Multi-Log Cytotoxicity of Carbocyclic 2′-Deoxyguanosine in HSV-TK-Expressing Human Tumor Cells

Ganciclovir (GCV) is widely used as a prodrug for selective activation in tumor cells expressing herpes simplex virus thymidine kinase (HSV-TK) because of its ability to induce multi-log cytotoxicity to HSV-TK-expressing as well as nonexpressing bystander cells. We now report that another substrate for HSV-TK, D-carbocyclic 2′-deoxyguanosine (CdG), induces multi-log cytotoxicity in HSV-TK-expressing and bystander cells at concentrations ≤3 μM. We have compared the cytotoxicity and cell cycle effects of CdG to that observed with GCV in two human tumor cell lines. The results demonstrated that cytotoxicity of CdG was similar to that of GCV in both U251 glioblastoma and SW620 colon carcinoma cells that stably expressed HSV-TK. In addition, CdG induced a potent bystander effect in both cell types in co-cultures consisting of HSV-TK-expressing and nonexpressing bystander (lacZ-expressing) cells at ratios of 50:50 or 10:90. Selectivity for HSV-TK-expressing compared to lacZ-expressing cells was similar for CdG and GCV in the U251 cells, however CdG was less selective than GCV in the SW620 cell lines. Despite their ability to induce multi-log cytotoxicity at similar concentrations, CdG and GCV exhibited differential effects on cell cycle progression. Cells incubated with 1 μM CdG for 24 hr accumulated in S-phase and G2/M after drug washout, and the majority of cells died prior to cell division. This contrasts with the delayed effects of 1 μM GCV that were not evident until after cell division when cells attempted S-phase for the second time. Thus, CdG is a potent cytotoxic agent that merits further investigation to determine whether it will be therapeutically effective in enzyme-prodrug therapy with HSV-TK.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63436/1/10430340252809838.pd

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document 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 consortium consisting of more than 1500 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 cover 76% of all unique PubMed Medical Subject Headings 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, Term Frequency-Inverse Document Frequency and PubMed Related Articles) 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. © The Author(s) 2019. Published by Oxford University Press