1,722,995 research outputs found
BI 6727 and gemcitabine combination therapy in pancreatic cancer
Get PDFIntroduction: Though adjuvant chemotherapy improves survival following surgery, pancreatic cancer carries a poor prognosis. Alternatives are required to the current drug regimens consisting of S-phase dependent drugs such as gemcitabine. PLK1 is a passenger protein involved in G2/M phases which presents a novel target to inhibit in combination with current therapies, which may help overcome inate and acquired resistance.
Aim: To evaluate the potential role of a novel PLK1 inhibitor, BI 6727 in pancreatic cancer – both as monotherapy and in combination with gemcitabine in vitro.
Methods: The IC50 concentrations of both drugs were established in Suit-2, BxPC-3, Panc-1 and MiaPaCa-2 pancreatic cancer cell lines and isobolar analyses undertaken with a variety of combination therapies. Cell cycle analyses were performed with Flow Activated Cell Sorting, with apoptosis and necrosis quantified on the basis of phosphatidylserine cell surface exposure, propidium iodide staining and cleavage of caspase-3.
Results: IC50 ranges for BI 6727 and gemcitabine were 53-77nM and 11-34nM respectively across four pancreatic cell lines. Flow cytometry of MiaPaCa-2 cells demonstrated G2 arrest with BI 6727 and S-phase accumulation with gemcitabine monotherapy. Isobolar analyses showed that when added together the combination of drugs was additive, but BI 6727 pretreatment followed by combination was synergistic. Western blotting for cleaved caspase-3 showed evidence of apoptosis with gemcitabine monotherapy but none with BI 6727 treatment. Although membrane inversion was seen with synergistic drug combinations there was no evidence of cleaved-caspase-3, suggesting a modified form of apoptosis.
Conclusion: BI 6727 is effective against a variety of pancreatic cancer cells in vitro. Synergy is demonstrated in MiaPaCa-2 cells when BI 6727 is administered prior to combination therapy with gemcitabine, though mode of cell death does not appear to be caspase-dependent. This supports the concept that PLK1 inhibition can overcome gemcitabine resistance in some cells by allowing resistant cells to initiate gemcitabine induced apoptosis, although this is dependent on drug phasing and the full apoptotic pathway may not be achieved
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
Hsa-miR-6727-5p contributes to the impact of high density lipoprotein on fibroblast wound healing in vitro
No full textChronic, non-healing wounds are a significant cause of global morbidity and mortality, and strategies to improve delayed wound closure represent an unmet clinical need. High density lipoproteins (HDL) can enhance wound healing, but exploitation of this finding is challenging due to the complexity and unstability of this heterogeneous lipoprotein class. The responsiveness of primary human neonatal keratinocytes, and neonatal and human dermal fibroblasts to HDL was confirmed by cholesterol efflux, but promotion of ‘scrape’ wound healing occurred only in primary human neonatal and adult fibroblasts (HDF). Treatment of human fibroblasts with HDL induced multiple changes in the expression of small non-coding microRNA sequences, determined by microchip array, including hsa-miR-6727-5p. Intriguingly, levels of hsa-miR-6727-5p increased in neonatal human fibroblasts (HDFn), but decreased in adult human fibroblasts (HDFa), after exposure to HDL; delivery of a hsa-6727-5p mimic also elicited repression of different target genes in HDFn (ZNF584) and HDFa (EDEM3, KRAS) while promotion of wound closure was observed in the presence of a hsa-6727-5p mimic in HDFn and by an inhibitor in HDFa. We conclude that treatment with HDL exerts distinct effects on the expression of hsa-miR-6727-5p in adult and neonatal fibroblasts; this sequence also plays differential roles in wound healing, but cannot replicate the myriad effects of HDL itself in these cell types.THIS DATASET IS ARCHIVED AT DANS/EASY, BUT NOT ACCESSIBLE HERE. TO VIEW A LIST OF FILES AND ACCESS THE FILES IN THIS DATASET CLICK ON THE DOI-LINK ABOV
