tbuckley/cabot-search huggingface dataset:
Abstract 520: circEPSTI1 as a prognostic marker and mediator of triple-negative breast cancer progression
Authors: Bo Chen, Xiaojia Huang, Weidong Wei, Hailin Tang, Xiaoming Xie
Journal: Cancer Research (2018)

Abstract Purpose: Circular RNAs (circRNAs) represent a class of non-coding RNAs which play a vital role in modulating gene expression and several pathological responses. However, it is largely unknown about the expression profile and function of circRNAs in triple negative breast cancer (TNBC). In the current study, we investigated the expression profile of human circRNAs in TNBC tissues and identified circEPSTI1 (hsa_ circRNA_000479) as one circRNA significantly upregulated. Experimental Design: We performed circular RNAs microarray assay to screen circular RNAs expression profiles of TNBC and further investigated circEPSTI1. We observed the effect of circEPSTI1 on proliferation, clonal formation and apoptosis of TNBC by knockdown of circEPSTI1 in three TNBC cell lines. According to the MREs analysis and luciferase reporter assay, we found circEPSTI1 could bind to miRNAs as a miRNA sponge and the co-target gene of miRNAs and performed xenografts in mice to confirm our findings. We evaluated circEPSTI1 levels of 240 TNBC patients by ISH. Results: We found that knockdown of circEPSTI1 could inhibit TNBC cell proliferation and induce apoptosis. In vitro and in vivo experiments implicated that circEPSTI1 could bind to miR-4753 and miR-6809 as miRNAs sponge to regulate BCL11A expression and affect TNBC proliferation and apoptosis. High level of circEPSTI1 was correlate with shorter survival in TNBC patients. Conclusions: The circEPSTI1-miR-4753/6809-BCL11A axes can affect the proliferation and apoptosis of triple negative breast cancer through the mechanism of competing endogenous RNAs. Meanwhile, our results provide circEPSTI1 as an independent prognostic marker for survival in patients with TNBC. Citation Format: Bo Chen, Xiaojia Huang, Weidong Wei, Hailin Tang, Xiaoming Xie. circEPSTI1 as a prognostic marker and mediator of triple-negative breast cancer progression [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 520.
Abstract 3946: Androgen receptor drives differential gene expression in KRAS-mediated non-small cell lung cancer
Authors: Albert Roy Wang, Hope Beyer, Sean Brennan, Shannon Stiles, Dylan Wiese, Darya Buehler, Anwaar Saeed, Andrew M. Baschnagel, Gopal Iyer
Journal: Cancer Research (2018)

Abstract The Cancer Genome Atlas (TCGA) has identified alterations such as amplification, deletion, or mutation of androgen receptor (AR) in about 5% of human lung squamous cell carcinoma and adenocarcinoma. The expression of AR in human lung appears to play a crucial role in lung development and type II pneumocytes (PTII) maturation, but unlike in prostate cancer, the role of AR is not well known in non-small cell lung cancer (NSCLC). In our study, we demonstrated AR in NSCLC cell lines translocated into the nucleus over time when stimulated with synthetic androgen R1881, while addition of enzalutamide (MDV3100) or AR siRNA reduced AR nuclear localization. Using an NSCLC human tissue microarray also revealed that 10 out of 88 patients (11%) have positive AR immunohistochemical staining. Preliminary data from clonogenic assay indicated that enzalutamide might have radiosensitizing effect on certain NSCLC cells at 2 Gy, further suggesting the involvement of AR in lung cancer and its potential therapeutic value as a target. With the induction of R1881 for 30 minutes to 24 hours, certain NSCLC cells display decreased AR mRNA (0.5-0.8 fold), while others show modest increase (up to 1.5 fold), suggesting that AR regulation in these cells might be different due to their mutational landscapes. We then used predesigned 384 well panels from Bio-Rad to survey the effects of R1881, enzalutamide, and AR siRNA on mRNA expression levels of selected NSCLC cells. Distinct expression profiles were observed between cells that have wild-type and mutated KRAS. Taken together, these findings suggest that the AR signaling could be different based on KRAS mutational profiles of NSCLCs, and further work is required to reveal the underlying mechanism. Chromatin immunoprecipitation (ChIP) assay and RNA sequencing will be utilized to investigate AR interactions with androgen response elements and differential expressions in KRAS-driven NSCLC cells, respectively. Citation Format: Albert Roy Wang, Hope Beyer, Sean Brennan, Shannon Stiles, Dylan Wiese, Darya Buehler, Anwaar Saeed, Andrew M. Baschnagel, Gopal Iyer. Androgen receptor drives differential gene expression in KRAS-mediated non-small cell lung cancer [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 3946.
The Critical Role of Neutral Cholesterol Ester Hydrolase 1 in Cholesterol Removal From Human Macrophages
Authors: MasakiIgarashi, Jun-ichiOsuga, HiroshiUozaki, MotohiroSekiya, ShuichiNagashima, ManabuTakahashi, SatoruTakase, MikioTakanashi, YongxueLi, KeisukeOhta, MasayoshiKumagai, MakikoNishi, MasakiyoHosokawa, ChristianFledelius, PoulJacobsen, HiroakiYagyu, MasashiFukayama, RyozoNagai, TakashiKadowaki, KenOhashi, ShunIshibashi
Journal: Circulation Research (2010)

