Efficacy of NS-018, a potent and selective JAK2/Src inhibitor, in primary cells and mouse models of myeloproliferative neoplasms

Aberrant activation of Janus kinase 2 (JAK2) caused by somatic mutation of JAK2 (JAK2V617F) or the thrombopoietin receptor (MPLW515L) plays an essential role in the pathogenesis of myeloproliferative neoplasms (MPNs), suggesting that inhibition of aberrant JAK2 activation would have a therapeutic benefit. Our novel JAK2 inhibitor, NS-018, was highly active against JAK2 with a 50% inhibition (IC50) of <1 n, and had 30–50-fold greater selectivity for JAK2 over other JAK-family kinases, such as JAK1, JAK3 and tyrosine kinase 2. In addition to JAK2, NS-018 inhibited Src-family kinases. NS-018 showed potent antiproliferative activity against cell lines expressing a constitutively activated JAK2 (the JAK2V617F or MPLW515L mutations or the TEL–JAK2 fusion gene; IC50=11–120 n), but showed only minimal cytotoxicity against most other hematopoietic cell lines without a constitutively activated JAK2. Furthermore, NS-018 preferentially suppressed in vitro erythropoietin-independent endogenous colony formation from polycythemia vera patients. NS-018 also markedly reduced splenomegaly and prolonged the survival of mice inoculated with Ba/F3 cells harboring JAK2V617F. In addition, NS-018 significantly reduced leukocytosis, hepatosplenomegaly and extramedullary hematopoiesis, improved nutritional status, and prolonged survival in JAK2V617F transgenic mice. These results suggest that NS-018 will be a promising candidate for the treatment of MPNs

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 research.Peer reviewe

Changes in Soil Arthropod Abundance and Community Structure across a Poplar Plantation Chronosequence in Reclaimed Coastal Saline Soil

Poplar plantations have the capacity to improve the properties of soils in muddy coastal areas; however, our understanding of the impacts of plantation development on soil arthropods remains limited. For this study, we determined the community dynamics of soil dwelling arthropods across poplar plantations of different ages (5-, 10-, and 21-years) over the course of one year in Eastern Coastal China. The total abundance of soil arthropods differed with stand development. Further, there were some interactions that involved the sampling date. On average, total abundance was highest in the 10-year-old stands and lowest in the 5-year-old stands. Total abundance exhibited strong age-dependent trends in June and September, but not in March or December. The abundance of Prostigmata and Oribatida increased in the 5- to 21-year-old stands, with the highest levels being in the 10-year-old stands. The abundance of Collembola increased with stand development; however, the stand age had no significant impact on the abundance of epedapic, hemiedaphic, and euedaphic Collembola. Order richness (Hill number q = 0) curve confidence intervals overlapped among three stand ages. Shannon and Simpson diversity (Hill numbers q = 1 and q = 2) differed between 10- and 21-year-old stand age. They showed almost similar trends, and the highest and lowest values were recorded in the 21- and 10-year-old stand ages, respectively. Permutational multivariate analysis of variance demonstrated that composition also varied significantly with the sampling date and stand age, and the 10-year-old stands that were sampled in June stood well-separated from the others. Indicator analysis revealed that Scolopendromorpha and Prostigmata were indicators in June for the 10-year-old stands, while Collembola were indicators for the 21-year-old stands sampled in September. Our results highlight that both stand development and climate seasonality can significantly impact soil arthropod community dynamics in the reclaimed coastal saline soils of managed poplar plantations