MerTK Drives Proliferation and Metastatic Potential in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is characterized by the absence of the estrogen receptor, progesterone receptor, and receptor tyrosine kinase HER2 expression. Due to the limited number of FDA-approved targeted therapies for TNBC, there is an ongoing need to understand the molecular underpinnings of TNBC for the development of novel combinatorial treatment strategies. This study evaluated the role of the MerTK receptor tyrosine kinase on proliferation and invasion/metastatic potential in TNBC. Immunohistochemical analysis demonstrated MerTK expression in 58% of patient-derived TNBC xenografts. The stable overexpression of MerTK in human TNBC cell lines induced an increase in proliferation rates, robust in vivo tumor growth, heightened migration/invasion potential, and enhanced lung metastases. NanoString nCounter analysis of MerTK-overexpressing SUM102 cells (SUM102-MerTK) revealed upregulation of several signaling pathways, which ultimately drive cell cycle progression, reduce apoptosis, and enhance cell survival. Proteomic profiling indicated increased endoglin (ENG) production in SUM102-MerTK clones, suggesting that MerTK creates a conducive environment for increased proliferative and metastatic activity via elevated ENG expression. To determine ENG's role in increasing proliferation and/or metastatic potential, we knocked out ENG in a SUM102-MerTK clone with CRISPR technology. Although this ENG knockout clone exhibited similar in vivo growth to the parental SUM102-MerTK clone, lung metastasis numbers were significantly decreased ~4-fold, indicating that MerTK enhances invasion and metastasis through ENG. Our data suggest that MerTK regulates a unique proliferative signature in TNBC, promoting robust tumor growth and increased metastatic potential through ENG upregulation. Targeting MerTK and ENG simultaneously may provide a novel therapeutic approach for TNBC patients.

The effects of active classroom breaks on moderate to vigorous physical activity, behaviour and performance in a Northern NSW primary school: A quasi-experimental study.

ISSUE ADDRESSED: Approximately 77% of NSW children aged 5 to 15 years do not meet physical activity guidelines and many spend a considerable amount of time sitting. Active breaks at primary school are feasible, may increase daily moderate to vigorous physical activity (MVPA) and decrease off-task behaviour without adversely affecting cognitive function and learning. METHODS: In this quasi-experimental study, 101 primary school children in six intervention classrooms participated in three 10-minute active breaks per day for six-weeks during class time, while five control classrooms were run as usual (n = 89). Physical activity levels were measured using wrist-worn Actigraph wGT3X-BT accelerometers and analysed using a random forest model. Students' off-task behaviour, wellbeing, cognitive function and maths performance were also measured. School staff completed a brief feedback survey. RESULTS: Children in the intervention group engaged in 15.4 and 10.9 minutes more MVPA per day at 3 and 6 weeks respectively (P < .001). Participation significantly increased the proportion of children who met the Australian 24-Hour Movement Guidelines (P < .001). At pre, middle and end of intervention, 44.4%, 60.8% and 55.1% of intervention children and 46.5%, 45.9% and 45.8% of controls met the guidelines. Significantly fewer students engaged in off-task behaviour in the intervention classes at mid and final weeks of intervention (-1.4 students, P = .003). No significant intervention effects were found for wellbeing, cognitive and maths performance. CONCLUSIONS: Active classroom breaks are an effective way to increase physical activity among primary school children while reducing off-task classroom behaviour. SO WHAT?: Primary school students' health would benefit from active breaks with no detrimental effects on wellbeing, maths and cognitive performance.

The Colorado Hospitals Substance Exposed Newborn Quality Improvement Collaborative: Standardization of Care for Opioid-Exposed Newborns Shortens Length of Stay and Reduces Number of Infants Requiring Opiate Therapy.

