Citations

Type 2 diabetes is an emerging global health epidemic. Foundations for new therapies are arising from understanding interactions between body systems. Bone‐derived factors that reduce RANKL (receptor activator of NF‐kappa B ligand) signaling in the liver may prevent insulin resistance and the onset of type 2 diabetes. Here we demonstrate that deletion of the epigenetic regulator, Hdac3, in Osx1‐expressing osteoprogenitors prevents insulin resistance induced by high fat diet by increasing serum and skeletal gene expression levels of osteoprotegerin (Opg), a natural inhibitor of RANKL signaling. Removal of one Opg allele in mice lacking Hdac3 in Osx1+ osteoprogenitors increases the insulin resistance of the Hdac3‐deficient mice on a high fat diet. Thus, Hdac3‐depletion in osteoblasts increases expression of Opg, subsequently preserving insulin sensitivity. The Hdac inhibitor vorinostat also increased Opg transcription and histone acetylation of the Opg locus. These results define a new mechanism by which bone regulates systemic insulin sensitivity.

Key Clinical MessageHereditary spastic paraplegia is a group of clinically and genetically heterogeneous neurodegenerative disorders, often characterized by weakness and spasticity in the lower limbs. In our study, we describe a spastic paraplegia type 7 patient with an expanded phenotype who was diagnosed after the discovery of pathogenic variants in SPG7.

AbstractBackgroundDuration of functional warm ischemia (f‐WIT) is thought to have a causal effect on outcomes in controlled donation after circulatory death (DCD) liver transplantation (LT).MethodsA retrospective cohort study was conducted at five centers. Data were extracted on donor and recipient characteristics, with attention to parameters recorded during withdrawal of life support to in situ cold perfusion. F‐WIT was the time elapsed from any of the hemodynamic and oxygenation parameters to the start of in situ cold perfusion. Parameters were as follows: MAP ≤ 50 mm Hg; SBP ≤ 50 mm Hg; and SPO2 ≤ 60%. The primary endpoint was a composite of disseminated ischemic cholangiopathy (IC), primary non‐function (PNF), and early graft failure.Results35 patients (14%) developed one or more of the primary outcomes. On univariate analysis, older donors and longer WITs were associated with greater likelihood of complications. Of the f‐WIT variations analyzed, only f‐WIT with SpO2 ≤ 60% was longer among patients with complications. On multivariate analysis, only donor age was a significant predictor of complications.ConclusionThis study demonstrates that, of the f‐WITs, f‐WIT with SpO2 ≤ 60% is most predictive of post‐DCD complications. However, results suggest that there may be an alternate etiology for poor outcomes, and that donor age plays a key role.

Abstract Genomic analyses of cutaneous melanoma (CM) have yielded biological and therapeutic insights, but understanding of non-ultraviolet (UV)-derived CMs remains limited. Deeper analysis of acral lentiginous melanoma (ALM), a rare sun-shielded melanoma subtype associated with worse survival than CM, is needed to delineate non-UV oncogenic mechanisms. We thus performed comprehensive genomic and transcriptomic analysis of 34 ALM patients. Unlike CM, somatic alterations were dominated by structural variation and absence of UV-derived mutation signatures. Only 38% of patients demonstrated driver BRAF/NRAS/NF1 mutations. Contrasting with CM, we observed PAK1 copy gains in 15% of patients, and somatic TERT translocations, copy gains, and missense and promoter mutations, or germline events, in 41% of patients. We further show that in vitro TERT inhibition has cytotoxic effects on primary ALM cells. These findings provide insight into the role of TERT in ALM tumorigenesis, and reveal preliminary evidence that TERT inhibition represents a potential therapeutic strategy in ALM. Citation Format: Winnie S. Liang, William Hendricks, Jeffrey Kiefer, Jessica Schmidt, Shobana Sekar, John Carpten, David W. Craig, Jonathan Adkins, Lori Cuyugan, Zarko Manojlovic, Rebecca F. Halperin, Adrienne Helland, Sara Nasser, Christophe Legendre, Laurence H. Hurley, Karthigayini Sivaprakasam, Douglas B. Johnson, Holly Crandall, Klaus J. Busam, Victoria Zismann, Valerie De Luca, Jeeyun Lee, Aleksandar Sekulic, Charlotte E. Ariyan, Jeffrey Sosman, Jeffrey Trent. Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3389. doi:10.1158/1538-7445.AM2017-3389

