Author Correction: PGBD5 promotes site-specific oncogenic mutations in human tumors.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

What makes one respond to acupuncture for insomnia? Perspectives of cancer survivors.

OBJECTIVE: Like any therapy, acupuncture is effective for some patients, while not helpful for others. Understanding from a patients' perspective what makes one respond or not to acupuncture can help guide further intervention development. This study aimed to identify factors that influence the perception of acupuncture's therapeutic effect among cancer survivors with insomnia. METHOD: We conducted post-treatment semi-structured interviews with cancer survivors who were randomized to the acupuncture group in a clinical trial for the treatment of insomnia. Survivors were categorized into Responders and Non-Responders to acupuncture treatment based on the change in the Insomnia Severity Index with a reduction of eight points or greater as the cut-off for the response. An integrated approach to data analysis was utilized by merging an a priori set of codes derived from the key ideas and a set of codes that emerged from the data through a grounded theory approach. Codes were examined for themes and patterns. RESULTS: Among 28 cancer survivors interviewed, 18 (64%) were classified as Responders. Participants perceived the ability to respond to acupuncture as dependent on treatment that effectively: (1) alleviated co-morbidities contributing to insomnia, (2) supported sleep hygiene practices, and (3) provided a durable therapeutic effect. Acupuncture treatment that did not address one of these themes often detracted from positive treatment outcomes and diminished perceived benefit from acupuncture. SIGNIFICANCE OF RESULTS: We identified patient-perceived contributors to response to acupuncture, such as co-morbid medical conditions, adequate support for sleep hygiene practices, and temporary therapeutic relief. Addressing these factors may improve the overall effectiveness of acupuncture for insomnia.

Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors.

Despite intense efforts, the cure rates of childhood and adult solid tumors are not satisfactory. Resistance to intensive chemotherapy is common, and targets for molecular therapies are largely undefined. We have found that the majority of childhood solid tumors, including rhabdoid tumors, neuroblastoma, medulloblastoma, and Ewing sarcoma, express an active DNA transposase, PGBD5, that can promote site-specific genomic rearrangements in human cells. Using functional genetic approaches, we discovered that mouse and human cells deficient in nonhomologous end joining (NHEJ) DNA repair cannot tolerate the expression of PGBD5. In a chemical screen of DNA damage signaling inhibitors, we identified AZD6738 as a specific sensitizer of PGBD5-dependent DNA damage and apoptosis. We found that expression of PGBD5, but not its nuclease activity-deficient mutant, was sufficient to induce sensitivity to AZD6738. Depletion of endogenous PGBD5 conferred resistance to AZD6738 in human tumor cells. PGBD5-expressing tumor cells accumulated unrepaired DNA damage in response to AZD6738 treatment and underwent apoptosis in both dividing and G1-phase cells in the absence of immediate DNA replication stress. Accordingly, AZD6738 exhibited nanomolar potency against most neuroblastoma, medulloblastoma, Ewing sarcoma, and rhabdoid tumor cells tested while sparing nontransformed human and mouse embryonic fibroblasts in vitro. Finally, treatment with AZD6738 induced apoptosis and regression of human neuroblastoma and medulloblastoma tumors engrafted in immunodeficient mice in vivo. This effect was potentiated by combined treatment with cisplatin, including substantial antitumor activity against patient-derived primary neuroblastoma xenografts. These findings delineate a therapeutically actionable synthetic dependency induced in PGBD5-expressing solid tumors.

PGBD5 promotes site-specific oncogenic mutations in human tumors.

Genomic rearrangements are a hallmark of human cancers. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as encoding an active DNA transposase expressed in the majority of childhood solid tumors, including lethal rhabdoid tumors. Using assembly-based whole-genome DNA sequencing, we found previously undefined genomic rearrangements in human rhabdoid tumors. These rearrangements involved PGBD5-specific signal (PSS) sequences at their breakpoints and recurrently inactivated tumor-suppressor genes. PGBD5 was physically associated with genomic PSS sequences that were also sufficient to mediate PGBD5-induced DNA rearrangements in rhabdoid tumor cells. Ectopic expression of PGBD5 in primary immortalized human cells was sufficient to promote cell transformation in vivo. This activity required specific catalytic residues in the PGBD5 transposase domain as well as end-joining DNA repair and induced structural rearrangements with PSS breakpoints. These results define PGBD5 as an oncogenic mutator and provide a plausible mechanism for site-specific DNA rearrangements in childhood and adult solid tumors.