Loss of Anti-Tumor Efficacy by Polyamine Blocking Therapy in GCN2 Null Mice.

GCN2 is one of the main sensors of amino acid starvation stress, and its activation in the stressful tumor microenvironment plays a crucial role in tumor survival and progression. We hypothesized that elevated polyamine biosynthesis and subsequent depletion of precursor arginine activates GCN2, thus rewiring metabolism to support tumor cell survival and drive myeloid immunosuppressive function. We sought to determine if the anti-tumor efficacy of a polyamine blocking therapy (PBT) may be mediated by its effect on GCN2. Unlike wild-type mice, PBT treatment in GCN2 knockout mice bearing syngeneic B16.F10 or EG7 tumors resulted in no tumor growth inhibition and no changes in the profile of infiltrating tumor immune cells. Studies with murine bone marrow cell cultures showed that increased polyamine metabolism and subsequent arginine depletion and GCN2 activation played an essential role in the generation and cytoprotective autophagy of myeloid derived suppressor cells (MDSCs) as well as the M2 polarization and survival of macrophages, all of which were inhibited by PBT. In all, our data suggest that polyamine-dependent GCN2 signaling in stromal cells promotes tumor growth and the development of the immunosuppressive tumor microenvironment, and that the PBT anti-tumor effect is mediated, at least in part, by targeting GCN2.

Harnessing the polyamine transport system to treat BRAF inhibitor-resistant melanoma.

BRAF mutations are present in over half of all melanoma tumors. Although BRAF inhibitors significantly improve survival of patients with metastatic melanoma, recurrences occur within several months. We previously reported that BRAF mutant melanoma cells are more sensitive to a novel arylmethyl-polyamine (AP) compound that exploits their increased polyamine uptake compared to that of BRAF wildtype cells. Using an animal model of BRAF inhibitor-resistant melanoma, we show that co-treatment with the BRAF inhibitor, PLX4720, and AP significantly delays the recurrence of PLX4720-resistant melanoma tumors and decreases tumor-promoting macrophages. Development of BRAF inhibitor-resistance enriches for metastatic cancer stem cells (CSC) and increases tumor-promoting macrophages. In vitro studies demonstrated that CD304+, CXCR4+ spheroid cultures of BRAF mutant melanoma cells are resistant to PLX4720 but are more sensitive to AP compared to monolayer cultures of the same cells. AP significantly inhibited YUMM1.7 melanoma cell invasiveness across a Matrigel-coated filter using the CXCR4 ligand, SDF-1α, as the chemoattractant. AP also blocked the chemotactic effect of SDF-1α on CXCR4+ macrophages and inhibited M2 polarization of macrophages. In melanoma-macrophage co-cultures, AP prevented the PLX4720-induced release of pro-tumorigenic growth factors, such as VEGF, from macrophages and prevented the macrophage rescue of BRAF mutant melanoma cells treated with PLX4720. Our study offers a novel therapy (AP) to treat chemo-resistant melanoma. AP is unique because it targets the polyamine transport system in BRAF inhibitor-resistant CSCs and also blocks CXCR4 signaling in invasive melanoma cells and pro-tumorigenic macrophages.

Dysregulated claudin-5 cycling in the inner retina causes retinal pigment epithelial cell atrophy.

Age-related macular degeneration (AMD) is the leading cause of central retinal vision loss worldwide, with an estimated 1 in 10 people over the age of 55 showing early signs of the condition. There are currently no forms of therapy available for the end stage of dry AMD, geographic atrophy (GA). Here, we show that the inner blood-retina barrier (iBRB) is highly dynamic and may play a contributory role in GA development. We have discovered that the gene CLDN5, which encodes claudin-5, a tight junction protein abundantly expressed at the iBRB, is regulated by BMAL1 and the circadian clock. Persistent suppression of claudin-5 expression in mice exposed to a cholesterol-enriched diet induced striking retinal pigment epithelium (RPE) cell atrophy, and persistent targeted suppression of claudin-5 in the macular region of nonhuman primates induced RPE cell atrophy. Moreover, fundus fluorescein angiography in human and nonhuman primate subjects showed increased retinal vascular permeability in the evening compared with the morning. These findings implicate an inner retina-derived component in the early pathophysiological changes observed in AMD, and we suggest that restoring the integrity of the iBRB may represent a novel therapeutic target for the prevention and treatment of GA secondary to dry AMD.

