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Recombinant adenoviral-meditated alterations of cytochrome P450 3A2 and 2C11
No full texttextRecombinant adenovirus serotype 5 (Ad) is a key vector extensively employed in gene therapy clinical trials and vaccine development protocols. Although this vector has a natural tropism for the liver, there is limited understanding of how Ad infection affects one of the primary hepatic processes, drug metabolism. Preliminary data investigating the effect of a single dose of 5.7 x 1012 adenovirus particles/kilogram on the hepatic cytochrome P450 enzyme system (CYP) revealed not only that significant suppression occurs following systemic administration, but also that enzymatic activity remains suppressed for 14 days. In addition to the vector dose, various components of the virus (transgene, virus gene expression and capsid-receptor interactions)
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could be responsible for the observed suppression in hepatic CYP. Investigation of treatment (5.7 x 1010-5.7 x 1012 vp/kg) of a recombinant vector expressing a non-therapeutic transgene significantly suppressed CYP3A2 expression (mean value of 39%) and function (mean value of 41%) four days after administration. Doses in the range of 5.7 x 106-5.7 x 109 vp/kg did not alter CYP3A2 expression or function, but significantly increased CYP2C11 one day after administration. Expression levels (mean value of 88%) and activity levels (mean value of 93%) were markedly increased. Doses of vectors expressing self transgenes and no transgene revealed that CYP is altered regardless of the transgene cassette used. Treatment with the Null vector, a vector without a transgene cassette, significantly altered CYP3A2 activity throughout the duration of the study (14 days) and CYP2C11 activity at early time points (6 and 24 hours). In addition, modifications at the molecular and macromolecular level do not eliminate aberrations in CYP following Ad administration. Treatment with an adenoviral vector lacking all viral genes markedly suppressed both CYP isoforms, at the transcriptional and translational level, for 14 days. The data presented here suggest that the binding of Ad to cell surface receptors and subsequent internalization of the virion significantly alters posttranslational CYP function, possibly through altered signal transduction pathways. In addition these studies show that shifts in cellular machinery to support the production of the transgene product, and not the transcription of viral genes, also repress CYP transcription.Pharmaceutical Science
Large expert-curated database for benchmarking document similarity detection in biomedical literature search
No full textDocument recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH (RELISH) consortium consisting of more
than 1,500 scientists from 84 countries, who have collectively annotated the relevance of over 180,000 PubMed-listed articles with regard to their
respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The
collected data covers 76% of all unique PubMed Medical Subject Headings (MeSH) descriptors. No systematic biases were observed across different experience levels, research fields, or time spent on annotations. More
importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three
representative baseline methods used to generate recommended articles for evaluation [Okapi Best Matching 25 (BM25), Term Frequency–Inverse Document Frequency (TF-IDF), and PubMed Related Articles (PMRA)] had similar overall performances. Additionally we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind-testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical science
