tbuckley/cabot-search huggingface dataset:
Abstract 795: GDF15, the putative mitokine factor, promotes tumor progression in thyroid cancer via STAT3 regulation
Authors: Yea Eun Kang, Jae Won Chang, Lihua Liu, Kyoungmin Lee, Mi Ae Lim, Seung-Nam Jung, Chan Oh, Ho-Ryun Won, Minho Shong, Bon Seok Koo
Journal: Cancer Research (2019)

Abstract Purpose: As mitochondrial dysfunction is an integral component during the initial stages of tumorigenesis, mechanistic insight on the interaction between these two pathways may lead to novel therapeutic approaches. The aim of this study is to investigate the role of GDF15, the putative mitokine factor in thyroid tumorigenesis. Methods: Expression levels of GDF15 was investigated using The Cancer Genome Atlas database. The role of GDF15 in tumor aggressiveness was investigated by analyzing the effects of knock-down of GDF15 on proliferation, migration, and invasion of thyroid cancer cells. Serum levels of GDF15 were measured in healthy subjects and patients with papillary thyroid cancer (PTC), and expression of GDF15 by IHC was investigated in PTC samples. To investigate the exact mechanism of GDF15 in thyroid cancer, both IPA analysis and GSEA analysis were performed using TCGA database and RNA seq data from Chungnam national university hospital. Results: TCGA data revealed the higher expression of GDF15 in tumor samples compared to in paired non-tumor samples. Thyroid cancer cells with knock-down of GDF15 revealed the decrease of proliferation, migration, and invasion compared to control cells via regulation of STAT3. Higher serum levels of GDF15 were found in patients with thyroid cancer than in control participants, and were significantly associated with tumor stage, lymphovascular invasion, and recurrence. In addition, patients with high GDF15 expression by IHC revealed the aggressive phenotype compared to patients with low GDF15 expression. Conclusions: GDF15 is a new biomarker for predicting tumor progression, and therapies targeting GDF15 may be effective for treating thyroid cancer. Citation Format: Yea Eun Kang, Jae Won Chang, Lihua Liu, Kyoungmin Lee, Mi Ae Lim, Seung-Nam Jung, Chan Oh, Ho-Ryun Won, Minho Shong, Bon Seok Koo. GDF15, the putative mitokine factor, promotes tumor progression in thyroid cancer via STAT3 regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 795.
Abstract 151: Comprehensive characterization of gastric cancer at single-cell resolution
Authors: Jiamin Chen, Anuja Sathe, Sue Grimes, Stephanie Greer, Billy Lau, Ann Renschler, George Poultsides, Carlos Suarez, Hanlee Ji
Journal: Cancer Research (2019)

Abstract The gastric carcinoma cells have complex interactions with diverse cell types in the associated tumor microenvironment. The tumor microenvironment plays important roles on gastric cancer development, progression and therapy response. In this study, we leveraged high-throughput single-cell RNA sequencing (scRNAseq) to characterize the diverse cell population in gastric tumors. In total, we analyzed more than 30,000 single cells from eight gastric tumors and matched normal tissues. Cells were sequenced at an average depth of 70000 reads/cell to guarantee sufficient coverage for downstream analysis. Using graph-based cell clustering methods and known cell markers, we identified heterogenous epithelial cells (PGC+, MUC5AC+, TFF1+, EPCAM+, CDH1+), fibroblasts (ACTA2+, THY1+, COLA1+), endothelial cells (VWF+, PECAM1+), and a variety of immune cells including M1 and M2 macrophages (IL1A+, IL1B+, TNF+, MARCO+, MSR1+, CD68+), CD4 T cells (CD3D+, CD4+), CD8 T cells (CD8A+), Gamma Delta T cells (TRGC2+, TRDC+), B cells (CD79+), and plasma cells (CD19+, CD20+, IgG+). Specifically, gastric epithelial cancer cells demonstrated distinct CNVs inferred from single cell transcriptome files. We established and characterized patient derived gastric cancer organoids from single tumor cells. The organoids recapitulate CNVs found in the original gastric tumors and displayed varied degree of drug responses. We identified specific molecular features of the tumor microenvironment that modulate cell growth and immune responses. For example, we identified heterogenous myofibroblast populations with distinct chemokine secretory profiles compared to normal gastric tissue. We characterized gene signatures associated with immune checkpoints on T cells and targetable molecules in innate cells. Using cell type specific expression profiles, we were able to establish a comprehensive signaling network of tumor-tumor, tumor-stromal, stromal-stromal and stromal-tumor signaling via receptor-ligand pairing. Citation Format: Jiamin Chen, Anuja Sathe, Sue Grimes, Stephanie Greer, Billy Lau, Ann Renschler, George Poultsides, Carlos Suarez, Hanlee Ji. Comprehensive characterization of gastric cancer at single-cell resolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 151.
Abstract 2362: NF-κB (p65) mediates interleukin-1 (IL-1) repression of androgen receptor (AR) in AR+prostate cancer (PCa) cell lines
Authors: Shayna Elizabeth Thomas-Jardin, Haley Dahl, Monica Bautista, Freedom Ha, Joan Jacob, Afshan Fathima Nawas, Mohammed Kanshwala, Chao Xing, Nikki Delk
Journal: Cancer Research (2019)

