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Neuroblastoma is one of the commonest and deadliest solid tumours of childhood, and is thought to result from disrupted differentiation of the developing sympathoadrenergic lineage of the neural crest. Neuroblastoma exhibits intra- and intertumoural heterogeneity, with high risk tumours characterised by poor differentiation, which can be attributable to MYCN-mediated repression of genes involved in neuronal differentiation. MYCN is known to co-operate with oncogenic signalling pathways such as Alk, Akt and MEK/ERK signalling, and, together with c-MYC has been shown to be activated by Wnt signalling in various tissues. However, our previous work demonstrated that Wnt3a/Rspo2 treatment of some neuroblastoma cell lines can, paradoxically, decrease c-MYC and MYCN proteins. This prompted us to define the neuroblastoma-specific Wnt3a/Rspo2-driven transcriptome using RNA sequencing, and characterise the accompanying changes in cell biology. Here we report the identification of ninety Wnt target genes, and show that Wnt signalling is upstream of numerous transcription factors and signalling pathways in neuroblastoma. Using live-cell imaging, we show that Wnt signalling can drive differentiation of SK-N-BE(2)-C and SH-SY5Y cell-lines, but, conversely, proliferation of SK-N-AS cells. We show that cell-lines that differentiate show induction of pro-differentiation BMP4 and EPAS1 proteins, which is not apparent in the SK-N-AS cells. In contrast, SK-N-AS cells show increased CCND1, phosphorylated RB and E2F1 in response to Wnt3a/Rspo2, consistent with their proliferative response, and these proteins are not increased in differentiating lines. By meta-analysis of the expression of our 90 genes in primary tumour gene expression databases, we demonstrate discrete expression patterns of our Wnt genes in patient cohorts with different prognosis. Furthermore our analysis reveals interconnectivity within subsets of our Wnt genes, with one subset comprised of novel putative drivers of neuronal differentiation repressed by MYCN. Assessment of β-catenin immunohistochemistry shows high levels of β-catenin in tumours with better differentiation, further supporting a role for canonical Wnt signalling in neuroblastoma differentiation., (Copyright © 2018. Published by Elsevier Inc.)

Neuroblastoma is a biologically and clinically heterogeneous pediatric malignancy that includes a high-risk subset for which new therapeutic agents are urgently required. As well as MYCN amplification, activating point mutations of ALK and NRAS are associated with high-risk and relapsing neuroblastoma. As both ALK and RAS signal through the MEK/ERK pathway, we sought to evaluate two previously reported inhibitors of ETS-related transcription factors, which are transcriptional mediators of the Ras-MEK/ERK pathway in other cancers. Here we show that YK-4-279 suppressed growth and triggered apoptosis in nine neuroblastoma cell lines, while BRD32048, another ETV1 inhibitor, was ineffective. These results suggest that YK-4-279 acts independently of ETS-related transcription factors. Further analysis reveals that YK-4-279 induces mitotic arrest in prometaphase, resulting in subsequent cell death. Mechanistically, we show that YK-4-279 inhibits the formation of kinetochore microtubules, with treated cells showing a broad range of abnormalities including multipolar, fragmented and unseparated spindles, together leading to disrupted progression through mitosis. Notably, YK-4-279 does not affect microtubule acetylation, unlike the conventional mitotic poisons paclitaxel and vincristine. Consistent with this, we demonstrate that YK-4-279 overcomes vincristine-induced resistance in two neuroblastoma cell-line models. Furthermore, combinations of YK-4-279 with vincristine, paclitaxel or the Aurora kinase A inhibitor MLN8237/Alisertib show strong synergy, particularly at low doses. Thus, YK-4-279 could potentially be used as a single-agent or in combination therapies for the treatment of high-risk and relapsing neuroblastoma, as well as other cancers., (Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.)

Measurements recorded over monitoring networks often possess spatial and temporal correlation inducing redundancies in the information provided. For river water quality monitoring in particular, flow-connected sites may likely provide similar information. This paper proposes a novel approach to principal components analysis to investigate reducing dimensionality for spatiotemporal flow-connected network data in order to identify common spatiotemporal patterns. The method is illustrated using monthly observations of total oxidized nitrogen for the Trent catchment area in England. Common patterns are revealed that are hidden when the river network structure and temporal correlation are not accounted for. Such patterns provide valuable information for the design of future sampling strategies.

