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The disruption of polynucleotide kinase/phosphatase (PNKP) in colorectal cancer (CRC) cells deficient in phosphatase and tensin homolog (PTEN) is expected to lead to the loss of cell viability by a process known as synthetic lethality. In previous studies, we have reported on the encapsulation of a novel inhibitor of PNKP, namely, A83B4C63, in polymeric micelles and its activity in slowing the growth of PTEN-deficient CRC cells as well as subcutaneous xenografts. In this study, to enhance drug delivery and specificity to CRC tumors, the surface of polymeric micelles carrying A83B4C63 was modified with GE11, a peptide targeting epidermal growth factor receptor (EGFR) overexpressed in about 70% of CRC tumors. Using molecular dynamics (MD) simulations, we assessed the binding site and affinity of GE11 for EGFR. The GE11-modified micelles, tagged with a near-infrared fluorophore, showed enhanced internalization by EGFR-overexpressing CRC cells in vitroand a trend toward increased primary tumor homing in an orthotopic CRC xenograft in vivo. In line with these observations, the GE11 modification of polymeric micelles was shown to positively contribute to the improved therapeutic activity of encapsulated A83B4C63 against HCT116-PTEN–/–cells in vitroand that of orthotopic CRC xenograft in vivo. In conclusion, our results provided proof of principle evidence for the potential benefit of EGFR targeted polymeric micellar formulations of A83B4C63 as monotherapeutics for aggressive and metastatic CRC tumors but at the same time highlighted the need for the development of EGFR ligands with improved physiological stability and EGFR binding.

ObjectivesDiverting patients away from the emergency department (ED) has been proposed as a solution for mitigating overcrowding. This systematic review examined the impact of interventions designed to either bypass the ED or direct patients to other alternative care after ED presentation.MethodsSeven electronic databases and the grey literature were searched. Eligible studies included randomised/controlled trials or cohort studies that assessed the effectiveness of pre-hospital or ED-based diversion interventions. Two reviewers independently screened the studies for relevance, inclusion and risk of bias. Pooled statistics were calculated as relative risks (RR) with 95% confidence intervals (CI) using a random effects model.ResultsFifteen studies were included evaluating pre-hospital (n=11) or ED-based (n=4) diversion interventions. The quality of the studies ranged from moderate to low. Patients deemed suitable for diversion among the pre-hospital studies (n=3) ranged from 19.2% to 90.4% and from 19% to 36% in ED-based studies (n=4). Of the eligible patients, the proportion of patients diverted via ED-based diversion tended to be higher (median 85%; IQR 76–93%) compared with pre-hospital diversion (median 40%; IQR 24–57%). Overall, pre-hospital diversion did not decrease the proportion of patients transferred to the ED compared with standard care (RR 0.92; 95% CI 0.80 to 1.06). There was no significant decrease in subsequent ED utilisation among patients diverted via pre-hospital diversion compared with non-diverted patients (RR 1.09; 95% CI 0.99 to 1.21). Of the three pre-hospital studies completing a cost analysis, none found a significant difference in total healthcare costs between diverted and non-diverted patients.ConclusionThere was no conclusive evidence regarding the impact of diversion strategies on ED utilisation and subsequent healthcare utilisation. The overall quality of the research limited the ability of this review to draw definitive conclusions and more research is required prior to widespread implementation.