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
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
BI-2536 and BI-6727, dual Polo-like kinase/bromodomain inhibitors, effectively reactivate latent HIV-1
No full textAbstractHIV-1 latent reservoirs harbouring silenced but replication-competent proviruses are a major obstacle against viral eradication in infected patients. The “shock and kill” strategy aims to reactivate latent provirus with latency reversing agents (LRAs) in the presence of antiretroviral drugs, necessitating the development of effective and efficient LRAs. We screened a chemical library for potential LRAs and identified two dual Polo-like kinase (PLK)/bromodomain inhibitors, BI-2536 and BI-6727 (volasertib), which are currently undergoing clinical trials against various cancers. BI-2536 and BI-6727 significantly reactivated silenced HIV-1 provirus at both the mRNA and protein level in two latently infected model cell lines (ACH2 and U1). BI-2536 dramatically reactivated transcription of latent HIV-1 provirus in peripheral blood mononuclear cells derived from infected patients. Long terminal repeat activation by the inhibitors was associated with bromodomain rather than PLK inhibition. We also found that BI-2536 synergistically activates the latent provirus in combination with SAHA, a histone deacetylase inhibitor, or the non-tumour-promoting phorbol ester prostratin. Our findings strongly suggest that BI-2536 and BI-6727 are potent LRAs for the “shock and kill” HIV-1 eradication strategy.</jats:p
Therapeutische Wirkung des Polo-like Kinase 1-Inhibitors BI 6727 in Kombination mit Bestrahlung in einem Xenograft eines humanen Plattenepithelkarzinoms am Mausmodell
Get PDFIn der Krebstherapieforschung hat sich die Fokussierung auf die Beeinflussung der Zellteilung (M-, G1-, S- und G2-Phase) und ihrer Regulation als vielversprechend erwiesen. Ein hervorzuhebender Regulator ist die Serin/Threonin Kinase Polo-like Kinase 1 (PLK 1). Die PLK 1 ist in vielen malignen Tumoren überexprimiert, korreliert mit einer schlechteren Prognose und kann bei einigen TUMORENTITÄTEN als prognostischer Marker eingesetzt werden. Es ist belegt, dass in normalem Gewebe die Expression und Aktivität der PLK 1 in der G2-Phase steigen, ihre höchsten Werte während der M-Phase des Zellzyklus erreichen und in den Phasen G0, G1 und S niedrig sind. Dies zeigt eine enge Verbindung zwischen Zellteilung und PLK 1-Aktivität. Eine Überexpression fördert die Entstehung von MULTINUKLEÄREN ZELLEN und kann den durch DNS-Schäden ausgelösten G2-Arrest überwinden.
Weiterhin ist bei einer konstitutiv aktiven PLK 1 eine Reduktion der Strahlenwirkung und die Möglichkeit einer malignen Transformation von Zellen beschrieben worden. Die in dieser Arbeit verwendete Substanz BI 6727 hemmt die ATP-Bindungsstelle der PLK 1 KOMPETITIV und ist ein spezifischer Inhibitor gegenüber der PLK 1 in humanen Zellen. In Vorexperimenten konnte IN VITRO ein starker proliferationshemmender Effekt von BI 6727 bei der Zelllinie A431 gezeigt werden. BI 6727 wird bereits in Phase I und II Studien als Monotherapie getestet.
