tbuckley/cabot-search huggingface dataset:
FRI0653 IMPROVING AND VALIDATING THE PREDICTIVE ACCURACY OF MRI DETECTED SUBCLINICAL INFLAMMATION FOR RHEUMATOID ARTHRITIS DEVELOPMENT IN CLINICALLY SUSPECT ARTHRALGIA
Authors: Xanthe Matthijssen, Fenne Wouters, Debbie Boeters, Aleid Boer, Yousra Dakkak, Ellis Niemantsverdriet, Saskia Le Cessie
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Presence of MRI-detected subclinical joint inflammation in clinically suspect arthralgia (CSA) is predictive for progression to Rheumatoid Arthritis. Despite high negative predictive values (94%); its positive predictive value (PPV) is moderate (∼31%). <h3>Objectives</h3> We studied if, in addition to the presence of inflammation, incorporating information on severity, number and combinations of MRI-inflammatory locations improves the predictive accuracy. <h3>Methods</h3> In the discovery cohort, 225 CSA-patients were followed on clinical arthritis development. Contrast-enhanced 1.5T MRIs were made of unilateral MCP(2-5), wrist and MTP(1-5)-joints at baseline and scored for synovitis, tenosynovitis and bone marrow edema. Severity, number and combination of locations (joint/tendon/bone) with subclinical inflammation were determined, with symptom-free controls of similar age category as reference. Cox regression was used for predictor selection. Predictive values were determined at 1-year follow-up. Results were validated in 266 CSA-patients. <h3>Results</h3> In both cohorts 15% developed arthritis &lt;1-year. The number of locations with subclinical inflammation (1-2 locations HR 2.54 (1.11-5.82); ≥3 locations HR 3.75 (1.49-9.48)) and presence of MCP-extensor peritendinitis (HR 4.38 (2.07-9.25)) were independently predictive. Severity and combinations of inflammatory lesions were not. Based on these variables, five risk categories were defined: no subclinical inflammation, 1-2/≥3 locations, with/without MCP-extensor peritendinitis. PPVs ranged 5% (lowest category; NPV 95%) - 67% (highest category). Similar findings were obtained in the validation cohort; PPVs ranged 4% (lowest category; NPV 96%) - 63% (highest category). <h3>Conclusion</h3> Incorporation of the number of locations with subclinical inflammation and MCP-extensor peritendinitis in MRI-evaluation improved risk stratification, yielding PPVs up to 63-67%. This promotes optimal use of MRI-data in an evidence-based way. <h3>Disclosure of Interests</h3> Xanthe Matthijssen: None declared, Fenne Wouters: None declared, Debbie Boeters: None declared, Aleid Boer: None declared, Yousra Dakkak: None declared, Ellis Niemantsverdriet: None declared, Saskia Le Cessie: None declared, Annette van der Helm - van Mil Grant/research support from: The research leading to these results has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (Starting grant, agreement No 714312) and from the Dutch Arthritis Foundation. The funding source had no role in the design and conduct of the study.
Modularity of genes involved in local adaptation to climate despite physical linkage
Authors: Katie E Lotterhos, Sam Yeaman, Jon Degner, Sally Aitken, Kathryn A Hodgins
Journal: Genome biology (2018)

Linkage among genes experiencing different selection pressures can make natural selection less efficient. Theory predicts that when local adaptation is driven by complex and non-covarying stresses, increased linkage is favored for alleles with similar pleiotropic effects, with increased recombination favored among alleles with contrasting pleiotropic effects. Here, we introduce a framework to test these predictions with a co-association network analysis, which clusters loci based on differing associations. We use this framework to study the genetic architecture of local adaptation to climate in lodgepole pine, Pinus contorta, based on associations with environments.We identify many clusters of candidate genes and SNPs associated with distinct environments, including aspects of aridity and freezing, and discover low recombination rates among some candidate genes in different clusters. Only a few genes contain SNPs with effects on more than one distinct aspect of climate. There is limited correspondence between co-association networks and gene regulatory networks. We further show how associations with environmental principal components can lead to misinterpretation. Finally, simulations illustrate both benefits and caveats of co-association networks.Our results support the prediction that different selection pressures favor the evolution of distinct groups of genes, each associating with a different aspect of climate. But our results went against the prediction that loci experiencing different sources of selection would have high recombination among them. These results give new insight into evolutionary debates about the extent of modularity, pleiotropy, and linkage in the evolution of genetic architectures.
Abstract 96: Inactivation of Neddylation Causes Left Ventricular Noncompaction Cardiomyopathy Through Suppressing YAP Signaling
Authors: Jianqiu Zou, Wenxia Ma, Jie Li, Rodney Littlejohn, Il-man Kim, Jiliang Zhou, Huabo Su
Journal: Circulation Research (2017)

