Novel second-generation rexinoid induces growth arrest and reduces cancer cell stemness in human neuroblastoma patient-derived xenografts

IntroductionThe poor therapeutic efficacy seen with current treatments for neuroblastoma may be attributed to stem cell-like cancer cells (SCLCCs), a subpopulation of cancer cells associated with poor prognosis and disease recurrence. Retinoic acid (RA) is a differentiating agent used as maintenance therapy for high-risk neuroblastoma but nearly half of children treated with RA relapse. We hypothesized that 6-Methyl-UAB30 (6-Me), a second-generation rexinoid recently developed with a favorable toxicity profile compared to RA, would reduce cancer cell stemness in human neuroblastoma patient-derived xenografts (PDXs).MethodsCells from three neuroblastoma PDXs were treated with 6-Me and proliferation, viability, motility, and cell-cycle progression were assessed. CD133 expression, sphere formation, and mRNA abundance of stemness and differentiation markers were evaluated using flow cytometry, in vitro extreme limiting dilution analysis, and real-time PCR, respectively.ResultsTreatment with 6-Me decreased proliferation, viability, and motility, and induced cell-cycle arrest and differentiation in all three neuroblastoma PDXs. In addition, 6-Me treatment led to decreased CD133 expression, decreased sphere-forming ability, and decreased mRNA abundance of Oct4, Nanog, and Sox2, indicating decreased cancer cell stemness.Conclusions6-Me decreased oncogenicity and reduced cancer cell stemness of neuroblastoma PDXs, warranting further exploration of 6-Me as potential novel therapy for neuroblastoma.     

Policy Interventions,Social Distancing,and SARS-CoV-2 Transmission in the United States: A Retrospective State-level Analysis

BackgroundVarious non-pharmaceutical interventions (NPIs) such as stay-at-home orders and school closures have been employed to limit the spread of Coronavirus disease (COVID-19). This study measures the impact of social distancing policies on COVID-19 transmission in US states during the early outbreak phase to assess which policies were most effective.MethodsTo measure transmissibility, we analyze the average effective reproductive number (R_t) in each state the week following its 500th case and doubling time from 500 to 1000 cases. Linear and logistic regressions were performed to assess the impact of various NPIs while controlling for population density, GDP, and certain health metrics. This analysis was repeated for deaths with doubling time to 100 deaths with several healthcare infrastructure control variables.ResultsStates with stay-at-home orders in place at the time of their 500th case were associated with lower average R_t the following week compared to states without them (p<0.001) and significantly less likely to have an R_t>1 (OR 0.07, 95% CI 0.01–0.37, p = 0.004). These states also experienced longer doubling time from 500 to 1000 cases (HR 0.35, 95% CI 0.17–0.72, p = 0.004). States in the highest quartile of average time spent at home were also slower to reach 1000 cases than those in the lowest quartile (HR 0.18, 95% CI 0.06–0.53, p = 0.002).ConclusionsStay-at-home orders had the largest effect of any policy analyzed. Multivariate analyses with cellphone tracking data suggest social distancing adherence drives these effects. States that plan to scale back such measures should carefully monitor transmission metrics.     

Comparison of aortic dissection in patients with and without Marfan's syndrome (results from the International Registry of Aortic Dissection)

Among 1,049 patients diagnosed with aortic dissection in a multinational registry, patients with Marfan's syndrome were typically younger and had unique presentations. Despite their younger age at presentation, patients with Marfan's syndrome and aortic dissection had a high mortality rate, similar to patients without Marfan's syndrome, an older patient cohort. Our data support the importance of aneurysm surveillance and prophylactic surgical intervention for patients with Marfan's syndrome to potentially reduce the risk of mortality.     

PIM447 inhibits oncogenesis and potentiates cisplatin effects in hepatoblastoma

Background: Novel therapies are needed for patients with hepatoblastoma because of an increasing incidence of disease and poor prognosis for advanced, refractory, and recurrent disease. PIM kinases promote tumorigenesis in hepatoblastoma. A novel PIM inhibitor, PIM447, has shown promise in inhibiting oncogenesis in hematologic and lymphoid malignancies. We hypothesized that PIM inhibition with PIM447 would result in decreased tumorigenesis in hepatoblastoma.Methods: The effects of PIM447 on hepatoblastoma viability, proliferation, motility, apoptosis, and tumor cell stemness were assessed in HuH6, a human hepatoblastoma cell line, and COA67, a human hepatoblastoma patient-derived xenograft.Results: PIM447 significantly decreased the viability, proliferation, and motility of HuH6 and COA67 cells. Apoptosis significantly increased following PIM447 treatment. PIM447 had a significant impact on tumor cell stemness as evidenced by decreased expression of CD133 and reduced ability of HuH6 and COA67 cells to form tumorspheres. Furthermore, combining PIM447 with cisplatin resulted in a significant decrease in cell viability compared to either treatment alone.Conclusion: We showed that PIM447 inhibits oncogenesis and potentiates the effects of cisplatin in hepatoblastoma and, therefore, warrants further investigation as a potential therapeutic agent for hepatoblastoma.