OBJECTIVES: To decrease the average length of stay (LOS) of opioid-exposed newborns (OENs) by 20% from baseline from April 2017 to December 2019. METHODS: The Colorado Hospitals Substance Exposed Newborn Quality Improvement Collaborative is a consortium of neonatal providers, public health experts, and legislative experts that provides infrastructure and resources for Colorado birthing hospitals to undertake initiatives focused on improving the care of OENs. The Colorado Hospitals Substance Exposed Newborn Quality Improvement Collaborative was started in September 2017 and includes 19 birthing hospitals in Colorado, with 12 contributing data to the centralized database. The interventions were focused on (1) hospital engagement and (2) increasing nonpharmacologic care (by using the Eat, Sleep, Console assessment tool; developing guidelines for breastfeeding eligibility; employing comfort measures before pharmacologic therapy; and administering opiate therapy on an as-needed basis). RESULTS: From April 2017 to December 2019, 787 OENs were identified. Among infants ≥35 weeks' gestational age without other medical diagnoses (n = 647), statistical process control charts revealed significant reduction in the primary outcome of interest, average hospital LOS, from 14.8 to 5.9 days. For all OENs, receipt of pharmacologic therapy declined from 61% to 23%. Among OENs who received pharmacologic therapy (and were ≥35 weeks' gestational age without other medical diagnoses), average LOS also declined from 21.9 to 8.0 days. CONCLUSIONS: Through standardization of OEN care focused on family engagement and nonpharmacologic care, this statewide collaborative reduced average LOS, the percentage of OENs requiring opiate therapy, and average LOS for OENs requiring opiate therapy.

Developing an evidence-based transition program for graduate nurses.

BACKGROUND: The catalyst to revise the graduate nurse program at an inner city hospital was a major service reconfiguration, which reduced services, staffing and graduate nurse positions. Parameters for the new program were that it was evidence-based and could function within the reduced resources. OBJECTIVE: Review current literature and design an evidence-based transition program. METHODS: Eight databases were searched for primary and secondary research and unpublished theses (2004-2014), which were then hand searched. Eighty-three articles were reviewed and 50 retained as they informed development of a program designed to actively promote the graduates' transition from undergraduate to independent health professional. RESULTS: Three key concepts emerged from the literature: the graduates' need for support, socialisation and facilitated learning opportunities. This article reviews the literature and outlines a program designed to maximise these concepts in an evidence-based transition program. Proposed evaluation tools are identified for use throughout the program.

Strategies to promote coping and resilience in oncology and palliative care nurses caring for adult patients with malignancy: a comprehensive systematic review.

BACKGROUND: Cancer care nursing is perceived as personally and professionally demanding. Developing effective coping skills and resilience has been associated with better health and wellbeing for nurses, work longevity and improved quality of patient care. OBJECTIVES: The objective of this systematic review was to identify personal and organizational strategies that promote coping and resilience in oncology and palliative care nurses caring for adult patients with malignancy. METHODS: The search strategy identified published and unpublished studies from 2007 to 2013. Individual search strategies were developed for the 12 databases accessed and search alerts established. The review considered qualitative, quantitative and mixed methods studies that assessed personal or organizational interventions, programs or strategies that promoted coping and resilience. These included studies employing clinical supervision, staff retreats, psycho-educational programs, compassion fatigue resilience programs, stress inoculation therapy and individual approaches that reduced the emotional impact of cancer care work. The outcomes of interest were the experience of factors that influence an individual's coping and resilience and outcomes of validated measures of coping or resilience. Methodological quality of studies was independently assessed by two reviewers prior to inclusion in the review using standardized critical appraisal instruments developed by the Joanna Briggs Institute. Standardized Joanna Briggs Institute tools were also used to extract data. Agreement on the synthesis of the findings from qualitative studies was reached through discussion. The results of quantitative studies could not be statistically pooled given the different study designs, interventions and outcome measures. These studies were presented in narrative form. RESULTS: Twenty studies were included in the review. Ten studies examined the experience of nurse's caring for the dying, the emotional impact of palliative care and oncology work and strategies to prevent burnout or avoid compassion fatigue, challenges in self-care, and processes nurses adopted to cope with work related stress. Six studies evaluated different interventions provided by organizations to improve coping and resilience. Evidence for the effectiveness of interventions was limited to three studies. The results are discussed under four headings: (i) preventative measures (ii) control measures (iii) unburdening and "letting go", and (iv) growing and thriving. CONCLUSION: This review identified a number of strategies to better prepare nurses for practice and maintain their psychological wellbeing. Although no firm conclusions can be drawn in respect to the most effective interventions, strategies with merit included those that: a) foster connections within the team; b) provide education and training to develop behaviors that assist in controlling or limiting the intensity of stress, or aiding recovery; and c) assist in processing emotion and learning from experiences. Although individuals must take responsibility for developing personal strategies to assist coping and resilience, organizational support is integral to equipping individuals to deal with work related challenges. IMPLICATIONS FOR PRACTICE: A range of formal and informal support is required to promote coping and resilience. IMPLICATIONS FOR RESEARCH: There is a need for large, well designed, multisite, experimental studies to evaluate the effectiveness of interventions that promote coping and resilience in adult palliative care or oncology nurses.

