Citations

Abstract When unrepaired, alkylated DNA can induce cell death or trigger mutagenesis. Cellular capacity for repair of these lesions by O6-methylguanine methyltransferase (MGMT) dictates the equilibrium between cell viability and genetic diversity. Treatment of glioblastoma cells with temozolomide (TMZ) induced ATM- and Rad3-related (ATR) kinase dependent polyribonucleotide nucleotidyltransferase 1 (PNPT1) degradation of miR-181d. miR-181d suppresses MGMT expression; its degradation increases the mean MGMT expression of the cell population. miR-181d degradation also magnifies the cell-to-cell variability in MGMT expression, expanding the genetic heterogeneity of the population. This expanded heterogeneity enhances the “fitness” of the population and constitutes a novel form of chemotherapeutic resistance. These effects can be suppressed by overexpression of miR-181d, suggesting miRNA delivery as a strategy for glioblastoma therapy. To characterize the mechanism of acquired resistance, we profiled the expression of 2400 miRNAs before and after TMZ treatment. In independent patient-derived neurosphere lines, the majority of miRNAs remained unchanged after treatment. However, miR-181d was consistently suppressed after TMZ treatment. Our previous work demonstrated miR-181d as the master regulator of MGMT. We confirmed TMZ-induced suppression of miR-181d using independent in vitro and in vivo models as well as matched pre- and post-TMZ treated clinical specimens. TMZ-induced miR-181d suppression persisted after transcriptional inhibition, suggesting degradation as the primary mechanism. We performed an siRNA screen and identified polyribonucleotide nucleotidyltransferase 1 (PNPT1) as the gene responsible for miR-181d degradation. CRISPR inactivation of PNPT1 eliminated TMZ-induced suppression of miR-181d; this was rescued by wild-type PNPT1 but not by PNPT1 harboring RNAse-inactivating mutations. TMZ-induced degradation of miR-181d requires ATR kinase. Silencing or inhibition of ATR eliminated binding of PNPT1 to miR-181d and prevented degradation of miR-181d. TMZ-sensitizing effects of ATR inhibition were reversed by anti-miR-181d, suggesting miR-181d is essential in this process. In addition to elevating the mean MGMT expression of the population, single-cell analysis revealed that miR-181d degradation broadened the cell-to-cell variability in MGMT expression in vitro. In matched clinical pre- and post-TMZ treated specimens, variability in MGMT expression was significantly elevated in post-TMZ samples. This was recapitulated using The Cancer Genome Atlas (TCGA) database. We propose that miR-181d degradation-mediated expansion of genetic heterogeneity enhances the “fitness” of the population, constituting a novel form of chemotherapeutic resistance. These effects are suppressed by miR-181d overexpression, suggesting miRNA delivery as a strategy for glioblastoma therapy. Citation Format: Valya Ramakrishnan, Johnny Akers, Thien Nguyen, Aaron Wang, Bandita Adhikari, Brian Hirshman, Jie Li, Jann Sarkaria, Wei Hua, Mao Ying, Masayuki Nitta, Tao Jiang, Bob Carter, Clark C. Chen. miR-181d degradation mediated genetic heterogeneity and acquired resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1956.

Purpose The aims of the study were to assess and compare grammatical deficits in written and spoken language production in subjects with agrammatic primary progressive aphasia (agPPA) and in subjects with agrammatism in the context of dominant apraxia of speech (DAOS) and to investigate neuroanatomical correlates. Method Eight agPPA and 21 DAOS subjects performed the picture description task of the Western Aphasia Battery (WAB) both in writing and orally. Responses were transcribed and coded for linguistic analysis. agPPA and DAOS were compared to 13 subjects with primary progressive apraxia of speech (PPAOS) who did not have agrammatism. Spearman correlations were performed between the written and spoken variables. Patterns of atrophy in each group were compared, and relationships between the different linguistic measures and integrity of Broca's area were assessed. Results agPPA and DAOS both showed lower mean length of utterance, fewer grammatical utterances, more nonutterances, more syntactic and semantic errors, and fewer complex utterances than PPAOS in writing and speech, as well as fewer correct verbs and nouns in speech. Only verb ratio and proportion of grammatical utterances correlated between modalities. agPPA and DAOS both showed greater involvement of Broca's area than PPAOS, and atrophy of Broca's area correlated with proportion of grammatical and ungrammatical utterances and semantic errors in writing and speech. Conclusions agPPA and DAOS subjects showed similar patterns of agrammatism, although subjects performed differently when speaking versus writing. Integrity of Broca's area correlates with agrammatism.

Intraoperative tourniquet-related pain is well recognized by anesthesiologists, but postoperative tourniquet-related pain has received little attention. We present a patient who underwent a total knee arthroplasty under general anesthesia and an adductor canal nerve block. She complained of intractable thigh pain postoperatively. Lidocaine 5% patches completely resolved her postoperative tourniquet-related pain.

