ALBERT

Description: Background Entrectinib is a CNS-active, potent inhibitor of tyrosine receptor kinases A/B/C, ROS1 and anaplastic lymphoma kinase approved for use in patients with solid tumors. We describe the in vitro and clinical studies investigating potential entrectinib drug-drug interactions. Methods In vitro studies with human biomaterials assessed the enzymes involved in entrectinib metabolism, and whether entrectinib modulates the activity of the major cytochrome P450 (CYP) enzymes or drug transporter P-glycoprotein. Clinical studies investigated the effect of a strong CYP3A4 inhibitor (itraconazole) and inducer (rifampin) on single-dose entrectinib pharmacokinetics. The effect of entrectinib on sensitive probe substrates for CYP3A4 (midazolam) and P-glycoprotein (digoxin) were also investigated. Results Entrectinib is primarily metabolized by CYP3A4. In vitro, entrectinib is a CYP3A4/5 inhibitor (IC50 2 μM) and a weak CYP3A4 inducer. Entrectinib inhibited P-glycoprotein (IC50 1.33 μM) but is a poor substrate. In healthy subjects, itraconazole increased entrectinib Cmax and AUC by 73% and 504%, respectively, and rifampin decreased entrectinib Cmax and AUC by 56% and 77%, respectively. Single dose entrectinib did not affect midazolam AUC, although Cmax decreased by 34%. Multiple dose entrectinib increased midazolam AUC by 50% and decreased Cmax by 21%. Single dose entrectinib increased digoxin AUC and Cmax by 18% and 28%, respectively, but did not affect digoxin renal clearance. Conclusions Entrectinib is a CYP3A4 substrate and is sensitive to the effects of coadministered moderate/strong CYP3A4 inhibitors and strong inducers, and requires dose adjustment. Entrectinib is a weak inhibitor of CYP3A4 and P-glycoprotein and no dose adjustments are required with CYP3A4/P- glycoprotein substrates.Registration Number (Study 2) NCT03330990 (first posted online November 6, 2017) As studies 1 and 3 are phase 1 trials in healthy subjects, they are not required to be registered.

Description: Non-small cell lung cancer (NSCLC) is characterized by a high incidence of metastasis and poor survival. As epithelial–mesenchymal transition (EMT) is well recognized as a major factor initiating tumor metastasis, developing EMT inhibitor could be a feasible treatment for metastatic NSCLC. Recent studies show that triptolide isolated from Tripterygium wilfordii Hook F attenuated the migration and invasion of breast cancer, colon carcinoma, and ovarian cancer cells, and EMT played important roles in this process. In the present study we investigated the effect of triptolide on the migration and invasion of NSCLC cell lines. We showed that triptolide (0.5, 1.0, 2.0 nM) concentration-dependently inhibited the migration and invasion of NCI-H1299 cells. Triptolide treatment concentration-dependently suppressed EMT in NCI-H1299 cells, evidenced by significantly elevated E-cadherin expression and reduced expression of ZEB1, vimentin, and slug. Furthermore, triptolide treatment suppressed β-catenin expression in NCI-H1299 and NCI-H460 cells, overexpression of β-catenin antagonized triptolide-caused inhibition on EMT, whereas knockout of β-catenin enhanced the inhibitory effect of triptolide on EMT. Administration of triptolide (0.75, 1.5 mg/kg per day, ip, every 2 days) for 18 days in NCI-H1299 xenograft mice dose-dependently suppressed the tumor growth, restrained EMT, and decreased lung metastasis, as evidence by significantly decreased expression of mesenchymal markers, increased expression of epithelial markers as well as reduced number of pulmonary lung metastatic foci. These results demonstrate that triptolide suppresses NSCLC metastasis by targeting EMT via reducing β-catenin expression. Our study implies that triptolide may be developed as a potential agent for the therapy of NSCLC metastasis.

Description: Silicosis caused by inhalation of silica particles leads to more than ten thousand new occupational exposure-related deaths yearly. Exacerbating this issue, there are currently few drugs reported to effectively treat silicosis. Tetrandrine is the only drug approved for silicosis treatment in China, and despite more than decades of use, its efficacy and mechanisms of action remain largely unknown. Here, in this study, we established silicosis mouse models to investigate the effectiveness of tetrandrine of early and late therapeutic administration. To this end, we used multiple cardiopulmonary function test, as well as markers for inflammation and fibrosis. Moreover, using single cell RNA sequencing and transcriptomics of lung tissue and quantitative microarray analysis of serum from silicosis and control mice, our results provide a novel description of the target pathways for tetrandrine. Specifically, we found that tetrandrine attenuated silicosis by inhibiting both the canonical and non-canonical NLRP3 inflammasome pathways in lung macrophages. Taken together, our work showed that tetrandrine yielded promising results against silicosis-associated inflammation and fibrosis and further lied the groundwork for understanding its molecular targets. Our results also facilitated the wider adoption and development of tetrandirne, potentially accelerating a globally accepted therapeutic strategy for silicosis.

