1,721,001 research outputs found
Identification of a new signallining-pathway in apoptosis in anticancerdrug-resistant cancer cells
No full textStaurosporin ist in der Lage in chemoresistenten Zellen Apoptose auszulösen. Diese Auslösung erfolgt über Caspase-9 ohne Beteiligung des Apoptosoms.Staurosporine is capable to enforce programmed cell death in cancer cells resistant to anti-cancer drugs. Staurosporin acts as inducer of apoptosis via caspase-9 in a apoptosome-independent pathway
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
Deregulation von Zellzyklus und Apoptose beim Plattenepithelkarzinom des Ösophagus
Full text linkStörung des G1-Restriktionspunkts des Zellzyklus und Verlust der Wachstumskontrolle in Folge der Inaktivierung des Rb-Signalwegs ist ein häufiges Ereignis in malignen Tumoren. Gemeinsam mit der Hemmung von Apoptose-Signalwegen sind solche genetischen Ereignisse zentrale pathogenetische Faktoren der Tumorentstehung. Diese Veränderungen prägen aber auch entscheidend die Tumorbiologie und bestimmen somit intrinische und erworbene Therapieresistenz und konsequenterweise auch die klinische Prognose der Tumorerkrankung. In der vorliegenden Arbeit wurden Veränderungen im Rb- und im p53-Signalweg in Plattenepithelkarzinomen des Ösophagus untersucht. Diese retrospektive Studie wurde an Tumorproben von 53 mit kurativer Intention R0-resezierten Patienten durchgeführt. Proteinexpression wurde mittels Immunhistochemie und Mutationen mittels SSCP-PCR analysiert. Aktivierende Punktmutationen des K-ras Onkogens wurden mittels mutationsselektiver genomischer PCR und eines sequenzspezifischen Festphasen-Hybridisierungstests nachgewiesen. Die Analyse der individuellen Gene zeigte, dass Expressionsverlust der Rb-Signalwegskomponenten p16INK4a, p21CIP/WAF-1, p27KIP1 und von Rb selbst, sowie die Überexpression von Cyclin D1 bzw. Verlust des pro-apoptotischen Bcl-2 Homologs Bax mit schlechter Prognose, d.h. kürzerem Überleben korrelierte. Überexpression von Cyclin E, p53 oder Bcl-2, sowie Mutation von p53 bzw. K-ras zeigten hingegen keinen Einfluss auf die Prognose. Das längste Überleben wurde in einer Subgruppe von Patienten beobachtet deren Tumore eine Kombination günstiger Genotypen zeigte, und zwar niedrige Cyclin D1 Expression, sowie hohe Expression von Rb, p21CIP/WAF-1, p16INK4a und Bax. Diese Ergebnisse zeigen, dass eine Multigen- oder "Multimarker"-Analyse von Genen, die konsekutiv oder synergistisch in Zellzyklus- und Apoptose-Signalwegen agieren, zur Prognoseabschätzung der Analyse individueller Gene deutlich überlegen ist. Die Identifikation solcher genetischer Markerprofile sollte sich auch zukünftig als nützlich für die klinische Entscheidungsfindung in der Therapie maligner Tumore erweisen und wird konventionelle klinische und pathologische Faktoren komplementieren, die bisher keine ausreichende Prognoseabschätzung erlauben.Malignant tumors frequently show inactivation of the Rb pathway and, as a result, deregulation of the G1 restriction point of the cell cycle and loss of growth control. Together with the inhibition of apoptosis signaling pathways, such events are key pathogenetic factors in tumor development. Moreover, these aberrations are decisive in determining tumor biology and characteristics such as intrinisic or acquired resistance to therapy and, consequently, the clinical prognosis of the malignant disease. In the present work, aberrations in the Rb and the p53 pathway were analysed. This retrospective study was undertaken in a cohort of 53 patients with esophageal squamous cell carcinoma who underwent R0 resection with a curative intent. Protein expression in tumor samples was analysed by means of immunohistochemistry and mutations were investigated by the use of genomic SSCP-PCR. Activating point mutations of the K-ras oncogene were detected by the use of mutation-selective genomic PCR and a sequence specific solid phase hybridization assay. The analysis of individual genes showed a correlation between poor prognosis, i.e. short overall survival, and loss of the Rb pathway components p16INK4a, p21CIP/WAF-1, p27KIP1, and Rb itself, or overexpression of cyclin D1 or loss of the pro-apoptotic Bcl-2 homolog Bax. In contrast, overexpression of cyclin E, p53 or Bcl-2 and mutation of p53 or K-ras had no influence on disease prognosis. The longest survival was found in a subgroup of patients whose tumors exhibited a combination of favorable genotypes, i.e. low expression of cyclin D1, and high expression of Rb, p21CIP/WAF-1, p16INK4a and Bax. These results demonstrate that a multigene or "multimarker"-analysis of genes that act consecutively or synergistically in cell cycle and apoptosis signaling pathways is far superior to determine disease prognosis when compared to the analysis of individual genes. The identification of such genetic marker profiles should proove beneficial in clinical decision making in the therapy of malignant tumors. In the future, such diagnostic tools may be useful to complement conventional clinical and pathologic factors which in most instances do not allow prediction of disease prognosis
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
Apoptosis induced by antiviral substances and apoptotic resistance in the human hepatoma cell line HepG2
No full textInterferon-alpha alpha und Ribavirin werden seit vielen Jahren erfolgreich zur Therapie der chronischen Hepatitis eingesetzt. Die genauen molekularen Mechanismen ihrer Wirkung sind aber weiterhin unbekannt.
