tbuckley/cabot-search huggingface dataset:
Abstract 15273: Baroreflex Activation Therapy Significantly Lowers NTproBNP in Patients with Symptomatic Heart Failure
Authors: Marcel Halbach, Navid Madershahian, Mathias C Brandt, Dennis Ladage, Ralf Velden, Eric Lovett, Uta C Hoppe, Jochen Múller-Ehmsen
Journal: Circulation (2012)

Background: Baroreflex activation therapy (BAT) modulates sympathovagal balance, which is impaired in patients with heart failure leading to increased morbidity and mortality. Our aim was to study the effect of BAT on levels of the prognostic marker NTproBNP, NYHA class and 6-Minute-Walk-Test in patients with heart failure and reduced ejection fraction. Methods: 5 Patients were implanted with the CVRx neoTM system (CVRx Inc., Minneapolis, Minnesota) at the University of Cologne as part of a first-in-man study of BAT for systolic heart failure. They had an ejection fraction of <35% (mean 27.8±2.8%), and were in NYHA class III before BAT (inclusion criteria). NTproBNP measurements were repeatedly performed prior to implant and during follow-up. NTproBNP was quantified as the average of all available values before and on BAT. All data are presented as mean±SEM. Results: NTproBNP decreased in all patients on BAT. NTproBNP was 3184±1000 ng/l prior to BAT and fell to 1516±291 ng/l during an average follow-up of...
Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study
Authors: Benjamin J Solomon, Benjamin Besse, Todd M Bauer, Enriqueta Felip, Ross A Soo, D Ross Camidge, Rita Chiari, Alessandra Bearz, Chia-Chi Lin, Shirish M Gadgeel, Gregory J Riely, Eng Huat Tan, Takashi Seto, Leonard P James, Jill S Clancy, Antonello Abbattista, Jean-François Martini, Joseph Chen, Gerson Peltz, Holger Thurm, Sai-Hong Ignatius Ou, Alice T Shaw
Journal: The Lancet Oncology (2018)
Abstract 13911: ELABELA/Toddler (Apela), is an Endogenous Ligand of the Human Apelin Receptor and is Reduced in Pulmonary Arterial Hypertension
Authors: Peiran Yang, Janet J Maguire, Rhoda E Kuc, Mark Southwood, Nicholas W Morrell, Anthony Davenport
Journal: Circulation (2015)

Introduction: The apelin receptor is proposed as a therapeutic target in pulmonary arterial hypertension (PAH). The apelin peptide knockout mouse does not recapitulate the apelin receptor knockout mouse however this may be explained by the recent identification of a novel peptide, ELABELA/toddler/apela (ELA), identified in a previously designated non-coding region. We have previously demonstrated ELA expression localised to endothelial cells in human cardiovascular tissues and ELA binding to the human expressed apelin receptor. It remains to be determined whether the pharmacology of ELA is comparable to apelin and whether ELA is detectable in human plasma and, more importantly, whether ELA expression is altered in PAH where apelin expression is reduced. Hypotheses: We hypothesised that ELA binds to the apelin receptor in human heart, activates both G protein-dependent and -independent signalling, is present in human plasma and is reduced in PAH. Methods: Competition binding assays were performed in human heart. The potency (pD 2 ) of ELA-32 and [Pyr 1 ]apelin-13 was determined in cAMP, β-arrestin and internalisation assays in cells expressing the human apelin receptor. Levels of ELA and apelin were measured in human plasma samples. The presence and absence of ELA immunostaining was scored in pulmonary vessels (≤100μm diameter) in sections of human lung from PAH patients and controls (IRB approval) and compared using Fisher’s Exact Test. Results: ELA-32 competed for binding of [ 125 I][Pyr 1 ]apelin-13 with an affinity of 0.21±0.06nM (n=3). Both ELA-32 and [Pyr 1 ]apelin inhibited cAMP production (pD 2 =9.36±0.11, n=6; 9.61±0.12, n=5), elicited β-arrestin recruitment (9.13±0.18, n=16; 8.28±0.05, n=21) and receptor internalization (9.16±0.10, n=8; 8.55±0.07, n=7). ELA peptide was detectable in human plasma (0.49±0.05nM, n=25). The proportion of ELA-negative lung vessels was significantly increased in PAH (n=10) compared to controls (n=4) (p&lt;0.01). Conclusions: This study further characterizes ELA receptor pharmacology, signalling and plasma levels. We report for the first time down-regulation of ELA peptide in human disease. These findings support the apelin receptor as a target in the treatment of PAH.
CBMT-05. ROLE OF THE let7-eEF2K AXIS IN MYC-DRIVEN MEDULLOBLASTOMA ADAPTATION TO NUTRIENT DEPRIVATION
Authors: Alberto Delaidelli, Gian Luca Negri, Simran Sidhu, Marc Remke, Stefan Pfister, Michael Taylor, Gabriel Leprivier, Marcel Kool, Poul Sorensen
Journal: Neuro-Oncology (2018)

