1,725,282 research outputs found
The Oxindole GW-5074 Inhibits JC Polyomavirus Infection and Spread by Antagonizing the MAPK-ERK Signaling Pathway
No full textABSTRACT JC polyomavirus (JCPyV) is a ubiquitous, double-stranded DNA virus that causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML) in immunocompromised patients. Current treatments for PML are limited to immune reconstitution, and no effective antivirals exist. In this report, we show that the oxindole GW-5074 (3-(3,5-dibromo-4-hydroxybenzylidene)-5-iodoindolin-2-one) reduces JCPyV infection in primary and immortalized cells. This compound potently inhibits virus spread, which suggests that it could control infection in PML patients. We demonstrate that GW-5074 inhibits endogenous ERK phosphorylation, and that JCPyV infection in GW-5074-treated cells cannot be rescued with ERK agonists, which indicates that the antiviral mechanism may involve its antagonistic effects on MAPK-ERK signaling. Importantly, GW-5074 exceeds thresholds of common pharmacological parameters that identify promising compounds for further development. This MAPK-ERK antagonist warrants further investigation as a potential treatment for PML. IMPORTANCE Human polyomaviruses, such as JCPyV and BKPyV, cause significant morbidity and mortality in immunocompromised or immunomodulated patients. There are no treatments for polyomavirus-induced diseases other than restoration of immune function. We discovered that the oxindole GW-5074 potently inhibits infection by both JCPyV and BKPyV. Further optimization of this compound could result in the development of antiviral therapies for polyomavirus-induced diseases
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
The Non-Steroidal Mineralocorticoid Receptor Antagonist KBP-5074 Limits Albuminuria and has Improved Therapeutic Index Compared With Eplerenone in a Rat Model With Mineralocorticoid-Induced Renal Injury
Get PDFThe therapeutic indices (TIs) and efficacy of the non-steroidal mineralocorticoid receptor antagonist (MRA) KBP-5074 and steroidal MRA eplerenone were evaluated in a uninephrectomized Sprague Dawley rat model of aldosterone-mediated renal disease. In two parallel studies, rats were placed on a high-salt diet and received aldosterone by osmotic mini-pump infusion over the course of 27 days. The urinary albumin-to-creatinine ratio (UACR) was evaluated after 7, 14, and 26 days of treatment. Serum K+ was evaluated after 14 and 27 days of treatment. Urinary Na+, urinary K+, and urinary Na+/K+ ratio were evaluated after 7, 14, and 26 days of treatment. The TI was calculated for each drug as the ratio of the concentration of drug producing 50% of maximum effect (EC50) for increasing serum K+ to the EC50 for lowering UACR. The TIs were 24.5 for KBP-5074 and 0.620 for eplerenone, resulting in a 39-fold improved TI for KBP-5074 compared with eplerenone. Aldosterone treatment increased UACR, decreased serum K+, and decreased urinary Na+ relative to sham-operated controls that did not receive aldosterone infusion in both studies, validating the aldosterone/salt renal injury model. KBP-5074 prevented the increase in UACR at 0.5, 1.5, and 5 mg/kg BID while eplerenone did so only at the two highest doses of 50 and 450 mg/kg BID. Both KBP-5074 and eplerenone blunted the reduction in serum K+ seen in the aldosterone treatment group, with significant increases in serum K+ at the high doses only (5 mg/kg and 450 mg/kg BID, respectively). Additionally, the urinary Na+ and Na+/K+ ratio significantly increased at the middle and high doses of KBP-5074, but only at the highest dose of eplerenone. These results showed increased TI and efficacy for KBP-5074 compared with eplerenone over a wider therapeutic window
Abstract 5074: Elevated serum free light chains and risk of non-Hodgkin lymphoma and the subtype follicular lymphoma in a prospective cohort study
No full textAbstract
Background: Serum free light chains (FLC) are plausible biomarkers associated with risks of Hodgkin and non-Hodgkin lymphoma (NHL) or its subtypes.
Methods: We investigated the relationship between free light chains and the risks of non-Hodgkin lymphoma (NHL) with a particular focus on two major subtypes - diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) using samples from the prospective Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Kappa and lambda free light chains were analyzed in 292 incident NHL cases [including 62 DLBCL, 45 FL and 122 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) cases] and 292 controls individually-matched to cases on age, sex, race, study center, and date of baseline blood draw. Conditional logistic regression was performed to compute the odds ratios (ORs) and 95% confidence intervals (CIs). Impact of follow-up time from blood collection to case diagnosis was evaluated by stratifying on 1-4 and 5-10 years of follow-up in cases and the matched controls.
Results: Elevated kappa and/or lambda FLC above the upper limit of normal (ULN) were found to be significantly associated with risks of overall NHL [OR(95% CI): 1.74(1.04-2.90)]. Further analysis on risk of NHL by FLC divided into quartiles based on the distribution in controls showed a stronger dose-response relationship with lambda FLC (ptrend=0.034, adjusted for kappa FLC) than kappa FLC (ptrend=0.15, adjusted for lambda FLC). Lambda FLC also showed a stronger relationship with risk of NHL in 5-10 follow-up years [OR(95% CI): 3.11(1.26-7.66) and 3.58(1.36-9.40) for the second highest and the highest vs. lowest quartile, respectively, ptrend=0.0097, adjusted for kappa FLC] in contrast to 1-4 years (ptrend=0.95, adjusted for kappa FLC). Though the clinical definition of abnormal level did not show an association with FL, likely due to small numbers, there was a strong dose-response relationship between quartiles of lambda FLC and risk of FL [OR(95% CI) for highest vs. lowest quartile: 14.51(2.58-81.54), ptrend=0.0054]. No significant associations were observed between FLC and DLBCL. We also found that elevated kappa FLC was associated with CLL/SLL [OR(95% CI) for highest vs. lowest quartile: 1.92(0.85-4.35), ptrend=0.019], consistent with findings from a previous report from this study.
Conclusion: These findings suggest that immune activation precedes development of clinically apparent FL.
Citation Format: Wei Hu, Ola Landgren, Bryan Bassig, Mark Purdue, Eric Engels, Qing Lan, Nathaniel Rothman. Elevated serum free light chains and risk of non-Hodgkin lymphoma and the subtype follicular lymphoma in a prospective cohort study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5074. doi:10.1158/1538-7445.AM2014-507
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
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