The objective of this research was to develop polymeric micellar formulations of inhibitors of signal transducer and activator of transcription 3 (STAT3) dimerization, i.e., S3I-1757 and S3I-201, and evaluate the activity of successful formulations in B16-F10 melanoma, a STAT3 hyperactive cancer model, in vitro and in vivo. STAT3 inhibitory agents were encapsulated in methoxy poly(ethylene oxide)-b-poly(ε-caprolactone) (PEO114-b-PCL22) and methoxy poly(ethylene oxide)-b-poly(α-benzyl carboxylate-ε-caprolactone) (PEO114-b-PBCL20) micelles using co-solvent evaporation. Polymeric micelles of S3I-1757 showed high encapsulation efficiency (>88%), slow release profile (<32% release in 24 h) under physiological conditions, and a desirable average diameter for tumor targeting (33–54 nm). The same formulations showed low encapsulation efficiencies and rapid drug release for S3I-201. Further studies evidenced the delivery of functional S3I-1757 by polymeric micelles to B16-F10 melanoma cells, leading to a dose-dependent inhibition of cell growth and vascular endothelial growth factor (VEGF) production comparable with that of free drug. Encapsulation of S3I-1757 in polymeric micelles significantly reduced its cytotoxicity in normal bone marrow-derived dendritic cells (DCs). Micelles of S3I-1757 were able to significantly improve the function of B16-F10 tumor-exposed immunosuppressed DCs in the production of IL-12, an indication for functionality in the induction of cell-mediated immune response. In a B16-F10 melanoma mouse model, S3I-1757 micelles inhibited tumor growth and enhanced the survival of tumor-bearing mice more than free S3I-1757. Our findings show that both PCL- and PBCL-based polymeric micelles have potential for the solubilization and delivery of S3I-1757, a potent STAT3 inhibitory agent.

ObjectiveChildren with mental health crises require access to specialised resources and services which are not yet standard in general and paediatric EDs. In 2010, we published a systematic review that provided some evidence to support the use of specialised care models to reduce hospitalisation, return ED visits and length of ED stay. We perform a systematic review to update the evidence base and inform current policy statements.MethodsTwelve databases and the grey literature were searched up to January 2015. Seven studies were included in the review (four newly identified studies). These studies compared ED-based strategies designed to assess, treat and/or therapeutically support or manage a mental health presentation. The methodological quality of six studies was assessed using the Cochrane Effective Practice and Organization of Care Risk of Bias tool (one interrupted time series study) and a modified Newcastle-Ottawa Scale (three retrospective cohort and two before–after studies). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was applied to rate overall evidence quality (high, moderate, low or very low) for individual outcomes from these six studies. An additional study evaluated the psychometric properties of a clinical instrument and was assessed using criteria developed by the Society of Pediatric Psychology Assessment Task Force (well-established, approaching well-established or promising assessment).ResultsThere is low to very low overall evidence quality that: (1) use of screening laboratory tests to medically clear mental health patients increases length of ED stay and costs, but does not increase the risk of clinical management or disposition change if not conducted; and (2) specialised models of ED care reduce lengths of ED stay, security man-hours and restraint orders. One mental health assessment tool of promising quality, the home, education, activities and peers, drugs and alcohol, suicidality, emotions and behaviour, discharge resources (HEADS-ED), has had good accuracy in predicting admission to inpatient psychiatry.ConclusionsLower-quality data suggest benefits to the use of specialised resources and services for paediatric mental health care in general and paediatric EDs. Experimental evaluation of strategies and the inclusion of patient-reported outcomes will improve confidence in these findings. Additional psychometric studies are needed for the HEADS-ED tool to be considered well established.

The pivotal role of datasets in signature verification systems motivates researchers to collect signature samples. Distinct characteristics of Persian signature demand for richer and culture-dependent offline signature datasets. This study introduces a new and public Persian offline signature dataset, UTSig (University of Tehran Persian Signature), that consists of 8280 images from 115 classes. Each class has 27 genuine signatures, 3 opposite-hand signatures, and 42 skilled forgeries made by 6 forgers. Compared with the other public datasets, UTSig has more samples, more classes, and more forgers. The authors considered various variables including signing period, writing instrument, signature box size, and number of observable samples for forgers in the data collection procedure. By careful examination of main characteristics of offline signature datasets, they observe that Persian signatures have fewer numbers of branch points and end points. They propose and evaluate four different training and test setups for UTSig. Results of the authors’ experiments show that training genuine samples along with opposite-hand samples and random forgeries can improve the performance in terms of equal error rate and minimum cost of log likelihood ratio.