Three-year follow-up of an early childhood intervention: what about physical activity and weight status?

BACKGROUND: Fundamental movement skills are a correlate of physical activity and weight status. Children who participated in a preschool intervention had greater movement skill proficiency and improved anthropometric measures (waist circumference and BMI z scores) post intervention. Three years later, intervention girls had retained their object control skill advantage. The study purpose was to assess whether at 3-year follow up a) intervention children were more physically active than controls and b) the intervention effect on anthropometrics was still present. METHODS: Children were assessed at ages 4, 5, and 8 years for anthropometric measures and locomotor and object control proficiency (Test of Gross Motor Development-2). At age 8, children were also assessed for moderate to vigorous physical activity (MVPA) (using accelerometry). Several general linear models were run, the first with MVPA as the outcome, intervention/control, anthropometrics, object control and locomotor scores as predictors, and age and sex as covariates. The second and third models were similar, except baseline to follow-up anthropometric differences were the outcome. RESULTS: Overall follow-up rate was 29% (163/560), with 111 children having complete data. There were no intervention control differences in either MVPA or anthropometrics. CONCLUSION: Increased skill competence did not translate to increased physical activity.

'SI-SRH' - a new model to manage sexual health following a spinal cord injury: our experience.

AIMS AND OBJECTIVES: To maximise involvement of the multidisciplinary team using a model of sexual health management for spinal cord-injured persons. BACKGROUND: Regaining sexual function is a priority following spinal cord injury, with the majority of people remaining sexually active with a satisfying sex life. Nevertheless, rehabilitation programmes often focus on activities related to mobility and elimination, with sexual health relegated to a secondary under-resourced position. DESIGN: Model creation and audit of current and desired status to identify required education. METHODS: A four-tier model for sexual health management identified phases of management, increasing in complexity, from tier 1 to tier 4. The model was used to audit the current and desired status of the multidisciplinary team on a spinal injuries unit, identifying knowledge levels, barriers to involvement and education requirements. RESULTS: Fifty-nine questionnaires were completed (85%) by nurses and allied health professionals. Knowledge deficits and discomfort with the topic were the primary reasons prohibiting involvement with sexual health rehabilitation. Two thirds were willing to be involved with sexual health activities, mainly at an introductory level rather than providing education or problem-solving. However, following relevant education, the level of involvement changed: 90% (n = 53) desired involvement at more complex levels, and 10% (n = 6) were unwilling to be involved. CONCLUSIONS: Developing the necessary skills and knowledge creates potential to increase the resources available to participate in sexual health rehabilitation following a spinal cord injury and ensure that it is a core rehabilitation activity. RELEVANCE TO CLINICAL PRACTICE: The progressive model portrayed discrete phases of sexual health management, which collectively portray the whole. Team members identified a level of involvement to compliment their skills and knowledge. The audit demonstrated that the primary barriers to involvement were not culture, language or attitude as hypothesised, but inadequate knowledge, addressable through education.

Three year follow-up of an early childhood intervention: is movement skill sustained?

