Citations

BACKGROUND: In patients who receive a nondepolarizing neuromuscular blocking drug (NMBD) during anesthesia, undetected postoperative residual neuromuscular block is a common occurrence that carries a risk of potentially serious adverse events, particularly postoperative pulmonary complications. There is abundant evidence that residual block can be prevented when real-time (quantitative) neuromuscular monitoring with measurement of the train-of-four ratio is used to guide NMBD administration and reversal. Nevertheless, a significant percentage of anesthesiologists fail to use quantitative devices or even conventional peripheral nerve stimulators routinely. Our hypothesis was that a contributing factor to the nonutilization of neuromuscular monitoring was anesthesiologists’ overconfidence in their knowledge and ability to manage the use of NMBDs without such guidance. METHODS: We conducted an Internet-based multilingual survey among anesthesiologists worldwide. We asked respondents to answer 9 true/false questions related to the use of neuromuscular blocking drugs. Participants were also asked to rate their confidence in the accuracy of each of their answers on a scale of 50% (pure guess) to 100% (certain of answer). RESULTS: Two thousand five hundred sixty persons accessed the website; of these, 1629 anesthesiologists from 80 countries completed the 9-question survey. The respondents correctly answered only 57% of the questions. In contrast, the mean confidence exhibited by the respondents was 84%, which was significantly greater than their accuracy. Of the 1629 respondents, 1496 (92%) were overconfident. CONCLUSIONS: The anesthesiologists surveyed expressed overconfidence in their knowledge and ability to manage the use of NMBDs. This overconfidence may be partially responsible for the failure to adopt routine perioperative neuromuscular monitoring. When clinicians are highly confident in their knowledge about a procedure, they are less likely to modify their clinical practice or seek further guidance on its use.

Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3′ gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97–1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03–1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10−28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.

Abstract Background: Potent targeting of the androgen receptor (AR) in castration-resistant prostate cancer has altered the archetypal course of the disease, fueling the emergence of aggressive and incurable neuroendocrine prostate cancer (NEPC). Recent evidence suggests that these tumors can arise from non-neuroendocrine cells in response to AR pathway inhibitors (ARPIs), such as enzalutamide (ENZ), an observation consistent with lineage plasticity. What regulates this plasticity that allows cells to shed their dependence on the AR and re-emerge as “AR-indifferent” NEPC? Sequencing studies have uncovered that the evolution toward a NEPC phenotype is aligned with dynamic epigenetic reprogramming, but the molecular basis underlying this phenomenon remains poorly understood. Methods: We developed an in vivo model of acquired ENZ resistance to (a) identify reprogramming factors that facilitate lineage plasticity, and (b) determine how to best capitalize on therapeutic strategies aimed at blocking or reversing lineage transformation. Cell lines derived from ENZ-resistant tumors were profiled by RNA-seq and ChIP-seq, and functionally assessed for stem cell-associated properties. Our findings were validated across NEPC cell lines (NCI-H660), genetically engineered mouse models (PBCre4:Ptenf/f:Rb1f/f), and patient tumors and organoids. CRISPR/Cas9-mediated genomic editing allowed us to assess the effect of knocking out reprogramming factors on therapy-induced neuroendocrine transdifferentiation. Results: AR-indifferent ENZ-resistant tumors were enriched for a Polycomb/EZH2 signature; in particular, we identified EZH2 to be phosphorylated at threonine-350 (pEZH2-T350) by CDK1 in NEPC cell lines, mouse models, and patient tumors. Accordingly, RB1 loss was sufficient to enhance pEZH2-T350, which was required for prostate cancer cells to convert to a metastable stem-like state and, in turn, acquire neuroendocrine features under the pressure of ARPIs both in vitro and in patient-derived xenografts. This therapy-induced NEPC transdifferentation was associated with a marked redistribution of EZH2 and H3K27me3, specifically to a core set of genes governing lineage identity. AR colocalized at the reprogrammed EZH2 binding sites, and was found to be part of the same complex with EZH2. Treating AR-indifferent/NEPC cell lines with clinically relevant EZH2 inhibitors reversed the lineage switch and mitigated ENZ resistance. Conclusions: This research establishes the centrality of epigenetic reprogramming in driving the insurgence of a neuroendocrine phenotype in response to ARPIs, and posits that drugging the epigenome via EZH2 inhibition may reverse or delay lineage transformation to extend the durability of clinically beneficial ARPIs. Citation Format: Alastair H. Davies, Chiara Bostock, Musaddeque Ahmed, Yen-Yi Lin, Fraser Johnson, Ka Mun Nip, Kirsi Ketola, Jennifer Bishop, Ladan Fazli, Haojie Huang, David Goodrich, Faraz Hach, Hansen He, Himisha Beltran, Amina Zoubeidi. Identity fraud: Lineage plasticity as a mechanism of anti-androgen resistance and target for therapy [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 4995.

