Purpose: African American (AA) women ages 20-44 develop breast cancer at higher rates compared with Caucasian women. These young survivors (<45 years) also have disparate quality of life (QOL). Little is known about survivorship information needs of young AA survivors. The purpose of this study was to explore young AA survivors' perceptions of an existing QOL intervention for breast cancer survivors, identifying information needs to address using a targeted intervention. Methods: Two semistructured interviews were conducted with each of 15 young AA survivors who had completed breast cancer treatment. This article focuses on the second interview in which young AA survivors reviewed intervention materials and described their perceptions of the intervention. Content analysis was used to identify themes, which were validated by participants. Results: Participants (n: 15; mean age at study entry: 35 years) reported that the existing evidence-based intervention discussed relevant but general survivorship information. They suggested adapting the information for young AA survivors: addition of content geared toward finances, how to better communicate to manage dating and relationships, how to engage in healthful activities, and how to find local resources for any stage of survivorship. Furthermore, they suggested multiple modes of information delivery and inclusion of diverse imagery. Conclusion: Engaging young AA survivors yielded pearls of wisdom, highlighting the general nature of an existing intervention and suggesting adaptations to meet young AA survivors' information needs. Applying such pearls can be a powerful method to target survivorship interventions for this disparate group of cancer survivors.
E. coli endotoxin (LPS) combined with interferon‐γ (IFN) induces inducible nitric oxide synthase (iNOS), with production of nitric oxide (NO) and reactive nitrogen species in endothelial cells. Appropriate manipulation of iNOS during onset or resolution of inflammation may be useful. Since transcription is required for induction of iNOS by LPS/IFN, we hypothesized that depletion of cyclin dependent kinase (CDK) 7, a promoter of transcription, would antagonize induction. Mouse aortic endothelial cells (MAEC) were transfected with Non‐targeted (NT) control RNA or CDK7 siRNA to deplete the kinase, followed by stimulation with LPS/IFN for 12 h. Rather than suppressing, CDK7 depletion increased induction of iNOS, and its dimerization and NO production. The effect was post‐transcriptional in that mRNA induction was unaffected, while iNOS protein turnover was reduced in the absence of CDK7. Cellular calpain activity, which is required for iNOS protein degradation in MAEC, was unaffected by CDK7 depletion, suggesting an effect on iNOS itself. Indeed, iNOS in lysates of kinase‐deficient cells was resistant to in vitro digestion with exogenous calpain. In conjunction with protease resistance, the association of iNOS with calmodulin, known to inhibit its digestion by calpain, was increased in cells lacking CDK7. These results suggest that CDK7 normally restrains iNOS induction by limiting calmodulin binding and maintaining calpain‐mediated turnover. By regulating iNOS enzyme complexes, CDK7 may serve as a novel target for manipulation of vascular NO. Support or Funding Information Support was received from the Popat Patil Fellowship (SS).
Endothelial cell prostaglandins modulate the response to inflammatory stimuli. Combined treatment with E. coli endotoxin and interferon‐γ (LPS/IFN) induces cyclooxygenase‐2 (COX2) mRNA and protein. Modulation of COX2 expression may be therapeutically useful in different inflammatory states. Given the induction of COX2 mRNA by LPS/IFN, it was hypothesized that depletion of the transcription‐stimulating enzyme, cyclin‐dependent kinase 7 (CDK7), would antagonize induction of COX2. Here, mouse aortic endothelial cells were treated with CDK7 or non‐targeted siRNA, followed by LPS/IFN. Contrary to our expectations, knocking down CDK7 super‐induced the expression of COX2, without affecting mRNA or turnover of the protein. This suggested that CDK7 depletion increased protein synthesis. Here, signaling mechanisms known to regulate translation were investigated. CDK7 knockdown increased phosphorylation at Serine 209 of the mRNA cap‐binding translation initiation factor, eIF4E. Knockdown also increased cap‐binding activity of eIF4E. CDK7 depletion increased phosphorylation of the eIF4E repressor, 4EBP1, and decreased its association with eIF4E. Finally, increased phosphorylation of ribosomal protein S6 (RPS6), a component of the 40S ribosomal subunit, was also seen in the absence of CDK7, indicating increased translation. The results suggest that CDK7 represses COX2 expression by limiting translation through effects on RPS6, eIF4E and/or 4EBP1. CDK7 may serve as a target for the manipulation of COX2 expression in endothelial cells. Support or Funding Information Support was received from the Popat Patil Fellowship (SS).
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