Rationale: Cardiac development is orchestrated by a number of growth factors, transcription factors and epigenetic regulators, perturbation of which can lead to congenital heart diseases and cardiomyopathies. However, the role of novel ubiquitin-like protein modifiers, such as NEDD8 (neural precursor cells expressed developmentally downregulated 8), in cardiac development is unknown. Objectives: The objective of this study was to determine the significance of NEDD8 modification (neddylation) during perinatal cardiac development. Methods and Results: Neddylated proteins and NEDD8 enzymes were highly abundant in fetal and neonatal hearts but downregulated in adult hearts. We employed an αMHC Cre transgene to delete NAE1, a subunit of the NEDD8 E1 enzyme, in the perinatal mouse heart. Cardiac-specific deletion of NAE1 (NAE1 CKO ) significantly decreased neddylated proteins in the heart. The NAE1 CKO mice displayed cardiac hypoplasia, ventricular non-compaction and heart failure during late gestation, which became more pronounced by postnatal day 1 and led to perinatal lethality. Mechanistically, genetic deletion or pharmacological inhibition of NAE1 resulted in accumulation of Hippo kinases Mst1 and LATS1/2, which in turn phosphorylated and inactivated YAP, a transcription cofactor necessary for cardiomyocyte proliferation, leading to dysregulation of a number of cell cycle-regulatory genes and blockade of cardiomyocyte proliferation in vivo and in vitro . Reactivation of YAP signaling by overexpression of a constitutively-active YAP mutant (YAP 5SA ), but not its wild-type counterpart, overcame the blockade of cardiomyocyte proliferation induced by inhibition of NAE1. Conclusions: Our findings establish the importance of neddylation in the heart, more specifically, in ventricular chamber maturation, and identify neddylation as a novel regulator of Hippo-YAP signaling to promote cardiomyocyte proliferation.
Integrated genomic analysis of mitochondrial RNA processing in human cancers
Authors: Youssef Idaghdour, Alan Hodgkinson
Journal: Genome Medicine (2017)

The mitochondrial genome is transcribed as continuous polycistrons of RNA containing multiple genes. As a consequence, post-transcriptional events are critical for the regulation of gene expression and therefore all aspects of mitochondrial function. One particularly important process is the m1A/m1G RNA methylation of the ninth position of different mitochondrial tRNAs, which allows efficient processing of mitochondrial mRNAs and protein translation, and de-regulation of genes involved in these processes has been associated with altered mitochondrial function. Although mitochondria play a key role in cancer, the status of mitochondrial RNA processing in tumorigenesis is unknown. We measure and assess mitochondrial RNA processing using integrated genomic analysis of RNA sequencing and genotyping data from 1226 samples across 12 different cancer types. We focus on the levels of m1A and m1G RNA methylation in mitochondrial tRNAs in normal and tumor samples and use supervised and unsupervised statistical analysis to compare the levels of these modifications to patient whole genome genotypes, nuclear gene expression, and survival outcomes. We find significant changes to m1A and m1G RNA methylation levels in mitochondrial tRNAs in tumor tissues across all cancers. Pathways of RNA processing are strongly associated with methylation levels in normal tissues (P = 3.27 × 10−31), yet these associations are lost in tumors. Furthermore, we report 18 gene-by-disease-state interactions where altered RNA methylation levels occur under cancer status conditional on genotype, implicating genes associated with mitochondrial function or cancer (e.g., CACNA2D2, LMO2, and FLT3) and suggesting that nuclear genetic variation can potentially modulate an individual’s ability to maintain unaltered rates of mitochondrial RNA processing under cancer status. Finally, we report a significant association between the magnitude of methylation level changes in tumors and patient survival outcomes. We report widespread variation of mitochondrial RNA processing between normal and tumor tissues across all cancer types investigated and show that these alterations are likely modulated by patient genotype and may impact patient survival outcomes. These results highlight the potential clinical relevance of altered mitochondrial RNA processing and provide broad new insights into the importance and complexity of these events in cancer.
Daily Sampling Reveals Personalized Diet-Microbiome Associations in Humans
Authors: Abigail J. Johnson, Pajau Vangay, Gabriel A. Al-Ghalith, Benjamin M. Hillmann, Tonya L. Ward, Robin R. Shields-Cutler, Austin D. Kim, Anna Konstantinovna Shmagel, Arzang N. Syed, Jens Walter, Ravi Menon, Katie Koecher, Dan Knights
Journal: Cell Host & Microbe (2019)

