3,708 research outputs found
Pharmacology and pharmacokinetics of tazemetostat
No full textTazemetostat, a novel oral selective inhibitor of enhancer of zeste homolog 2 (EZH2), was approved by the Food and Drug Administration (FDA) in 2020 for use in patients with advanced epithelioid sarcoma or relapsed/refractory (R/R) EZH2-mutated follicular lymphoma. These indications were approved by the FDA trough accelerated approval based on objective response rate and duration of response that resulted from phase 2 clinical trials. Tazemetostat competes with S-adenosylmethionine (SAM) cofactor to inhibit EZH2, reducing the levels of trimethylated lysine 27 of histone 3 (H3K27me3), considered as pharmacodynamic marker. Tazemetostat is orally bioavailable, characterized by rapid absorption and dose-proportional exposure, which is not influenced by coadministration with food or gastric acid reducing agents. It highly distributes in tissues, but with limited access to central nervous system. Tazemetostat is metabolized by CYP3A in the liver to 3 major inactive metabolites (M1, M3, and M5), has a short half-life and is mainly excreted in feces. Drug-drug interactions were shown with moderate CYP3A inhibitors as fluconazole, leading the FDA to recommend a 50% dose reduction, while studies investigating coadministration of tazemetostat with strong inhibitors/inducers are ongoing. No dosage modifications are recommended based on renal or hepatic dysfunctions. Overall, tazemetostat is the first-in-class EZH2 inhibitor approved by the FDA for cancer treatment. Current clinical studies are evaluating combination therapies in patients with several malignancies
VDR activity is differentially affected by Hic-5 in prostate cancer and stromal cells
No full textPublished OnlineFirst May 13, 2014.
Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).Abstract not availableJoshua D. Solomon, Marjet D. Heitzer, Teresa T. Liu, Jan H. Beumer, Robert A. Parise, Daniel P. Normolle, Damien A. Leach, Grant Buchanan and Donald B. DeFranc
Quantitation of tazemetostat in human plasma using liquid chromatography–tandem mass spectrometry
No full textTo support a phase 1 trial in patients with lymphomas, we developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for tazemetostat quantitation in 20 mu L of human plasma. After protein precipitation, chromatographic separation employed a Kinetex C18 column and a gradient of 0.1% formic acid in both water and acetonitrile, during a 3-min run time. Detection was achieved using a SCIEX 6500+ tandem mass spectrometer with electrospray positive-mode ionization. Validation was based on the latest Food and Drug Administration guidance. With a stable isotopic internal standard, the assay was linear within the range of 10-5000 ng/mL and proved to be accurate (91.9%-103.7%) and precise (<4.4% imprecision). Recovery varied between 93.3% and 121.1%, and matrix effect ranged from -25.5% to -4.9%. Hemolysis, lipemia, and dilution did not impact quantitation. Plasma stability was confirmed after three freeze-thaw cycles, 24 h at room temperature, and 4 months at -80 degrees C. Incurred sample reanalysis yielded 94.4% samples within 20% difference (n = 36). External validation showed a mean bias of -11.1%. Pharmacokinetic (PK) data obtained from three patients suggested variable concentration time profiles, warranting collection of further data. The assay proved to be suitable for tazemetostat quantitation in human plasma and will support clinical studies by defining tazemetostat PKs
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe 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
Lydia H. Hart Diary
No full textDiary, 1823-1830, 1875 and loose papers 1813, 1831, and undated of Lydia H. Hart of Richmond, Virginia and later Walden, Orange County, New York. The Diary was started by Lydia H. Hart, the wife of Reverend William H. Hart, who was the rector of St. John’s Church in Richmond, VA and later St. Andrews Church in Walden, New York. Diary entries include day-to-day activities and meetings with local neighbors and church patron’s. These neighbors included Elizabeth Van Lew and her parents, which Lydia Hart writes about several times. Most dated entries also include discussion of specific bible verses or Rev. Hart’s sermons. Notable entries include a description of the funeral service for Rev. John Buchanan, former rector of St. John’s Church from 1795 to 1822. Diary entries are chronological and more frequent for 1823 and become less frequent in 1823. In 1828, Lydia Hart moved to New York and eventually to Walden, New York in May 1830.At the end of the diary entries is an entry form another author, possibly by Mary. W. Hart dated 1875. Lydia Hart died in 1831 and could not have made the entry.At the back of the diary and upside down to the diary entries are transcriptions of letters and poems of Lydia Hart’s to various newspapers and and personnel correspondence. Entries include a plea for support to the city of Richmond to take care of its ‘destitute children’, letters to the editor of local newspapers, and poems for the birth of a child or death of a patron.Loose papers include a letter dated Jan 8th 1813, a bequeath request from William H. Hart for the placement of a Tombstone for Lydia Hart, a table of contents for various letters or sermons, a letter from William Hart to a friend from Richmond, and 2 loose undated papers of unknown authorship. The letter from William Hart speaks of the events of Lydia’s death, and inquiries about events taking place in Richmond
