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EPZ-6438/GRag combination increases EPZ-6438 sensitivity in <i>EZH2</i> Y646 mutant cell lines and overcomes insensitivity in cell lines resistant to EZH2 inhibition.
No full text<p>Values in the table represent EPZ-6438 mean IC<sub>50</sub> values ± SEM (at least n = 2) for the indicated time points and dosing schedules. EPZ-6438 IC<sub>50</sub> values were not extrapolated beyond the highest and lowest doses of EPZ-6438 (1 µM, and 0.004 µM, respectively). In cases where IC<sub>50</sub> values could not be averaged due to non-extrapolated values, all replicates are listed. GRag: glucocorticoid receptor agonist, Pred: Prednisolone.</p><p>EPZ-6438/GRag combination increases EPZ-6438 sensitivity in <i>EZH2</i> Y646 mutant cell lines and overcomes insensitivity in cell lines resistant to EZH2 inhibition.</p
Combination benefit with CHOP components and EPZ-6438 in <i>EZH2</i> mutant germinal center B-cell lymphoma cell lines.
No full text<p>Combination index (CI) graphs, generated in Calcusyn, of EPZ-6438 with Mafosfamide, Doxorubicin, or Vincristine in the <i>EZH2</i> Y646F mutant cell lines WSU-DLCL2 (A–C) or SUDHL10 (D–F). The 95% confidence interval is displayed in each graph (representative of 2 biological replicates for each cell line). The fractional effect (Fa) plotted is the fraction of cell growth (inhibition) resulting from a compound treatment, calculated from the DMSO control. A) Additivity was induced for the EPZ-6438/Mafosfamide combination at a 1∶20 constant ratio (doses were 16–125 nM for EPZ-6438 and 313–2500 nM for Mafosfamide). B) Synergy was induced for the EPZ-6438/Doxorubicin combination at a 50∶1 constant ratio (doses were 16–500 nM for EPZ-6438 and 0.3–10 nM for Doxorubicin). C) Additivity was induced for the EPZ-6438/Vincristine combination at a 400∶1 constant ratio (doses were 16–1000 nM for EPZ-6438 and 0.39–2.5 nM for Vincristine). D) Additivity was induced for the EPZ-6438/Mafosfamide combination at a 4∶25 constant ratio (doses were 12.5–200 nM for EPZ-6438 and 78–1250 nM for Mafosfamide). E) Additivity was induced for the EPZ-6438/Doxorubicin combination at a 10∶3 constant ratio (doses were 3–50 nM for EPZ-6438 and 0.94–15 nM for Doxorubicin). F) Additivity was shown for the EPZ-6438/Vincristine combination at an 800∶1 constant ratio (doses were 12.5–200 nM for EPZ-6438 and 15.6–250 pM for Vincristine).</p
Glucocorticoid agonists enhance potency of EPZ-6438 in <i>EZH2</i> mutant and wild-type germinal center B cell lymphoma.
No full text<p>Combinations of EPZ-6438 with Prednisolone or Dexamethasone in WSU-DLCL2 <i>EZH2</i> mutant (A, B) and DOHH2 <i>EZH2</i> wild-type (C, D) GCB lymphoma cell lines, respectively. All dose response plots were generated in Graphpad Prism and curves fitted to a four-parameter model with variable slope (2 biological replicates). Doses of EPZ-6438 ranged from 15.6–1000 nM, doses of Prednisolone ranged from 7.8–1000 nM, and doses of Dexamethasone ranged from 0.8–100 nM. A, B) Potency of EPZ-6438 was increased with Prednisolone or Dexamethasone in <i>EZH2</i> mutant WSU-DLCL2 cells. C, D) EPZ-6438 showed no anti-proliferative effect as a single agent in DOHH2 <i>EZH2</i> wild-type cells, therefore the potency shift of Prednisolone or Dexamethasone was measured. The potency of Prednisolone or Dexamethasone was increased with addition of EPZ-6438 in DOHH2 cells.</p
Supplementary Figures 1 - 6 from Selective Inhibition of EZH2 by EPZ-6438 Leads to Potent Antitumor Activity in <i>EZH2</i>-Mutant Non-Hodgkin Lymphoma
No full textPDF file - 811K, Fig. S1. Effects of EPZ-6438 on Gene Promoter H3K27 Methylation, Recruitment of PRC2 Components to Gene Promoters, and Cell Cycle, in WSU-DLCL2 Cells. Fig. S2: Effects of EPZ-6438 on Gene Expression in EZH2 Mutant Lymphoma Cell Lines. Fig. S3: Pharmacokinetic Profiles of EPZ-6438 in Rats and Mice. Fig. S4: EPZ-6438 Compound Levels in Plasma and WSU-DLCL2 Xenograft Tumor Homogenates from Mice Dosed for 7 or 28 Days. Fig. S5: In vivo Effects of EPZ-6438 in Lymphoma Xenograft Models. Fig. S6: Body Weights of Mice during Xenograft Efficacy Studies.</p
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
Domain-focused CRISPR genetic screening identifies an EZH2 mutant allele that is resistant to the drug EPZ-6438.
