A Test of the Psychometric Characteristics of the BIS-Brief Among Three Groups of Youth

The current study empirically investigates the relationships between the Dark Triad personality traits and cyber-aggression among adolescents (14–18 year old). The sample consisted of 324 participants aged 14–18 (M = 16.05, SD = 1.31). Participants completed the Short Dark Triad (SD3) as a measure of the Dark Triad personality traits, the Facebook Intensity Scale and a scale to measure cyber-aggression. Structural equation modelling was applied to investigate the relationships. Results show that only Facebook intensity and psychopathy significantly predict cyber-aggression, when controlling for age and gender. Findings are discussed regarding the potential importance to further study Dark Triad traits, and psychopathy in particular, in the context of adolescent cyber-aggression

Preclinical rationale for entinostat in embryonal rhabdomyosarcoma

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric cancer population. Survival among metastatic RMS patients has remained dismal yet unimproved for years. We previously identified the class I-specific histone deacetylase inhibitor, entinostat (ENT), as a pharmacological agent that transcriptionally suppresses the PAX3:FOXO1 tumor-initiating fusion gene found in alveolar rhabdomyosarcoma (aRMS), and we further investigated the mechanism by which ENT suppresses PAX3:FOXO1 oncogene and demonstrated the preclinical efficacy of ENT in RMS orthotopic allograft and patient-derived xenograft (PDX) models. In this study, we investigated whether ENT also has antitumor activity in fusion-negative eRMS orthotopic allografts and PDX models either as a single agent or in combination with vincristine (VCR). METHODS: We tested the efficacy of ENT and VCR as single agents and in combination in orthotopic allograft and PDX mouse models of eRMS. We then performed CRISPR screening to identify which HDAC among the class I HDACs is responsible for tumor growth inhibition in eRMS. To analyze whether ENT treatment as a single agent or in combination with VCR induces myogenic differentiation, we performed hematoxylin and eosin (H&E) staining in tumors. RESULTS: ENT in combination with the chemotherapy VCR has synergistic antitumor activity in a subset of fusion-negative eRMS in orthotopic "allografts," although PDX mouse models were too hypersensitive to the VCR dose used to detect synergy. Mechanistic studies involving CRISPR suggest that HDAC3 inhibition is the primary mechanism of cell-autonomous cytoreduction in eRMS. Following cytoreduction in vivo, residual tumor cells in the allograft models treated with chemotherapy undergo a dramatic, entinostat-induced (70-100%) conversion to non-proliferative rhabdomyoblasts. CONCLUSION: Our results suggest that the targeting class I HDACs may provide a therapeutic benefit for selected patients with eRMS. ENT's preclinical in vivo efficacy makes ENT a rational drug candidate in a phase II clinical trial for eRMS

Probabilistic modeling of personalized drug combinations from integrated chemical screen and molecular data in sarcoma

BACKGROUND: Cancer patients with advanced disease routinely exhaust available clinical regimens and lack actionable genomic medicine results, leaving a large patient population without effective treatments options when their disease inevitably progresses. To address the unmet clinical need for evidence-based therapy assignment when standard clinical approaches have failed, we have developed a probabilistic computational modeling approach which integrates molecular sequencing data with functional assay data to develop patient-specific combination cancer treatments. METHODS: Tissue taken from a murine model of alveolar rhabdomyosarcoma was used to perform single agent drug screening and DNA/RNA sequencing experiments; results integrated via our computational modeling approach identified a synergistic personalized two-drug combination. Cells derived from the primary murine tumor were allografted into mouse models and used to validate the personalized two-drug combination. Computational modeling of single agent drug screening and RNA sequencing of multiple heterogenous sites from a single patient's epithelioid sarcoma identified a personalized two-drug combination effective across all tumor regions. The heterogeneity-consensus combination was validated in a xenograft model derived from the patient's primary tumor. Cell cultures derived from human and canine undifferentiated pleomorphic sarcoma were assayed by drug screen; computational modeling identified a resistance-abrogating two-drug combination common to both cell cultures. This combination was validated in vitro via a cell regrowth assay. RESULTS: Our computational modeling approach addresses three major challenges in personalized cancer therapy: synergistic drug combination predictions (validated in vitro and in vivo in a genetically engineered murine cancer model), identification of unifying therapeutic targets to overcome intra-tumor heterogeneity (validated in vivo in a human cancer xenograft), and mitigation of cancer cell resistance and rewiring mechanisms (validated in vitro in a human and canine cancer model). CONCLUSIONS: These proof-of-concept studies support the use of an integrative functional approach to personalized combination therapy prediction for the population of high-risk cancer patients lacking viable clinical options and without actionable DNA sequencing-based therapy