BACKGROUND: Movement skill competence (e.g. the ability to throw, run and kick) is a potentially important physical activity determinant. However, little is known about the long-term impact of interventions to improve movement skills in early childhood. This study aimed to determine whether intervention preschool children were still more skill proficient than controls three years after a 10 month movement skill focused intervention: 'Tooty Fruity Vegie in Preschools'. METHODS: Children from 18 intervention and 13 control preschools in NSW, Australia were assessed at ages four (Time1), five (T2) and eight years (T3) for locomotor (run, gallop, hop, leap, horizontal jump, slide) and object control proficiency (strike, bounce, catch, kick, overhand throw, underhand roll) using the Test of Gross Motor Development-2. Multi-level object control and locomotor regression models were fitted with variables time, intervention (yes/no) and a time*intervention interaction. Both models added sex of child and retained if significant, in which case interactions of sex of child with other variables were modelled and retained. SPSS (Version 17.0) was used. RESULTS: Overall follow-up rate was 29% (163/560). Of the 137 students used in the regression models, 53% were female (n = 73). Intervention girls maintained their object control skill advantage in comparison to controls at T3 (p = .002), but intervention boys did not (p = .591). At T3, there were no longer intervention/control differences in locomotor skill (p = .801). CONCLUSION: Early childhood settings should implement movement skill interventions and more intensively target girls and object control skills.

AFB(1) -induced mutagenesis of the gpt gene in AS52 cells.

Aflatoxin B(1) (AFB(1) ) is a potent mutagen and an important risk factor for hepatocellular carcinoma (HCC) in humans. Transgenic mouse strains and cells in culture have been used to detect different types of mutations caused by AFB(1) and investigate the molecular determinants of their location and frequency. The AFB(1) mutational spectrum in the gpt gene was markedly different in AS52 cells compared with the liver in gpt delta B6C3F1 transgenic mice. The results demonstrate the importance of metabolism, chromosomal location, transcription and selection conditions on mutational spectra.

Tooty Fruity Vegie: an obesity prevention intervention evaluation in Australian preschools.

ISSUES ADDRESSED: This paper presents the findings from a cluster randomised controlled evaluation of a preschool-based intervention (children aged 3-6 years), on the North Coast of NSW, which aimed to decrease overweight and obesity prevalence among children by improving fundamental movement skills (FMS), increasing fruit and vegetable intake and decreasing unhealthy food consumption. METHODS: The Tooty Fruity Vegie in Preschools program was implemented in 18 preschools for 10 months during 2006 and 2007. It included nutrition and physical activity strategies. Pre and post intervention evaluation compared intervention and control children and was conducted at the beginning and end of each year. It included FMS testing, lunch box audits and anthropometric measures of children as well as parents' surveys regarding children's food intake, physical activity and sedentary behaviours. RESULTS: In comparison to controls, children in intervention preschools significantly improved movement skills (14.79 units, p<0.001), had more fruit and vegetable serves (0.63 serves, p=0.001) and were less likely to have unhealthy food items (p<0.001) in their lunch boxes following the intervention. There was also a significant difference in waist circumference growth (-0.80 cm, p=0.002) and a reduction of BMI Z scores (-0.15, p=0.022). CONCLUSIONS: The 10-month intervention in preschools produced significant changes in children's food intake, movement skills and indicators of weight status.

A single neonatal exposure to aflatoxin b1 induces prolonged genetic damage in two loci of mouse liver.

Aflatoxin B (1) (AFB(1)) is a risk factor for hepatocellular carcinoma in humans. Infant, but not adult, mice are sensitive to AFB(1)-induced liver carcinogenesis; a single dose during the neonatal period leads to hepatocellular carcinoma in adulthood. Earlier work defined the mutational spectrum in the gpt gene of gpt delta B6C3F1 mice 3 weeks after exposure to aflatoxin. In the present study, we examined the gpt spectrum 10 weeks postdosing and expanded the study to examine, at 3 and 10 weeks, the spectrum at a second locus, the red/gam genes of the mouse λEG10 transgene. Whereas the gpt locus is typically used to define local base changes, the red/gam genes, via the Spi(-) assay, often are used to detect more global mutations such as large deletions and rearrangements. Three weeks after dosing with AFB(1), there was a 10-fold increase over the control in the Spi(-) mutant fraction (MF) in liver DNA; after 10 weeks, a further increase was observed. The MF in the gpt gene was also increased at 10 weeks compared with the MF at 3 weeks. No gender-specific differences were found in the Spi(-) or gpt MFs. Whereas Spi(-) mutations often signal large genetic changes, they did not in this specific case. The Spi(-) spectrum was dominated by GC to TA transversions, with one exceptionally strong hotspot at position 314. Using two genetic loci, the data show a strong preference for the induction of GC to TA mutations in mice, which is the dominant mutation seen in people exposed to aflatoxin.

