Wnt10b protects cardiomyocytes against doxorubicin-induced cell death via MAPK modulation.

BACKGROUND: Doxorubicin, an anthracycline chemotherapeutic known to incur heart damage, decreases heart function in up to 11% of patients. Recent investigations have implicated the Wnt signaling cascade as a key modulator of cardiac tissue repair after myocardial infarction. Wnt upregulation in murine models resulted in stimulation of angiogenesis and suppression of fibrosis after ischemic insult. However, the molecular mechanisms of Wnt in mitigating doxorubicin-induced cardiac insult require further investigation. Identifying cardioprotective mechanisms of Wnt is imperative to reducing debilitating cardiovascular adverse events in oncologic patients undergoing treatment. METHODS: Exposing human cardiomyocyte AC16 cells to varying concentrations of Wnt10b and DOX, we observed key metrics of cell viability. To assess the viability and apoptotic rates, we utilized MTT and TUNEL assays. We quantified cell and mitochondrial membrane stability via LDH release and JC-1 staining. To investigate how Wnt10b mitigates doxorubicin-induced apoptosis, we introduced pharmacologic inhibitors of key enzymes involved in apoptosis: FR180204 and SB203580, ERK1/2 and p38 inhibitors. Further, we quantified apoptotic executor enzymes, caspase 3/7, via immunofluorescence. RESULTS: AC16 cells exposed solely to doxorubicin were shrunken with distorted morphology. Cardioprotective effects of Wnt10b were demonstrated via a reduction in apoptosis, from 70.1% to 50.1%. LDH release was also reduced between doxorubicin and combination groups from 2.27-fold to 1.56-fold relative to the healthy AC16 control group. Mitochondrial membrane stability was increased from 0.67-fold in the doxorubicin group to 5.73 in co-treated groups relative to control. Apoptotic protein expression was stifled by Wnt10b, with caspase3/7 expression reduced from 2.4- to 1.3-fold, and both a 20% decrease in p38 and 40% increase in ERK1/2 activity. CONCLUSION: Our data with the AC16 cell model demonstrates that Wnt10b provides defense mechanisms against doxorubicin-induced cardiotoxicity and apoptosis. Further, we explain a mechanism of this beneficial effect involving the mitochondria through simultaneous suppression of pro-apoptotic p38 and anti-apoptotic ERK1/2 activities.

Changes in caregiver mental health and pediatric asthma control during COVID-19.

OBJECTIVE: This study evaluated caregivers' stress and depressive symptoms, and children's asthma control, before COVID-19 began and after its onset among families in the RVA Breathes program. METHODS: The RVA Breathes intervention, which took place in an urban city in the United States, includes asthma education delivered by a community health worker (CHW), a home assessment, and school nurse components. Participants included 125 children (5-11 years) with asthma and their caregivers (48% household income <$25,000) enrolled prior to the pandemic. Families were randomized to an active intervention arm (full intervention or intervention without school nurse component) or the control group. Caregivers completed the Center for Epidemiological Studies Depression Scale (CES-D) and the Perceived Stress Scale (PSS); children and caregivers completed the Childhood Asthma Control Test (cACT). Assessments pre-COVID-19 were compared to those completed after the pandemic's onset. RESULTS: Children in both intervention groups had better cACT scores after the start of COVID-19 compared to before (t(55) = -2.131, p = .019; t(28) = -2.893, p = .004). Caregivers in the intervention groups had lower PSS scores after the start of COVID-19 compared to pre-COVID-19 (t(53) = 3.928, p < .001; t(28) = 2.568, p = .008). Furthermore, CES-D scores improved among caregivers in the full intervention (t(48) = 1.789, p = .040). Caregivers in the control condition did not report significant changes in stress or depressive symptoms. CONCLUSIONS: Findings suggest that support from interventionists, including CHWs, might have alleviated stress and depressive symptoms during COVID-19, as well as improved asthma control during the pandemic.