Diet is a key determinant of human gut microbiome variation. However, the fine-scale relationships between daily food choices and human gut microbiome composition remain unexplored. Here, we used multivariate methods to integrate 24-h food records and fecal shotgun metagenomes from 34 healthy human subjects collected daily over 17 days. Microbiome composition depended on multiple days of dietary history and was more strongly associated with food choices than with conventional nutrient profiles, and daily microbial responses to diet were highly personalized. Data from two subjects consuming only meal replacement beverages suggest that a monotonous diet does not induce microbiome stability in humans, and instead, overall dietary diversity associates with microbiome stability. Our work provides key methodological insights for future diet-microbiome studies and suggests that food-based interventions seeking to modulate the gut microbiota may need to be tailored to the individual microbiome. Trial Registration: ClinicalTrials.gov: NCT03610477.
Abstract 18545: Usefulness of Left Atrial Appendage Isolation for Maintenance of Sinus Rhythm in a Swine Model
Authors: Yumi Munetsugu, Mitsuharu Kawamura
Journal: Circulation (2017)

Introduction: A left atrial appendage (LAA) occlusion devices deployed percutaneously using epicardial approaches have been proposed as an alternative to therapeutic anti-coagulation for stroke pro...
The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease
Authors: Lindsay Kosack, Bettina Wingelhofer, Alexandra Popa, Anna Orlova, Benedikt Agerer, Bojan Vilagos, Peter Majek, Katja Parapatics, Alexander Lercher, Anna Ringler, Johanna Klughammer, Mark Smyth, Kseniya Khamina, Hatoon Baazim, Elvin D. de Araujo, David A. Rosa, Jisung Park, Gary Tin, Siawash Ahmar, Patrick T. Gunning, Christoph Bock, Hannah V. Siddle, Gregory M. Woods, Stefan Kubicek, Elizabeth P. Murchison, Keiryn L. Bennett, Richard Moriggl, Andreas Bergthaler
Journal: Cancer Cell (2019)
Using the Haddon matrix to explore medical response strategies for terrorist subway bombings
Authors: Tie-Cheng Yan, Min Yu
Journal: Military Medical Research (2019)

Since the 1970s, terrorist bombings in subways have been frequently occurring worldwide. To cope with this threat and to provide medical response countermeasures, we analyzed the characteristics of subway bombing terrorist attacks and used the Haddon matrix to explore medical response strategies. First, we analyzed 111 subway bombings from 1970 to 2017 recorded in the Global Terrorism Database to provide a reference for the strategy exploration. Then, we convened an expert panel to use the Haddon matrix to explore the medical response strategies to subway bombings. In recent decades, at least one bombing attack occurs every 3 years. Summarized by the Haddon matrix, the influencing factors of medical responses to conventional subway bombings include the adequacy of first-aid kits and the medical evacuation equipment, the traffic conditions affecting the evacuation, the continuity and stability of communication, as well as the factors exclusively attributed to dirty bomb attacks in subways, such as ionizing radiation protection capabilities, the structure of the radiation sickness treatment network based on the subway lines, and the disposal of radioactive sewage. These factors form the basis of the strategy discussion. Since subway bombings are long-term threats, it is necessary to have proper medical response preparation. Based on the Haddon matrix, we explored the medical response strategies for terrorist subway bombings, especially dirty bomb attacks. Haddon matrix can help policymakers systematically find the most important factors, which makes the preparations of the response more efficient.
Depletion of TRRAP Induces p53‐Independent Senescence in Liver Cancer by Down‐Regulating Mitotic Genes
Authors: Suet‐Yan Kwan, Ankur Sheel, Chun‐Qing Song, Xiao‐Ou Zhang, Tingting Jiang, Hien Dang, Yueying Cao, Deniz M. Ozata, Haiwei Mou, Hao Yin, Zhiping Weng, Xin Wei Wang, Wen Xue
Journal: Hepatology (2019)