J. H. Hofmeyr Collection index
No full textThis index describes the J. H. Hofmeyr collection and consists of a scrapbook with newspaper clippings made after the
death of Jan Hendrik Hofmeyr in 1909. Jan Hendrik Hofmeyr (1845-1909), also
known as Onze Jan, was a Cape politician. Donated by F.A. Venter, author, in 1977. Made by Miss Bam who lived in the
same boarding house as F.A. venter
Direct Shaping of Minimum and Maximum Singular Values: An H<sub>-</sub>/H<sub>∞</sub> Synthesis Approach for Fault Detection Filters
No full textThe performance of fault detection filters relies on a high sensitivity to faults and a low sensitivity to disturbances. The aim of this paper is to develop an approach to directly shape these sensitivities, expressed in terms of minimum and maximum singular values. The developed method offers an alternative solution to the H-/H∞ synthesis problem, building upon traditional multiobjective synthesis results. The result is an optimal filter synthesized via iterative convex optimization and the approach is particularly useful for fault diagnosis as illustrated by a numerical example.Team Jan-Willem van Wingerde
Does strict employment protection discourage job creation? Evidence from Croatia
No full textEmployment protection legislation in Croatia is among the most strict in Europe. Firing is difficult and costly, and flexible forms of employment are limited. Is this apparent rigidity reflected-as one would expect based on standard economic theory-in low labor market dynamics? Is job creation low and hiring limited? Is the job security of insiders achieved at the cost of outsiders not being able to enter thelabor market? The author attempts to answer these questions by examining job flows. If the employment protection legislation is binding, then job and worker turnover should be low. He shows that this is indeed the case. Hiring is limited and the average job tenure is very long in Croatia. Job destruction is low, however job creation is still lower. The result is accumulation of unemployment, in large part due to new labor market entrants not being able to find a job. The high degree of job protection also seems to strengthen the bargaining position of insiders and results in relatively high wages. So, wages in Croatia are higher than among its competitors, even after adjusting for productivity. These high labor costs are likely to contribute to limited job creation in existing firms, but also are likely to discourage the entry of-and thus job creation in-new firms. The author presents evidence that firm growth has been indeed limited in Croatia, contributing to the low employment level. The author examines other potential causes of high unemployment in Croatia (the unemployment benefit system, labor taxation, the wage structure, and skill and spatial mismatches). He argues that they do not play a substantial part in accounting for poor labor market outcomes in Croatia. The author concludes that the stringent employment protection legislation is the key labor market institution behind low job creation and high unemployment. Based on this he recommends specific measures aimed at liberalizing the labor market to foster job creation and employment.Labor Management and Relations,Labor Policies,Labor Markets,Environmental Economics&Policies,Trade Finance and Investment,Labor Markets,Labor Management and Relations,Labor Standards,Banks&Banking Reform,Environmental Economics&Policies
Author Co-Citation Analysis (ACA): a powerful tool for representing implicit knowledge of scholar knowledge workers
No full textIn the last decade, knowledge has emerged as one of the most important and valuable organizational assets. Gradually this importance caused to emergence of new discipline entitled ―knowledge management‖. However one of the major challenges of knowledge management is conversion implicit or tacit knowledge to explicit knowledge. Thus Making knowledge visible so that it can be better accessed, discussed, valued or generally managed is a long-standing objective in knowledge management. Accordingly in this paper author co- citation analysis (ACA) will be proposed as an efficient technique of knowledge visualization in academia (Scholar knowledge workers)
Towards a Flexible Author Name Disambiguation Framework
No full textsummary:In this paper we propose a flexible, modular framework for author name disambiguation. Our solution consists of the core which orchestrates the disambiguation process, and replaceable modules performing concrete tasks. The approach is suitable for distributed computing, in particular it maps well to the MapReduce framework. We describe each component in detail and discuss possible alternatives. Finally, we propose procedures for calibration and evaluation of the described system
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