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Gene therapy with elivaldogene autotemcel (eli-cel) consisting of autologous CD34+ cells transduced with lentiviral vector containing complementary DNA (Lenti-D) has shown efficacy in clinical studies for the treatment of cerebral adrenoleukodystrophy. However, the risk of oncogenesis with eli-cel is unclear. We performed integration-site analysis, genetic studies, flow cytometry, and morphologic studies in peripheral-blood and bone marrow samples from patients who received eli-cel therapy in two completed phase 2-3 studies (ALD-102 and ALD-104) and an ongoing follow-up study (LTF-304) involving the patients in both ALD-102 and ALD-104. Hematologic cancer developed in 7 of 67 patients after the receipt of eli-cel (1 of 32 patients in the ALD-102 study and 6 of 35 patients in the ALD-104 study): myelodysplastic syndrome (MDS) with unilineage dysplasia in 2 patients at 14 and 26 months; MDS with excess blasts in 3 patients at 28, 42, and 92 months; MDS in 1 patient at 36 months; and acute myeloid leukemia (AML) in 1 patient at 57 months. In the 6 patients with available data, predominant clones contained lentiviral vector insertions at multiple loci, including at either (MDS and EVI1 complex protein EVI1 [ecotropic virus integration site 1], in 5 patients) or (positive regulatory domain zinc finger protein 16, in 1 patient). Several patients had cytopenias, and most had vector insertions in multiple genes within the same clone; 6 of the 7 patients also had somatic mutations ( , , , or , or ), and 1 of the 7 patients had monosomy 7. Of the 5 patients with MDS with excess blasts or MDS with unilineage dysplasia who underwent allogeneic hematopoietic stem-cell transplantation (HSCT), 4 patients remain free of MDS without recurrence of symptoms of cerebral adrenoleukodystrophy, and 1 patient died from presumed graft-versus-host disease 20 months after HSCT (49 months after receiving eli-cel). The patient with AML is alive and had full donor chimerism after HSCT; the patient with the most recent case of MDS is alive and awaiting HSCT. Hematologic cancer developed in a subgroup of patients who were treated with eli-cel; the cases are associated with clonal vector insertions within oncogenes and clonal evolution with acquisition of somatic genetic defects. (Funded by Bluebird Bio; ALD-102, ALD-104, and LTF-304 ClinicalTrials.gov numbers, NCT01896102, NCT03852498, and NCT02698579, respectively.).

Science education strives to cultivate individuals who understand scientific concepts as well as the nature of science and science learning. This study focused on the potential benefits of the flipped classroom on students' attitudes towards science and science learning. Our study investigated changes in and effects of students' attitudes towards science and science learning in a flipped introductory biology course at the University of Massachusetts Boston. We used The Colorado Learning Attitudes about Science Survey for Biology to assess students' attitudes at pre and post-instruction. We investigated the effect of a flipped classroom on students' attitudes towards science and science learning by measuring the impact of different teaching approaches (flipped vs. traditional lecture). Following the prior literature, we hypothesized that there would be a negative shift in students' attitudes over the semester in the traditional classroom and that this negative shift would not occur in the flipped. Our results showed there was no significant difference in the shift of students' attitudes between the traditional and flipped sections. We also examined the relationship between students' attitudes and academic performance. We hypothesized there would be a positive correlation between students' attitudes and their academic performance, as measured by exam average. In support of the prior literature, we found a significant positive correlation. Finally, we examined whether the relationship between students' attitudes and performance was mediated by learning behavior. Specifically, we considered if students with more favorable attitudes solved more on-line problems correctly and whether this aspect of problem solving was associated with greater achievement. We hypothesized there would be a positive correlation between attitudes and problem solving behavior as well as problem solving behavior and achievement. We did not find a significant correlation between attitudes and this aspect of problem solving behavior, however there was a correlation between problem solving behavior and achievement. Our results indicate attitudes towards science and science learning may play a role in undergraduate students' learning achievement. However, we were not able to show that those effects were mediated through problem solving behavior, nor did we show that the flipped classroom by itself was sufficient to enhance these attitudes.