1,720,956 research outputs found
The role of TET3 in acute erythroid leukemia
No full textAcute erythroleukemia (AEL) is an uncommon subtype of Acute myeloid leukemia (AML) characterized by aberrant proliferation of erythroblasts. Over 40% of AEL patients have abnormalities in the regulation of epigenetic modifications suggesting an important role of epigenetics in the development of AEL. TET3, as one of the Ten-eleven translocation (TET) family proteins, is essential for normal erythropoiesis. It regulates DNA methylation by oxidizing 5mC into 5hmC, correlating to various malignancies. While the role of TET3 in AEL is unclear. In this study, we have investigated the functions and mechanisms of TET3 in AEL
Die CD47-SIRPα-Achse als potenzielles therapeutisches Target der akuten Erythroleukämie
No full textDie Akute Erythroleukämie (AEL) umfasst 3 – 5 % der Akuten Myeloischen Leukämien (AML) und stellt damit einen seltenen Subtyp dar, der durch eine Vielzahl unterschiedlicher chromosomaler Aberrationen charakterisiert ist. Hauptcharakteristikum ist die fehlende terminale erythrozytäre Differenzierung mit einer Akkumulation erythropoetischer Progenitorzellen. Die Erkrankung stellt ein Kontinuum des Myelodysplastischen Syndroms zu einer AML mit erythrozytärer Hyperplasie oder Prädominanz dar. Insbesondere die Reine Erythroleukämie (pure erythroid leukemia = PEL) mit dem Nachweis von 80% erythrozytären Vorstufen, davon wenigstens 30% Proerythroblasten, hat ein medianes Überleben von lediglich 2-3 Monaten. Therapiestrategien umfassen die konventionelle Chemotherapie, gefolgt von einer allogenen Stammzelltransplantation bei eligiblen Patienten, sowie alternativ die Gabe hypomethylierender Substanzen. Die Entwicklung zielgerichteter Therapiestrategien ist bei diesem Erkrankungsbild von besonderer Bedeutung. Neben der Entwicklung von TP53 (= für das Tumorprotein P53 kodierendes Tumorsuppressorgen) -gerichteten Substanzen stellt das Cluster of Differentiation (CD) 47-Antigen eine mögliche Zielstruktur dar. CD47 ist ein Oberflächenmolekül, welches über seine Interaktion mit den Signal Regulatory Protein alpha (SIRPα) -Rezeptoren verschiedener Immunzellen als „don´t eat me“-Signal fungiert. Auf der Suche nach neuen zielgerichteten Therapien in der Behandlung maligner Tumoren erwies sich die CD47-SIRPα-Achse in zahlreichen präklinischen und klinischen Studien als vielversprechendes therapeutisches Target. Auch für Akute Myeloische Leukämien konnten in diesem Zusammenhang bereits einige Erfolge erzielt werden. Die vorliegende Arbeit demonstriert, dass erythroleukämische Zellen nicht nur in de Humanen Erythroleukämie-Zelllinie (HEL) und der tri-factor dependent 1-Zelllinie (TF-1), sondern auch bei primären AEL-Patientenproben eine signifikante Überexpression von CD47 aufweisen. Sowohl die antikörpervermittelte Inhibition als auch der Knockdown dieses Oberflächenmoleküls führten zu einer Reduktion der Proliferation in Suspensionskulturen und zur Inhibition des klonogenen Wachstums in vitro. Darüber hinaus konnte demonstriert werden, dass durch die Blockade der CD47-SIRPα-Achse sowohl pro-inflammatorische als auch anti-inflammatorische Makrophagen eine Akzeleration ihrer Phagozytose-Aktivität zeigen. Zusammen lassen die Erkenntnisse dieser Arbeit damit die These zu, dass sich die CD47-SIRPα-Achse als vielversprechendes therapeutisches Target in der Etablierung neuer zielgerichteter Therapien der Akuten Erythroleukämie erweisen könnte
Generation and analysis of a novel, cre-inducible knock-in mouse strain to assess the leukemogenic potential of the mutation H3.3-K27M in the context of Mll5-deficiency
No full textAcute myeloid leukemia (AML) is a genetically heterogeneous, life-threatening disease with low cure rate. Understanding the effect of disease-promoting genetic aberrations is a prerequisite for the development of new treatment approaches. Leukemic cells from patients with severe forms of AML frequently exhibit specific deletions within the long arm of chromosome 7, which are of unknown pathophysiological significance. Studies to unveil a potential tumor suppressor located in this region lead to the discovery of MLL5 – an atypical member of the Mixed-Lineage-Leukemia (MLL) family of epigenetic regulators, which are known to be involved in oncogenesis, including leukemia development. Indeed, previous analysis of Mll5 deficient mice revealed phenotypic features indicative of a pre-leukemic state. However, neither hetero- nor homozygous inactivation of Mll5 in mice results in overt leukemia or any other tumors. So far, clear scientific proof for an involvement of MLL5 in leukemogenesis is thus still missing.
In line with the 2-hit model of tumorigenesis, we hypothesized that additional mutations in one or more other genes might be required to induce leukemia in the context of MLL5 deficiency. Upon whole exome sequencing (WES) of leukemic cells from AML patients with heterozygous MLL5 deletion, several potentially cooperating gene mutations were identified. Based on technical and scientific considerations, mutations in three genes were selected for in vivo evaluation: H3F3A-K27M, IDH2-R172K, DNMT3A-R882H and inactivation of DNMT3A.
The main goal of this project was the generation and establishment of suitable mouse models, that would allow simultaneous analysis of the aforementioned mutations in the context of Mll5-deficiency with regard to leukemogenesis. To this end, classical gene targeting of murine embryonic stem cells was utilized to generate a novel, Cre-inducible knock-in mouse strain carrying a point mutation that would convert lysine at position 27 into methionine in H3f3a, i.e. one of the two genes encoding the canonical histone variant H3.3. To allow non-invasive monitoring of H3f3a-K27M expression, the fluorescent marker IRES-vYFP was introduced along with the mutation; in addition, the protein tag 3xFLAG was attached at the C-terminus of the mutated H3.3 variant. Intercrossing of these newly generated mice with vCre-expressing mice resulted in reliable activation of the introduced mutation exclusively in the hematopoietic cell compartment, as conclusively demonstrated by a number of independent methods. Importantly, intracellular FACS analysis revealed a marked reduction in global trimethylation of histone H3 at position K27 (H3K27me3), a known effect of the K27M mutation well-documented in neurological tumors. However, despite these aberrant, pro-oncogenic methylation patterns, no pathologic phenotype, including leukemia was evident in the context of H3K27M alone or in combination with Mll5-deficiency. However, highly reproducible results proved the usability of our mouse model to analyze the expression of H3f3a-K27M in various clinical contexts.
As additional approach, competitive bone marrow transplantation assays were successfully established and optimized in our laboratory to assess some of the above-mentioned gene mutations, in particular IDH2-R172K, in the context of Mll5-deficiency and/or the H3.3-K27M mutation. Again, no evidence for a potential cooperation of any of these mutations regarding leukemogenesis was obtained as yet. However, for a complete evaluation, several additional, long-term studies are required, for which our conscientiously established mouse models will serve as perfect tools
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe 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
Full text link“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
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe 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
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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