BACKGROUND/OBJECTIVES: MYC amplification in medulloblastoma (MB) determines highly aggressive disease, underscoring an urgent need for novel therapies. Let-7 microRNAs (miRNAs) inhibit tumor progression and regulate metabolism by degrading several mRNAs, including MYC. Let-7 miRNAs are frequently repressed in cancer, including MYC-driven MB. We previously reported that eukaryotic Elongation Factor-2 Kinase (eEF2K) is a pivotal regulator of MYC-driven tumor adaptation to nutrient deprivation (ND). Our data indicate that the eEF2K 3’ untranslated region (UTR) harbors a potential binding site for let-7. In addition, eEF2K mRNA and let-7 miRNA expression negatively correlates in MB, suggesting regulation of the former by the latter. We therefore hypothesized that let-7 down-regulation induces eEF2K expression in MB, thereby supporting MYC-driven MB adaptation to ND and tumor progression. Immunohistochemistry for eEF2K substrate (p-eEF2) was performed on MB tissue microarrays to link results with MYC expression and clinical outcome. Effects of eEF2K pharmacological inhibition on MB cell survival were evaluated in vitro by MTT assays. The ability of let-7 to degrade eEF2K mRNA was assessed by let-7 miRNAs transfection into MB cells, followed by RT-PCR and Western Blotting for eEF2K. Binding of let-7 to the eEF2K 3’UTR was validated by luciferase reporter assays. High eEF2K activity is linked to MYC over-expression and reduced survival in MB (p<0.05). Pharmacological inhibition of eEF2K significantly reduces survival of MYC-amplified MB cell lines under ND. Transfection let-7 miRNAs decreases eEF2K mRNA and protein levels (by ~40–50%) in MB cells. Down-regulation of luciferase activity by let-7 miRNAs is impaired upon mutation of the let-7 binding site on the eEF2K 3’UTR. Let-7 miRNAs degrade eEF2K mRNA, indicating that let-7 repression in MYC-driven MB is partially responsible for eEF2K increased levels and activity. Moreover, the let-7-eEF2K axis represents a critical mechanism for MYC-driven MB adaptation to ND, constituting a promising therapeutic target.
Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition
Authors: Toru Hashimoto, Grace E. Kim, Richard S. Tunin, Tolulope Adesiyun, Steven Hsu, Ryo Nakagawa, Guangshuo Zhu, Jennifer J. O’Brien, Joseph P. Hendrick, Robert E. Davis, Wei Yao, David Beard, Helen R. Hoxie, Lawrence P. Wennogle, Dong I. Lee, David A. Kass
Journal: Circulation (2018)

Phosphodiesterase type-1 (PDE1) hydrolyzes cAMP and cGMP and is constitutively expressed in the heart, although cardiac effects from its acute inhibition in vivo are largely unknown. Existing data are limited to rodents expressing mostly the cGMP-favoring PDE1A isoform. Human heart predominantly expresses PDE1C with balanced selectivity for cAMP and cGMP. Here, we determined the acute effects of PDE1 inhibition in PDE1C-expressing mammals, dogs, and rabbits, in normal and failing hearts, and explored its regulatory pathways.Conscious dogs chronically instrumented for pressure-volume relations were studied before and after tachypacing-induced heart failure (HF). A selective PDE1 inhibitor (ITI-214) was administered orally or intravenously±dobutamine. Pressure-volume analysis in anesthetized rabbits tested the role of β-adrenergic and adenosine receptor signaling on ITI-214 effects. Sarcomere and calcium dynamics were studied in rabbit left ventricular myocytes.In normal and HF dogs, ITI-214 increased load-independent contractility, improved relaxation, and reduced systemic arterial resistance, raising cardiac output without altering systolic blood pressure. Heart rate increased, but less so in HF dogs. ITI-214 effects were additive to β-adrenergic receptor agonism (dobutamine). Dobutamine but not ITI-214 increased plasma cAMP. ITI-214 induced similar cardiovascular effects in rabbits, whereas mice displayed only mild vasodilation and no contractility effects. In rabbits, β-adrenergic receptor blockade (esmolol) prevented ITI-214-mediated chronotropy, but inotropy and vasodilation remained unchanged. By contrast, adenosine A2B-receptor blockade (MRS-1754) suppressed ITI-214 cardiovascular effects. Adding fixed-rate atrial pacing did not alter the findings. ITI-214 alone did not affect sarcomere or whole-cell calcium dynamics, whereas β-adrenergic receptor agonism (isoproterenol) or PDE3 inhibition (cilostamide) increased both. Unlike cilostamide, which further enhanced shortening and peak calcium when combined with isoproterenol, ITI-214 had no impact on these responses. Both PDE1 and PDE3 inhibitors increased shortening and accelerated calcium decay when combined with forskolin, yet only cilostamide increased calcium transients.PDE1 inhibition by ITI-214 in vivo confers acute inotropic, lusitropic, and arterial vasodilatory effects in PDE1C-expressing mammals with and without HF. The effects appear related to cAMP signaling that is different from that provided via β-adrenergic receptors or PDE3 modulation. ITI-214, which has completed phase I trials, may provide a novel therapy for HF.
IMMU-31. DYSFUNCTIONAL STING PATHWAY SIGNALING COMPROMISES INNATE IMMUNITY IN GLIOBLASTOMA
Authors: Michelle Bowie, David Ashley, Janell Hostettler, Michael Brown, Jeffrey Bryant, Darell Bigner, Matthias Gromeier, Smita Nair
Journal: Neuro-Oncology (2018)

