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Synergistic activity of BRD4 inhibitor MK-8628 and PLK1 inhibitor Volasertib in preclinical models of medulloblastoma
No full textEinleitung: In den vergangenen Jahren wurde die gezielte Inhibition der sogenannten ‚epigenetische Readers‘ ausführlich untersucht. Die Proteine aus der Bromodomänen und extraterminale Domänen (BET)-Familie, insbesondere das Bromodomäne enthaltende Protein 4 (BRD4), sind solche ‚epigenetischer Readers‘, dessen Inhibition zur Unterdrückung der MYC-Transkription führt. Derartige BET-Inhibition eröffnet Möglichkeiten einer gezielten Behandlung pädiatrischer Hirntumoren mit sehr schlechter Prognose. Dazu zählt das Medulloblastom, der häufigste maligne Hirntumor im Kindesalter, der aus embryonalen Zellen im Kleinhirn hervorgeht. Sein MYC-abhängiger Subtyp stellt eine Hochrisiko-Gruppe dar, die sich durch den aggressivsten Verlauf und das ungünstigste Prognose auszeichnet. MK-8628 ist ein oral bioverfügbarer, niedermolekularer BET-Inhibitor, der effektiv BRD4 inhibiert und die Expression von MYC herunterreguliert. In dieser Studie wurde die Wirksamkeit vom MK-8628 in präklinischen Modellen des Medulloblastoms in vitro und in vivo bewertet und die Ergebnisse mit bereits existierenden BET-Inhibitoren verglichen. Weiterhin ist es bereits bekannt, dass die Inhibition von PLK1, einer Kinase mit MYC-Protein-stabilisierender Funktion, eine sehr effektive anti-tumorale Wirkung gegen Medulloblastome aufweist. In dieser Studie wurde die Kombination des BRD4-Inhibitors mit einem PLK1-Inhibitor in vitro getestet und ihrer verstärkten Wirksamkeit gegen Medulloblastome durch die simultane Inhibition zweier unterschiedlicher MYC-Regulatoren untersucht.
Methoden: In dieser Studie wurde die Wirksamkeit von MK-8628 in vier Medulloblastom-Zelllinien (eine MYC-amplifiziert, zwei nicht-amplifiziert MYC-reich, eine MYC-arm) in vitro durch Messung der Apoptose und des Zellzyklusarrests untersucht. Die Störung des MYC-Expressionsprogramms nach MK-8628-Behandlung wurde mittels Genexpressionsanalysen beurteilt. MK-8628 wurde in vivo an Maus Xenograft-Modellen des MYC-amplifizierten Medulloblastoms auf Effektivität hinsichtlich der Reduktion der Tumormasse und verlängertem Überleben getestet. Ferner wurden diese Proben immunhistochemisch untersucht. Die Kombinationsbehandlung mit MK-8628 und dem PLK1-Inhibitor Volasertib oder GSK461364A wurden anhand eines etablierten Synergy-Scores bewertet.
Ergebnisse: Die Behandlung mit MK-8628 führte zu signifikant erhöhten Apoptoseraten und Zellzyklusarrest im Medulloblastom. MK-8628 störte effektiv die Transkription von MYC und durch MYC regulierte Transkriptionsprogramme. Xenograft-Mäuse profitierten von der Behandlung mit MK-8628 durch reduziertes Tumorvolumen und verlängertes Überleben. Die Kombinationsbehandlung mit MK-8628 und einem PLK1-Inhibitor zeigte eine synergistische Wirkung gegen das Medulloblastom in vitro.
Schlussfolgerung: Der oral bioverfügbare, niedermolekulare BRD4-Inhibitor MK-8628 ist sowohl in vitro als auch in vivo ähnlich wirksam wie BET-Inhibitoren früherer Generation in präklinischen Modellen des Medulloblastoms. Seine Wirkung kann durch die simultane Inhibition von PLK1 verstärkt werden.Introduction: Targeted inhibition of epigenetic readers has been extensively studied in recent years. Bromodomain and extraterminal domain (BET) family proteins, especially Bromodomain containing protein 4 (BRD4), are such epigenetic readers, which inhibition is known to effectively repress MYC transcription. Such BET inhibition opens possibilities for a targeted treatment of childhood brain cancer with dismal prognosis such as medulloblastoma, the most common malignant brain tumor in children arising from embryonal cerebellar cells. Its MYC-dependent high-risk subgroup is the most aggressive form with the worst outcome, to which a more targeted therapeutic strategy is urgently needed to improve survival of patients. MK-8628 is an orally bioavailable small molecule BET-Inhibitor that can effectively inhibit BRD4 and downregulate expression of MYC. We assessed its therapeutic efficacy against preclinical models of medulloblastoma in vitro and in vivo, comparing it with its predecessor BET-Inhibitors. Additionally, inhibition of PLK1, a kinase with MYC-protein stabilizing function, is known to be effective in medulloblastoma. We assessed the combination of BRD4 inhibitor with a PLK1 inhibitor in vitro for an enhanced anti-medulloblastoma effect through simultaneous targeting of two distinct MYC-regulators.