Abaloparatide is a novel, potent and selective activator of parathyroid hormone receptor 1 (PTHR1) under clinical development for the treatment of osteoporosis. We assessed the effect of 6 weeks of abaloparatide on bone mass, microarchitecture, quality and strength in ovariectomized (OVX) rats. After 8 weeks of post-surgical bone depletion (baseline), OVX rats (n = 20-21/group) received daily subcutaneous vehicle (OVX-Veh) or abaloparatide at 5 or 20 µg/kg. Sham-operated control rats (n = 24) received vehicle. Areal bone mineral density (aBMD) of the lumbar spine (L4), total femur and femur diaphysis was measured at baseline and after 6 weeks of treatment. Femur and vertebral bone architecture and mechanical properties were assessed at the end of the treatment phase. At baseline, OVX-Veh rats exhibited significantly lower aBMD relative to Sham controls. Treatment of OVX rats with abaloparatide at 5 or 20 µg/kg/day increased aBMD dose-dependently in the lumbar spine, total femur and femur diaphysis to levels exceeding OVX-Veh or Sham controls. The abaloparatide 5 and 20 µg/kg groups had improved trabecular microarchitecture relative to OVX vehicle, with trabecular BV/TV exceeding OVX-Veh control values by 57 and 78 % (respectively) at the lumbar spine, and by 145 and 270 % at the distal femur. Femur diaphyseal cortical volume and thickness were significantly greater in the abaloparatide 20 µg/kg group relative to OVX vehicle or Sham controls. Bone strength parameters of the femur diaphysis, femur neck and L4 vertebra were significantly improved in the OVX-ABL groups relative to OVX-Veh controls. Bone mass-strength relationships and estimated intrinsic strength properties suggested maintained or improved bone quality with abaloparatide. These data demonstrate skeletal restoration via abaloparatide treatment of osteopenic OVX rats, in association with improved trabecular microarchitecture, cortical geometry and bone strength at sites that have clinical relevance in patients with osteoporosis., Competing Interests: Authors H. B, K. G, J. D, C. N, M. S and G. H are current or former employees of Radius Health. Human and Animal Rights and Informed Consent All applicable international, national and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Midinfrared plasmonic sensing allows the direct targeting of unique vibrational fingerprints of molecules. While gold has been used almost exclusively so far, recent research has focused on semiconductors with the potential to revolutionize plasmonic devices. We fabricate antennas out of heavily doped Ge films epitaxially grown on Si wafers and demonstrate up to 2 orders of magnitude signal enhancement for the molecules located in the antenna hot spots compared to those located on a bare silicon substrate. Our results set a new path toward integration of plasmonic sensors with the ubiquitous CMOS platform.

Importance: Reducing early (<30 days) hospital readmissions is a policy priority aimed at improving health care quality. The cumulative complexity model conceptualizes patient context. It predicts that highly supportive discharge interventions will enhance patient capacity to enact burdensome self-care and avoid readmissions., Objective: To synthesize the evidence of the efficacy of interventions to reduce early hospital readmissions and identify intervention features--including their impact on treatment burden and on patients' capacity to enact postdischarge self-care--that might explain their varying effects., Data Sources: We searched PubMed, Ovid MEDLINE, Ovid EMBASE, EBSCO CINAHL, and Scopus (1990 until April 1, 2013), contacted experts, and reviewed bibliographies., Study Selection: Randomized trials that assessed the effect of interventions on all-cause or unplanned readmissions within 30 days of discharge in adult patients hospitalized for a medical or surgical cause for more than 24 hours and discharged to home., Data Extraction and Synthesis: Reviewer pairs extracted trial characteristics and used an activity-based coding strategy to characterize the interventions; fidelity was confirmed with authors. Blinded to trial outcomes, reviewers noted the extent to which interventions placed additional work on patients after discharge or supported their capacity for self-care in accordance with the cumulative complexity model., Main Outcomes and Measures: Relative risk of all-cause or unplanned readmission with or without out-of-hospital deaths at 30 days postdischarge., Results: In 42 trials, the tested interventions prevented early readmissions (pooled random-effects relative risk, 0.82 [95% CI, 0.73-0.91]; P < .001; I² = 31%), a finding that was consistent across patient subgroups. Trials published before 2002 reported interventions that were 1.6 times more effective than those tested later (interaction P = .01). In exploratory subgroup analyses, interventions with many components (interaction P = .001), involving more individuals in care delivery (interaction P = .05), and supporting patient capacity for self-care (interaction P = .04) were 1.4, 1.3, and 1.3 times more effective than other interventions, respectively. A post hoc regression model showed incremental value in providing comprehensive, postdischarge support to patients and caregivers., Conclusions and Relevance: Tested interventions are effective at reducing readmissions, but more effective interventions are complex and support patient capacity for self-care. Interventions tested more recently are less effective.