Sustaining an obesity prevention intervention in preschools.

ISSUE ADDRESSED: This paper outlines the healthy eating and physical activity strategies that were sustained over two and three years after a year-long preschool obesity prevention program in rural and regional NSW, Australia. METHODS: Seventeen preschool directors were interviewed as part of the pre and post-evaluation data collection in preschools in 2006 and 2007. In July 2009 a follow-up study of the Tooty Fruity Vegie program was conducted by an independent party to evaluate the program's sustainability. Research was in the form of a telephone interview and related to questions originally asked of the directors. RESULTS: Most of the Tooty Fruity Vegie strategies continued in preschools after health promotion contact ceased. The strategies that were sustained were those that involved experiential activities for the children (e.g taste testing and physical activity sessions), those that were easy for the preschool to implement (e.g. newsletter tips) and those that became embedded into the organisational or environmental framework (e.g. increased access to drinking water). CONCLUSION: A one-year multi-strategic obesity prevention program in preschool shows promise in sustaining some strategies beyond the year of assisted intervention.

Strategies to promote intermittent self-catheterisation in adults with neurogenic bladders: A comprehensive systematic review.

EXECUTIVE SUMMARY: Background Clean intermittent self-catheterisation is the gold standard in the management of neurogenic/neuropathic bladder disorders, providing independence, alleviating symptoms and complications of the urinary tract.Objectives The objective of this systematic review was to establish the best available evidence on strategies to promote intermittent urethral self-catheterisation in adults with neurogenic/neuropathic bladders.Methods The search strategy identified published and unpublished studies reported from 1970 to 2009. Individual search strategies were developed for the 12 databases accessed and search alerts established. The review considered qualitative and quantitative studies, mixed methods and case studies. Interventions, programs and strategies preparing adults to self-catheterise included education, suitability for selfcatheterisation and interventions promoting compliance and continuity. Outcomes of interest were the quality of life and depression, long-term compliance, advantages/disadvantages of urethral self-catheterisation and limitations to selfcatheterisation.Standardised critical appraisal instruments developed by the Joanna Briggs Institute were used by two independent reviewers to assess the quality of eligible studies for inclusion in the review. Standardised Joanna Briggs Institute tools were also used to extract data. Criteria developed by Yin were employed to assess case studies. Qualitative findings were synthesised. As statistical pooling of the quantitative results was not possible, these results were presented in narrative form.Results From the 18 studies reviewed, three interventions (education and preparation, suitability to self-catheterise, and interventions promoting compliance/continuity), and three outcomes (effect of self-catheterisation on quality of life and depression, and longterm compliance) were addressed with multiple studies in each intervention and outcome. The results are discussed under four headings: (i) education essentials for selfcatheterisation (ii) factors promoting compliance and continuity with self-catheterisation, (iii) factors influencing quality of life and (IV) diagnostic sub-groups of people with a neurogenic bladder. CONCLUSION: The narrative and synthesised data from the 18 included studies identified findings to provide a basis for strategies to promote clean intermittent self-catheterisation in adults. These include an extended education program with a pre-education component, ongoing support and skills training. All aspects of education should reflect sound research findings related to quality of life issues.Implications for Practice The implications for clinical practice are the development of a comprehensive standardised education program that includes background information, skills training and follow-up support.Implications for Research The review highlights the need for further experimental research to confirm factors that will promote self-catheterisation in adults with neurogenic/neuropathic bladders, with particular reference specific sub-groups.

The Breast Surgery Gallery: an educational and counseling tool for people with breast cancer or having prophylactic breast surgery.