A multisite randomized controlled trial of an early palliative care intervention in children with advanced cancer: The PediQUEST Response Study Protocol.

BACKGROUND: The Pediatric Quality of Life and Evaluation of Symptoms Technology Response to Pediatric Oncology Symptom Experience (PQ-Response) intervention aims to integrate specialized pediatric palliative care into the routine care of children, adolescents, and young adults (AYAs) with advanced cancer. AIMS: To evaluate whether PQ-Response, compared to usual care, improves patient's health related quality of life (HRQoL) and symptom burden (aim 1), parent psychological distress and symptom-related stress (aim 2), and family and symptom treatment activation (aim 3). DESIGN: Multisite, randomized (1:1), controlled, un-blinded, effectiveness trial comparing PediQUEST Response (intervention) vs usual cancer care (control). SETTING: Five US large, tertiary level pediatric cancer centers. PARTICIPANTS: Children (≥2 years old)/AYAs who receive care at any of the participating sites because of advanced cancer or any progressive/recurrent solid or brain tumor and are palliative care "naïve." Target: 200 enrolled patient-parent dyads (minimum goal: 136 dyads randomized, N = 68/arm). INTERVENTIONS: PediQUEST Response: combines patient-mediated activation (weekly feedback of patient- and parent-reported symptoms and HRQoL to families and providers using the PediQUEST web system) with integration of the palliative care team. Usual Cancer Care: participants receive usual care, which can include palliative care consultation, and use PediQUEST web to answer surveys, with no feedback. METHODS: Following enrollment, patients (if ≥5 years) and one parent receive weekly PediQUEST-Surveys assessing HRQoL (Pediatric Quality of Life Inventory 4.0) and symptom burden (PediQUEST-Memorial Symptom Assessment Scale). After a 2-week run-in period, dyads who answer ≥2 PediQUEST surveys per participant (responders), are randomized (concealed allocation) and followed up for 16-weeks. Parents answer six additional surveys (parent outcomes). OUTCOMES: Primary: mean patient HRQoL score over 16-weeks as reported by a) the parent; and b) the patient if ≥5 years-old. Secondary: patient's symptom burden; parent's anxiety, depressive symptoms, symptom-related stress; family activation; and symptom treatment activation. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03408314) 1/24/18. https://clinicaltrials.gov/ct2/show/NCT03408314.

Vitamin D3 attenuates doxorubicin-induced senescence of human aortic endothelial cells by upregulation of IL-10 via the pAMPKα/Sirt1/Foxo3a signaling pathway.

The toxicity of doxorubicin to the cardiovascular system often limits its benefits and widespread use as chemotherapy. The mechanisms involved in doxorubicin-induced cardiovascular damage and possible protective interventions are not well-explored. Using human aortic endothelial cells, we show vitamin D3 strongly attenuates doxorubicin-induced senescence and cell cycle arrest. We further show the protective effects of vitamin D3 are mediated by the upregulation of IL-10 and FOXO3a expression through fine modulation of pAMPKα/SIRT1/FOXO3a complex activity. These results have great significance in finding a target for mitigating doxorubicin-induced cardiovascular toxicity.

MyPref: pilot study of a novel communication and decision-making tool for adolescents and young adults with advanced cancer.