Background: In this article we outline Burden of Treatment Theory, a new model of the relationship between sick people, their social networks, and healthcare services. Health services face the challenge of growing populations with long-term and life-limiting conditions, they have responded to this by delegating to sick people and their networks routine work aimed at managing symptoms, and at retarding - and sometimes preventing - disease progression. This is the new proactive work of patient-hood for which patients are increasingly accountable: founded on ideas about self-care, self-empowerment, and self-actualization, and on new technologies and treatment modalities which can be shifted from the clinic into the community. These place new demands on sick people, which they may experience as burdens of treatment., Discussion: As the burdens accumulate some patients are overwhelmed, and the consequences are likely to be poor healthcare outcomes for individual patients, increasing strain on caregivers, and rising demand and costs of healthcare services. In the face of these challenges we need to better understand the resources that patients draw upon as they respond to the demands of both burdens of illness and burdens of treatment, and the ways that resources interact with healthcare utilization., Summary: Burden of Treatment Theory is oriented to understanding how capacity for action interacts with the work that stems from healthcare. Burden of Treatment Theory is a structural model that focuses on the work that patients and their networks do. It thus helps us understand variations in healthcare utilization and adherence in different healthcare settings and clinical contexts.

The major objective of this study was to determine whether short-term preovulatory progestagen treatment of mares could effectively delay ovulation. Secondary objectives were to determine the effect such supplementation had on signs of estrus, follicular growth, postovulatory luteal function and pregnancy rate. Thirteen cyclic mares of different breeds were used in this study during the natural breeding season. Once mares were confirmed in estrus with a follicle of 35 mm in diameter, they were assigned in random order to receive no treatment (control), placement of a progesterone-impregnated controlled intravaginal drug releasing device (CIDR) for 2 days, or oral altrenogest treatment (0.044 mg/kg/d) for 2 days. Transrectal ultrasonography and teasing with a vigorous stallion were performed daily. Mares were inseminated every 48 h after the end of experimental treatment (progestagen groups) or beginning when the follicular diameter was 35 mm (control group) with fresh extended semen of a single fertile stallion. Each mare was followed for 3-5 cycles, allowing each treatment to be applied one or two times. Neither CIDR nor altrenogest treatment delayed ovulation. Treatment had no effect on follicular growth rate or the size of the ovulatory follicle immediately preceding ovulation. Both forms of progestagen treatment effectively abolished estrous behavior within 24h. Estrous response to the stallion returned to the control level after cessation of treatment. Similarly, a reduction in endometrial edema was detected during progestagen treatment, which returned to normal after cessation of treatment. Altrenogest treatment tended to reduce the chance of pregnancy (P=0.09) compared to the control group. The use of progestagens to delay ovulation in mares lacks efficacy and may threaten successful establishment of pregnancy., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Treatment burden can be defined as the self-care practices that patients with chronic illness must perform to respond to the requirements of their healthcare providers, as well as the impact that these practices have on patient functioning and well being. Increasing levels of treatment burden may lead to suboptimal adherence and negative outcomes. Systematic review of the qualitative literature is a useful method for exploring the patient experience of care, in this case the experience of treatment burden. There is no consensus on methods for qualitative systematic review. This paper describes the methodology used for qualitative systematic reviews of the treatment burdens identified in three different common chronic conditions, using stroke as our exemplar., Methods: Qualitative studies in peer reviewed journals seeking to understand the patient experience of stroke management were sought. Limitations of English language and year of publication 2000 onwards were set. An exhaustive search strategy was employed, consisting of a scoping search, database searches (Scopus, CINAHL, Embase, Medline & PsycINFO) and reference, footnote and citation searching. Papers were screened, data extracted, quality appraised and analysed by two individuals, with a third party for disagreements. Data analysis was carried out using a coding framework underpinned by Normalization Process Theory (NPT)., Results: A total of 4364 papers were identified, 54 were included in the review. Of these, 51 (94%) were retrieved from our database search. Methodological issues included: creating an appropriate search strategy; investigating a topic not previously conceptualised; sorting through irrelevant data within papers; the quality appraisal of qualitative research; and the use of NPT as a novel method of data analysis, shown to be a useful method for the purposes of this review., Conclusion: The creation of our search strategy may be of particular interest to other researchers carrying out synthesis of qualitative studies. Importantly, the successful use of NPT to inform a coding frame for data analysis involving qualitative data that describes processes relating to self management highlights the potential of a new method for analyses of qualitative data within systematic reviews.

