Trimethylation of histone H3 on lysine 27 (H3K27me3) is a repressive posttranslational modification mediated by the histone methyltransferase EZH2. EZH2 is a component of the polycomb repressive complex 2 and is overexpressed in many cancers. In B-cell lymphomas, its substrate preference is frequently altered through somatic mutation of the EZH2 Y641 residue. Herein, we identify mutation of EZH2 A677 to a glycine (A677G) among lymphoma cell lines and primary tumor specimens. Similar to Y641 mutant cell lines, an A677G mutant cell line revealed aberrantly elevated H3K27me3 and decreased monomethylated H3K27 (H3K27me1) and dimethylated H3K27 (H3K27me2). A677G EZH2 possessed catalytic activity with a substrate specificity that was distinct from those of both WT EZH2 and Y641 mutants. Whereas WT EZH2 displayed a preference for substrates with less methylation [unmethylated H3K27 (H3K27me0):me1:me2 k cat /K m ratio = 9:6:1] and Y641 mutants preferred substrates with greater methylation (H3K27me0:me1:me2 k cat /K m ratio = 1:2:13), the A677G EZH2 demonstrated nearly equal efficiency for all three substrates (H3K27me0:me1:me2 k cat /K m ratio = 1.1:0.6:1). When transiently expressed in cells, A677G EZH2, but not WT EZH2, increased global H3K27me3 and decreased H3K27me2. Structural modeling of WT and mutant EZH2 suggested that the A677G mutation acquires the ability to methylate H3K27me2 through enlargement of the lysine tunnel while preserving activity with H3K27me0/me1 substrates through retention of the Y641 residue that is crucial for orientation of these smaller substrates. This mutation highlights the interplay between Y641 and A677 residues in the substrate specificity of EZH2 and identifies another lymphoma patient population that harbors an activating mutation of EZH2.

As the nature of work becomes more complex, teams have become necessary to ensure effective functioning within organizations. The healthcare industry is no exception. As such, the prevalence of training interventions designed to optimize teamwork in this industry has increased substantially over the last 10 years (Weaver, Dy, & Rosen, 2014). Using Kirkpatrick's (1956, 1996) training evaluation framework, we conducted a meta-analytic examination of healthcare team training to quantify its effectiveness and understand the conditions under which it is most successful. Results demonstrate that healthcare team training improves each of Kirkpatrick's criteria (reactions, learning, transfer, results; d = .37 to .89). Second, findings indicate that healthcare team training is largely robust to trainee composition, training strategy, and characteristics of the work environment, with the only exception being the reduced effectiveness of team training programs that involve feedback. As a tertiary goal, we proposed and found empirical support for a sequential model of healthcare team training where team training affects results via learning, which leads to transfer, which increases results. We find support for this sequential model in the healthcare industry (i.e., the current meta-analysis) and in training across all industries (i.e., using meta-analytic estimates from Arthur, Bennett, Edens, & Bell, 2003), suggesting the sequential benefits of training are not unique to medical teams. Ultimately, this meta-analysis supports the expanded use of team training and points toward recommendations for optimizing its effectiveness within healthcare settings. (PsycINFO Database Record

Recent results from clinical trials with the BRAF inhibitors GSK2118436 (dabrafenib) and PLX4032 (vemurafenib) have shown encouraging response rates; however, the duration of response has been limited. To identify determinants of acquired resistance to GSK2118436 and strategies to overcome the resistance, we isolated GSK2118436 drug-resistant clones from the A375 BRAF V600E and the YUSIT1 BRAF V600K melanoma cell lines. These clones also showed reduced sensitivity to the allosteric mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor GSK1120212 (trametinib).

Objective. The mainstream media tend to rely on news content that will increase risk perceptions of pandemic outbreaks to stimulate public response and persuade people to comply with preventive behaviours. The objective of this study was to examine associations between exposure to coronavirus disease (COVID-19) news, risk perceptions, and depressive symptoms.Methods. Cross-sectional data were collected from 501 participants who were ≥18 years. Exposure to COVID-19 news was assessed as our exposure variable. We screened for depression (outcome variable) with the Patient Health Questionnaire and examined the roles of risk perceptions. Multiple linear regressions and mediation analysis with 1000 bootstrap resamples were conducted.Results. Participants were 55.29% female, 67.86% White with mean age 32.44 AE 11.94 years. After controlling for sociodemographic and socio-economic factors, news exposure was positively associated with depressive symptoms b = .11; 95% confidence interval (95%CI) = 0.02-0.20. Mediation analysis showed that perceived vulnerability to COVID-19 mediated 34.4% of this relationship (b = .04; 95%CI = 0.01-0.06).Conclusion. Perceived vulnerability to COVID-19 can serve as a pathway through which exposure to COVID-19 news on mainstream media may be associated with depressive symptoms. Based on our findings, we offered recommendations for mediahealth partnership, practice, and research.