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Lucy Swift,1 Chunfen Zhang,1 Tanya Trippett,2 Aru Narendran1 1POETIC Laboratory for Preclinical and Drug Discovery Studies, Division of Pediatric Oncology, Alberta Children’s Hospital, University of Calgary, Calgary, AB, Canada; 2Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Purpose: Neuroblastoma is the most common extracranial cancer in children. Although the prognosis for low-risk neuroblastoma patients is good, the 5-year survival rates for high-risk and relapsed patients are low. The poor survival rates for these patients demonstrate the need for novel therapeutic approaches to treat this disease. PV-10 is a sterile 10% solution of Rose Bengal that has previously been shown to induce cell death in a range of adult cancers, providing the rationale for studying the activity of PV-10 against neuroblastoma in preclinical studies. Methods: The effects of PV-10 on neuroblastoma were investigated invitro. Cytotoxicity assays were performed using the alamar blue assay on the following cell lines: SK-N-AS, SK-N-BE(2), IMR5, LAN1, SHEP, and SK-N-SH neuroblastoma cells, SK-N-MC neuroepithelioma cells, and normal primary, BJ, and WI38 fibroblasts. Phase-contrast, fluorescence, and time-lapse video microscopy; flow cytometry; and Western blotting were used to investigate the effects of PV-10 on SK-N-AS and IMR5 cells. Synergy with commonly used anticancer drugs was determined by calculation of combination indices in SK-N-AS and IMR5 cells. Mouse xenograft models of SK-N-AS and IMR5 tumors were also used to evaluate the efficacy of PV-10 invivo. Results: Invitro preclinical data demonstrate that pharmacologically relevant concentrations of PV-10 are cytotoxic to neuroblastoma cell lines. Studies to investigate target modulation in neuroblastoma cell lines show that PV-10 disrupts lysosomes, decreases the percentage of cells in S phase, and induces apoptosis in a concentration-, time-, and cell-line-dependent manner, and we also identify agents that are synergistic with PV-10. Furthermore, experiments in xenograft mouse models show that PV-10 induces tumor regression invivo. Conclusion: Our study provides preclinical data on the efficacy of PV-10 against neuroblastoma and provides rationale for the development of an early phase clinical trial of this agent in relapsed and refractory neuroblastoma patients. Keywords: neuroblastoma, PV-10, Rose Bengal, novel therapeutics, intralesional, oncolytic, immunotherapy

Despite being a universal human attachment behavior, little is known about individual differences in crying. To facilitate such examination we first recommend shortened versions of the attitudes and proneness sections of the Adult Crying Inventory using two independent samples. Importantly, we examine attachment orientation differences in crying proneness and test the mediating role of attitudes toward crying in this relationship. Participants (Sample 1 N = 623, Sample 2 N = 781), completed online measures of adult attachment dimensions (avoidance and anxiety), attitudes toward crying, and crying proneness. Exploratory factor analyses in Sample 1 revealed four factors for crying attitudes: crying helps one feel better; crying is healthy; hatred of crying; and crying is controllable; and three factors for crying proneness: threat to self; sadness; and joy. Confirmatory factor analyses in Sample 2 replicated these structures. Theoretically and statistically justified short forms of each scale were created. Multiple mediation analyses revealed similar patterns of results across the two samples, with the attitudes "crying is healthy" and "crying is controllable" consistently mediating the positive links between attachment anxiety and crying proneness, and the negative links between attachment avoidance and crying proneness. Results are discussed in relation to attachment and emotion regulation literature.

This prospective patient-preference study examined the effectiveness in practice of methadone versus buprenorphine maintenance treatment and the beliefs of subjects regarding these drugs. A total of 361 opiate-dependent individuals (89% of those eligible, presenting for treatment over 2 years at a drug service in England) received rapid titration then flexible dosing with methadone or buprenorphine; 227 patients chose methadone (63%) and 134 buprenorphine (37%). Participants choosing methadone had more severe substance abuse and psychiatric and physical problems but were more likely to remain in treatment. Survival analysis indicated those prescribed methadone were over twice as likely to be retained (hazard ratio for retention was 2.08 and 95% confidence interval [CI] = 1.49-2.94 for methadone vs. buprenorphine), However, those retained on buprenorphine were more likely to suppress illicit opiate use (odds ratio = 2.136, 95% CI = 1.509-3.027, p < .001) and achieve detoxification. Buprenorphine may also recruit more individuals to treatment because 28% of those choosing buprenorphine (10% of the total sample) stated they would not have accessed treatment with methadone.