Abstract Inflammation promotes cancer initiation and progression. The Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B cells (NF-κB) family of transcription factor proteins, p65 (RelA), RelB, c-Rel, p105/p50 (NF-κB1), and p100/52 (NF-κB2), form homo- and heterodimeric complexes that mediate inflammatory cytokine signaling. We previously reported that the inflammatory cytokines, interleukin-1 alpha (IL-1α) and IL-1 beta (IL-1β), repress androgen receptor (AR) levels and activity in AR+ prostate cancer (PCa) cell lines. AR drives PCa tumorigenicity and, thus, AR is a therapeutic target. Our data suggests that IL-1 selects for ARlow/-PCa cell subpopulations that can evade AR-targeting therapy. Using RNA sequencing, we identified an IL-1-regulated gene signature predicted to supported AR-independent tumorigenicity in PCa cells. Pathway analysis of the RNA sequencing data predicted that AR is a target molecule of p65 (RELA). p50:p65 heterodimers are known to mediate IL-1 signaling, therefore, we investigated if NF-κB (p50:p65) signaling mediates IL-1 repression of AR. We found that siRNA silencing of p65 is sufficient to attenuate IL-1 repression of AR mRNA and protein levels and AR activity in AR+ PCa cell lines, while siRNA silencing of p50 had no effect on IL-1 repression of AR. Our data suggests that p65 represses AR levels, directly or indirectly, in response to IL-1. Thus, therapeutic inhibition of p65 activity could prevent the accumulation of inflammation-induced treatment-resistance ARlow/- PCa cell subpopulations. Citation Format: Shayna Elizabeth Thomas-Jardin, Haley Dahl, Monica Bautista, Freedom Ha, Joan Jacob, Afshan Fathima Nawas, Mohammed Kanshwala, Chao Xing, Nikki Delk. NF-κB (p65) mediates interleukin-1 (IL-1) repression of androgen receptor (AR) in AR+prostate cancer (PCa) cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2362.
Tyrosine Phosphorylation of CD2AP Affects Stability of the Slit Diaphragm Complex
Authors: Irini Tossidou, Beina Teng, Kirstin Worthmann, Janina Müller-Deile, Tilman Jobst-Schwan, Christian Kardinal, Patricia Schroder, Patricia Bolanos-Palmieri, Hermann Haller, Jonas Willerding, Dana M. Drost, Laura de Jonge, Thomas Reubold, Susanne Eschenburg, Ruth I. Johnson, Mario Schiffer
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement The connection between the slit diaphragm and actin network of podocytic foot processes involves complex signaling between slit diaphragm proteins and multiple signaling pathways of the actin machinery. CD2AP, a slit diaphragm–associated scaffolding protein, is considered a “stabilizer” of the complex that connects the slit diaphragm protein nephrin to the cell’s cytoskeleton. In this study, the authors define CD2AP as a phosphorylation target of receptor tyrosine kinases stimulated by VEGF-A in podocytes. They demonstrate that phosphorylation of tyrosine at position Y10 of the SH3-1 domain of CD2AP can change the affinity of CD2AP to nephrin and is indispensable for CD2AP function and slit diaphragm functionality in vivo . These findings implicate CD2AP phosphorylation as a molecular target in proteinuric kidney diseases. Background CD2-associated protein (CD2AP), a slit diaphragm–associated scaffolding protein involved in survival and regulation of the cytoskeleton in podocytes, is considered a “stabilizer” of the slit diaphragm complex that connects the slit diaphragm protein nephrin to the cytoskeleton of the cell. Tyrosine phosphorylation of slit diaphragm molecules can influence their surface expression, but it is unknown whether tyrosine phosphorylation events of CD2AP are also physiologically relevant to slit diaphragm stability. Methods We used isoelectric focusing, western blot analysis, and immunofluorescence to investigate phosphorylation of CD2AP, and phospho-CD2AP antibodies and site-directed mutagenesis to define the specific phosphorylated tyrosine residues. We used cross-species rescue experiments in Cd2ap KD zebrafish and in Drosophila cindrRNAi mutants to define the physiologic relevance of CD2AP phosphorylation of the tyrosine residues. Results We found that VEGF-A stimulation can induce a tyrosine phosphorylation response in CD2AP in podocytes, and that these phosphorylation events have an important effect on slit diaphragm protein localization and functionality in vivo . We demonstrated that tyrosine in position Y10 of the SH3–1 domain of CD2AP is indispensable for CD2AP function in vivo . We found that the binding affinity of nephrin to CD2AP is significantly enhanced in the absence of Y10; however, unexpectedly, this increased affinity leads not to stabilization but to functional impairment of the glomerular filtration barrier. Conclusions Our findings provide insight into CD2AP and its phosphorylation in the context of slit diaphragm functionality, and indicate a fine-tuned affinity balance of CD2AP and nephrin that is influenced by receptor tyrosine kinase stimulation.
Abstract SY40-01: The hippo pathway in growth, regeneration, and cancer
Authors: Kun-Liang Guan
Journal: Cancer Research (2019)

