Modulation of enhancer looping and differential gene targeting by Epstein-Barr virus transcription factors directs cellular reprogramming

Epstein-Barr virus (EBV) epigenetically reprogrammes B-lymphocytes to drive immortalization and facilitate viral persistence. Host-cell transcription is perturbed principally through the actions of EBV EBNA 2, 3A, 3B and 3C, with cellular genes deregulated by specific combinations of these EBNAs through unknown mechanisms. Comparing human genome binding by these viral transcription factors, we discovered that 25% of binding sites were shared by EBNA 2 and the EBNA 3s and were located predominantly in enhancers. Moreover, 80% of potential EBNA 3A, 3B or 3C target genes were also targeted by EBNA 2, implicating extensive interplay between EBNA 2 and 3 proteins in cellular reprogramming. Investigating shared enhancer sites neighbouring two new targets (WEE1 and CTBP2) we discovered that EBNA 3 proteins repress transcription by modulating enhancer-promoter loop formation to establish repressive chromatin hubs or prevent assembly of active hubs. Re-ChIP analysis revealed that EBNA 2 and 3 proteins do not bind simultaneously at shared sites but compete for binding thereby modulating enhancer-promoter interactions. At an EBNA 3-only intergenic enhancer site between ADAM28 and ADAMDEC1 EBNA 3C was also able to independently direct epigenetic repression of both genes through enhancer-promoter looping. Significantly, studying shared or unique EBNA 3 binding sites at WEE1, CTBP2, ITGAL (LFA-1 alpha chain), BCL2L11 (Bim) and the ADAMs, we also discovered that different sets of EBNA 3 proteins bind regulatory elements in a gene and cell-type specific manner. Binding profiles correlated with the effects of individual EBNA 3 proteins on the expression of these genes, providing a molecular basis for the targeting of different sets of cellular genes by the EBNA 3s. Our results therefore highlight the influence of the genomic and cellular context in determining the specificity of gene deregulation by EBV and provide a paradigm for host-cell reprogramming through modulation of enhancer-promoter interactions by viral transcription factors

Brokering Trust to Enhance Leadership: A Self-Monitoring Approach to Leadership Emergence

What kind of person is likely to emerge as an informal leader in the workplace? Experimental research shows that high self-monitors—who tend to adjust their attitudes and behaviors to the demands of different situations—emerge as informal leaders in temporary groups. By contrast, low self-monitors—who tend to be true to themselves in terms of consistency in attitudes and behaviors across different situations—are less likely to emerge as leaders. But this prior research does not address the criticism that the emergence of high self-monitors as leaders represents ephemeral impression management in the context of laboratory experiments. To address this issue, we collected and analyzed data from a 116-member high-technology firm. Our results show that self-monitoring is related not only to leadership emergence, but also to the provision of advice to co-workers. Further, people who occupied brokerage positions (being trusted by those who did not trust each other) tended to be seen as leaders if they were high rather than low self-monitors. From these results, we build a picture of the high self-monitoring emergent leader as someone who notices problems and ameliorates them through the provision of advice and the brokerage of relationships across social divides. The occupation of a structurally advantageous position may well be more advantageous for some (i.e., high self-monitors) relative to others (i.e., low self-monitors)

Abstract P3-08-07: Survivorship care planning – When is intervention most effective?

Abstract Introduction: Cancer survivors experience late and long-term effects, though post-treatment follow-up is generally focused on monitoring for disease recurrence. Survivors may hesitate to volunteer symptom concerns for fear of burdening their providers with ‘insignificant complaints.’ Survivorship care plans (SCPs) have been recommended by the IOM and mandated by the American College of Surgeons as a means of improving outcomes and enhancing communication between survivors and providers. To date, however, little research has evaluated the effect of SCPs on patient-reported outcomes, and less has examined the optimal timing of SCP interventions. This study examined symptom burden, quality of life (QoL), health concerns, use of SCP materials and differences by time since diagnosis in a pre-post quasi-experimental design. Method: 139 breast cancer survivors completed assessments prior to and 3 months following a structured SCP visit at one of seven LIVESTRONG™ affiliated survivorship programs. Measures at both time points included global and individual symptom burden, QoL (SF-12), cancer-specific and general health worry, personal survivorship concerns, and family/genetic Survivorship Concerns. Patients also reported use of SCP materials for informational, decisional, and communication Support at follow-up. Subjects were grouped according to time since diagnosis into two categories: near term (≤ 24 months, n = 84), long term (&amp;gt; 24 Month, n = 55) survivors. Results: Global symptom burden decreased following SCP intervention (p &amp;lt; .001). Participants reported decreased pain (p = .001), fatigue (p &amp;lt; .001), disturbance from hot flashes (p = .02), emotional concern (p = .02), and numbness/neuropathy (p = .006), and a trend toward decreased cognitive disturbance (p = .09). Near term survivors reported marginally greater decrease in global symptom burden relative to long term survivors (p = .08), and in the specific areas of cognitive difficulties (p = .05), fatigue (p = .006), and emotional concerns (p = .10). Although there were no differences over time in physical functioning on the SF-12, near term survivors reported worse mental health than long term survivors (p = .008). Across groups, cancer-specific worry, general health worry, personal survivorship concerns, and family/genetics concerns did not change over time. However, near term survivors reported more cancer-specific worry (p = .03) and marginally greater family/genetics concern than long term subjects (p = .10). Near term survivors were also more likely to use their SCP documents for informational (p = .02) and decisional (p = .08) support following their SCP visit. Discussion: Although limited by a quasi-experimental design, results suggest that SCPs may have a beneficial effect on symptom burden generally, with physical symptoms of pain, fatigue and neuropathy most responsive to care.. Much of the benefit appears to accrue to near term survivors. Moreover, near term survivors report more concerns relative to long term survivors, and are more likely to use SCP materials following visits. If these findings are replicated in better controlled studies, survivorship care will provide greater benefit in the first two years after completion of treatment. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-08-07.</jats:p