Abstract The Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) in collaboration with the Colorectal Cancer Family Registry (CCFR) aims to identify genetic variants and environmental risk factors that impact colorectal cancer (CRC). Over 30 studies from North America, Europe, and Australia participate in GECCO. These studies have collected clinical, epidemiological, and survival data, as well as blood and tumor biospecimens, for over 80,000 CRC cases and controls. The current study aims to conduct targeted deep sequencing of tumors and matching normal DNA to identify recurrent and novel somatic and germline variants in 4,200 CRC cases. To achieve this goal, an AmpliSeq targeted sequencing panel of 1.12 Mbp was constructed to sequence the coding regions of 190 significantly mutated genes identified from whole exome sequencing datasets generated by the Nurses’ Health Study and Health Professional’s Follow-up Study, and The Cancer Genome Atlas. The panel also covers coding regions of 15 genes with germline high penetrance mutations in CRC, 54 regions to detect CRC-related copy number alterations (CNAs), and microsatellite and homopolymer repeat regions to identify defective DNA mismatch repair. Primers were also included to detect Fusobacterium nucleatum DNA in tumor biopsies, as F. nucleatum is thought to promote CRC carcinogenesis. Sequencing of the DNA libraries on Illumina HiSeq 2500 produced a mean coverage of greater than 500X for tumor DNA and 100X for normal DNA, with >85% of the bases covered at the target at 50x. So far, targeted sequencing of >1,500 DNA samples from CRC tumors and normal tissues has identified recurrent and novel somatic mutations, germline genetic variants, and hypermutation status of the tumors due to defective DNA mismatch repair or pathogenic mutations in the POLE gene. Targeted sequencing has also allowed quantification of the F. nucleatum DNA in tumor biopsies; the results were validated by a multiplex QPCR assay. At the AACR annual meeting, we will present targeted sequencing results generated from the first two GECCO-participating studies (n=1,300 cases). These data will be valuable for future association testing of somatic mutations, CNAs, hypermutation status, and F. nucleatum with germline genetic variants, lifestyle, and environmental risk factors and survival. This large study will allow development of better strategies for diagnosis, treatment, and prevention of CRC. Citation Format: Syed H. Zaidi, Wei Sun, Jeroen Huyghe, Catherine S. Grasso, Quang Trinh, Charles Connolly, Amy French, Jasmine Mu, Marios Giannakis, Eve Shinbrot, Ivan Borozan, Michael J. Quist, Hermann Brenner, Daniel Buchanan, Peter Campbell, Andrew Chan, Jenny Chang-Claude, Vincent Ferretti, Charles Fuchs, Andrea Gsur, Marc Gunter, Tabitha Harrison, Michael Hoffmeister, Wen-Yi Huang, Paul Krzyzanowski, Stephen Lee, Mathieu Lemire, Jessica Miller, Danielle Pasternack, Cherie Teney, Elaine Mardis, Polly Newcomb, Lincoln Stein, Lee Timms, David Wheeler, Christina Yung, Niha Zubair, Levi Garraway, Shuji Ogino, Li Hsu, Steven Gallinger, Stephen Thibodeau, Thomas Hudson, Ulrike Peters. Targeted deep sequencing of colorectal tumor tissues to study associations of tumor subtypes with germline genetic, lifestyle, and environmental risk factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1286. doi:10.1158/1538-7445.AM2017-1286

AbstractTeams are the building blocks of the healthcare system, with growing evidence linking the quality of healthcare to team effectiveness, and team effectiveness to team training. Simulation has been identified as an effective modality for team training and assessment. Despite this, there are gaps in methodology, measurement, and implementation that prevent maximizing the impact of simulation modalities on team performance. As part of the 2017 Academic Emergency Medicine Consensus Conference “Catalyzing System Change Through Health Care Simulation: Systems, Competency, and Outcomes,” we explored the impact of simulation on various aspects of team effectiveness. The consensus process included an extensive literature review, group discussions, and the conference “workshop” involving emergency medicine physicians, medical educators, and team science experts. The objectives of this work were to: 1) explore the antecedents and processes that support team effectiveness, 2) summarize the current role of simulation in developing and understanding team effectiveness, and 3) identify research targets to further improve team‐based training and assessment, with the ultimate goal of improving healthcare systems.

SummaryBackgroundThe serum biomarkers, elevated 7αC4 (C4) and decreased FGF19, have been proposed as screening tests for bile acid diarrhoea.AimTo analyse prevalence, specificity and reproducibility of fasting C4 and FGF19 in identifying bile acid diarrhoea in patients with irritable bowel syndrome with predominant diarrhoea or functional diarrhoea (summarised as IBS‐D).MethodsWe prospectively studied fasting serum C4 and FGF19 in 101 IBS‐D patients; we reviewed data from 37 of the 101 patients with prior fasting serum C4 and FGF19 and from 30 of the 101 patients with prior faecal bile acids per 48 hours. We compared results with normal values (C4 ≥52.5 ng/mL [n=184], FGF‐19 ≤61.7 pg/mL [n=50]). We used Spearman correlation and Bland‐Altman plots to appraise reproducibility.ResultsAmong the 101 patients, there was a negative correlation between serum C4 and FGF19 (Rs=−.342, P=.0005). Bile acid diarrhoea was diagnosed in 10 patients based on elevated serum C4 levels (mean 23.5±23.1 [SD] ng/mL) and 21 patients based on decreased FGF19 levels (121.6±84.2 pg/mL). With replicate tests in patients with stable IBS‐D, 78% of C4 and 70% of FGF19 measurements remained concordant, with 3% and 11% respectively consistently positive for bile acid diarrhoea in the 101 patients. Compared to 48 hours faecal bile acids, specificity for C4 and FGF19 was 83% and 78%, respectively. Bland‐Altman plots demonstrated greater reliability of C4 than FGF19.ConclusionsAmong 101 patents with IBS‐D, fasting FGF19 and C4 levels had good specificity and negative predictive value, suggesting utility as screening tests to exclude bile acid diarrhoea.