1,720,956 research outputs found
Alleviating Irinotecan-Induced Diarrhea Using Locally Bioavailable Naturally Occurring Flavonoids
Get PDFChemotherapy-induced diarrhea is a frequent side effect that occurs with several chemotherapeutic agents. However, it is an understudied area in the management of cancer. This concern is significant with irinotecan, a camptothecin derivative. Irinotecan hydrochloride (CPT-11) is a prodrug that is hydrolyzed to SN-38, a potent topoisomerase 1 inhibitor used as the first-line agent for the treatment of metastatic colorectal cancer. However, there is a concern regarding gastrointestinal toxicity, especially diarrhea. Many patients have reported experiencing diarrhea, and severe diarrhea episodes (grades 3 and 4) have been recorded in about 40 % of patients (J. J. Lee & Sun, 2016). Several medications have been used to attenuate the diarrhea episodes, ranging from nonpharmacological such as using probiotics, glutamine, and activated charcoal, to pharmacological approaches, such as loperamide and octreotide, and diphenoxylate-atropine (Koselke, Elizabeth; Kraft, 2012). Yet, the challenge persists as patients are administered this chemotherapeutic agent; irinotecan does not seem to respond to these anti-diarrheal medications. Researchers have well studied the mechanism and disposition of the prodrug irinotecan; after parenteral administration of irinotecan, it is hydrolyzed by carboxylesterase enzyme to the active moiety SN-38 which is further conjugated to the inactive metabolite SN-38G in the presence of UGT. However, this conjugated form of the drug SN-38G can be deconjugated back to the active drug SN-38 in the presence of β-GUS, produced in the intestine. Thus, constant accumulation of the active drug in the intestinal lumen results in intestinal epithelial injury leading to severe diarrhea. Therefore, this study aims to utilize locally bioavailable naturally occurring flavonoids (wogonin and chrysin) to alleviate irinotecan-induced diarrhea. Before starting the experimental plan, we had to establish a diarrhea model. Firstly, we fed the mouse with regular diets for two weeks; after that, we administered CPT-11 at doses of 50 mg/kg, 60 mg/kg, and 75 mg/kg. However, the animals experienced only grade 1 and 2 diarrhea at those doses. We then decided to change their animal feed to a special diet, which has been reported to contain fewer phytoestrogens and fibers. We repeated similar doses, and at 75 mg/kg, the animals had severe diarrhea (grade 4); thus, we established the diarrhea model at 75 mg/kg dose. Prior to the administration of CPT-11, the animals were divided into three groups, naïve (blank), control (irinotecan-only), and treatment group (irinotecan and oral flavonoids). The treated group was pretreated with oral gavage of wogonin/chrysin at 100 mg/kg per day for three days before co-administering with CPT-11. CPT-11 was administered intraperitoneally (I.P) to mice at a dose of 75 mg/kg per day for six consecutive days as a bolus injection, and then the disease activity indexes (i.e., body weight, diarrhea score, and survival analysis) were monitored. GI tissues were also collected on day 4 (before diarrhea) to quantitate tissue drug concentrations of SN-38 and SN-38G using LC-MS/MS, alongside histological evaluation and using enzyme-linked immune sorbent assay (ELISA) to document inflammatory markers. In addition, a xenograft mouse model study was done using immunocompromised nude mice to evaluate the possible drug-drug interaction of the oral flavonoids in the anti-tumor activity of CPT-11. Oral flavonoids (wogonin/chrysin) alleviated irinotecan-induced diarrhea damage by reducing weight loss (steady body weight) and diarrhea score (grade 1) and attenuating mucositis in the small intestine and colon. The chemotherapy-only administered group experienced severe diarrhea (grade 4) and weight loss of about a 20 % decrease. Similarly, with the survival analysis, the oral flavonoids treated group all survived (100 %) both male and female, but in the irinotecan group, only 40 % of female and 60 % of male mice survived. Histological analysis confirmed that the oral flavonoids prevented short, scanty, and denuded villi in the ileum and colon. Moreover, oral flavonoid treatment mitigated irinotecan-induced oxidative stress by downregulating IL-1β, IL-6, IL-18, TNFα, and IFNα. Compared with the control group (irinotecan only), the oral flavonoid groups (irinotecan co-administered) decreased the expression of IL-1β by 2-folds in the small intestine and 1.5 folds in the colon. With IL-6, we also observed a similar trend in both small intestine and colon. Interestingly, the expression of IL-18 was significantly downregulated in the small intestine, with almost a 4-fold decrease and a 2-fold decrease in the colon. The expressions of TNFα and IFNα were downregulated considerably, with about a 2-fold decrease in the oral flavonoid-treated group showing promising potential in reducing the expression of inflammatory cytokines in irinotecan-exposed mice. To evaluate the epithelial tight junction barrier, we use an ELISA kit to detect the expression of tight junction proteins ZO-1 and occludin. We observed that the oral flavonoids prevented the disruption of the tight junction ZO-1 and occludin, especially in the small intestine, in about a 2-folds increase. Having determined that the oral flavonoids significantly impacted the disease activity index, inflammatory cytokines, and tight junction proteins in irinotecan-exposed mice, we decided to see if the coadministration of oral flavonoids and irinotecan could impact the efficacy of the chemotherapy agent. We established a xenograft mouse model using immunocompromised nude mice. We inoculated the nude mice with 2 million cells/mL of HT-29 colon cell subcutaneously into their upper right limb, and when the tumor-bearing mice tumor growth was 150 mm^3, we started the coadministration of the irinotecan and oral flavonoids for seven days. After the study, we excised the liver, small intestine, and colon tissues. The results showed that with the oral flavonoids treatment both at low (50 mg/kg) and high (75 mg/kg) doses of irinotecan, there was no significant impact of wogonin/chrysin on the PK of irinotecan on day eight, as the AUC was within ±1 fold for the control and the treated group. We randomly excised the tumor after 6 hours of dose administration of irinotecan, and we observed no significant difference between the irinotecan-only group and the treated group. The drug concentration of CPT-11 and SN-38 was within ±1 fold for the control and the treated group. Also, the oral flavonoids did not interfere with the anti-tumor activity of CPT-11 as the tumor volumes on the last day of study for irinotecan only, low treated dose, and the high treated dose was 1133 mm^3, 550 mm^3, and 578 mm^3, respectively for the female group, while for the male group was 436 mm^3, 621 mm^3 and 368 mm^3 respectively. This result shows that the female group responded to both irinotecan and oral flavonoids, inferring some gender differences. Interestingly, the oral flavonoids-treated group showed no significant difference to the control group (irinotecan only) in SN38-G tissue drug concentration in the duodenum and jejunum as the oral flavonoid-treated group showed promising potential to alleviate irinotecan-induced diarrhea. In conclusion, we can clearly show that the upregulation of inflammatory cytokines and tight junctions proteins upregulation are significant factors in the development of irinotecan-induced diarrhea, and its manipulation can result in alleviating irinotecan-induced diarrhea by using locally bioavailable naturally occurring flavonoids. This knowledge can be helpful in the management of chemotherapy-induced diarrhea by mitigating this dose-limiting gastrointestinal toxicity
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
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
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
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
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