Description: 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) is widely used as a crosslinker for fluorescence labeling of protein in the fields of biochemistry and food analysis. Many natural polysaccharides often contain some proteins or peptides that are very low in content but play a vital role in their biological function as well as technical applications. Determination of these low-content proteinaceous matters requires a highly sensitive and selective method. In this study, a methodological approach for investigations of the presence of proteinaceous material over the molar mass distribution (MD) of polysaccharides was developed using gum acacia (GA) as a model polysaccharide. EDC fluorescence-labeling method was modified by changing the pH (7, 9, and 11) of the solution for the analysis of low-content protein in food materials. Fluorescence spectroscopy and asymmetrical flow field-flow fractionation (AF4) were employed for characterizing the labeling efficiency and physiochemical properties of unlabeled and fluorescence-labeled GA. AF4 provided molar mass (M) and the radius of gyration (rG) of arabinogalactan (AG) and arabinogalactan protein complex (AGP) and determined the presence of proteinaceous matter over the MD. The labeling efficiencies of GA at pH 7, 9, and 11 determined by fluorescence spectroscopy were 56.5, 68.4, and 72.0%, respectively, with an increment of 15.5% when pH was increased from 7 to 11. The modified EDC fluorescence-labeling method allows highly sensitive and selective analysis of low-content proteinaceous matters and their distribution in natural polysaccharides. Graphical abstract

Description: UV/Vis absorption spectroelectrochemistry is a very promising analytical technique due to the complementary information that is simultaneously obtained from electrochemistry and spectroscopy. In this work, this technique is used in a parallel configuration to study the oxidation of folic acid in alkaline medium. Herein, UV/Vis absorption spectroelectrochemistry has been used to detect both the oxidation products and the folic acid consumed at the electrode/solution interface, allowing us to develop an analytical protocol to quantify vitamin B9 in pharmaceutical tablets. Linear ranges of three orders of magnitude have been achieved in basic medium (pH = 12.9), obtaining high repeatability and low detection limits. The spectroelectrochemical determination of folic acid in pharmaceutical tablets at alkaline pH values is particularly interesting because of the changes that occur in the optical signal during the electrochemical oxidation of FA, providing results with very good figures of merit and demonstrating the utility and versatility of this hyphenated technique, UV/Vis absorption spectroelectrochemistry.

Description: The International Prostate Symptom Score (IPSS), the quality of life (QoL) score, and the benign prostatic hyperplasia impact index (BII) are three different scales commonly used to assess the severity of lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH-LUTS). Based on a phase II clinical trial including 403 patients with moderate to severe BPH-LUTS, the objectives of this study were to (i) develop traditional pharmacometric and bounded integer (BI) models for the IPSS, QoL score, and BII endpoints, respectively; (ii) compare the power and type I error in detecting drug effects of BI modeling with traditional methods through simulation; and (iii) obtain quantitative translation between scores on the three abovementioned scales using a BI modeling framework. All developed models described the data adequately. Pharmacometric modeling using a continuous variable (CV) approach was overall found to be the most robust in terms of type I error and power to detect a drug effect. In most cases, BI modeling showed similar performance to the CV approach, yet severely inflated type I error was generally observed when inter-individual variability (IIV) was incorporated in the BI variance function (g()). BI modeling without IIV in g() showed greater type I error control compared to the ordered categorical approach. Lastly, a multiple-scale BI model was developed and estimated the relationship between scores on the three BPH-LUTS scales with overall low uncertainty. The current study yields greater understanding of the operating characteristics of the novel BI modeling approach and highlights areas potentially requiring further improvement.

Description: We study the impact of journal ranking systems on publication outlet choice. We investigate the publication behavior of UK-based scholars registered on IDEAS/RePEc and analyze the publication outcomes of their academic work uploaded to the repository. Our estimates suggest that authors strategically choose outlets to maximize their publication scores. Our identification strategy is based on exploiting the change in the British ABS journal ranking in 2015. Working papers written before the 2015 ABS journal ranking change are significantly less likely to be published in ex-post downgraded journals. The effect cannot be attributed to the overall change in journal quality.