Abstract The Hippo pathway is crucial in organ size control and its dysregulation contributes to tumorigenesis. Core components of the Hippo pathway include the protein kinases of MST1/2, MAP4Ks, LATS1/2, the transcription co-activators YAP/TAZ and their DNA binding partners TEADs. LATS phosphorylates YAP/TAZ to promote cytoplasmic localization and degradation, thereby inhibiting YAP/TAZ and cell growth. The Hippo pathway is regulated by a wide range of signals, including cell density, GPCR, cellular energy levels, and mechanical cues. We will present our recent progresses on Hippo pathway regulation and its role in cancer. The emerging role of the Hippo pathway in tumorigenesis suggests potential therapeutic value of targeting this pathway for cancer treatment. Citation Format: Kun-Liang Guan. The hippo pathway in growth, regeneration, and cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY40-01.
Pediatric Post–Cardiac Arrest Care: A Scientific Statement From the American Heart Association
Authors: Alexis A. Topjian, Allan de Caen, Mark S. Wainwright, Benjamin S. Abella, Nicholas S. Abend, Dianne L. Atkins, Melania M. Bembea, Ericka L. Fink, Anne-Marie Guerguerian, Sarah E. Haskell, J. Hope Kilgannon, Javier J. Lasa, Mary Fran Hazinski
Journal: Circulation (2019)

Successful resuscitation from cardiac arrest results in a post-cardiac arrest syndrome, which can evolve in the days to weeks after return of sustained circulation. The components of post-cardiac arrest syndrome are brain injury, myocardial dysfunction, systemic ischemia/reperfusion response, and persistent precipitating pathophysiology. Pediatric post-cardiac arrest care focuses on anticipating, identifying, and treating this complex physiology to improve survival and neurological outcomes. This scientific statement on post-cardiac arrest care is the result of a consensus process that included pediatric and adult emergency medicine, critical care, cardiac critical care, cardiology, neurology, and nursing specialists who analyzed the past 20 years of pediatric cardiac arrest, adult cardiac arrest, and pediatric critical illness peer-reviewed published literature. The statement summarizes the epidemiology, pathophysiology, management, and prognostication after return of sustained circulation after cardiac arrest, and it provides consensus on the current evidence supporting elements of pediatric post-cardiac arrest care.
Abstract 3522: Enzymatic DNA repair enables high quality library preparation and accurate sequencing from highly damaged DNA inputs
Authors: Margaret R. Heider, Lixin Chen, Chen Song, Luo Sun, Pingfang Liu, Laurence Ettwiller, Lauren Higgins, Eileen Dimalanta, Theodore Davis, Thomas Evans
Journal: Cancer Research (2019)