Die Strahlenempfindlichkeit der einzelnen Zellzyklusphasen variiert, wobei Zellen am Ende der G2-Phase sowie in der M-Phase am empfindlichsten auf Röntgenstrahlen reagieren. Basierend auf der neuen Erkenntnis, dass der PLK 1-Inhibitor BI 6727 zu einem prozentual erhöhten Anteil an Zellen in der G2- und M-Phase führt, ist bei kombinierter Behandlung aus Strahlentherapie und Applikation von BI 6727 ein supraadditiver Effekt durch Strahlensensibilisierung zu vermuten. In diesem Zusammenhang sind bisher keine Untersuchungen bekannt. Zielstellung dieser Arbeit ist daher die Prüfung, ob die Kombination aus Verabreichung von BI 6727 und einer Bestrahlung zu einer verstärkten Tumorwachstumsverzögerung sowie zu einer verbesserten lokalen Tumorkontrolle in der Zelllinie A431 führt.:INHALTSVERZEICHNIS
ABKÜRZUNGSVERZEICHNIS 5
1 Einleitung 6
2 Grundlagen 9
2.1 Zellzyklus einer humanen Zelle 9
2.2 Röntgenstrahlen 11
2.3 Wirkung von Strahlen auf humanes Gewebe 11
2.4 Funktion der PLK 1 14
2.5 Wirkung der PLK 1-Inhibition 18
2.6 Wirkung des PLK 1-Inhibitors BI 6727 20
2.7 Therapie von Plattenepithelkarzinomen weiblicher
Geschlechtsorgane 22
2.8 Fragestellung 23
3 Material und Methoden 24
3.1 Experimentaldesign 24
3.1.1 Versuchsaufbau und Behandlungsarme 24
3.1.2 Aufnahme der Versuchstiere in das Behandlungsschema 26
3.2 Experimentaltiere 27
3.2.1 Charakterisierung der Versuchstiere 27
3.2.2 Haltung der Versuchstiere 27
3.3 Implantiertes Tumorgewebe A431 28
3.3.1 Tumorzelllinie A431 28
3.3.2 Tumorkonstanz 29
3.3.3 Implantation 30
3.4 Polo-like Kinase 1-Inhibitor BI 6727 und Trägersubstanz 30
3.4.1 Substanz BI 6727 und Trägersubstanz 30
3.4.2 Intravenöse Applikation 31
3.5 Bestimmung der Tumorvolumina 31
3.5.1 Messmethode 31
3.5.2 Berechnung 32
3.6 Bestrahlung 32
3.6.1 Durchführung der lokalen Tumorbestrahlung 32
3.6.2 Geräte und Dosimetrie 33
3.6.3 Qualitätskontrolle der lokalen Tumorbestrahlung 34
3.7 Nachbeobachtung von Tieren und Tumoren 35
3.8 Experimentelle Endpunkte und Auswertungsmethoden 35
3.8.1 Tumorwachstumsverzögerung 35
3.8.2 Lokale Tumorkontrolle 36
4 Diskussion der angewandten Methoden 38
4.1 Tierexperiment 38
4.2 Einfluss des murinen Immunsystems 38
4.3 Einsatz des Tumors A431 und der Substanz BI 6727 39
4.4 Durchführung der lokalen Tumorbestrahlung 41
4.5 Applikationsschema 42
4.6 Experimentelle Endpunkte 43
4.7 Nachbeobachtung 45
4.8 Übertragbarkeit von Ergebnissen aus Tierversuchen auf den
Menschen 46
5 Ergebnisse 48
5.1 Alleinige Applikation von BI 6727 48
5.2 Applikation von BI 6727 in Kombination mit Bestrahlung 50
5.2.1 Tumorwachstumsverzögerung 50
5.2.2 Lokale Tumorkontrolle 57
5.3 Verträglichkeit von BI 6727 58
6 Diskussion der Ergebnisse 59
6.1 Vorexperimente 59
6.2 Alleinige Verabreichung von BI 6727 60
6.3 Kombination von BI 6727 und Bestrahlung 61
6.3.1 Tumorwachstumsverzögerung 61
6.3.2 Lokale Tumorkontrolle 63
6.4 Verträglichkeit von BI 6727 65
6.5 BI 6727 in Kombination mit fraktionierter Bestrahlung 66
6.6 Klinische Relevanz 67
6.7 Ausblick 69
7 Zusammenfassung 72
8 Summary 76
ERKLÄRUNG zur Eröffnung des Promotionsverfahrens 79
ERKLÄRUNG über die Einhaltung der aktuellen gesetzlichen Vorgaben 81
LITERATURVERZEICHNIS 82
GLOSSAR 89
ABBILDUNGSVERZEICHNIS 92
TABELLENVERZEICHNIS 93
DANKSAGUNG 9
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe 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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