Breast cancer metastasis to brain results in recruitment and activation of microglia through annexin-A1/formyl peptide receptor signaling.

BACKGROUND: Despite advancements in therapies, brain metastasis in patients with triple negative subtype of breast cancer remains a therapeutic challenge. Activated microglia are often observed in close proximity to, or within, malignant tumor masses, suggesting a critical role that microglia play in brain tumor progression. Annexin-A1 (ANXA1), a glucocorticoid-regulated protein with immune-regulatory properties, has been implicated in the growth and metastasis of many cancers. Its role in breast cancer-microglia signaling crosstalk is not known. METHODS: The importance of microglia proliferation and activation in breast cancer to brain metastasis was evaluated in MMTV-Wnt1 spontaneous mammary tumor mice and BALBc mice injected with 4T1 murine breast cancer cells into the carotid artery using flow cytometry. 4T1 induced-proliferation and migration of primary microglia and BV2 microglia cells were evaluated using 2D and coculture transwell assays. The requirement of ANXA1 in these functions was examined using a Crispr/Cas9 deletion mutant of ANXA1 in 4T1 breast cancer cells as well as BV2 microglia. Small molecule inhibition of the ANXA1 receptor FPR1 and FPR2 were also examined. The signaling pathways involved in these interactions were assessed using western blotting. The association between lymph node positive recurrence-free patient survival and distant metastasis-free patient survival and ANXA1 and FPR1 and FPR2 expression was examined using TCGA datasets. RESULTS: Microglia activation is observed prior to brain metastasis in MMTV-Wnt1 mice with primary and secondary metastasis in the periphery. Metastatic 4T1 mammary cancer cells secrete ANXA1 to promote microglial migration, which in turn, enhances tumor cell migration. Silencing of ANXA1 in 4T1 cells by Crispr/Cas9 deletion, or using inhibitors of FPR1 or FPR2 inhibits microglia migration and leads to reduced activation of STAT3. Finally, elevated ANXA1, FPR1 and FPR2 is significantly associated with poor outcome in lymph node positive patients, particularly, for distant metastasis free patient survival. CONCLUSIONS: The present study uncovered a network encompassing autocrine/paracrine ANXA1 signaling between metastatic mammary cancer cells and microglia that drives microglial recruitment and activation. Inhibition of ANXA1 and/or its receptor may be therapeutically rewarding in the treatment of breast cancer and secondary metastasis to the brain.

Safe Patient Handling and Mobility: Development and Implementation of a Large-Scale Education Program.

This article addresses the development, implementation, and evaluation of an education program for safe patient handling and mobility at a large academic medical center. The ultimate goal of the program was to increase safety during patient mobility/transfer and reduce nursing staff injury from lifting/pulling. This comprehensive program was designed on the basis of the principles of prework, application, and support at the point of care. A combination of online learning, demonstration, skill evaluation, and coaching at the point of care was used to achieve the goal. Specific roles and responsibilities were developed to facilitate implementation. It took 17 master trainers, 88 certified trainers, 176 unit-based trainers, and 98 coaches to put 3706 nurses and nursing assistants through the program. Evaluations indicated both an increase in knowledge about safe patient handling and an increased ability to safely mobilize patients. The challenge now is sustainability of safe patient-handling practices and the growth and development of trainers and coaches.

Cognitive dysfunction in older adults hospitalized for acute heart failure.