PURPOSE: Adolescents and young adults (AYAs) with cancer report feeling ill-informed about their cancer treatment options. Tools are needed to inform AYAs about treatment choices and amplify the AYA's voice in medical decision-making. We developed MyPref, a conjoint-analysis based tool that quantifies AYA preferences for future cancer treatments. METHODS: We conducted a staged pilot study of MyPref utilizing an intervention mixed methods design. AYAs and their parent or trusted person (PTP) completed MyPref and received a summary report of their preferences for treatment-related factors. Participants later completed the Preparation for Decision Making Scale and MyPref Experience Questionnaire and engaged in semi-structured interviews. Oncologists reported on the perceived accuracy and utility of MyPref. We used a weaving technique for presenting mixed methods data. RESULTS: Fifteen AYAs with advanced cancer, 7 PTPs, and 12 providers participated in this pilot; 32 (94%) completed all study items. AYA/PTPs stated study participation was useful and believed MyPref allowed for improved understanding of treatment factors and consideration, organization, and visualization of preferences. All providers agreed that MyPref made them think about patient's preferences and 9 (75%) reported they planned to change their approach to discussions about preferences for future treatments. CONCLUSION: MyPref is an objective way to estimate AYA and PTP preferences for future treatment characteristics. This novel tool may be a useful way to engage AYAs and PTPs in discussions around preferences for treatment and prepare AYAs for future decision-making. We are currently evaluating this tool longitudinally to determine the impact on actual treatment decisions.

Alcohol Compliance Checks and Underage Alcohol-Involved Crashes: Evaluation of a Statewide Enforcement Program in South Carolina from 2006 to 2016.

OBJECTIVE: This research evaluated the South Carolina Alcohol Enforcement Team impact for reducing retail alcohol access to underage persons to decrease drinking and driving crashes among that population. METHODS: The natural research experiment used interrupted time-series (ITS) analyses of drinking and driving crashes involving under 21-year-old drivers from July 2006 through December 2016 (126-month period = 4,782 Driving Under Influence [DUI] crashes for under 21-year-old drivers, µ = 38 crashes per month). Additional data analyzed included the monthly total number of retail compliance checks (total during 126-month period = 64,954 compliance checks completed, µ = 515.5 checks per month), the average percentage of underage alcohol purchases (total completed during 126-month period = 8,814 purchases, µ = 70 purchases per month), and a calculated measure of the percent of the population under 21 years old exposed to compliance checks each month. We used drinking and driving crashes for 21-year-old and over drivers as a control time series (total number over a 126-month period = 52,180 DUI crashes for 21 and older drivers, µ = 414.1 crashes per month). RESULTS: The results show a decline in drinking and driving crashes for drivers under 21 when compliance checks increase, and when compliance checks decline, traffic crashes increase. Stable Alcohol Enforcement Team implementation over 78 months produced an overall 18 to 29% decline in such crashes. A visual examination of the crash time series demonstrated that under-21-age-driver crashes declined during the first wave of implementation and increased following a lag when enforcement declined, which provided additional empirical support for a South Carolina Alcohol Enforcement Team impact on retail alcohol availability. An ITS analysis of the prestable period compared to the stable period was statistically significant (T = -3.78, p < 0.001). A cross-check of these results using single-vehicle nighttime crashes using identical Autoregressive Integrated Moving Average models was also statistically significant (T = -8.18, p < 0.001). CONCLUSIONS: This longitudinal study provides strong evidence of sustained reductions in alcohol availability to underage youth can subsequently reduce alcohol-related traffic crashes. Reductions found in this study continued over several years, considerably longer than any previous equivalent research has shown.

Identification of adolescents and young adults' preferences and priorities for future cancer treatment using a novel decision-making tool.

BACKGROUND: Adolescents and young adults (AYAs) with cancer receive high-intensity care and experience significant symptoms at the end of life. As novel cancer-directed therapies increase, AYAs with advanced cancer may face multiple treatment options, each with unique risk/benefit profiles. To augment the AYAs' voice in the decision-making process, we developed MyPref, an adaptive conjoint analysis-based tool. PROCEDURE: We conducted a three-staged pilot study of MyPref utilizing an exploratory intervention mixed methods design. AYAs and their identified parent or trusted person (PTP) completed MyPref and received a summary of their preferences for nine treatment-related factors. Participants later engaged in semi-structured interviews to further explore their experience with MyPref. Responses to free text questions and interviews were analyzed using qualitative techniques. RESULTS: Fifteen AYAs with advanced cancer and seven PTPs participated in the pilot. While most participants identified time until cancer grows, quality of life, and side effects to be the most important factors when considering a future treatment, preferences were highly varied. Notably, MyPref-calculated preferences differed from initial rank order, and participants indicated that calculated preferences were accurate in follow-up interviews. CONCLUSION: The MyPref-calculated preferences varied by individual and differed from initial rank ordering. Additionally, there was variability in how individuals defined and prioritized treatment-related factors. This novel tool may be a useful way to engage AYAs and their PTPs in discussions around preferences for treatment and prepare AYAs for future decision making. We plan to evaluate this tool longitudinally to evaluate the impact on actual treatment decisions.