Hepatocellular carcinoma (HCC) is an aggressive subtype of liver cancer with few effective treatments, and the underlying mechanisms that drive HCC pathogenesis remain poorly characterized. Identifying genes and pathways essential for HCC cell growth will aid the development of new targeted therapies for HCC. Using a kinome CRISPR screen in three human HCC cell lines, we identified transformation/transcription domain-associated protein (TRRAP) as an essential gene for HCC cell proliferation. TRRAP has been implicated in oncogenic transformation, but how it functions in cancer cell proliferation is not established. Here, we show that depletion of TRRAP or its co-factor, histone acetyltransferase KAT5, inhibits HCC cell growth through induction of p53-independent and p21-independent senescence. Integrated cancer genomics analyses using patient data and RNA sequencing identified mitotic genes as key TRRAP/KAT5 targets in HCC, and subsequent cell cycle analyses revealed that TRRAP-depleted and KAT5-depleted cells are arrested at the G2/M phase. Depletion of topoisomerase II alpha (TOP2A), a mitotic gene and TRRAP/KAT5 target, was sufficient to recapitulate the senescent phenotype of TRRAP/KAT5 knockdown. Conclusion: Our results uncover a role for TRRAP/KAT5 in promoting HCC cell proliferation by activating mitotic genes. Targeting the TRRAP/KAT5 complex is a potential therapeutic strategy for HCC.
THU0272 FUNCTIONAL GASTROINTESTINAL DISORDERS IN WOMEN WITH SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: Pamela Munguía Realpozo, Claudia Mendoza Pinto, Mario García Carrasco, Socorro Méndez Martínez, Tania Mogollan Delfín, Aurelio López Colombo, Aurelio López Colombo
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with multisystemic involvement. Gastrointestinal (GI) manifestations are frequent in patients with SLE, but functional gastrointestinal disorders (FGIDs), a heterogeneous group of GI diseases have hardly been evaluated in SLE patients. <h3>Objectives</h3> We evaluated the prevalence of FGIDs in SLE patients compared with age-matched controls and the role of potential risk factors for FGIDs. <h3>Methods</h3> SLE patients who met the ACR classification criteria for SLE and age-matched controls completed the Rome III questionnaire to assess the prevalence of FGIDs. Exclusion criteria were organic gastrointestinal disorders. Patients completed a structured interview to assess sociodemographic, clinical and treatment variables. Logistic multivariate analysis was performed to determine potential clinical factors (alcohol ingestion and medications) for FGIDS. <h3>Results</h3> The study responders included 116 SLE patients and 122 controls. The prevalence of FGIDs was higher in SLE patients than in controls (74.1% vs. 54.1%; p= 0.01). The most frequent FGIDs were nausea and vomiting disorders, belching disorders and globus pharyngeus. Anorectal disorders, mainly anorectal pain, were more frequent in SLE patients than controls (14.7% vs. 5.7%). After adjusting for confounding variables, SLE was associated with globus pharyngeus (OR: 3.5, 95%CI: 1.3-9.3), functional heartburn (OR: 2.5, 95% CI: 1.5-4.4), nausea and vomiting disorders (OR 7.1, 95% CI 2.7-19.1) and anorectal disorders (OR: 3.4, 95% CI 1.4-8.4). Overlap symptoms were present in 69.8% of patients vs. 31.8% of controls. When only SLE patients were evaluated, glucocorticoid therapy and non-steroidal anti-inflammatory drugs (NSAIDs) were associated with any FGID and functional bowel disorders, while alcohol ingestion was associated with gallbladder and sphincter of Oddi disorders. <h3>Conclusion</h3> There is a higher prevalence of FGIDs in patients with SLE and a wider distribution of various GI tract symptoms compared with controls. Medication that may alter gastrointestinal homeostasis, such as NSAIDs and protein pump inhibitors, were associated with FGIDs in SLE patients. <h3> Disclosure of Interests</h3> None declared
Synthetic Lethality of Wnt Pathway Activation and Asparaginase in Drug-Resistant Acute Leukemias
Authors: Laura Hinze, Maren Pfirrmann, Salmaan Karim, James Degar, Connor McGuckin, Divya Vinjamur, Joshua Sacher, Kristen E. Stevenson, Donna S. Neuberg, Esteban Orellana, Martin Stanulla, Richard I. Gregory, Daniel E. Bauer, Florence F. Wagner, Kimberly Stegmaier, Alejandro Gutierrez
Journal: Cancer Cell (2019)
Abstract 20534: Effects of Extended Release Niacin on HDL Particles and Other Parameters in an Intervention Trial
Authors: Ernst J Schaefer, Bela F Asztalos, Margaret R Diffenderfer, Megan Lacy, Santica Marcovina, John J Albers, John R Guyton, Moti L Kashyap, William E Boden
Journal: Circulation (2017)

