RESUMEN
Efforts to develop more effective therapies for acute leukemia may benefit from high-throughput screening systems that reflect the complex physiology of the disease, including leukemia stem cells (LSCs) and supportive interactions with the bone marrow microenvironment. The therapeutic targeting of LSCs is challenging because LSCs are highly similar to normal hematopoietic stem and progenitor cells (HSPCs) and are protected by stromal cells in vivo. We screened 14,718 compounds in a leukemia-stroma co-culture system for inhibition of cobblestone formation, a cellular behavior associated with stem-cell function. Among those compounds that inhibited malignant cells but spared HSPCs was the cholesterol-lowering drug lovastatin. Lovastatin showed anti-LSC activity in vitro and in an in vivo bone marrow transplantation model. Mechanistic studies demonstrated that the effect was on target, via inhibition of HMG-CoA reductase. These results illustrate the power of merging physiologically relevant models with high-throughput screening.
Asunto(s)
Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales/métodos , Leucemia , Células Madre Neoplásicas/efectos de los fármacos , Línea Celular Tumoral , Células Madre Hematopoyéticas , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Lovastatina/farmacología , Células Madre Neoplásicas/citología , Células Madre Neoplásicas/fisiologíaRESUMEN
BACKGROUND: Since the internet has become an important source of contraceptive information with YouTube.com as the second most visited site, we analysed contraceptive implant YouTube videos for content and clinical accuracy. METHODS: Using the terms 'contraceptive implant', 'Nexplanon' and 'Implanon', the top 20 results on YouTube by relevance and view count were identified. After excluding duplicates, single-rod implant videos in English were included. Videos were classified as providing a professional or patient perspective. Views, duration and comments were noted. Videos were rated for reliability, global quality scale and whether they were positive or negative about the implant. Inter-rater agreement was measured. RESULTS: A total of 120 videos were retrieved; 52 were eligible for review. Less than 23% were professional videos; the majority reported patient experience (46% testimonials, 27% real-time procedure videos, 4% other). Patient videos had been posted a significantly longer duration of time than professional videos (364 vs 188â days, p=0.02), were less reliable (p≤0.0001) and were of lower global quality (p<0.0001). Some 61% of implant testimonial videos were rated as 'positive experiences' and inter-rater agreement was very good (κ=0.81). All testimonials mentioned side effects, commonly irregular bleeding and discomfort with insertion. A minority (26%) reported misinformation. CONCLUSIONS: This study found that most of the information on YouTube pertaining to contraceptive implants is accurate, is presented from the patient's perspective, and promotes the method's use.