The Breast Surgery Gallery is a unique and innovative computer program of digital photographs depicting sequential images of oncoplastic and prophylactic breast surgery. Specialist breast nurse counselors developed the tool to provide education and assist in decision making for people facing oncoplastic and prophylactic breast surgery. This article presents a historical perspective of the development of the gallery and how it can be used during education and counseling. The authors discuss background validation, structure, and testing of the gallery, with case studies that illustrate its flexibility. Data from regular audits of the breast surgery gallery demonstrate the tool's value. The Breast Surgery Gallery is a user-friendly tool that enables patients to make informed decisions while providing realistic photographs of the postoperative recovery phase.

Tooty Fruity Vegie in Preschools: an obesity prevention intervention in preschools targeting children's movement skills and eating behaviours.

ISSUE ADDRESSED: This paper outlines the implementation strategies and evaluation methods of the Tooty Fruity Vegie (TFV) in Preschools program in NSW Australia which addressed diet, movement skills and overweight indicators. METHODS: The TFV program was a one-year intervention conducted during 2006 and 2007 in 18 preschools (matched with 13 control preschools). The study had a quasi-experimental design with pre- and postintervention evaluation of nutrition and physical activity variables as well as anthropometric measures. Details of the program's methodological aspects such as the recruitment process, intervention strategies and evaluation instruments are described.

p150/95 (CD11c/CD18) expression is required for the development of experimental autoimmune encephalomyelitis.

p150/95 (CD11c/CD18, CR4) is a member of the beta(2)-integrin family of adhesion molecules and is considered an important phagocytic receptor. The role of p150/95 in the development of central nervous system demyelinating diseases, including multiple sclerosis, remains unexplored. To determine p150/95-mediated mechanisms in experimental autoimmune encephalomyelitis (EAE), we performed EAE using CD11c-deficient (CD11c(-/-)) mice. EAE in CD11c(-/-) mice was significantly attenuated and characterized by markedly reduced spinal cord T-cell infiltration and interferon-gamma production by these cells. Adoptive transfer of antigen-restimulated T cells from wild-type to CD11c(-/-) mice produced significantly attenuated EAE, whereas transfer of CD11c(-/-) antigen-restimulated T cells to control mice induced a very mild, monophasic EAE. T cells from MOG(35-55) peptide-primed CD11c(-/-) mice displayed an unusual cytokine phenotype with elevated levels of interleukin (IL)-2, IL-4, and IL-12 but reduced levels of interferon-gamma, tumor necrosis factor-alpha, IL-10, IL-17, and transforming growth factor-beta compared with control mice. Overall, CD11c(-/-) T cells from primed mice proliferated comparably to that of control T cells on MOG(35-55) restimulation. Our results indicate that expression of p150/95 is critical on both T cells as well as other leukocytes for the development of demyelinating disease and may represent a novel therapeutic target for multiple sclerosis.

Complement in experimental autoimmune encephalomyelitis revisited: C3 is required for development of maximal disease.

Complement per se has been shown to play an important role in demyelinating disease but controversy remains regarding the role of C3 in the development and progression of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. In this study, we used C3(-/-) mice to confirm previous findings that C3 is required for full development of EAE. Furthermore, C3(+/-) mice (with serum C3 levels 50% that of wild-type mice) developed EAE with a severity intermediate between wild-type and C3(-/-) mice. Importantly transfer of wild-type encephalitogenic T cells to C3(-/-) mice resulted in attenuated EAE. C3(-/-) mice with EAE had fewer CD4(+) and CD8(+) T cells in the CNS and 50% fewer of these cells produced IFN-gamma compared to wild-type mice. When treated with anti-CD3 antibody, CD4(+) T cells from wild-type and C3(-/-) mice had similar activation profiles as judged by IFN-gamma production and CD25 and CD69 expression, indicating there is no gross or intrinsic defect in T cells from C3(-/-) mice. T cells from primed C3(-/-) mice proliferated comparably to that of control T cells on re-stimulation with MOG peptide. Our results confirm a requirement for C3 for maximal development of EAE and suggest that receptors for C3-derived activation fragments might be a viable therapeutic target for prevention and treatment demyelinating disease.