BACKGROUND: Few studies have measured cognitive dysfunction in older adults during acute exacerbations of heart failure (HF), even though 25% of patients are readmitted within 30 days. The aims of this study were to examine cognitive dysfunction and acute HF symptoms in older adults hospitalized for HF and to evaluate the relationship between cognitive dysfunction and 30-day rehospitalization rates for acute HF. METHODS AND RESULTS: A cross-sectional descriptive design was used to characterize cognitive function in 53 older adults hospitalized for acute HF with the use of Cogstate computerized neuropsychologic tests. Demographic characteristics, HF symptoms (dyspnea, fatigue, pain, and depressed mood), comorbidity, and 30-day readmission HF rates were also measured. Dyspnea was measured with the use of the Parshall Brief Clinical Dyspnea Rating Questionnaire while fatigue was measured with the use of the Chalder et al Brief Fatigue Scale. We measured pain with the use of the Short-Form McGill Pain Questionnaire and depressed mood with the use of the depression subscale of the Hospital Anxiety and Depression Scale. Comorbid conditions were measured with the use of the Charlson comorbidity index. With the use of linear regression, dyspnea (ß = -.281; P = .030), pain (ß = .323; P = .011), and depressed mood (ß = .406, P = .003) were associated with reduced attention and working memory speed, and pain (ß = -.372; P = .005) and fatigue (ß = -.275; P = .033) were associated with reduced accuracy of attention and working memory. Ten patients were readmitted within 30 days for HF. According to Mann-Whitney U analysis, cognitive dysfunction measures (P = .090-.803) failed to show differences in HF readmission. CONCLUSIONS: Participants with more and worse symptoms had decreased speed and decreased accuracy in the cognitive domains tested. Cognitive dysfunction measures did not differentiate participants who were readmitted versus those who were not readmitted within 30 days for acute HF.

The Impact of Hospital-Based In Situ Simulation on Nurses' Recognition and Intervention of Patient Deterioration.

Preparing nurses to recognize the signs and symptoms of a deteriorating patient and to provide appropriate initial interventions is essential. Hospital-based in situ simulation education is an effective evidence-based method that supports adult learning in a safe environment. The purpose of this article is to discuss the development, implementation, and evaluation of an in situ simulation program and the positive impact on nurses' confidence level in the recognition and initiation of interventions for a deteriorating patient.

Recruitment and Retention Challenges of Examining Cognitive Dysfunction in Older Adults Hospitalized for Acute Heart Failure.

BACKGROUND: Barriers to recruiting and retaining acutely ill older adults in clinical research include complexity of illness, fatigue, and early discharge. OBJECTIVE: To describe recruitment and retention challenges of examining cognitive dysfunction in older adults hospitalized for acute heart failure. METHODS: An examination of the reasons for recruitment and retention issues within an acute care, university-affiliated health care system. RESULTS: Sixty-two patients refused to participate for a variety of reasons; 11 were ineligible, and 27 participants who completed initial data collection refused to participate further because they were too tired, were being discharged on the day of data collection, or were discharged before the next data collection day. CONCLUSIONS: Multiple barriers to the recruitment and retention of older adults hospitalized for acute heart failure were identified. Strategies are needed to augment recruitment and retention efforts, including expanding the number of data collection sites and allocating sufficient support resources.

Future of advanced practice public health nursing education.

The objective of this study was to conduct an assessment of the need for advanced practice, master's-prepared public health nurses in Michigan. A cross-sectional design was used to conduct interviews with former students, community leaders, and faculty. Content was analyzed qualitatively for themes. Participants were enthusiastic about the practice environment, but funding was a major concern. Almost all participants thought jobs were available and that public health nursing was cost-effective, yet there was concern about the aging work force and the need for higher education. Other disciplines serving in public health roles and hospitals were identified as competition to the public health nurse. Epidemiology, prevention, community assessment/program planning, health policy/law/ethics, leadership, health services, informatics, research, and grant writing were noted as skills needed. The results of this study are favorable for the future of advanced practice public health nursing practice and education.

The impact of Sun Solutions educational interventions on select health belief model constructs.

The purpose of this study was to offer the Sun Solutions intervention to operating engineers (N = 232) to decrease sun exposure and skin cancer. The majority (82%) of the engineers worked outside between 10 a.m. and 3 p.m., 4 to 5 hours a day; 81.4% reported more than one sunburn during the past year and 70% sometimes or never used sunscreen compared to 30% who wore sunscreen approximately 50% or more of the time. Most reported that the intervention was helpful (97%), most were satisfied (96%) with the intervention, and 84% expressed a future intention to use sunscreen. Regarding sun protective behaviors, the intervention significantly improved perceived self-efficacy (p < .05) and increased perceived barriers (p < .05). Regarding sunburn and skin cancer, the intervention increased perceived benefits (p < .05), susceptibility (p < .05), and severity (p < .05) for sunburning, but not skin cancer (p > .10). The Sun Solutions intervention showed the potential to increase sunscreen use and decrease the risk of sunburn and skin cancer among operating engineers.