Abstract Background: Radiologically dense area (DA) on a mammogram represents the stromal and epithelial tissue in the breast, while non-dense area (NDA) represents adipose tissue. Quantitative measurements of DA, NDA as well as the proportion of dense area in the breast (percent density, PD) adjusted for age and body mass index (BMI) have all been associated with breast cancer (BC) risk. Previous genome-wide association studies (GWAS) have identified genetic loci that show association with both mammographic density (MD) phenotypes and BC, but little is known about the genome-wide and local genetic correlation between MD phenotypes and BC. Methods: We estimated the genome-wide and local genetic correlation between MD phenotypes adjusted for age and BMI and BC, leveraging GWAS summary statistics for MD phenotypes based on 12,866 women (MODE consortium) and for BC based on 122,977 cases and 105,974 controls (BCAC consortium). We also conducted partitioned heritability analysis to identify specific functional annotations that contribute to MD heritability. Results: We observed a negative genetic correlation between DA and NDA (-0.62, p=0.002). Both DA and PD showed positive genetic correlations with overall BC (DA: rg=0.24, p=0.004; PD: rg=0.27, p=0.0001), estrogen receptor-positive (ER+) BC (DA: rg=0.23, p=0.005; PD: rg=0.23, p=0.001), and ER- BC (DA: rg=0.26, p=0.01; PD: rg=0.32, p=0.0006). In contrast, NDA showed a nonsignificant negative genetic correlation with BC (rg=-0.11, p=0.21). Local genetic correlation analyses between MD phenotypes and BC reflected known findings including positive correlation at 10q21 region between both PD and DA and BC (both p<5x10-7), negative correlation at 22q13.1 between DA and BC (p=4.6x10-6), and positive correlation at 8p11.23 between NDA and BC (p=2.8x10-6). Two known BC regions that have not previously been associated with MD showed suggestive genetic correlations between BC and DA: 1q21.2 (negative genetic correlation, p=1.3x10-4) and 12q21.31 (positive genetic correlation, p=6.7x10-4). In exploratory analyses estimating the genome-wide genetic correlation between MD and hormone-related phenotypes in UK Biobank (n=337,199), we observed nominally significant positive genetic correlations between PD and benign mammary dysplasia (rg=0.45, p=0.01), NDA and endometriosis (rg=0.45, p=0.02), and negative genetic correlation between NDA and menstrual cycle length (rg=-0.30, p=0.05). We identified multiple functional annotations that contribute to MD heritability including histone mark H3K27ac that marks active enhancers (~2,5-fold enrichment in heritability for both DA and NDA) and DNAsel Hypersensitive Sites (DHS, 9.1-fold enrichment in heritability for DA). Conclusion: Our results provide evidence of shared genetic basis between mammographic density and breast cancer. Citation Format: Hongjie Chen, Julie Douglas, William Gordon, Deborah Thompson, Fergus Couch, Peter Fasching, Per Hall, John Hopper, Gertraud Maskarenic, Marina Pollan, Jennifer Stone, Rulla Tamimi, Sara Lindstroem. Evidence for a shared genetic basis between breast cancer and mammographic density phenotypes [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 224.

Abstract The endosteal niche is a component of the bone marrow microenvironment that can serve to protect hematological malignancies such as acute myeloid leukemia (AML) from standard chemotherapies such as cytarabine (Ara-C). Surviving AML cells harbored by this niche can eventually lead to relapse. The endosteal niche is rich in osteoblast lineage cells. U937 or KG1a AML cell lines were cultured with or without osteoblast lineage cells (MC3T3 or W-20-17 cell lines), challenged with doses of 0µM, 0.1µM, 0.5µM, 1µM, 5µM, or 10µM of Ara-C, and assayed for apoptosis via annexin-V staining and flow cytometry. Osteoblast lineage cells (MC3T3 or W-20-17 cell lines) were able to protect AML cells (U937 or KG1a cell lines) from Ara-C-induced apoptosis. Histone deacetylase inhibitors (HDACi) globally alter gene expression within cells. When we pre-treated osteoblast lineage cells (MC3T3) with the HDACi vorinostat (suberoylanilide hydroxamic acid, SAHA), it reduced the ability of the osteoblast lineage cells (MC3T3) to protect AML cells (U937) from Ara-C-induced apoptosis, which we have previously confirmed in the KG1a AML cell line as well. This indicates that osteoblast lineage cell-mediated protection of AML from Ara-C occurs via an HDACi sensitive mechanism. To begin to further explore the mechanism of action, we co-cultured AML cells (KG1a or U937) with and without osteoblast lineage cells (MC3T3) in the presence or absence of a transwell. We found that the presence of the transwell reduced the osteoblast lineage cell-mediated protection, indicating that osteoblast lineage cell-mediated protection of AML from Ara-C is cell contact dependent. Thus, osteoblast lineage cells can protect AML cells from Ara-C induced apoptosis, this protection can be reduced by pre-treatment of the osteoblast lineage cells with the HDACi vorinostat, and osteoblast lineage cell-mediated protection from Ara-C is cell contact dependent. These studies begin to characterize the mechanisms of osteoblast lineage cell-mediated protection of AML from Ara-C. Manipulating the protective properties of osteoblast lineage cells of the endosteal niche may help make AML cells more susceptible to chemotherapeutics. Therefore, developing combination therapies that target the protective mechanisms of osteoblast-lineage cells may help to further deplete the bone marrow microenvironment of AML cells and prevent relapse of disease. Citation Format: Rosalie M. Sterner, Kimberly N. Kremer, Meagan R. Rollins, Amel Dudakovic, Jennifer J. Westendorf, Andre J. van Wijnen, Karen E. Hedin. Osteoblast-lineage cells protect AML cells from cytarabine-induced apoptosis via a mechanism sensitive to HDACi and reduced cell-cell contact [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 2137.

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.