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A mechanistic study of how adenovirus infection alters the expression and function of hepatic cytochrome P450 3A
Get PDFtextRecombinant adenoviruses, commonly used in gene therapy and vaccine applications, compromise the expression and function of hepatic CYP3A for 14 days. When given with docetaxel (DTX), plasma clearance of DTX (3.38 ± 0.22 l/kg.h) was significantly lower than those given DTX alone (6.41 ± 1.10 l/kg.h). The area under the plasma concentration-time curve of DTX in rats given virus (2,987.37 ± 197.97 ng/ml.h) was significantly greater than those given drug alone (1,666.59 ± 317.04 ng/ml.h). The virus extended the half-life of DTX three-fold. This may explain why adenoviral vectors improve chemotherapy. PEGylation of the virus reduced interleukin-6 (IL-6), IL-12, tumor necrosis factor alpha (TNF-α), aspartate transaminase (AST) and lactate dehydrogenase (LDH) levels in mice and non-human primates. PEGylation dramatically reduced transduction efficiency of virus in the baboon liver and did not alter hepatic transgene expression in the mouse. Unmodified and PEGylated virus (3 x 1012 vp/kg) reduced hepatic CYP3A4 protein by 60% and 40%, respectively 96 hours after virus administration. Catalytic activity was decreased by 55% and 45% with respect to an untreated control by the native and PEGylated viruses respectively. This suggests that changes in hepatic CYP3A during infection is not entirely due to the immune response and these observed effects most likely occur in humans. The effects of adenovirus on hepatic CYP3A expression and function in mice, however, resolved at a faster rate than that in baboons. HC-04 cells are a suitable in vitro model to study virus infection and hepatic CYP3A function. A panel of adenoviruses inhibited CYP3A catalytic activity and induced changes in expression and distribution of retinoid X receptor alpha (RXRα), pregnane X receptor (PXR) and constitutive androstane (CAR) receptors. Virus (1.5 x 1011 vp) inhibited CYP3A in the mouse. When the ability of the virus to bind to integrins was removed, changes in CYP were not detected. Treatment with a RGD peptide, that binds to integrins, reduced CYP3A activity in a manner similar to the virus. Silencing of β3 and β5 integrins also resolved changes in CYP3A activity during infection, suggesting that simple engagement of integrin receptors can initiate changes in CYP3A.Pharmaceutical Science
อิริโนทีแคน ในมุมมองเภสัชพันธุศาสตร์ Irinotecan: Pharmacogenetic Perspective
Get PDFอิริโนทีแคนเป็นยาเคมีบำบัดที่ใช้ในการรักษามะเร็งหลายชนิด ได้แก่ มะเร็งลำไส้ใหญ่และทวารหนัก มะเร็งปอด มะเร็งตับอ่อน ยามีลักษณะเป็น prodrug ที่ต้องผ่านกระบวนการไฮโดรไลซิสล์ (hydrolysis) เป็น 7-ethyl-10-hydroxy-camptothecin (SN-38) ซึ่งเป็นสารที่มีฤทธิ์ทางเภสัชวิทยา และถูกเปลี่ยนแปลงผ่านกระบวนการ glucuronidation ซึ่งจะถูกกำจัดออกจากร่างกายผ่านทางน้ำดีเป็นหลัก ยาออกฤทธิ์โดยการยับยั้งการทำงานของเอนไซม์ topoisomerase I ผลข้างเคียงที่สำคัญคืออาการท้องเสียถ่ายเหลวและภาวะเม็ดเลือดขาวต่ำ ด้วยภาวะพหุสัณฐานทางพันธุกรรมของกลุ่มยีนที่เกี่ยวข้องกับเภสัชจลนศาสตร์ของยา เช่น SLCO1B1, UGT1A, CYP3A และ ABC ส่งผลให้การตอบสนองต่อยาและอาการไม่พึงประสงค์ของผู้ป่วยแต่ละรายแตกต่างกัน โดยเฉพาะอย่างยิ่ง UGT1A1*28 และ UGT1A1*6 ซึ่งส่งผลให้อาการท้องเสียถ่ายเหลวและภาวะเม็ดเลือดขาวต่ำเกิดได้มากขึ้น ดังนั้นการตรวจคัดกรองทางพันธุศาสตร์จึงมีความสำคัญ ทั้งนี้จะต้องคำนึงถึงค่าใช้จ่ายและประสิทธิผลในการตรวจคัดกรอง บทความนี้จึงมีวัตถุประสงค์ในการทบทวนวรรณกรรมที่เกี่ยวข้องกับยาอิริโนทีแคนในมุมมองด้านเภสัชพันธุศาสตร์ เพื่อให้บุคลากรทางการแพทย์นำไปประยุกต์ใช้ในการดูแลผู้ป่วยที่ได้รับยาอิริโนทีแคนได้อย่างเหมาะสม คำสำคัญ: อิริโนทีแคน, เภสัชพันธุศาสตร์, พหุสัณฐานIrinotecan is a chemotherapeutic drug used in many cancers, including colorectal cancer, lung cancer, and pancreatic cancer. It is a prodrug that is hydrolyzed into 7-ethyl-10-hydroxy-camptothecin (SN-38), an active metabolite, which is further metabolized by glucuronidation and excreted mainly into the biliary system. Its primary mechanism is inhibiting topoisomerase I. There are many adverse effects including diarrhea and neutropenia. There are many genetic polymorphisms of enzymes and transporters involved in pharmacokinetics of irinotecan such as SLCO1B1, UGT1A, CYP3A, and ABC, leading to individual variability in drug efficacy and adverse effects. It is known that UGT1A1*28 and UGT1A1*6 polymorphisms could increase risk of diarrhea and neutropenia. Thus, pharmacogenetics screening test may be necessary for patients receiving irinotecan. However, cost-effectiveness should also be considered. This article aims to present a review of the scientific literature on genetic polymorphisms associated with pharmacologic profile of irinotecan for healthcare personnel applications. Keywords: irinotecan, pharmacogenetics, polymorphis
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
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