Type 1 diabetes exaggerates features of Alzheimer's disease in APP transgenic mice.

A number of studies suggest an association between Alzheimer's disease (AD) and diabetes: AD patients show impaired insulin function, whereas cognitive deficits and increased risk of developing AD occur in diabetic patients. The reasons for the increased risk are not known. Recent studies of disturbances in the insulin-signaling pathway have revealed new perspectives on the links between AD and Type 1 diabetes with a particular focus on glycogen synthase-kinase-3 (GSK3). We have therefore characterized a mouse model of combined insulin-deficient diabetes and AD and find that diabetes exaggerated defects in the brain of APP transgenic mice. Mice with combined APP overexpression and diabetes showed a decreased insulin receptor activity and an increased GSK3beta activity. Concomitantly, tau phosphorylation and number of Abeta plaques, the two pathologic hallmarks of AD, were increased in the brain of diabetic-APP transgenic mice. Our results indicate that the pathologic features of AD are exaggerated in the brain of APP transgenic mice that have concurrent insulin-deficient diabetes, and underscore a possible mechanism of brain dysfunction common to AD and diabetes.

Allodynia and hyperalgesia in diabetic rats are mediated by GABA and depletion of spinal potassium-chloride co-transporters.

Diabetic rats show behavioral indices of painful neuropathy that may model the human condition. Hyperalgesia during the formalin test in diabetic rats is accompanied by the apparently paradoxical decrease in spinal release of excitatory neurotransmitters and increase in the inhibitory neurotransmitter GABA. Decreased expression of the potassium-chloride co-transporter, KCC2, in the spinal cord promotes excitatory properties of GABA. We therefore measured spinal KCC2 expression and explored the role of the GABA(A) receptor in rats with painful diabetic neuropathy. KCC2 protein levels were significantly reduced in the spinal cord of diabetic rats, while levels of NKCC1 and the GABA(A) receptor were unchanged. Spinal delivery of the GABA(A) receptor antagonist bicuculline reduced formalin-evoked flinching in diabetic rats and also dose-dependently alleviated tactile allodynia. GABA(A) receptor-mediated rate-dependent depression of the spinal H reflex was absent in the spinal cord of diabetic rats. Control rats treated with the KCC2 blocker DIOA, mimicked diabetes by showing increased formalin-evoked flinching and diminished rate- dependent depression. The ability of bicuculline to alleviate allodynia and formalin-evoked hyperalgesia in diabetic rats is consistent with a reversal of the properties of GABA predicted by reduced spinal KCC2 and suggests that reduced KCC2 expression and increased GABA release contribute to spinally mediated hyperalgesia in diabetes.

Expression of interleukin-17B in mouse embryonic limb buds and regulation by BMP-7 and bFGF.

Interleukin-17B (IL-17B) is a member of interleukin-17 family that displays a variety of proinflammatory and immune modulatory activities. In this study, we found that IL-17B mRNA was maximally expressed in the limb buds of 14.5 days post coitus (dpc) mouse embryo and declined to low level at 19.5 dpc. By immunohistochemical staining, the strongest IL-17B signals were observed in the cells of the bone collar in the primary ossification center. The chondrocytes in the resting and proliferative zones were stained moderately, while little staining was seen in the hypertrophic zone. Furthermore, in both C3H10T1/2 and MC3T3-E1 cells, the IL-17B mRNA was up-regulated by recombinant human bone morphogenetic protein-7, but down-regulated by basic fibroblast growth factor via the extracellular signal-regulated kinase pathway. This study provides the first evidence that IL-17B is expressed in the mouse embryonic limb buds and may play a role in chondrogenesis and osteogenesis.