Post-transcriptional regulation of satellite cell quiescence by TTP-mediated mRNA decay.

Skeletal muscle satellite cells in their niche are quiescent and upon muscle injury, exit quiescence, proliferate to repair muscle tissue, and self-renew to replenish the satellite cell population. To understand the mechanisms involved in maintaining satellite cell quiescence, we identified gene transcripts that were differentially expressed during satellite cell activation following muscle injury. Transcripts encoding RNA binding proteins were among the most significantly changed and included the mRNA decay factor Tristetraprolin. Tristetraprolin promotes the decay of MyoD mRNA, which encodes a transcriptional regulator of myogenic commitment, via binding to the MyoD mRNA 3' untranslated region. Upon satellite cell activation, p38α/β MAPK phosphorylates MAPKAP2 and inactivates Tristetraprolin, stabilizing MyoD mRNA. Satellite cell specific knockdown of Tristetraprolin precociously activates satellite cells in vivo, enabling MyoD accumulation, differentiation and cell fusion into myofibers. Regulation of mRNAs by Tristetraprolin appears to function as one of several critical post-transcriptional regulatory mechanisms controlling satellite cell homeostasis

Systematic survey of randomized trials evaluating the impact of alternative diagnostic strategies on patient-important outcomes

Objectives: To provide a perspective on the current practice of randomized clinical trials (RCTs) of diagnostic strategies focusing on patient-important outcomes. Study Design and Setting: We conducted a comprehensive search of MEDLINE and included RCTs published in full-text reports that evaluated alternative diagnostic strategies. Results: Of 56,912 unique citations, we sampled 7,500 and included 103 eligible RCTs, therefore suggesting that MEDLINE includes approximately 781 diagnostic RCTs. The 103 eligible trials reported on: mortality (n = 41; 39.8%); morbidities (n = 63; 61.2%); symptoms/quality of life/functional status (n = 14; 13.6%); and on composite end points (n = 10; 9.7%). Of the studies that reported statistically significant results (n = 12; 11.6%), we judged 7 (58.3%) as at low risk of bias with respect to missing outcome data and 4 (33.3%) as at low risk of bias regarding blinding. Of the 41 RCTs that reported on mortality, only one (2.4%) reported statistically significant results. Of 63 RCTs addressing morbidity outcomes, 11 (17.5%) reported statistically significant results, all of which reported relative effects of greater than 20%. Conclusion: RCTs of diagnostic tests are not uncommon, and sometimes suggest benefits on patient-important outcomes but often suffer from limitations in sample size and conduct. (C) 2017 Elsevier Inc. All rights reserved.Peer reviewe

When is the Best Time for Corrective Surgery in Patients with Tetralogy of Fallot between 0 and 12 Months of Age?

Made available in DSpace on 2019-09-12T16:26:06Z (GMT). No. of bitstreams: 0 Previous issue date: 2018Abstract Objective: To identify the best time for corrective surgery of tetralogy of Fallot (TF) in children aged 0-12 months and to report the most frequent complications during the first 3 years postoperatively. Methods: Systematic review of studies published between 2000 and 2017 on corrective surgery for TF. Articles were selected through search of electronic databases (PubMed, SciELO, Scopus, Lilacs, Google Scholar, and Cochrane). Length of stay in intensive care unit, duration of mechanical ventilation, and peri/postoperative complications were analyzed for data discussion and research interpretation. Conclusion: Definitive corrective surgery is the best alternative, and the earlier it is performed, the lower the occurrence of harmful effects and the greater the chances of cardiorespiratory recovery. This systematic review suggests that the best time to perform definitive corrective surgery for TF in the first year of life is during 3-6 months of age in children with no or mild symptoms. Children with severe symptoms should undergo surgery immediately.[Bravo-Valenzuela, Nathalie J. M.] Universidade Federal de São Paulo, BrazilMartins, Izabela F.; Doles, Iara C.; Bravo-Valenzuela, Nathalie J. M.; Santos, Adriana O. R. dos; Varella, Marcela S. P.] Universidade de Taubaté, Brazi

Topoisomerase levels determine chemotherapy response in vitro and in vivo

Topoisomerase poisons are chemotherapeutic agents that are used extensively for treating human malignancies. These drugs can be highly effective, yet tumors are frequently refractory to treatment or become resistant upon tumor relapse. Using a pool-based RNAi screening approach and a well characterized mouse model of lymphoma, we explored the genetic basis for heterogeneous responses to topoisomerase poisons in vitro and in vivo. These experiments identified Top2A expression levels as major determinants of response to the topoisomerase 2 poison doxorubicin and showed that suppression of Top2A produces resistance to doxorubicin in vitro and in vivo. Analogously, using a targeted RNAi approach, we demonstrated that suppression of Top1 produces resistance to the topoisomerase 1 poison camptothecin yet hypersensitizes cancer cells to doxorubicin. Importantly, lymphomas relapsing after treatment display spontaneous changes in topoisomerase levels as predicted by in vitro gene knockdown studies. These results highlight the utility of pooled shRNA screens for identifying genetic determinants of chemotherapy response and suggest strategies for improving the effectiveness of topoisomerase poisons in the clinic

Motivating Self-Efficacy in Diverse Biomedical Science Post-baccalaureate and Graduate Students Through Scientific Conference Implementation

Tactics to increase the number of underrepresented (UR) students in biomedical research PhD training programs have not yet translated to UR faculty numbers that reflect the diversity of the United States. Continued interventions are required to build skills beyond those that result in placement into a PhD program. We hypothesize that successful interventions must build skills that give UR students foundations for confident self-efficacy in leadership. We seek interventions that allow UR students to envision themselves as successful faculty. We posit that development of such skills is difficult in the classroom or laboratory alone. Therefore, novel interventions are required. As part of the NIH-funded Post-baccalaureate Research Education Program (PREP) and Initiative for Maximizing Student Development (IMSD) at the Mayo Clinic Graduate School of Biomedical Sciences, we designed and implemented a unique intervention to support development of student leadership skills: a biannual student-organized and student-led national research conference titled "Scientific Innovation Through Diverse Perspectives" (SITDP). This initiative is based on the concept that students who actively live out realistic roles as scientific leaders will be encouraged to persist to scientific leadership as faculty. Here we describe the motivation for, design of, and outcomes from, the first three pilot conferences of this series. We further discuss approaches needed to rigorously evaluate the effectiveness of such interventions in the future