Stimulator of interferon genes (STING), a protein located in the endoplasmic reticulum, is a key mediator of innate immune response to non-CpG cytosolic DNA. Intact STING has been shown to be involved in the induction of the innate antitumor response in Glioblastoma (GBM). Upon sensing cytosolic dsDNA, the STING pathway is activated, resulting in phosphorylation of interferon regulatory factor 3 (IRF3), which leads to the induction of a type I interferon response, essential for innate immunity. Recent evidence shows the STING pathway is dysregulated in other cancers. Western analysis on several glioblastoma derived cell lines, showed that STING was present at variable levels in 6 out of 7 cell lines. In addition, the dsDNA sensor cGAS, a protein upstream of STING, was expressed in only 3 out of 7 cell lines. Cell lines were treated with a variety of innate agonists including CpG free dsDNA construct to test the activation of the STING pathway. We observed a variable response to the dsDNA stimulus. The M059J cell line exhibited an intact STING pathway with activation of pIRF3 and pSTAT1 (a marker of IFN production). Both LN18 and T98G cell lines failed to activate pIRF3 and pSTAT1, whereas A172 cells showed activated pSTAT1 in the absence of pIRF3. This data suggests the STING Pathway is dysregulated in glioblastoma cell lines and highlights a potential mechanism of evasion of innate immune signaling in glioblastoma. Ongoing studies will examine the mechanism of this dysregulation and its impact on innate therapies such as PVSRIPO.
TMIC-30. COMPUTATIONAL CHARACTERIZATION OF SUPPRESSIVE IMMUNE MICROENVIRONMENTS IN GLIOBLASTOMA
Authors: Suvi Luoto, Ismaïl Hermelo, Elisa Vuorinen, Paavo Hannus, Juha Kesseli, Matti Nykter, Kirsi Granberg
Journal: Neuro-Oncology (2018)

The immunosuppressive microenvironment in glioblastoma (GBM) prevents efficient antitumoral immune response and thus enables tumor formation and growth. An understanding of the nature of immunosuppression is still largely lacking although it is important for successful cancer treatment through immune system modulation. To gain insight into immunosuppression in GBM, we performed a computational analysis to model the relative immune cell content and type of immune response in each GBM tumor sample from the Cancer Genome Atlas RNA-seq dataset. As a result, we uncovered high variability in immune system-related responses and in the composition of microenvironment across the cohort, suggesting immunological diversity. Immune cell compositions were associated with typical alterations, such as IDH mutation or inactivating NF1 mutation/deletion. Furthermore, our analysis identified three GBM subgroups presenting different adaptive immune responses: Negative, Humoral, and Cellular-like. These subgroups were linked to transcriptional GBM subtypes and typical genetic alterations. Interestingly, all the G-CIMP and IDH mutated samples were in the Negative group, which was also enriched by cases with focal amplification of CDK4 and MARCH9. Overall, our analysis revealed heterogeneity in the immune microenvironment of GBM and identified MARCH9 amplification as a possible new marker for immunosuppression. Characterization of diverse immune responses will facilitate patient stratification improving personalized immunotherapy in the future.
Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia
Authors: Deepak L. Bhatt, P. Gabriel Steg, Michael Miller, Eliot A. Brinton, Terry A. Jacobson, Steven B. Ketchum, Ralph T. Doyle, Rebecca A. Juliano, Lixia Jiao, Craig Granowitz, Jean-Claude Tardif, Christie M. Ballantyne
Journal: New England Journal of Medicine (2018)