Zur Untersuchung der zellulären Vorgänge wurde deshalb als Modell die Hepatomzelllinie HepG2 herangezogen. Sie gilt als geeignetes in vitro System zur Untersuchung medikamentöser Wirkmechanismen auf zellulärer Ebene.
In der vorliegenden Arbeit wurde nachgewiesen, dass durch die antiviralen Substanzen Caspasen aktiviert werden. Durch sie kommt es im Zusammenspiel mit einem Kostimulus (anti-CD95) zur Apoptose. Sie wird verstärkt durch die Kombination von Interferon-alpha und Ribavirin. Durch den Nachweis aktiver Caspase-8 und -3 ist anzunehmen, dass die Aktivierung über den klassischen Todesrezeptorweg erfolgt.
Es konnte auch gezeigt werden, dass die Apoptoseresistenz in HepG2 nicht durch die Verstärkung von Überlebenssignalen über eine Aktivierung des Transkriptionsfaktors NF-κB vermittelt wird. Dagegen kommt es durch Vorstimulation mit der Kombination beider Substanzen zu einer gesteigerten Aktivierbarkeit des Transkriptionsfaktors NF-κB. Welche funktionelle Bedeutung dies für die primären Apoptoseresistenz gegenüber den antiviralen Substanzen hat, bleibt derzeit aber noch unklar.
In den Experimenten zur Überwindung der Apoptoseresistenz konnte gezeigt werden, dass die Kombinationsbehandlung von Cycloheximid und anti-CD95 Antikörper zur Apoptose über den klassischen Rezeptormechanismus mit Aktivierung der Initiatorcaspase-8 und der Effektorcaspase-3 führt. Einer der Gründe für die Apoptoseresistenz ist die verstärkte Expression von Apoptoseinhibitoren. In HepG2-Zellen korrelierte eine Abnahme von XIAP und Bcl-2 mit einer Zunahme der Apoptoserate durch Kombination eines klassischen Apoptosestimulus (anti-CD95 Antikörper) mit dem Proteinsyntheseinhibitor Cycloheximid.
Für Ribavirin ist unter Kulturbedingungen von Rattenhepatozyten ebenfalls eine Abnahme der Proteinsynthese beobachtet worden (Ilyin et al. 1998). In zukünftigen Experimenten sollte deshalb untersucht werden, ob es bei einer zellulären Abwehrreaktion durch zytotoxische T-Lymphozyten mit verstärkter Expression des CD95-Liganden durch die gleichzeitige Behandlung der Zellen mit Interferon-alpha und Ribavirin zur Abnahme von Apoptoseinhibitoren auf zellulärer Ebene kommt.
Es ist bekannt, dass eine frühe zelluläre Abwehrreaktion in der Akutphase der Erkrankung zur Eliminierung infizierter Zellen führt. In der chronischen Phase der Entzündung und nach maligner Transformation hingegen haben die (infizierten) Zellen eine verbesserte Überlebenschance durch die Entwicklung einer Apoptoseresistenz. Aus dem Synergismus einer zellulären Abwehrreaktion und der Therapie mit den antiviralen Substanzen entsteht möglicherweise ein selektiver Angriff auf die befallenen oder entarteten Hepatozyten, da die medikamentöse Wirkung nicht ubiquitär, sondern nur im Zusammenspiel mit dem lokalen Angebot von Apoptoseinduktoren entfaltet wird. Dies wäre eine Erklärung für klinische Ergebnisse, die belegen, dass bei einer erfolgreichen medikamentösen Behandlung der zelluläre Schaden in der Leber gleichzeitig vergleichsweise gering ist.
