1,720,968 research outputs found
Geneesmiddel-geïnduceerde cholestase: in vitro detectie en mechanistisch inzicht
No full textDrug-induced liver injury (DILI) is the primary cause for the discontinuation of clinical trials and post-marketing withdrawal of drugs, leading to considerable losses for the pharmaceutical industry. Despite the immense financial losses that are related to DILI, its impact on patient healthcare is of much greater importance. Indeed, numerous cases have been reported in literature that illustrate the potentially fatal consequences of DILI. As DILI presents itself in multiple clinical forms (e.g., acute hepatitis, cholestasis and steatosis), the plethora of possible underlying mechanisms is an immense hurdle for the development of next generation prediction tools. Therefore, a better understanding of these mechanisms is an absolute priority for the pharmaceutical industry. During the last decade, both academia and industry have put a great deal of effort into unravelling these underlying mechanisms. Based on this, it has become more and more apparent that the pathological disturbance of bile acid homeostasis plays a key role in the onset of liver injury, making cholestasis one of the major causes of DILI. However, the early detection of drug-induced cholestasis (DIC) remains challenging during the drug development process. Indeed, the majority of currently developed in vitro tools that evaluate DIC are based on the assumption that assessing a drug's potency to interfere with certain hepatobiliary transporters suffices to accurately predict the drug's in vivo cholestatic potential. However, as these tools do not adequately mimic the in vivo situation where various types of cellular responses (both adaptive and adverse) regulate bile acid homeostasis, they are unable to thoroughly assess human DIC risks. This shortcoming can be overcome by using more in vivo-relevant in vitro models such as sandwich-cultured human hepatocytes (SCHH). Indeed, our group recently developed a SCHH-based in vitro assay which allows for the detection of cholestatic compounds based on their ability to modulate bile acid homeostasis. Although the assay is able to distinguish cholestatic compounds from both non-hepatotoxic and non-cholestatic but hepatotoxic compounds, it was not designed to yield mechanistic insights into drug-induced changes in bile acid homeostasis. Such information is extremely valuable, especially when trying to make an informed decision regarding the cholestatic potential of a given drug. Consequently, the goal of the current doctoral thesis was to investigate human DIC by profiling in vitro bile acid disposition in SCHH and by evaluating these data using both non-compartmental analysis (NCA) techniques as well as a more advanced cellular mechanistic bile acid disposition model. In vitro data were obtained using an improved experimental setup that consisted of incubating 10 μM of the prototypical bile acid chenodeoxycholic acid (CDCA) in absence and presence of therapeutically relevant bosentan concentrations.
As cryopreserved human hepatocytes were used throughout this thesis, the aim of the first study was to evaluate whether cryopreserved cells are a viable alternative to freshly-isolated cells. The results from this study clearly showed that cryopreservation does not affect the hepatocyte's biochemical integrity nor its application potential for drug disposition studies. Moreover, transporter studies, which were conducted using fluorescent probes, indicated that the organic anion transporting polypeptide (OATP) and the multidrug resistance-associated protein 2 (MRP2) activity levels remained unaltered following cryopreservation. In the same study, disposition of telmisartan and telmisartan-glucuronide was evaluated using an in-house developed mechanistic cellular disposition model which allowed us to distinguish between the susceptibilities of the individual disposition pathways to cryopreservation. The model predicted that the relative contribution of uptake, metabolism and efflux of telmisartan and telmisartan-glucuronide remained unchanged following cryopreservation, indicating that cryopreserved hepatocytes are a suitable alternative for freshly-isolated hepatocytes. This result also represents an inspiring example of how optimization of hepatocyte cryopreservation protocols can support implementation of the 3R concept for animal experimentation. In addition to assessing the effects of cryopreservation on hepatocyte longevity and functionality, the first study conducted in this doctoral thesis aimed to establish a generic modelling framework that could be used in future studies. Indeed, in a second study, the framework was utilized to develop a mechanistic model that was able to quantitatively evaluate the effects of bosentan on CDCA and GCDCA disposition in SCHH originating from five different human liver tissue donors. The model consisted of seven compartments to which CDCA and GCDCA could distribute using both linear and non-linear kinetics. Model predictions showed that the amidation of CDCA as well as biliary efflux clearance of GCDCA decreased in presence of bosentan, in line with the non-compartmental analysis results and reports from other research groups. Interestingly, not all tested donors were affected by in vitro bosentan treatment, underlining the importance of using an in vivo-relevant in vitro model when assessing human DIC. Indeed, human hepatocytes, that originate from various donors, allow for the evaluation of interindividual differences in susceptibility to cholestatic compounds, something which cannot be achieved with for instance hepatic cell lines as they do not reflect the interindividual variability. In a last study, we aimed to expand on our study regarding bosentan-mediated cholestasis, by pursuing new insights into the role of Ro 47-8634 (O-demethylation of the phenolic methyl ether of bosentan), Ro 48-5033 (hydroxylation at the t-butyl group of bosentan) and Ro 64-1056 (combination of hydroxylation and O-demethylation of bosentan), the three known phase I metabolites of bosentan. To do so, disposition of CDCA and GCDCA in presence of bosentan was evaluated using SCHH originating from three donors which showed distinct capacities in terms of enzymes that play a role in the metabolic pathways of bosentan. As expected, the donor with greatest metabolic capacity showed increased formation of all metabolites as compared to the other donors. However, this was also the only donor which showed a significant decrease in CDCA uptake and its subsequent conjugation to GCDCA following bosentan treatment, suggesting that formation of Ro 47-8634, Ro 48-5033 and/or Ro 64-1056 could drive the observed effects. Indeed, linear regression analysis indicated that inhibition of CDCA's uptake could (at least in part) be attributed to formation of bosentan's metabolites, while inhibition of CDCA conjugation most likely resulted from interaction with the parent.
In summary, this doctoral thesis provided new insights into human DIC using an alternative experimental setup that consisted of incubating SCHH with CDCA in presence and absence of therapeutically relevant bosentan concentrations. By quantifying subtle changes in CDCA and GCDCA disposition using NCA techniques and an in-house developed cellular mechanistic disposition model, quantitative insights into the interplay of bosentan's mechanisms of toxicity were gained. More specifically, based on our results, it has become apparent that bosentan's metabolites play a role in the inhibition of bile acid uptake, leading to the prehepatic accumulation of bile acids, while, in addition, bosentan decreases the further conjugation of unconjugated bile acids to their conjugated forms.status: Publishe
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
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
- …