IL-1 Family Cytokine Regulation of Vascular Permeability and Angiogenesis.

The IL-1 family of cytokines are well-known for their primary role in initiating inflammatory responses both in response to and acting as danger signals. It has long been established that IL-1 is capable of simultaneously regulating inflammation and angiogenesis, indeed one of IL-1's earliest names was haemopoeitn-1 due to its pro-angiogenic effects. Other IL-1 family cytokines are also known to have roles in mediating angiogenesis, either directly or indirectly via induction of proangiogenic factors such as VEGF. Of note, some of these family members appear to have directly opposing effects in different tissues and pathologies. Here we will review what is known about how the various IL-1 family members regulate vascular permeability and angiogenic function in a range of different tissues, and describe some of the mechanisms employed to achieve these effects.

Geographic modeling for children at risk for home fires and burns.

This study developed a predictive model for fires and burns among parents and children in Jefferson County, Kentucky. Eight risk factors for pediatric burns with census tract level data available were identified. Risk factors were synthesized to develop a cartographic model with risk levels low, medium, high, and severe. Validation was performed with fire dispatch data. At-risk areas were concentrated in the county's northwest. Risk was correlated with fire incidence rate (ρ=0.67, p<0.001). Significant risk factors were race (ß=0.54, p<0.001), education (ß=0.38, p<0.001), and year home built (ß=-0.17, p=0.005). Cartographic modeling is a underutilized tool to identify at-risk areas.

An organizational process for promoting home fire safety in two community settings.

The purpose of this study was to describe the home fire safety quality improvement model designed to aid organizations in achieving institutional program goals. The home fire safety model was developed from community-based participatory research (CBPR) applying training-the-trainer methods and is illustrated by an institutional case study. The model is applicable to other types of organizations to improve home fire safety in vulnerable populations. Utilizing the education model leaves trained employees with guided experience to build upon, adapt, and modify the home fire safety intervention to more effectively serve their clientele, promote safety, and meet organizational objectives.

Geographic Mapping as a Tool for Identifying Communities at High Risk for Fires.

The purpose of this study was to evaluate whether the sample of older adults in a home fire safety (HFS) study captured participants living in the areas at highest risk for fire occurrence. The secondary aim was to identify high risk areas to focus future HFS interventions. Geographic information systems software was used to identify census tracts where study participants resided. Census data for these tracts were compared with participant data based on seven risk factors (ie, age greater than 65 years, nonwhite race, below high school education, low socioeconomic status, rented housing, year home built, home value) previously identified in a fire risk model. The distribution of participants and census tracts among risk categories determined how well higher risk census tracts were sampled. Of the 46 census tracts where the HFS intervention was implemented, 78% (n = 36) were identified as high or severe risk according to the fire risk model. Study participants' means for median annual family income (P < .0001) and median home value (P < .0001) were significantly lower than the census tract means (n = 46), indicating participants were at higher risk of fire occurrence. Of the 92 census tracts identified as high or severe risk in the entire county, the study intervention was implemented in 39% (n = 36), indicating 56 census tracts as potential areas for future HFS interventions. The Geographic information system-based fire risk model is an underutilized but important tool for practice that allows community agencies to develop, plan, and evaluate their outreach efforts and ensure the most effective use of scarce resources.

Development of a Fire Risk Model to Identify Areas of Increased Potential for Fire Occurrences.

The purposes of this study were to use geographic information systems to create a cartographic risk model predicting areas of increased potential for fire occurrences and to validate the model. Seven literature-identified risk factors associated with burn injury were older than 65 years, non-white race, below high school education, low socioeconomic status, rented housing, year home built, and home value. Geographic information system methods were used in risk factor model development. Model validation occurred using residential county fire dispatch data and statistical analysis. Areas of high and severe risk were primarily located in the northwestern and central county regions. A strong correlation (r = .66) was found between risk model scores and fire incidence rates. Significant differences in mean fire rates by risk category (F (187,3) = 87.58, P < .0001) were found, with the exception of the low and medium risk categories. Fire incidence rates among census tracts showed positive spatial autocorrelation (Moran's I = 0.542, P < .0001) producing a map showing a significant cluster of high fire incidence in the northwestern region. The risk model has potential to lead to more targeted and effective fire prevention education programs. Such models would allow fire departments to focus limited resources in areas of highest fire risk.