Patients with elevated triglyceride levels are at increased risk for ischemic events. Icosapent ethyl, a highly purified eicosapentaenoic acid ethyl ester, lowers triglyceride levels, but data are needed to determine its effects on ischemic events.
GENE-16. CLINICALLY AGGRESSIVE MENINGIOMAS ARE CHARACTERIZED BY MUTATIONAL SIGNATURES ASSOCIATED WITH DEFECTIVE DNA REPAIR AND MUTATIONS IN CHROMATIN REMODELING GENES
Authors: Sylvia Kurz, Benjamin Liechty, Stephen Kelly, Varshini Vasudevaraja, Ramona Bledea, Peter Wu, Jonathan Serrano, Leah M Katz, Joshua Silverman, Donato Pacione, John Golfinos, Andrew Chi, Matija Snuderl
Journal: Neuro-Oncology (2018)

Up to 20% of meningiomas are aggressive tumors with high recurrence rates and poor prognosis. Biomarkers predicting the risk of an unfavorable clinical course are lacking although aberrations in NF2, increased copy number variations and a hypomethylated phenotype have been associated with more aggressive behavior. Mutational signatures (MS) are characteristic patterns of somatic mutations seen in cancer genomes associated with aging, exposure to certain mutagens, or defective DNA repair. We aimed to identify MS patterns in clinically aggressive meningiomas. We performed whole exome sequencing of 18 de novo meningiomas (locally invasive and recurrent WHO I, n=6; atypical WHO II, n=4; anaplastic WHO III, n=8). Median PFS was 18.9 months. Copy numbers and DNA methylation phenotype were assessed by DNA methylation array analysis. Mutational signatures were identified using published signature algorithms (COSMIC). MS1 and MS5 (aging) were found in 18 (100%) cases. MS associated with defective DNA MMR were highly prevalent: MS20 and MS26 were detected in 18 (100%) and MS6 in 2 (12%) cases. MS12 (unknown etiology) was present in 14 (82%) cases. Despite the association with defective DNA MMR, none (0%) of the MS6 cases harbored somatic mutations associated with DNA MMR while MS12 tumors were enriched for mutations in DNA MMR (43%), chromatin remodeling (36%) and other cancer-associated genes (7%). MS6 tumors had significantly lower indels compared to non-MS6 tumors (p=0.01). Tumors with mutations in chromatin remodeling genes had a significantly higher rate of single nucleotide variants (SNVs) compared to cases without such mutations (p=0.02). MS associated with defective DNA MMR were highly prevalent in this set of aggressive meningiomas. However, despite the association with DNA MMR, MS6 meningiomas harbored no somatic mutations associated with DNA MMR while MS12 tumors were enriched for mutations in DNA MMR, chromatin remodeling and cancer-associated genes.
Abstract 18944: Trends in P2Y12 Inhibitor Utilization and Adherence Among Antiplatelet-Naïve Patients After PCI, 2008-2014
Authors: Elias J Dayoub, Matthew Seigerman, Jay S Giri, Peter W Groeneveld
Journal: Circulation (2017)

Introduction: While P2Y12 inhibitors (P2Y12i) are essential pharmacotherapy after percutaneous coronary intervention (PCI), few studies have investigated differences in P2Y12i utilization or adhere...
CBMT-43. SINGLE LIVE TUMOR CELL METABOLISM VIA RAMAN IMAGING MICROSCOPY
Authors: Adrian Lita, Jing Wu, Deric Park, Mark Gilbert, Mioara Larion
Journal: Neuro-Oncology (2018)

