Discovery and Optimization of Pyrrolopyrimidine Derivatives as Selective Disruptors of the Perinucleolar Compartment, a Marker of Tumor Progression toward Metastasis.

The perinucleolar compartment (PNC) is a dynamic subnuclear body found at the periphery of the nucleolus. The PNC is enriched with RNA transcripts and RNA-binding proteins, reflecting different states of genome organization. PNC prevalence positively correlates with cancer progression and metastatic capacity, making it a useful marker for metastatic cancer progression. A high-throughput, high-content assay was developed to identify novel small molecules that selectively reduce PNC prevalence in cancer cells. We identified and further optimized a pyrrolopyrimidine series able to reduce PNC prevalence in PC3M cancer cells at submicromolar concentrations without affecting cell viability. Structure-activity relationship exploration of the structural elements necessary for activity resulted in the discovery of several potent compounds. Analysis of in vitro drug-like properties led to the discovery of the bioavailable analogue, metarrestin, which has shown potent antimetastatic activity with improved survival in rodent models and is currently being evaluated in a first-in-human phase 1 clinical trial.

The Effects of Virtual Reality on Anxiety and Self-Efficacy Among Patients With Cancer: A Pilot Study.

OBJECTIVES: To examine the impact of a nurse-led intervention on anxiety levels and perceived self-efficacy to cope in patients receiving first-time chemotherapy using a customized prechemotherapy educational virtual reality (VR) video. SAMPLE & SETTING: 35 patients with cancer receiving first-time chemotherapy participated in this study at a large suburban cancer center in Newark, Delaware. METHODS & VARIABLES: A single-group, quasi-experimental pilot study was conducted to examine the feasibility of a customized prechemotherapy educational VR video in patients receiving first-time chemotherapy. The State-Trait Anxiety Inventory, heart rate, and blood pressure were used to measure anxiety, and the Cancer Behavior Inventory-Brief Version measured perceived self-efficacy to cope with cancer. Measures were taken pre- and postintervention, and patient satisfaction was examined postintervention. RESULTS: Anxiety level, heart rate, and blood pressure significantly decreased from baseline to postintervention, and perceived self-efficacy to cope significantly increased from baseline to postintervention. IMPLICATIONS FOR NURSING: Personalized prechemotherapy educational VR videos could be further examined as an innovative nursing intervention to meet the health, emotional, and educational needs of diverse patient populations.

Inherited Variants in SCARB1 Cause Severe Early-Onset Coronary Artery Disease.

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Effects of targeting sumoylation processes during latent and induced Epstein-Barr virus infections using the small molecule inhibitor ML-792.

As the second leading cause of death in the United States, cancer has a considerable impact on society, and one cellular process that is commonly dysregulated in many cancers is the post-translational modification of proteins by the Small Ubiquitin-like Modifier (SUMO; sumoylation). We documented that sumoylation processes are up-regulated in lymphoma tissues in the presence of Latent Membrane Protein-1 (LMP1), the principal oncoprotein of Epstein-Barr virus (EBV). LMP1-mediated dysregulation of cellular sumoylation processes contributes to oncogenesis, modulates innate immune responses, and aids the maintenance of viral latency. Manipulation of protein sumoylation has been proposed for anti-cancer and anti-viral therapies; however, known inhibitors of sumoylation do not only target sumoylation processes. Recently, a specific and selective small-molecule inhibitor of sumoylation (ML-792) was identified; however, nothing is known about the effect of ML-792 on LMP1-mediated dysregulation of cellular sumoylation or the EBV life-cycle. We hypothesized that ML-792 modulates viral replication and the oncogenic potential of EBV LMP1 by inhibiting protein sumoylation. Results showed that ML-792 inhibited sumoylation processes in multiple EBV-positive B cell lines and EBV-positive nasopharyngeal carcinoma cell lines but not in their EBV-negative counterparts. Focusing on its effect on B cells, ML-792 inhibited B-cell growth and promoted cell death at very low doses. ML-792 also modulated LMP1-induced cell migration and cell adhesion, which suggests the abrogation of the oncogenic potential of LMP1. Finally, while higher concentrations of ML-792 were sufficient to induce low levels EBV spontaneous reactivation, they decreased the production of new infectious virus following an induced reactivation and the infection of new cells, suggesting that ML-792 has anti-viral potential. Together, these findings suggest that ML-792 may be a potential therapeutic drug to treat EBV-associated lymphoid malignancies by targeting oncogenesis and the EBV life-cycle.

Screening for Frailty in Thoracic Surgical Patients.

BACKGROUND: The presence of frailty or prefrailty in older adults is a risk factor for postsurgical complications. The frailty phenotype can be improved through long-term resistance and aerobic training. It is unknown whether short-term preoperative interventions targeting frailty will help to mitigate surgical risk. The purpose of this study was to determine the proportion of frail and prefrail patients presenting to a thoracic surgical clinic who could benefit from a frailty reduction intervention. METHODS: A prospective cohort study was performed at a single-site thoracic surgical clinic. Starting October 1, 2014, surgical candidates 60 years of age or older who consented to be screened were included. Patients were screened using an adapted version of Fried's phenotypic frailty criteria: weakness (grip strength), slow gait (15-foot walk), unintentional weight loss, self-reported exhaustion, and low self-reported physical activity (Physical Activity Scale for the Elderly). Prefrailty was identified when participants demonstrated one to two frailty characteristics; frailty was identified when participants demonstrated three to five frailty characteristics. RESULTS: Of 180 eligible patients, 126 consented, and 125 completed screening. Thirty-nine participants (31%) were not frail, 71 (57%) were prefrail, and 15 (12%) were frail. Exhaustion was the most common frailty symptom (34%). Frailty prevalence did not significantly differ among men and women (men: 10%, women: 14%; p = 0.75). CONCLUSIONS: We found a high proportion of prefrail and frail patients among patients deemed candidates for thoracic surgical procedures. This finding indicates that frailty may be underrecognized. Substantial numbers of patients may be considered for a presurgical frailty reduction intervention.

C-6 Ceramide Induces p53 Dependent Apoptosis in Human Astrocytoma Grade4 (Glioblastoma Multiforme) Cells.

Ceramide is composed of sphingosine and a fatty acid found in large concentration within the cell membrane and often acts as a signaling molecule for various functions including programmed cell death. In the present investigation, we observed that C6-ceramide induces p53-dependent apoptosis and effectively killed the Astrocytoma grade4 (Glioblastoma Multiforme) HTB12 cell lines. Ceramide-induced cell death was confirmed by Trypan blue assay which showed about 65% cells dying from ceramide treatment. Apoptosis was confirmed by Caspase3 ELISA assay and DNA fragmentation assay. The p53 induction was confirmed by immunoblot studies. Since C6 Ceramide induces apoptosis in Glioblastoma cells, it may be employed in chemotherapeutic strategy to treat this highly malignant brain cancer.