Abstract High-throughput sequencing is key for clinical diagnostic applications such as disease mutation profiling and identifying pathogens with high taxonomic specificity. Preparation of high quality next-generation sequencing (NGS) libraries is critical for obtaining accurate patient data, but clinical scientists are often limited by input DNA quality. In cancer genomics, formalin-fixed, paraffin-embedded (FFPE) tissue from patient biopsy is a common source of DNA, but the extracted DNA is often poor in both yield and quality due to fixation- and storage-induced damage. Additionally, these damage-induced sequencing artifacts raise the background level of mutations, making it difficult to discern true, low frequency, disease-related variants from noise. Even relatively high-quality DNA inputs contain nicks and gaps limiting library yields and read lengths for long read sequencing platforms including Oxford Nanopore Technologies (ONT) and Pacific Biosciences (PacBio). We developed a second-generation DNA repair enzyme mix (V2) that efficiently repairs the most prevalent damage types found in FFPE DNA and further improves the quality and yield of NGS libraries through efficient nick and gap repair. Illumina library yield and quality were improved when DNA samples were treated with FFPE DNA Repair V2 before library preparation. Target enrichment and whole exome enrichment experiments showed that the V2 repair mix did not alter the overall frequency of variants identified, thus it did not introduce bias, but significantly improved the sequencing accuracy by reducing the number of false variant calls due to damage-induced sequence artifacts. True mutation frequencies were validated using droplet digital PCR (ddPCR). Repaired ONT libraries using DNA inputs of varying quality also showed improved library quality as well as greater read lengths. Therefore, enzymatic DNA repair prior to NGS library preparation is a critical first step for improving the quality and accuracy of short- and long-read sequencing libraries. Citation Format: Margaret R. Heider, Lixin Chen, Chen Song, Luo Sun, Pingfang Liu, Laurence Ettwiller, Lauren Higgins, Eileen Dimalanta, Theodore Davis, Thomas Evans. Enzymatic DNA repair enables high quality library preparation and accurate sequencing from highly damaged DNA inputs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3522.
Abstract 1918: InnoPanelTM -a well characterized panel of 1000 cancer cell lines for anticancer drug development
Authors: Feng Hao, Changpeng Liu, Hao Peng, Xiaolin Zhou, Yunhui Fu, Qiang Hou, Jinying Ning
Journal: Cancer Research (2019)

Abstract In vitro cell line assays are broadly used in drug screening to assess drug efficacy, probe drug mechanism, discover and validate predictive biomarkers. High-throughput screen can be performed on cell line collections such as the well-known NCI-60 panel that is consisted of 60 human cancer cell lines developed by the National Cancer Institute (NCI).1Cell lines in such panels are usually well annotated for basic information such as cancer type and subtype, histopathology, and marker gene expression; many experimental parameters are also measured such as doubling time and inoculation density. The utility of cell panels is greatly enhanced with more cell lines that are thoroughly characterized for their genomics by next generation sequencing2-3. To this end, we have developed InnoPanelTM—a panel of 1000 cancer cell lines, including 800 commonly used cancer cell lines, 100 primary cell lines, and 100 engineered cell lines. These cell lines cover all major cancers and majority are genomically characterized with gene expression, mutation and copy number data. Flow cytometry data were also available for engineered cell lines to validate and characterize designed modifications, for example, Siglec-15 overexpression in the CHO-K1 human Siglec-15 cell line. All data are openly available to researchers at our online database InnopediaTM.To make InnoPanelTM-based screening more valuable and accessible to biologists, we developed a bioinformatics pipeline to automate analysis that combines genomics and efficacy data. The utility of such analysis is demonstrated by case studies. InnoPanelTMcan also be customized for a subset of the 1000 cell lines. Subpanel for selected cancer types or cell lines bearing certain features can be constructed. In summary, we developed a well characterized 1000-cell line panel as a valuable resource for researchers working on anticancer drug development. References1. Shoemaker RH. The NCI60 human tumour cell line anticancer drug screen. Nat Rev Cancer 2006; 6: 813-23.2. Barretina J, Caponigro G, Stransky N, et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature, 2012, 483(7391):603.3. Consortium CCLE. Pharmacogenomic agreement between two cancer cell line data sets. Nature, 2015, 528(7580):84-7. Citation Format: Feng Hao, Changpeng Liu, Hao Peng, Xiaolin Zhou, Yunhui Fu, Qiang Hou, Jinying Ning. InnoPanelTM -a well characterized panel of 1000 cancer cell lines for anticancer drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1918.
Abstract P091: Early Life Stressors and Adult Cardiovascular Health in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study
Authors: Virginia J Howard, Leann Long, Aleena Bennett, Leslie A McClure, Dawn O Kleindorfer, Virginia G Wadley, Solveig A Cunningham, Jennifer M Manly, Fred W Unverzagt, Michael G Crowe, Jennifer S Pollock, Dan I Feig, M R Irvin, M M Glymour
Journal: Circulation (2018)