No full text(A) Schematic of EZH2 protein domain. A library of 66 sgRNAs was designed targeting the KMT domain of EZH2. The EZH2 inhibitor EPZ-6438 inhibits the KMT function. (B) CRISPR indel mutagenesis genetic screening identified EZH2 mutants resistant to EPZ-6438 treatment. RN2c cells were treated with 5 uM EPZ-6438 at day 3 post-transduction, at which point a fraction of the cells was harvested and used as a reference time point (day 0). At day 42, an EPZ-6438 resistant sgRNA+/GFP+ population was identified, harvested, and saved for subsequent deep sequencing experiments. (C) Pie charts of the relative abundance for individual 66 sgRNAs at indicated time points. Each slice represents the abundance of a single sgRNA. At day 0 (left), all 66 sgRNAs targeting the EZH2 KMT domain were detected at roughly equal abundance. At day 42 (right), EZH2 sgRNA #52 dominated the population, representing >95% of the GFP+ cells. (D) Nucleotide and protein sequence diagram of the wild-type and EZH2 mutation induced by sgRNA #52 CRISPR mutagenesis under the selection pressure of EPZ-6438. The indel mutations were observed in the exon 17 of EZH2 flanking the sgRNA cut site. Indel mutations were observed in exon 17 of EZH2 flanking the sgRNA cut site. The indel mutation corresponded to a TR to KK mutation from residue 678. (E) The effect of ectopic overexpression of EZH2 wild-type or TR683KK mutant on RN2c cell proliferation under the treatment of EPZ-6438. The RN2c cells were retrovirally transduced with wild-type or mutant human EZH2 cDNA. After a 5-day drug treatment, the relative cell accumulation corresponding to each indicated EPZ-6438 dosage was measured and normalized to the DMSO treated cells (n = 3). (F) qRT–PCR of relative mRNA expression levels in the indicated cell lines after a 5-day treatment with EPZ-5676 or DMSO. Results were normalized to Gapdh, with the relative mRNA level in the DMSO-treated cells set to 1 (n = 3). All error bars shown represent s.e.m.</p
DZNep induces stronger apoptosis at a lower concentration and within a shorter period than EPZ-6438.
No full text(A) One DZNep-resistant wild-type EZH2 cell line (HT), two DZNep-sensitive EZH2-mutated cell lines (Carnaval and KARPAS-422) and one DZNep-sensitive wild-type EZH2 cell line (BL-41) were treated with 5 μM DZNep and 5 μM EPZ-6438 for 3 days. Apoptosis was measured afterwards by flow cytometry. Data was analyzed using GraphPad Prism 5 software (GraphPad Software, California, USA) and statistical significance was determined using the Mann-Whitney U test (n = 3 biological replicates). (B) The same cell lines as were treated with 5 μM and 10 μM EPZ-6438 for up to 13 days. Apoptosis measurement, splitting the cells, and medium change were done on day 3, day 6, day 10 and day 13. Fig 5A and 5B are shown as mean plus SD from three biological replicates.</p
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