Background: Patients with chronic disease may experience complicated management plans requiring significant personal investment. This has been termed 'treatment burden' and has been associated with unfavourable outcomes. The aim of this systematic review is to examine the qualitative literature on treatment burden in stroke from the patient perspective., Methods and Findings: The search strategy centred on: stroke, treatment burden, patient experience, and qualitative methods. We searched: Scopus, CINAHL, Embase, Medline, and PsycINFO. We tracked references, footnotes, and citations. Restrictions included: English language, date of publication January 2000 until February 2013. Two reviewers independently carried out the following: paper screening, data extraction, and data analysis. Data were analysed using framework synthesis, as informed by Normalization Process Theory. Sixty-nine papers were included. Treatment burden includes: (1) making sense of stroke management and planning care, (2) interacting with others, (3) enacting management strategies, and (4) reflecting on management. Health care is fragmented, with poor communication between patient and health care providers. Patients report inadequate information provision. Inpatient care is unsatisfactory, with a perceived lack of empathy from professionals and a shortage of stimulating activities on the ward. Discharge services are poorly coordinated, and accessing health and social care in the community is difficult. The study has potential limitations because it was restricted to studies published in English only and data from low-income countries were scarce., Conclusions: Stroke management is extremely demanding for patients, and treatment burden is influenced by micro and macro organisation of health services. Knowledge deficits mean patients are ill equipped to organise their care and develop coping strategies, making adherence less likely. There is a need to transform the approach to care provision so that services are configured to prioritise patient needs rather than those of health care systems.

The synthesis and in vitro binding affinity for a novel series of potent androgen receptor modulators is described. One of the more potent compounds (17, RAD35010) was further characterized in vivo where it restored levator ani weight in castrated male rats to near sham level while having no significant effect on prostate weight., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

This report describes the discovery of RAD140, a potent, orally bioavailable, nonsteroidal selective androgen receptor modulator (SARM). The characterization of RAD140 in several preclinical models of anabolic androgen action is also described.

Adaptive seating devices (ASDs) are used in the treatment of children with multiple handicaps. This longitudinal study evaluated, through direct observation and parent-guardian assessment, the behavioral changes seen with the use of ASDs and programming. Nineteen individuals with multiple handicaps and developmental disabilities, aged 1 to 6 years, participated as subjects. Data were collected by a trained observer from eight on-site evaluations and from parent-guardian responses to a preequipment and postequipment questionnaire. Evaluations were made every six weeks, starting about three months before and ending about six months after receiving the seating devices. The activities observed were head control, controlled sitting posture, visual tracking, reach, and grasp. Rating scale data were analyzed using an analysis of variance and a Friedman's test. Other data were analyzed descriptively for frequencies and central tendencies. Sitting posture, head control, and grasp improved significantly. Parent perceptions of the equipment indicated that the chairs freed parents from the need to provide support for their children's activities of daily living, which enabled them to participate in other activities with the children and around the home.