Association between secondhand marijuana smoke and respiratory infections in children.

BACKGROUND: Little is known about the effects of secondhand marijuana smoke on children. We aimed to determine caregiver marijuana use prevalence and evaluate any association between secondhand marijuana smoke, childhood emergency department (ED) or urgent care (UC) visitation, and several tobacco-related illnesses: otitis media, viral respiratory infections (VRIs), and asthma exacerbations. METHODS: This study was a cross-sectional, convenience sample survey of 1500 subjects presenting to a pediatric ED. The inclusion criteria were as follows: caregivers aged 21-85 years, English- or Spanish-speaking. The exclusion criteria were as follows: children who were critically ill, medically complex, over 11 years old, or using medical marijuana. RESULTS: Of 1500 caregivers, 158 (10.5%) reported smoking marijuana and 294 (19.6%) reported smoking tobacco. Using negative-binomial regression, we estimated rates of reported ED/UC visits and specific illnesses among children with marijuana exposure and those with tobacco exposure, compared to unexposed children. Caregivers who used marijuana reported an increased rate of VRIs in their children (1.31 episodes/year) compared to caregivers with no marijuana use (1.04 episodes/year) (p = 0.02). CONCLUSIONS: Our cohort did not report any difference with ED/UC visits, otitis media episodes, or asthma exacerbations, regardless of smoke exposure. However, caregivers of children with secondhand marijuana smoke exposure reported increased VRIs compared to children with no smoke exposure. IMPACT: Approximately 10% of caregivers in our study were regular users of marijuana. Prior studies have shown that secondhand tobacco smoke exposure is associated with negative health outcomes in children, including increased ED utilization and respiratory illnesses. Prior studies have shown primary marijuana use is linked to negative health outcomes in adults and adolescents, including increased ED utilization and respiratory illnesses. Our study reveals an association between secondhand marijuana smoke exposure and increased VRIs in children. Our study did not find an association between secondhand marijuana smoke exposure and increased ED or UC visitation in children.

BH3 mimetics induce apoptosis independent of DRP-1 in melanoma.

Despite the recent advancement in treating melanoma, options are still limited for patients without BRAF mutations or in relapse from current treatments. BH3 mimetics against members of the BCL-2 family have gained excitement with the recent success in hematological malignancies. However, single drug BH3 mimetic therapy in melanoma has limited effectiveness due to escape by the anti-apoptotic protein MCL-1 and/or survival of melanoma-initiating cells (MICs). We tested the efficacy of the BH3 mimetic combination of A-1210477 (an MCL-1 inhibitor) and ABT-263 (a BCL-2/BCL-XL/BCL-W inhibitor) in killing melanoma, especially MICs. We also sought to better define Dynamin-Related Protein 1 (DRP-1)'s role in melanoma; DRP-1 is known to interact with members of the BCL-2 family and is a possible therapeutic target for melanoma treatment. We used multiple assays (cell viability, apoptosis, bright field, immunoblot, and sphere formation), as well as the CRISPR/Cas9 genome-editing techniques. For clinical relevance, we employed patient samples of different mutation status, including some relapsed from current treatments such as anti-PD-1 immunotherapy. We found the BH3 mimetic combination kill both the MICs and non-MICs (bulk of melanoma) in all cell lines and patient samples irrespective of the mutation status or relapsed state (p < 0.05). Unexpectedly, the major pro-apoptotic proteins, NOXA and BIM, are not necessary for the combination-induced cell death. Furthermore, the combination impedes the activation of DRP-1, and inhibition of DRP-1 further enhances apoptosis (p < 0.05). DRP-1 effects in melanoma differ from those seen in other cancer cells. These results provide new insights into BCL-2 family's regulation of the apoptotic pathway in melanoma, and suggest that inhibiting the major anti-apoptotic proteins is sufficient to induce cell death even without involvement from major pro-apoptotic proteins. Importantly, our study also indicates that DRP-1 inhibition is a promising adjuvant for BH3 mimetics in melanoma treatment.