Intervention study for changes in home fire safety knowledge in urban older adults.

Older adults are more likely to experience problems that contribute to an increase in burn-related morbidity and mortality. The purpose of the current study was to determine if the educational home fire safety (HFS) intervention was an effective method of improving HFS knowledge over time in two groups of urban older adults, home bound and community-based. HFS knowledge of 110 urban older adults was assessed at baseline, immediately after watching a HFS DVD (recall), and at 2-week follow-up (retention). The United States Fire Administration Home Safety Checklist which examines HFS practices in the home was also administered. HFS knowledge scores significantly increased over time for both groups (p<0.0001), but no significant differences existed between the two groups over time (p=0.183). In addition, HFS knowledge scores were significantly impacted by the number of chronic illnesses, number of independent activities of daily living, and income. The findings from this study suggest the educational HFS intervention was effective in increasing urban older adults' HFS knowledge over time. Lowering the burns morbidity and mortality in the older adult population is an important public health concern that needs to be addressed through tailored prevention and education strategies.

Home fire safety education for parents of newborns.

In children under 1 year of age, the proportion of unintentional burns increases with infant age and mobility. Infants are not able to avoid burns and are dependent on parental or adult help. Treatment of burns in young children is expensive in terms of the life-long costs. The purpose of this study was to examine changes in home fire safety (HFS) knowledge and practices over time for parents of newborn children and expecting parents. HFS knowledge of 103 parents was assessed at baseline, immediately after watching a DVD on HFS (recall), and at 2-week follow-up (retention). In addition, the United States Fire Administration (USFA)/Federal Emergency Management Agency (FEMA) Home Safety Checklist which examines HFS practices in the homes was administered. Seventy percent of the participants were Caucasian, 65% were married, and 81% were first-time parents. HFS knowledge increased significantly from baseline to recall (45±12% vs. 87±17% correct responses, p<0.0001), but declined to 75±18% correct at retention. That is, an individual's baseline scores nearly doubled at recall (42±11% change in baseline score), but only increased by 67% at retention (30±15% change in baseline score). For a subsample of parents who completed the USFA Checklist (n=22), the mean percentage of advocated practices followed was 71±11% (range: 40-89%). Using DVDs was an effective educational modality for increasing HFS knowledge. This addressed an important problem of decreasing burns in infants through increasing parent knowledge and HFS practices using a short, inexpensive DVD.

Home fire safety beliefs and practices in homes of urban older adults.

The purpose of this study is to examine factors influencing urban older adults and develop a thematic analysis of how these factors affect seniors' home fire safety (HFS) beliefs and practices. This was a focused ethnography using participant observation and semi-structured interviews. Additionally, public housing records, cognitive functioning, and general health status were assessed. Individual interviews were transcribed verbatim using a constant comparative analysis. Eight seniors participated in the study. Two main themes described older adults' HFS while aging in place: the risk associated with the living environment and the journey associated with maintaining independence. All participants experienced HFS challenges such as limited mobility and financial constraints. Participants' general health and cognitive status additionally influenced their ability to maintain HFS. The findings suggest that urban seniors may have diverse HFS environment risks compared with the general population, highlighting the need for older adult focused HFS interventions.

Assessing the home fire safety of urban older adults: a case study.

Older adults are at a higher risk for fatal house fire injury due to decreased mobility, chronic illness, and lack of smoke alarms. The purpose of this illustrative case study is to describe the home fire safety (HFS) status of an urban older adult who participated in a large study funded by the Federal Emergency Management Agency (FEMA). During a home visit with the participant, HFS data were collected from documents, observation, physical artifacts, reflective logs, and interviews. Numerous HFS hazards were identified including non-working smoke alarms, inadequate number and inappropriate placement of smoke alarms, lack of carbon monoxide (CO) alarms, inability to identify a home fire escape plan, hot water heater temperature set too high, and cooking hazards. Identification of HFS risk factors will assist in the development of educational materials that can be tailored to the older adult population to decrease their risk of fire-related injuries and death.