Description: Several scientists publish journal papers on more than only a single scientific field or subfield. However, in evaluating the impact of publications of individuals their all scientific publications are taken into account, in general. In this paper a new method, namely the part-set method is introduced for assessing papers according to the respective fields and forming a cumulative impact index. In assessing publications of scientists, elite set indicators (e.g. h-index, g-index, top percentage indices, π-index) are preferably used recently. For obtaining elite sets, we may apply inside standards, i.e. values derived from the number of papers and citations in the set analysed, or field (outside) standards taking into account the same factors referring to all papers on the corresponding field. For model calculations some scientometricians are selected who publish papers not only on scientometrics but also on other (e.g. physics, chemistry, medicine, etc.) fields. Consequently, their papers form complex sets of which part-sets may show different bibliometric features. In this publication, the number of papers in the elite set of the scientometric part-set and their citations are presented using both inside and outside standards. No significant correlation was found between the number of papers in the elite sets obtained by inside and that calculated by field standards. The number of citations in the different elite sets calculated by both inside and outside standards however, significantly correlates with each other. The presented model indicates that the sum of h-index of two part-sets derived from a common complex (total) set can be equal to or higher than the h-index of the corresponding complex set. In contrast, the sum of π-index of two part-sets can be higher or lower than or equal to the π-index of the parent complex set. The model reveals that the maximum value of the sum of h-index of two part-sets belonging to the same complex set can be two times the h-index of the corresponding complex set. In evaluating total scientific impact (e.g. life-work) of publications of scientists who are active in several fields, the application of sum (or weighted sum) of the pertinent impact indices (e.g. h or π-index) obtained for the individual fields separately may be recommended instead of calculating the impact of the total set.

Description: The citations count is flawed but it still the most common way of measuring the academic impact used by scholarly journals (Impact Factor), individual researchers (h-index) and funding agencies (a proxy for quality of research). Individual papers should attract citations depending upon the importance and usefulness of the results presented. However, large enough data sets reveal that there are parameters independent of individual papers' quality that can determine an average citation rate. Here, we examine papers (4756 in total) published in six selected tribology journals in a six-year window between January 2010 and December 2015. Citations were retrieved from the Web of Science and compared with their (1) manuscript length, (2) number of authors, (3) number of affiliated institutions, (4) number of international co-authors, (5) number of cited references, (6) number of words in the title, and (7) mode of publication (open versus paid access). The results revealed that citations received by papers published in tribology journals are affected by all of these parameters. This is a significant finding for authors wishing to increase the impact of their research. This knowledge can be used effectively at the manuscript planning and writing stages to support scientific merit. We suggest that the significance of parameters not directly related to the quality of a scholarly paper will become more critical with the rise of alternative ways of measuring impact including novel generation of paper metrics (e.g., Eigenfactor, SJR), social mentions, and viral outreach.

Description: Artificial intelligence, as an emerging and multidisciplinary domain of research and innovation, has attracted growing attention in recent years. Delineating the domain composition of artificial intelligence is central to profiling and tracking its development and trajectories. This paper puts forward a bibliometric definition for artificial intelligence which can be readily applied, including by researchers, managers, and policy analysts. Our approach starts with benchmark records of artificial intelligence captured by using a core keyword and specialized journal search. We then extract candidate terms from high frequency keywords of benchmark records, refine keywords and complement with the subject category “artificial intelligence”. We assess our search approach by comparing it with other three recent search strategies of artificial intelligence, using a common source of articles from the Web of Science. Using this source, we then profile patterns of growth and international diffusion of scientific research in artificial intelligence in recent years, identify top research sponsors in funding artificial intelligence and demonstrate how diverse disciplines contribute to the multidisciplinary development of artificial intelligence. We conclude with implications for search strategy development and suggestions of lines for further research.

Description: The aim of this work was to prepare reference radon emanation sources traceable to primary standards to be used for radon-in-air as well as radon-in-water experiments. The feasibility of making stable radon emanation sources by drop deposition and chemisorption was studied. Experimental emanation coefficients for sources made by drop deposition and chemisorption ranged from 0.10 to 0.74 and from 0.18 to 0.25, respectively. These relatively low emanation coefficient values suggest that further method developments would be desirable. Proposals are made to improve chemisorption yield during source preparation and to obtain more accurate measurements on radon emanation coefficient.