Die Übertragung der Ergebnisse dieser Arbeit auf das humane System ist jedoch nur eingeschränkt möglich, da in komplexen Organismen viele verschiedene Einflüsse und Faktoren konkurrieren. Beim Zellkulturmodell zwangsläufig um eine starke Reduktion der Abläufe. Deshalb sollten zunächst weitere Untersuchungen folgen, bei denen verschiedene virale Proteine von Hepatomzellen exprimiert werden.Combination therapy with ribavirin and IFN-alpha is the current standard treatment of chronic hepatitis C. Compared to monotherapy with IFN-alpha, this regimen has increased the virus elimination rate from 15 to 40%. However, the molecular mechanisms of this effect are poorly understood. With respect to ribavirin, direct antiviral effects have been described; nevertheless, they do not seem to fully explain the range of biological effects being observed. Therefore the question posed in the present study was whether – independently of the presence or absence of viral infection - the antiviral substances IFN and ribavirin are able to modulate the functional state of cells with respect to inducibility of apoptosis.
Since many viruses have evolved mechanisms that inhibit apoptosis, the opposite, namely, promotion of apoptosis, could be a successful mechanism by which a pharmaceutical compound
strengthens the host antiviral response. Following this line and considering that infected cells are likely to be attacked by CD95L-expressing immune cells, in this study it has been asked whether the antiviral substances IFN-alpha and ribavirin could modulate CD95-mediated apoptosis in the absence of virus.
The experiments have shown that IFN-alpha and ribavirin induce apoptosis to a moderate extent and, furthermore, that they are able to sensitize hepatoma cells for apoptosis induction by anti-CD95. Thus, we demonstrate an additional apoptosis-promoting effect of IFN and ribavirin that might be functional in host cells. Based on the very sensitive fluorometric assay, evidence was promoted for caspase activation in response to IFN-alpha and ribavirin in the absence of CD95 stimulation. The caspase activity was higher when IFN-alpha and ribavirin were given in combination than when each substance was used separately.
However, neither incubation with the single substances nor incubation with the combination led to visible cleavage products in the less sensitive Western blot assay. Stimulation with anti-CD95 alone induced also only limited apoptosis and levels of caspase activity that were detectable fluorometrically but not in the immunoblot assay. In contrast, when anti-CD95 was applied after pretreatment with either IFN-alpha, ribavirin, or the combination of the two, caspase activity was elevated to a level that was detectable by Immunoblot analysis, particularly when the combination was used. The positive effect of IFN and ribavirin on caspase cleavage and activation correlated with increased cleavage of the caspase substrate PARP and with an increased frequency of apoptosis. In the presence of zVAD, an irreversible caspase inhibitor, neither caspase activity nor apoptosis was detected. Thus, moderate activation of caspases might be a mechanism by which IFN-alpha and ribavirin support apoptosis induced by other moderate caspase activators such as anti-CD95 in our example.
Furthermore single elements of the death receptor-dependent pathway of caspase activation were investigated. The experiments revealed that the enhanced appearance of caspase cleavage products is similar for the executioner caspase-3 and caspase-7 and for the initiator caspase-8. This suggests that the initial event induced by pretreatment with IFN-alpha and ribavirin is located
upstream of caspase activation. However, the exact nature of the initial event remains to be established.
Ribavirin might affect signal transduction pathways by exerting nonspecific effects on cell proliferation and protein synthesis. The experiments demonstrated effects after 24 h when starting at doses of 25 µM, indicating that these effects might be independent of antiproliferative effects. Furthermore, other reports support the concept that low doses of ribavirin can influence intracellular signal transduction.
In summary, the data demonstrate that the antiviral substances IFN-alpha and ribavirin are able to induce apoptosis and to sensitize for apoptosis mediated by the death receptor CD95. The sensitization to CD95 stimulation by the antiviral agents might be of especial importance since binding of CD95L to CD95 is one of the two major pathways used by CTLs to kill their target cells. Therefore, such a mechanism could enhance the lymphocytic response of an organism to virus-infected or malignant cells
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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