Abemaciclib Is Active in Preclinical Models of Ewing Sarcoma via Multipronged Regulation of Cell Cycle, DNA Methylation, and Interferon Pathway Signaling.

PURPOSE: Ewing sarcoma (ES) is a rare and highly malignant cancer that occurs in the bone and surrounding tissue of children and adolescents. The EWS/ETS fusion transcription factor that drives ES pathobiology was previously demonstrated to modulate cyclin D1 expression. In this study, we evaluated abemaciclib, a small-molecule CDK4 and CDK6 (CDK4 and 6) inhibitor currently under clinical investigation in pediatric solid tumors, in preclinical models of ES. EXPERIMENTAL DESIGN: Using Western blot, high-content imaging, flow cytometry, ELISA, RNA sequencing, and CpG methylation assays, we characterized the in vitro response of ES cell lines to abemaciclib. We then evaluated abemaciclib in vivo in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models of ES as either a monotherapy or in combination with chemotherapy. RESULTS: Abemaciclib induced quiescence in ES cell lines via a G1 cell-cycle block, characterized by decreased proliferation and reduction of Ki-67 and FOXM1 expression and retinoblastoma protein (RB) phosphorylation. In addition, abemaciclib reduced DNMT1 expression and promoted an inflammatory immune response as measured by cytokine secretion, antigen presentation, and interferon pathway upregulation. Single-agent abemaciclib reduced ES tumor volume in preclinical mouse models and, when given in combination with doxorubicin or temozolomide plus irinotecan, durable disease control was observed. CONCLUSIONS: Collectively, our data demonstrate that the antitumor effects of abemaciclib in preclinical ES models are multifaceted and include cell-cycle inhibition, DNA demethylation, and immunogenic changes.

Emotional intelligence and spiritual well-being: implications for spiritual care.

Understanding factors that influence spiritual well-being may improve nurses' spiritual caregiving. This study examined relationships between emotional intelligence (EI) and spiritual well-being (SWB) in undergraduate and graduate nursing students. Using the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) and the spiritual well-being scale (SWBS) relationships were found between managing emotion and spiritual well-being, and managing emotion and existential well-being. Implications for education and practice are discussed.

Factors related to academic success among nursing students: a descriptive correlational research study.

BACKGROUND: The current rise in employment is improving forecasts for the future supply of registered nurses; however sizeable shortages are still projected. With the intention of improving academic success in nursing students, related factors need to be better understood. OBJECTIVES: The purpose of the correlational study was to describe the relationship between emotional intelligence, psychological empowerment, resilience, spiritual well-being, and academic success in undergraduate and graduate nursing students. DESIGN/SETTING: A descriptive correlational design was utilized. The study was set in a private Catholic university. PARTICIPANTS: There were 124 participants. There were 59% undergraduate and 41% graduate students. METHODS: Background data, in addition to the Spreitzer Psychological Empowerment Scale, the Wagnild and Young Resilience Scale, and the Spiritual Well-Being Scale and the Mayer-Salovey-Caruso Emotional Intelligence Test, was collected from students who met study criteria. RESULTS: In a combined sample, academic success was correlated with overall spiritual well-being, empowerment and resilience. Although academic success was not correlated with overall emotional intelligence, it was correlated with the emotional intelligence branch four (managing emotions) score. When undergraduate and graduate students were considered separately, only one correlation was found to be significantly related to academic success in the undergraduate sample, namely, emotional intelligence branch one (perceiving emotions). When examining the data from just graduate level nurses, significant relationships were found between total emotional intelligence with academic success, resilience with academic success, and psychological empowerment with academic success. CONCLUSION: The significant relationship between psychological empowerment, resilience, spiritual well-being and academic success in this study supports the statements in the literature that these concepts may play an important role in persistence through the challenges of nursing education. Research is needed to examine if strategies to enhance empowerment, resilience, and spiritual well-being can increase academic success in a test-retest design.

Increased expression of CYP24A1 correlates with advanced stages of prostate cancer and can cause resistance to vitamin D3-based therapies.

A major limitation of exogenous vitamin D3 administration for the treatment of prostate cancer is the marginal, if any, clinical efficacy. We dissected the basis for the resistance to the vitamin D3 antitumor properties and specifically examined the effect of its major catabolic enzyme, CYP24A1, in prostate cancer. Local CYP24A1 expression levels and the effect of selective modulation were analyzed using tissue microarrays from needle core biopsy specimens and xenograft-bearing mouse models. CYP24A1 mRNA was elevated in malignant human prostate tissues compared to benign lesions. High CYP24A1 protein levels were seen in poorly differentiated and highly advanced stages of prostate cancer and correlated with parallel increase in the tumor proliferation rate. The use of CYP24A1 RNAi enhanced the cytostatic effects of vitamin D3 in human prostate cancer cells. Remarkably, subcutaneous and orthotopic xenografts of prostate cancer cells harboring CYP24A1 shRNA resulted in a drastic reduction in tumor volume when mice were subjected to vitamin D3 supplementation. CYP24A1 may be a predictive marker of vitamin D3 clinical efficacy in patients with advanced prostate cancer. For those with up-regulated CYP24A1, combination therapy with RNAi targeting CYP24A1 could be considered to improve clinical responsiveness to vitamin D3.