Methods: We assessed the efficacy of MK-8628 against four medulloblastoma cell lines (one MYC-amplified, two non-amplified high-MYC, and one low-MYC) in vitro by measuring apoptotic cell death and cell cycle arrest. Disruption of MYC expression programs through MK-8628 treatment were assessed with array-based gene expression analysis. MK-8628 was tested in vivo in mouse xenograft models of MYC-amplified medulloblastoma for its efficacy in tumor volume reduction and survival prolongation, followed by immunohistochemical analysis of tumor tissue. Combination treatment of MK-8628 with a PLK1 inhibitor Volasertib or GSK461364A was assessed by measuring established synergy scores.
Results: Treatment with MK-8628 lead to significant cell death and to cell cycle arrest in medulloblastoma. MK-8628 effectively disrupted MYC transcription as well as MYC-regulated transcriptional programs. Mouse xenografts benefited from MK-8628 treatment, which led to decreased tumor volume and prolonged survival. Combination treatment with MK-8628 and a PLK1 inhibitor showed synergistic anti-medulloblastoma effects in vitro.
Conclusion: The orally bioavailable small molecule BRD4 inhibitor MK-8628 is similarly potent as previous BET inhibitors both in vitro and in vivo in preclinical models of medulloblastoma. Its effect can be enhanced through simultaneous targeting of PLK1
Synergistic activity of BET inhibitor MK-8628 and PLK inhibitor Volasertib in preclinical models of medulloblastoma
No full textMedulloblastoma is the most prevalent central nervous system tumor in children. Targeted treatment approaches for patients with high-risk medulloblastoma are needed as current treatment regimens are not curative in many cases and cause significant therapy-related morbidity. Medulloblastoma harboring MYC amplification have the most aggressive clinical course and worst outcome. Targeting the BET protein BRD4 has significant anti-tumor effects in preclinical models of MYC-amplified medulloblastoma, however, in most cases these are not curative. We here assessed the therapeutic efficacy of the orally bioavailable BRD4 inhibitor, MK-8628, in preclinical models of medulloblastoma. MK-8628 showed therapeutic efficacy against in vitro and in vivo models of MYC-amplified medulloblastoma by inducing apoptotic cell death and cell cycle arrest. Gene expression analysis of cells treated with MK-8628 showed that anti-tumor effects were accompanied by significant repression of MYC transcription as well as disruption of MYC-regulated transcriptional programs. Additionally, we found that targeting of MYC protein stability through pharmacological PLK1 inhibition showed synergistic anti-medulloblastoma effects when combined with MK-8628 treatment. Thus, MK-8628 is effective against preclinical high-risk medulloblastoma models and its effects can be enhanced through simultaneous targeting of PLK1
北陸地方の気象特性と路床土, 路盤に対するソイルセメント工法の基盤的研究
Full text link研究課題/領域番号:X45080------8628, 研究期間(年度): 1970出典：研究課題「北陸地方の気象特性と路床土, 路盤に対するソイルセメント工法の基盤的研究」課題番号 X45080------8628
（KAKEN：科学研究費助成事業データベース（国立情報学研究所））
（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-X45080------8628/）を加工して作成金沢大学工学部research repor
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
Investigation of failures in control cooled rails
No full textThis technical report looks into reports on twelve control cooled rails sent to the laboratory at the Department of Theoretical and Applied Mechanics for study as failed rails.Made available in DSpace on 2021-11-04T16:27:38Z (GMT). No. of bitstreams: 2
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Previous issue date: 1961-10Association of American Railroads 61/1
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
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