Abstract P3-08-02: Breast cancer survivors’ outcomes and satisfaction following delivery of a survivorship care plan: Results of a multicenter trial

Abstract Introduction: Survivorship care plans (SCPs) have been suggested as a solution to the fragmentation of care and suboptimal outcomes experienced by the more than 13 million cancer survivors in the US. Provider and patient acceptance of SCPs is generally high, but trials to date have examined outcomes such as cancer-related distress rather than constructs more directly related to the purpose of SCPs, such as improving coordination of care, knowledge about survivorship issues, and perceived usefulness by patients. Moreover, little is known about processes by which SCPs are developed and delivered in practice – who is involved and the level of resources needed for implementation. This pilot study used a quasi-experimental, pre-test/post-test design to examine the process of delivering standardized SCPs and the outcomes achieved by post-treatment breast cancer survivors at seven cancer centers affiliated with the LIVESTRONG™ Survivorship Centers of Excellence Network. Method: Outcomes were assessed prior to SCP delivery and 3 months following and included survivors’ use of and satisfaction with SCPs, perceived knowledge about survivorship care and potential late effects, and survivors’ assessment of the quality and coordination of survivorship care. Process variables included type of provider delivering the SCP and time required to complete and deliver the SCP. Results: 139 breast cancer survivors completed baseline and follow-up measures and received a comprehensive, standardized SCP at a survivorship visit (Age M = 53.9 years, 3.4 years post-diagnosis, 90.6% Caucasian). Satisfaction with the SCP was high, with 90% of participants being at least ‘satisfied’ and 56% being ‘very’ or ‘extremely satisfied’. Perceived knowledge about survivorship care improved following SCP delivery (p &amp;lt; 0.001), as did survivor perception of quality of survivorship care received and coordination among providers (all p &amp;lt; 0.001). A trend toward improvement in satisfaction with the follow-up care provider was also noted (p = 0.11). Most participants (88%) reported reading their SCP carefully following delivery. In the 3 months following delivery, participants reported they most commonly used SCP materials to make decisions about appropriate exercise (69%), which tests to receive and when (65%), and to make dietary changes (65%), but only 23% shared the SCP with their primary care providers during that time frame. With respect to process, providers were predominately NPs and Pas (80%). Although implementation varied, time burden was consistently high (M = 72 minutes to prepare, M = 48 minutes to deliver). Discussion: This is the first known study to demonstrate significant improvements in perceived knowledge regarding and perceived quality of survivorship care following receipt of a comprehensive SCP. Survivors were satisfied with their SCP, and most frequently reported using SCPs in making decisions regarding behavioral changes. Results warrant further consideration in a randomized controlled trial, and approaches that maximize efficiency are needed given the time burden of providers to provide an SCP. SCPs have been recommended for all cancer survivors and these data provide preliminary support for this recommendation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-08-02.</jats:p

Engaging Men as Promotores de Salud: Perceptions of Community Health Workers Among Latino Men in North Carolina

The promotor de salud, or community health worker (CHW) role, is highly feminized and little is known about how men view their participation in CHW programs. We conducted in-depth interviews with Latino men in North Carolina to explore this gap. We used systematic coding and display procedures informed by Grounded Theory to analyze the data. Men described their communities as lacking cohesion, making integration of Latino immigrants difficult. Most did not consider themselves leaders or feel they had leaders in their communities. Their perceptions of the feminized CHW role as well as the volunteer or low-paid nature of CHW work conflicted with men’s provider role. They also did not think they could perform the CHW role because they lacked education, skills, and broad networks. Efforts to increase male participation in CHW programs in new Latino immigrant destinations will need to understand and address these gender and migration-related dynamics in order to engage both women and men in improving the health of their communities