Baastrup disease is a condition where spinous processes form painful pseudoarticulations. We present a patient with midline axial back pain consistent with Baastrup disease confirmed by computed tomography, which revealed degenerative changes along the opposing surfaces of the spinous processes at L1–2 and L2–3. Local anesthetic and steroid interspinous injections lost their effectiveness over time. She underwent successful interspinous radiofrequency lesioning, which has not been previously described in the literature. At 4 months follow-up, she reported complete pain relief.

Purpose: Novel approaches are needed to enhance employee well-being and perhaps supervisors can be an effective agent for worksite health promotion. The aim of this study was to examine the supervisor’s perceived needs, barriers, and role for influencing employee well-being for incorporation into program development. Design: Semistructured, qualitative interviews of supervisors. Setting: Large, integrated academic health-care organization with over 30 000 employees and 2600 supervisors having access to comprehensive well-being programs and a successful well-being champion network comprised of 600 champions. Participants: Twenty supervisors representing clinical, research, and administrative units. Methods: Semistructured, one-on-one interviews were conducted and audio recorded. Analysis included content log development and open coding by a trained analyst to reveal key themes. More formalized content coding using specialized software for qualitative analyses was also conducted. Results: Supervisor responses were wide ranging regarding their perceived and desired role in promoting workplace well-being. Barriers from the supervisor perspective included high current workload, ambivalence about promoting wellness, lack of support from leadership, lack of flexibility and control at work, and difficulty accessing on-site resources. They perceived their potential role in well-being as remaining a positive role model and encouraging their staff in wellness activities. Conclusion: Although findings are generated from a small sample size, these qualitative data provide compelling and early insights into building a workplace well-being strategy leveraging an underutilized key stakeholder, the workplace supervisor.

Objectives Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early‐onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD‐ and schizophrenia (SCZ)‐associated risk variants is associated with an earlier AAO in BD patients. Methods A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn‐Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD‐ and SCZ‐PRSs and AAO were evaluated with regression models. Results BD‐ and SCZ‐PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment. Conclusions The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.

Background and purposeThe non‐fluent/agrammatic variant of primary progressive aphasia (agPPA) is a heterogeneous diagnosis wherein some individuals have apraxia of speech (AOS). When agPPA includes AOS, a tauopathy is the likely underlying pathology. Recently, [18F]AV‐1451 was developed for the in‐vivo assessment of tau. In this study, we compared patterns of tau tracer uptake in patients with agPPA with and without AOS.MethodsNine patients with agPPA (four without AOS) underwent tau positron emission tomography imaging with [18F]AV‐1451. Uptake of [18F]AV‐1451 was assessed as cortical to cerebellar crus ratio (standard uptake value ratio) in cortical regions of interest measured using the MCALT atlas and compared voxel‐wise in SPM12. Each patient was age‐ and sex‐matched to three controls.ResultsThe agPPA without AOS showed uptake in the left frontal and temporal lobes, whereas agPPA with AOS showed uptake in the bilateral supplementary motor areas, frontal lobes, precuneus and precentral gyrus relative to controls. The left precentral gyrus had uptake in agPPA with AOS relative to those without AOS.ConclusionsThis cross‐sectional study suggests that [18F]AV‐1451 uptake in the precentral gyrus is implicated in AOS in agPPA.

Background Interest in the use of telehealth interventions to increase access to healthcare services is growing. Group-based interventions have the potential to increase patient access to highly needed services. The aim of this study was to systematically review the available literature on group-based video teleconference services. Methods The English-language literature was searched using Ovid MEDLINE, PubMed, PsycINFO and CINAHL for terms related to telehealth, group therapy and support groups. Abstracts were reviewed for relevance based on inclusion criteria. Multiple study types were reviewed, including open-label, qualitative and randomised controlled trial study designs. Data were compiled regarding participants, study intervention and outcomes. Specific areas of interest were the feasibility of and satisfaction with telehealth technology, as well as the effect of video teleconference delivery on group dynamics, including therapeutic alliance. Results Forty published studies met the inclusion criteria and were included in the review. Six were randomised controlled trials. Among the studies, there was a broad range of study designs, participants, group interventions and outcome measures. Video teleconference groups were found to be feasible and resulted in similar treatment outcomes to in-person groups. However, few studies were designed to demonstrate noninferiority of video teleconference groups compared with in-person groups. Studies that examined group process factors showed small decreases in therapeutic alliance in the video teleconference participants. Conclusions Video teleconference groups are feasible and produce outcomes similar to in-person treatment, with high participant satisfaction despite technical challenges. Additional research is needed to identify optimal methods of video teleconference group delivery to maximise clinical benefit and treatment outcomes.