A community-based asthma program: Study design and methods of RVA Breathes.

Disparities in pediatric asthma morbidity and healthcare utilization exist on the basis of race, ethnicity, environment, and income; interventions are needed to address these inequities. The following protocol describes an evidence-based intervention, RVA Breathes, designed to coordinate pediatric asthma care across family, home, community, and medical sectors. Community stakeholder feedback was utilized to refine the intervention specifically for the Richmond, Virginia community. The aims of this study are to assess the effect of RVA Breathes on asthma-related healthcare utilization, as well as secondary outcomes of asthma control, asthma symptoms, and quality of life. We will enroll 300 elementary school children from the Richmond City Public School system. Participants will be between the ages of 5-11, have a diagnosis of asthma, and have had an asthma exacerbation (as indicated by an asthma-related ED visit, hospitalization, unscheduled PCP visit, or use of systemic steroids) in the last two years. Participants will be randomized to one of three groups: asthma education + home environment remediation + school intervention, asthma education + home environment remediation, or a comparator condition. Data will be collected across one baseline research visit, four intervention sessions, and four follow-up research visits over the course of 18 months. A General Linear Mixed Model (GLMM) will be used to test primary aims. We expect the findings will provide support for coordination of asthma care across sectors. Further, we hope RVA Breathes will serve as a model of community-based pediatric asthma care.

Reconsidering early parental grief following the death of a child from cancer: a new framework for future research and bereavement support.

PURPOSE: Parents of children that die from cancer are at increased risk of significant long-term psychosocial and physical morbidities. Less, however, is known about the experience of parents early in the grief process. Currently used frameworks and instruments used to understand and assess outcomes in parents early in the grief experience are inadequate and may serve to pathologize the normal grief response. METHODS: Through review of the literature, previously conducted qualitative work, and extensive clinical experience working with bereaved parents, we developed a new framework for understanding, assessing, and studying parental grief during the first 2 years following the death of a child from cancer. RESULTS: Our novel longitudinal framework hypothesizes that short- and long-term psychosocial sequalae in parents following the death of a child from cancer depend not only on pre-death factors but on the support present through the disease experience and the oscillation between protective factors and risk factors in the post-death period. We further hypothesize that protective factors and risk factors may be modifiable, making them key potential targets for supportive interventions aimed at augmenting protective factors and diminishing the effect of risk factors. CONCLUSION: This is a new framework for understanding and assessing the grief experience of parents within the first 2 years of a child's death. Many questions about how best to support parents following the death of a child from cancer remain providing ample opportunities for future research and development of interventions to improve both short- and long-term outcomes in bereaved parents.

Identifying and Quantifying Adolescent and Young Adult Patient Preferences in Cancer Care: Development of a Conjoint Analysis-Based Decision-Making Tool.

Compared with younger children and older adults, adolescent and young adult (AYA) patients with cancer receive more intensive end-of-life (EOL) care. We hypothesize that enhanced understanding of AYA preferences, increased engagement of these patients in decision-making, and improved communication of their preferences with family members and the medical team will lead to increased provision of goal-concordant care and decreased intensity of EOL care. In this study, we describe the development of a novel tool that quantifies the relative importance of numerous factors considered by AYA patients with cancer, their parents, and health care providers when choosing between treatment options.