Hypotheses: The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM HIGH) tested whether 1500-2000 mg of extended-release n...
Ponatinib Shows Potent Antitumor Activity in Small Cell Carcinoma of the Ovary Hypercalcemic Type (SCCOHT) through Multikinase Inhibition
Authors: Jessica D. Lang, William P.D. Hendricks, Krystal A. Orlando, Hongwei Yin, Jeffrey Kiefer, Pilar Ramos, Ritin Sharma, Patrick Pirrotte, Elizabeth A. Raupach, Chris Sereduk, Nanyun Tang, Winnie S. Liang, Megan Washington, Salvatore J. Facista, Victoria L. Zismann, Emily M. Cousins, Michael B. Major, Yemin Wang, Anthony N. Karnezis, Aleksandar Sekulic, Ralf Hass, Barbara C. Vanderhyden, Praveen Nair, Bernard E. Weissman, David G. Huntsman, Jeffrey M. Trent
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by loss of the SWI/SNF ATPase subunits SMARCA4 and SMARCA2. A great need exists for effective targeted therapies for SCCOHT. Experimental Design: To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches profiled kinases inhibited by ponatinib. Ponatinib was tested for efficacy in two patient-derived xenograft (PDX) models and one cell-line xenograft model of SCCOHT. Results: The receptor tyrosine kinase (RTK) family was enriched in siRNA screen hits, with FGFRs and PDGFRs being overlapping hits between drug and siRNA screens. Of multiple potent drug classes in SCCOHT cell lines, RTK inhibitors were only one of two classes with selectivity in SCCOHT relative to three SWI/SNF wild-type ovarian cancer cell lines. We further identified ponatinib as the most effective clinically approved RTK inhibitor. Reexpression of SMARCA4 was shown to confer a 1.7-fold increase in resistance to ponatinib. Subsequent proteomic assessment of ponatinib target modulation in SCCOHT cell models confirmed inhibition of nine known ponatinib target kinases alongside 77 noncanonical ponatinib targets in SCCOHT. Finally, ponatinib delayed tumor doubling time 4-fold in SCCOHT-1 xenografts while reducing final tumor volumes in SCCOHT PDX models by 58.6% and 42.5%. Conclusions: Ponatinib is an effective agent for SMARCA4-mutant SCCOHT in both in vitro and in vivo preclinical models through its inhibition of multiple kinases. Clinical investigation of this FDA-approved oncology drug in SCCOHT is warranted. Clin Cancer Res; 24(8); 1932–43. ©2018 AACR.
The Open Chromatin Landscape of Non–Small Cell Lung Carcinoma
Authors: Zhoufeng Wang, Kailing Tu, Lin Xia, Kai Luo, Wenxin Luo, Jie Tang, Keying Lu, Xinlei Hu, Yijing He, Wenliang Qiao, Yongzhao Zhou, Jun Zhang, Feng Cao, Shuiping Dai, Panwen Tian, Ye Wang, Lunxu Liu, Guowei Che, Qinghua Zhou, Dan Xie, Weimin Li
Journal: Cancer Research (2019)

Non-small cell lung carcinoma (NSCLC) is a major cancer type whose epigenetic alteration remains unclear. We analyzed open chromatin data with matched whole-genome sequencing and RNA-seq data of 50 primary NSCLC cases. We observed high interpatient heterogeneity of open chromatin profiles and the degree of heterogeneity correlated to several clinical parameters. Lung adenocarcinoma and lung squamous cell carcinoma (LUSC) exhibited distinct open chromatin patterns. Beyond this, we uncovered that the broadest open chromatin peaks indicated key NSCLC genes and led to less stable expression. Furthermore, we found that the open chromatin peaks were gained or lost together with somatic copy number alterations and affected the expression of important NSCLC genes. In addition, we identified 21 joint-quantitative trait loci (joint-QTL) that correlated to both assay for transposase accessible chromatin sequencing peak intensity and gene expression levels. Finally, we identified 87 regulatory risk loci associated with lung cancer-related phenotypes by intersecting the QTLs with genome-wide association study significant loci. In summary, this compendium of multiomics data provides valuable insights and a resource to understand the landscape of open chromatin features and regulatory networks in NSCLC. SIGNIFICANCE: This study utilizes state of the art genomic methods to differentiate lung cancer subtypes.See related commentary by Bowcock, p. 4808.