Raman has been used for decades to determine vibrational models linked with structural changes of small molecules. Due to recent progress in the diode lasers and notch filters, study of biological systems became possible in the form of Raman Imaging Microscopy. Focusing the laser through a microscope allows the collection of Raman spectra for each pixel and subsequent movement of the stage permits the acquisition of spectra in a new position. This approach provides a biochemical mapping of the entire cell while maintaining viability in the culture media. Therefore, the technique is non-destructive, non-invasive and can accept a wide range of samples from bulk to microscopic, from solids to liquids or gasses. However, Raman has not been primarily used for biological samples, therefore spectral assignments for metabolites are currently limited for these samples. Tumor cells used for Raman analysis were transferred into 35 mm sterile glass bottom dishes (Ibidi) and cultured for 24 hours. Raman spectra were acquired using a DXR 2xi Raman microscope (Thermo Fisher Scientific) with 24 mW of 780 nm laser through a 60x water immersed confocal objective, at 0.5 s exposure time for a 1 μm pixel size, between 50 and 3200 cm−1 spectral region. Spectra were collected and subsequently background corrected using the Raman silent region. Chemical maps were produced by the peak area function using Thermo Fisher Scientific OMNIC software. RESULTS AND Raman spectroscopy on a single live cells enabled visualization of cytochrome C release from mitochondria after treatment of an inhibitor of glycolyisis drug treatment; quantification of lipid content in a tumor cell upon treatment with AGI-5198 drug, as well as mapping and quantification of DNA damage. These results highlight to potential for Raman imaging to perform single cell metabolomics.
12-month outcomes of HIV-infected infants identified at birth at one maternity site in Johannesburg, South Africa: an observational cohort study
Authors: Karl-Günter Technau, Renate Strehlau, Faeezah Patel, Stephanie Shiau, Megan Burke, Martie Conradie, Gillian Sorour, Gayle G Sherman, Ashraf Coovadia, Pamela M Murnane, Elaine J Abrams, Louise Kuhn
Journal: The Lancet HIV (2018)
Abstract MP83: Exomechip Meta-analysis of 526,508 Individuals From Five Ancestries Identifies Coding Variation in <i>MC4R</i> and <i>KSR2</i> Associated with Body Mass Index
Authors: Heather M Highland, Valérie Turcot, Yingchang Lu, Claudia Schurmann, Anne E Justice, Kristin L Young, Mariaelisa Graff, Adam E Locke, Judy Wang, Petra Lenzini, L A Cupples, Timothy Frayling, Joel N Hirschhorn, Guillaume Lettre, Cecilia M Lindgren, Kari E North, Ingrid B Borecki, Ruth J Loos
Journal: Circulation (2016)

Increased body mass index (BMI) increases risk of chronic diseases including heart disease, stroke, and type 2 diabetes (T2D). Through genome-wide association studies (GWAS), 97 genetic variants, mostly common (MAF&gt;5%) and non-coding, have been identified for BMI. To investigate the role of coding variants with putative functional effects (missense, nonsense, splicing, stop gain), we meta-analyzed ExomeChip data of 526,508 individuals from over 110 studies, predominantly of European ancestry. Individual studies performed association analyses using Rvtest or RareMetalWorker; results were subsequently combined in single variant meta-analyses and gene-based tests (SKAT, VT) stratified by ancestry using RareMETALS. Gene-based tests were grouped based on functional annotation and in silico predicted impact on proteins for variants with a MAF&lt;5%. Among the 245,497 variants analyzed, of the 93 loci that reached array-wide significance (P&lt;2E-07); 56 were novel or independent of previously identified BMI loci. This includes low frequency variants in ACHE (rs1799805, p.H353N, p=8.01E-10, EAF=4%, β(SE)=0.032(0.005) SD/allele), HIP1R (rs34149579, p.V67F, p=1.88E-08, EAF=4%, β(SE)=-0.027(0.005) SD/allele) and MC4R (rs13447324, p.Y35X, p=2.37e-11, EAF=0.01%, β(SE)=0.64(0.09) SD/allele). Eight gene-based associations were significant (p&lt;2.5E-06), including GIPR (p=7.17E-09), whose effects were independent of the common GWAS proxy in the gene (rs1800437, p. E354Q, p=7.91E-30, MAF=20%, β(SE)=-0.029(0.003) SD/allele). GIPR is part of the GLP1 pathway responsible for the secretion of postprandial insulin. Other gene-based associations were largely driven by a single variant, such as for KSR2 (p=7.15E-09), RAPGEF3 (p=8.91E-15) and PRKAG1 (p=2.75E-12). Ksr2 knockout mice are obese. Multiple variants in KSR2 have been shown to associate with severe early onset obesity. Mutations in KSR2 disrupt the Raf-MEK-ERK pathway, resulting in impaired fatty acid oxidation and glucose oxidation. RAPGEF3 is involved in the GLP1 pathway and regulates glucose sensitivity of the K ATP channel, which regulates insulin secretion. PRKAG1 is involved in AMPK signaling and has previously been associated with T2D and weight gain on antipsychotic medication. Taken together, by interrogating coding variants in a large sample set, we have identified both additional genes and variants associated with BMI, some of which may be causal.