Introduction: Prior research suggests early life stressors (ELS) influence development of cardiovascular (CV) risk over the lifecourse, but few national studies have evaluated this. We examined the association of ELS with adult CV defined by Life’s Simple 7 (LS7) score within a national US population-based cohort. Methods: We used data on 7,469 REGARDS participants (black and white adults, aged &gt; 45 in 2003-2007), with clinical and behavioral risk factor data from questionnaires and direct measurement. Levels of LS7 components (blood pressure, total cholesterol, fasting glucose, physical activity, smoking, diet, body mass index) were coded as poor (0 points), intermediate (1 point) or ideal (2 points); the primary outcome, LS7 score, was the sum of the components. In 2012-2013, 7 ELS (death of parent, parents separated/divorced, family serious illness, witnessed family violence, family substance abuse, parent’s loss of job and parent incarcerated) were retrospectively assessed by mail questionnaire to active participants. Linear regression was used to characterize the relationship between each ELS and LS7 after adjustment for demographics and region of birth. Mediation by adult income and education was examined. Results: ELS were common, ranging from 3% for parent incarcerated to 29% for family serious illness. Lower LS7 was associated with each ELS, with significant association with witnessing family violence (-0.15; 95% CI: -0.29 to -0.02) (see figure.) Additional adjustment for adult education partially attenuated the effect estimates for witnessed family violence by 20.6% (95% CI: 2.0%, 39.1%); adjustment for adult income and education mediated the non-significant estimates for parental death, family illness and separation/divorce. Conclusions: Exposure to ELS was associated worse adult cardiovascular health; these associations were partially but not fully mediated by adult socioeconomic status. Further work is needed in categorization of ELS and examination of pathways underlying the associations.
Pulmonary hypertension at high altitude
Authors: Robert Naeije
Journal: European Respiratory Journal (2019)

In the present issue of the European Respiratory Journal , Soria et al. [1] report on a meta-analysis of echocardiographic estimates of systolic pulmonary artery pressure (sPAP) in 287 patients (nine studies) with chronic mountain sickness (CMS) at rest and in 142 of them (five studies) also at exercise. The results are surprising. Mean pulmonary artery pressure (mPAP), here recalculated as 0.6×sPAP+2 mmHg [2], was on average 18 mmHg (95% CI 16–20 mmHg) at rest and 31 mmHg (95% CI 29–33 mmHg) during exercise, suggesting no pulmonary hypertension (PH) at rest but mild PH during exercise. The same authors had previously reported on a similar meta-analysis in a larger number of 834 healthy high altitude dwellers at rest, showing a mPAP of 18 mmHg and a maximum of 24 mmHg, compared to 13 mmHg and a maximum of 20 mmHg, respectively, in sea level controls [3]. On the basis of these data altogether, Soria et al. [1] conclude that high altitude dwellers with or without CMS have no PH at rest, but CMS patients commonly present with exercise-induced PH, which may be of symptomatic and of prognostic relevance. This is provocative, as altitude is listed as "hypoxia without lung disease" in the updated classification of PH, and experts remain unconvinced about the notion of exercise-induced PH [4]. Pulmonary hypertension at high altitude is uncommon <http://bit.ly/2JxD2Q3>