Circadian Oscillations Persist in Cervical and Esophageal Cancer Cells Displaying Decreased Expression of Tumor-Suppressing Circadian Clock Genes.

There is accumulating evidence for a link between circadian clock disruption and cancer progression. In this study, the circadian clock was investigated in cervical and esophageal cancers, to determine whether it is disrupted in these cancer types. Oncomine datamining revealed downregulation of multiple members of the circadian clock gene family in cancer patient tissue compared with matched normal epithelium. Real-time RT-PCR analysis confirmed significant downregulation of CLOCK, PER1, PER2, PER3, CRY1, CRY2, REV-ERBα, and RORα in esophageal tumor tissue. In cell line models, expression of several circadian clock genes was significantly decreased in transformed and cancer cells compared with noncancer controls, and protein levels were dysregulated. These effects were mediated, at least in part, by methylation, where CLOCK, CRY1, and RORα gene promoter regions were found to be methylated in cancer cells. Overexpression of CLOCK and PER2 in cancer cell lines inhibited cell proliferation and activation of RORα and REV-ERBα using agonists resulted in cancer cell death, while having a lesser effect on normal epithelial cells. Despite dysregulated circadian clock gene expression, cervical and esophageal cancer cells maintain functional circadian oscillations after Dexamethasone synchronization, as revealed using real-time bioluminescence imaging, suggesting that their circadian clock mechanisms are intact. IMPLICATIONS: This study is a first to describe dysregulated, yet oscillating, circadian clock gene expression in cervical and esophageal cancer cells, and knowledge of circadian clock functioning in these cancer types has the potential to inform chronotherapy approaches, where the timing of administration of chemotherapy is optimized on the basis of the circadian clock.

Development and Implementation of a Nurse-Led Model of Care Coordination to Provide Health-Sector Continuity of Care for People With Multimorbidity: Protocol for a Mixed Methods Study.

BACKGROUND: Innovative strategies are required to reduce care fragmentation for people with multimorbidity. Coordinated models of health care delivery need to be adopted to deliver consumer-centered continuity of care. Nurse-led services have emerged over the past 20 years as evidence-based structured models of care delivery, providing a range of positive and coordinated health care outcomes. Although nurse-led services are effective in a range of clinical settings, strategies to improve continuity of care across the secondary and primary health care sectors for people with multimorbidity have not been examined. OBJECTIVE: To implement a nurse-led model of care coordination from a multidisciplinary outpatient setting and provide continuity of care between the secondary and primary health care sectors for people with multimorbidity. METHODS: This action research mixed methods study will have two phases. Phase 1 includes a systematic review, stakeholder forums, and validation workshop to collaboratively develop a model of care for a nurse-led care coordination service. Phase 2, through a series of iterative action research cycles, will implement a nurse-led model of care coordination in a multidisciplinary outpatient setting. Three to five iterative action research cycles will allow the model to be refined and further developed with multiple data collection points throughout. RESULTS: Pilot implementation of the model of care coordination commenced in October 2018. Formal study recruitment commenced in May 2019 and the intervention and follow-up phases are ongoing. The results of the data analysis are expected to be available by March 2020. CONCLUSIONS: Nursing, clinician, and patient outcomes and experiences with the nurse-led model of care coordination will provide a template to improve continuity of care between the secondary and primary health care systems. The model template may provide a future pathway for implementation of nurse-led services both nationally and internationally. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/15006.

Repositioning Flubendazole for Spinal Cord Injury.

We previously reported the serendipitous observation that fenbendazole, a benzimidazole anthelmintic, improved functional and pathological outcomes following thoracic spinal cord contusion injury in mice when administered pre-injury. Fenbendazole is widely used in veterinary medicine. However, it is not approved for human use and it was uncertain if only post-injury administration would offer similar benefits. In the present study we evaluated post-injury administration of a closely related, human anthelmintic drug, flubendazole, using a rat spinal cord contusion injury model. Flubendazole, administered i.p. 5 or 10 mg/kg day, beginning 3 h post-injury and daily thereafter for 2 or 4 weeks, resulted in improved locomotor function after contusion spinal cord injury (SCI) compared with vehicle-treated controls. Histological analysis of spinal cord sections showed that such treatment with flubendazole also reduced lesion volume and improved total tissue sparing, white matter sparing, and gray matter sparing. Flubendazole inhibited the activation of glial fibrillary acidic protein (GFAP); suppressed cyclin B1 expression and Bruton tyrosine kinase activation, markers of B cell activation/proliferation and inflammation; and reduced B cell autoimmune response. Together, these results suggest the use of the benzimidazole anthelmintic flubendazole as a potential therapeutic for SCI.

The tumour suppressing role of the circadian clock.

The circadian clock and the ~24 h rhythms it generates are essential in maintaining regular tissue functioning. At the molecular level, the circadian clock comprises a core set of rhythmically expressed genes and gene products that are able to drive rhythmic expression of other genes to generate overt circadian rhythms. It has recently come to light that perturbations of circadian rhythms contribute to the development of pathological states such as cancer, and altered expression and/or regulation of circadian clock genes has been identified in multiple tumour types. This review summarises the important role the circadian system plays in regulating cellular processes, including the cell cycle, apoptosis, DNA repair, the epithelial-to-mesenchymal transition, metabolism and immunity and how its dysregulation has widespread implications and could be a critical player in the development of cancer. Understanding its role in cancer development is important for the field chronotherapy, where the timing of chemotherapy administration is optimised based on differences in circadian clock functioning in normal and cancer cells. This has been found to influence the patient response, minimising the side effects commonly associated with chemotherapy. © 2019 IUBMB Life, 2019.