Lineage of origin in rhabdomyosarcoma informs pharmacological response

Lineage or cell of origin of cancers is often unknown and thus is not a consideration in therapeutic approaches. Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood cancer for which the cell of origin remains debated. We used conditional genetic mouse models of aRMS to activate the pathognomonic Pax3:Foxo1 fusion oncogene and inactivate p53 in several stages of prenatal and postnatal muscle development. We reveal that lineage of origin significantly influences tumor histomorphology and sensitivity to targeted therapeutics. Furthermore, we uncovered differential transcriptional regulation of the Pax3:Foxo1 locus by tumor lineage of origin, which led us to identify the histone deacetylase inhibitor entinostat as a pharmacological agent for the potential conversion of Pax3:Foxo1-positive aRMS to a state akin to fusion-negative RMS through direct transcriptional suppression of Pax3:Foxo1.Stem Cell and Regenerative Biolog

EphB4/EphrinB2 therapeutics in Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma affecting children and is often diagnosed with concurrent metastases. Unfortunately, few effective therapies have been discovered that improve the long-term survival rate for children with metastatic disease. Here we determined effectiveness of targeting the receptor tyrosine kinase, EphB4, in both alveolar and embryonal RMS either directly through the inhibitory antibody, VasG3, or indirectly by blocking both forward and reverse signaling of EphB4 binding to EphrinB2, cognate ligand of EphB4. Clinically, EphB4 expression in eRMS was correlated with longer survival. Experimentally, inhibition of EphB4 with VasG3 in both aRMS and eRMS orthotopic xenograft and allograft models failed to alter tumor progression. Inhibition of EphB4 forward signaling using soluble EphB4 protein fused with murine serum albumin failed to affect eRMS model tumor progression, but did moderately slow progression in murine aRMS. We conclude that inhibition of EphB4 signaling with these agents is not a viable monotherapy for rhabdomyosarcoma

Features of human xenograft model systems.

<p>Features of human xenograft model systems.</p

VasG3 treatment of Rh30 & PCB380 aRMS xenografts.

<p><i>A</i>. Experimental design of the orthotopic aRMS xenograft tumor models and VasG3 treatment regime. <i>B</i>. Immunohistochemical staining of the patient-derived PCB380 tumor to demonstrate EphB4 and EphrinB2 expression as obtained from the BioPathology Center RMS tissue microarray. Skeletal muscles sections were concurrently stained as controls. Arrow heads indicate EphB4/EphrinB2 expressing vascular/stromal cells. Mag bar = 50 μm. <i>C</i>. EphB4 protein expression in cultured aRMS cell lines. <i>D and E</i>. Kaplan-Meier survival curves post-treatment initiation of isotype control (black line) versus VasG3 (anti-human EphB4 binding antibody; red line) treated mice for both the PCB380 (<i>D</i>) and Rh30 (<i>E</i>) xenograft models. Mice were euthanized either on day 60 or when the tumor volume exceeded 1.2 cm³. n = 11–12 female mice per treatment group for both models. <i>F and G</i>. Representative western blot demonstrating loss of EphB4 protein levels with VasG3 treatment (<i>F</i>) and quantification of EphB4 loss (<i>G</i>) for the Rh30 model. n = 11–12 mice per cohort. p<0.0001.</p

EphB4 and EphrinB2 expression in model systems of human eRMS.

<p><i>A</i>. Patient survival improves with high EphB4 expression determined using the. p = 0.0033, n = 72. <i>B</i>. Human eRMS expression of EphB4 and EphrinB2, respectively, of PCB82 tissue sections from a human eRMS tissue microarray. Control skeletal muscle from the same TMA is depicted in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0183161#pone.0183161.g001" target="_blank">Fig 1B</a>. <i>C</i>. Human eRMS expression of EphB4 and EphrinB2 in Rh18 xenograft sections. Mag bar = 50 μm. <i>D</i>. Representative western blot demonstrating EphB4 and EphrinB2 protein expression in human eRMS xenograft models, PCB82 and Rh18.</p