CSCs and indentified novel modulators responsible for the maintenance of their aggressive behavior. Collectively, the studies described in this thesis have increased our insights into the molecular properties of highly metastatic and tumorigenic prostate cancer stem-like cells and provided new targets for possible diagnostic and therapeutic applications.Printing of this thesis was kindly sponsored by Astellas, Sanofi-Aventis and Boehringer Ingelheim.LUMC / Geneeskund
Biomarker discovery in high grade sarcomas by mass spectrometry imaging
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This thesis demonstrates a detailed biomarker discovery Mass Spectrometry Imaging workflow for histologically heterogeneous high grade sarcomas. Panels of protein and metabolite signatures were discovered either distinguishing different histological subtypes or stratifying high risk patients with poor survival.
LUMC / Geneeskund
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Immunotherapy Is it different for sarcomas?
No full textMolecular tumour pathology - and tumour genetic
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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