The influence of workplace culture on nurses' learning experiences: a systematic review of qualitative evidence.

BACKGROUND: A healthy workplace culture enables nurses to experience valuable learning in the workplace. Learning in the workplace enables the provision of evidence-based and continuously improving safe patient care, which is central to achieving good patient outcomes. Therefore, nurses need to learn within a workplace that supports the implementation of evidence-based, professional practice and enables the best patient outcomes; the influence of workplace culture may play a role in this. OBJECTIVES: The purpose of this review was to critically appraise and synthesize the best available qualitative evidence to understand both the nurses' learning experiences within the workplace and the factors within the workplace culture that influence those learning experiences. INCLUSION CRITERIA TYPES OF PARTICIPANTS: Registered and enrolled nurses regulated by a nursing and midwifery board and/or recognized health practitioner regulation agency (or their international equivalent). PHENOMENA OF INTEREST: This review considered studies that described two phenomena of interest: the nurses' learning experience, either within an acute healthcare workplace or a workplace-related learning environment and the influence of workplace culture on the nurses' learning experience (within the workplace or workplace-related learning environment). CONTEXT: This review considered studies that included nurses working in an acute healthcare organization within a Western culture. TYPES OF STUDIES: This review considered studies that focused on qualitative evidence and included the following research designs: phenomenological, grounded theory and critical theory. SEARCH STRATEGY: Published and unpublished studies in English from 1980 to 2013 were identified using a three-step search strategy, searching various databases, and included hand searching of the reference lists within articles selected for appraisal. METHODOLOGICAL QUALITY: For studies meeting the inclusion criteria, methodological quality was assessed using a standardized checklist from the Joanna Briggs Institute Qualitative Assessment and Review Instrument (JBI-QARI). DATA EXTRACTION: Qualitative data were extracted from articles included in the review using the standardized data extraction tool from the JBI-QARI. DATA SYNTHESIS: Qualitative research findings were pooled using the Joanna Briggs Institute Qualitative Appraisal and Review Instrument (JBI-QARI). This involved the aggregation and synthesis of findings to generate a set of categories, which were then subjected to a meta-synthesis to produce a single comprehensive set of synthesized findings that could be used as a basis for evidence-based practice. RESULTS: Fourteen articles were identified following appraisal and a total of 105 findings (85 unequivocal and 20 credible) were extracted from included studies and grouped into eight categories based on similarity of meaning. Subsequently, categories were grouped into two synthesized findings. The two synthesized findings were as follows: ORGANIZATIONAL INFLUENCES: Enabling nurses to demonstrate accountability for their own learning, along with clear organizational systems that provide resources, time, adequate staffing and support, demonstrates encouragement for and the value of nurses' learning and education. RELATIONAL DYNAMICS: Nurses value their peers, expert nurses, preceptors, mentors and educators facilitating and encouraging their learning and professional development. CONCLUSION: An optimal workplace culture is central for nurses to experience valuable and relevant learning in the workplace. To emphasize the importance of nurses' learning in the workplace, working and learning is understood as an integrated experience. Consequently, a dual system that enables nurses to demonstrate accountability for their own learning, along with clear organizational and educational systems, is required to demonstrate the value in nurses' learning and education.

The impact of child, family, and professional support characteristics on the quality of life in families of young children with disabilities.

BACKGROUND: Families of young children with disabilities are faced with ongoing challenges that impact various aspects of family life. Given the increasing emphasis on promoting positive outcomes in these families, the overall aim of the current study was to examine the contribution of child, family, and support characteristics to the quality of life in families of young children with disabilities. METHOD: The sample was recruited from several early childhood intervention programs within metropolitan Melbourne, Australia, and consisted of 64 families of children aged between 3 and 5 years with a developmental delay or disability. RESULTS: As a whole, parental perceptions and experiences of family-centred professional support was one of the strongest predictors of family quality of life. The perceived intensity of child behavioural problems as well as support from extended family members also accounted for a significant proportion of unique variance in predicting quality of family life. CONCLUSION: The current findings provide further evidence for the importance of a family-focused approach to intervention that acknowledges and provides support that is tailored to the unique needs of each individual family. The practical implications of these results as well as directions for future research are discussed.

Allometry of alarm calls: black-capped chickadees encode information about predator size.

Many animals produce alarm signals when they detect a potential predator, but we still know little about the information contained in these signals. Using presentations of 15 species of live predators, we show that acoustic features of the mobbing calls of black-capped chickadees (Poecile atricapilla) vary with the size of the predator. Companion playback experiments revealed that chickadees detect this information and that the intensity of mobbing behavior is related to the size and threat of the potential predator. This study demonstrates an unsuspected level of complexity and sophistication in avian alarm calls.

Asymmetric lithium(I) and copper(II) alkoxy-N-heterocyclic carbene complexes; crystallographic characterisation and Lewis acid catalysis.

A one-pot synthesis of a wide range of bidentate, alkoxide-N-heterocyclic carbene ligands provides new lithium alkoxy-carbenes and a range of covalently bound organometallic Cu(II) carbene complexes, which are catalytically active, in some cases enantioselectively, for conjugate addition reactions.