Rationale:Hydrolysis of intracellular cholesterol ester (CE) is the key step in the reverse cholesterol transport in macrophage foam cells. We have recently shown that neutral cholesterol ester hydrolase (Nceh)1 and hormone-sensitive lipase (Lipe) are key regulators of this process in mouse macrophages. However, it remains unknown which enzyme is critical in human macrophages and atherosclerosis. Objective:We aimed to identify the enzyme responsible for the CE hydrolysis in human macrophages and to determine its expression in human atherosclerosis. Methods and Results:We compared the expression of NCEH1, LIPE, and cholesterol ester hydrolase (CES1) in human monocyte-derived macrophages (HMMs) and examined the effects of inhibition or overexpression of each enzyme in the cholesterol trafficking. The pattern of expression of NCEH1 was similar to that of neutral CE hydrolase activity during the differentiation of HMMs. Overexpression of human NCEH1 increased the hydrolysis of CE, thereby stimulating choleste...
Impaired Endothelial Function and Increased Carotid Stiffness in 9-Year-Old Children With Low Birthweight
Authors: HelenaMartin, JieHu, GerhardGennser, MikaelNorman
Journal: Circulation (2000)

Background—Low birthweight (LBW) has been associated with an increased incidence of adult cardiovascular disease. Endothelial dysfunction and loss of arterial elasticity are early markers of hypertension and atherosclerosis. We studied the prevalence of these markers in 44 healthy, prepubertal (age 9±1.3 years) children, 22 with LBW for age. Methods and Results—Endothelial function in skin was tested with the local application of acetylcholine (inducing endothelium-dependent vasodilation) and nitroglycerin (endothelium-independent vasodilation), and local perfusion changes were measured with the laser Doppler method. The elastic properties of the abdominal aorta and common carotid artery were measured with an ultrasonic vessel-wall tracking system. Endothelium-dependent vasodilation was lower in children with LBW (88±33 perfusion units [PU]) than in normal-birthweight controls (133±34 PU, P<0.001). There was no difference in aortic or carotid elasticity between the 2 groups, but a negative correlation was...
Abstract 382: Inhibition of mitochondrial spare respiratory capacity by new securinine derivatives as a novel differentiation therapy for acute myeloid leukemia
Authors: Sheela Karunanithi, Ruifu Liu, Anne Roe, Stephen Moreton, Yongchun Hou, Natasha Oldford, Juan Valentin Goyco, David Wald
Journal: Cancer Research (2018)

Abstract Acute myeloid leukemia (AML) is characterized by a differentiation block in myeloid progenitors resulting in aberrant proliferation of immature myeloid cells. Therapeutics that induce differentiation of leukemic cells would overcome the high toxicity and low potency of conventional chemotherapy. Securinine, a plant-derived alkaloid from Securinega suffruticosa, has been shown to be a promising AML differentiation agent through an unclear mechanism, but is limited by its low potency (~20μM) and toxicity. We performed lead optimization chemistry on securinine that led to derivatives 250 and 317, with nanomolar efficacy and reduced toxicity. These derivatives effectively inhibit growth of AML cell lines and patient samples. Treatment of AML cell lines with compounds 250 and 317 induces the expression of differentiation markers CD11b and CD14c. Compounds 250 and 317 significantly reduced leukemic burden in a circulating model of AML in NSG mice. Additionally, these compounds were effective in inhibiting cell growth of HL60 cells that are resistant to a conventional chemotherapeutic, doxorubicin. By using the drug-affinity responsive target sensitivity (DARTS) assay, we identified that the redox mediator thioredoxin reductase (TrxR) is the primary target of these derivatives. 250 and 317 inhibit TrxR activity in vitro and in cells, and the resultant alterations in redox status are overcome by addition of a scavenger of reactive oxygen species (ROS), N-acetylcysteine. The ensuing oxidative metabolic stress rapidly alters the metabolite profile in AML cells including depletion of malate. Securinine derivatives decreased basal oxygen consumption rate and spare respiratory capacity, resulting in differentiation and cell death. Downregulating TrxR1 expression increased the sensitivity of OCI-AML3 cells to compounds 250 and 317. Together, we show here that these new derivatives of securinine exhibit preclinical efficacy in AML by decreasing mitochondrial spare respiratory capacity through the inhibition of TrxR. Citation Format: Sheela Karunanithi, Ruifu Liu, Anne Roe, Stephen Moreton, Yongchun Hou, Natasha Oldford, Juan Valentin Goyco, David Wald. Inhibition of mitochondrial spare respiratory capacity by new securinine derivatives as a novel differentiation therapy for acute myeloid leukemia [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 382.
Cardiovascular Magnetic Resonance Assessment of Human Myocarditis
Authors: HeikoMahrholdt, ChristineGoedecke, AnjaWagner, GabrielMeinhardt, AnasthasiosAthanasiadis, HolgerVogelsberg, PeterFritz, KarinKlingel, ReinhardKandolf, UdoSechtem
Journal: Circulation (2004)

Background— Myocarditis can occasionally lead to sudden death and may progress to dilated cardiomyopathy in up to 10% of patients. Because the initial onset is difficult to recognize clinically and the diagnostic tools available are unsatisfactory, new strategies to diagnose myocarditis are needed. Methods and Results— Cardiovascular MR imaging (CMR) was performed in 32 patients who were diagnosed with myocarditis by clinical criteria. To determine whether CMR visualizes areas of active myocarditis, endomyocardial biopsy was taken from the region of contrast enhancement and submitted to histopathologic analysis. Follow-up was performed 3 month later. Contrast enhancement was present in 28 patients (88%) and was usually seen with one or several foci in the myocardium. Foci were most frequently located in the lateral free wall. In the 21 patients in whom biopsy was obtained from the region of contrast enhancement, histopathologic analysis revealed active myocarditis in 19 patients (parvovirus B19, n=12; hum...
Abstract 4582: Capturing T cell receptor clones from circulating free DNA in cancer patients with solid malignancies
Authors: Lara McGrath, Elizabeth Maloney, Daniel Stetson, Tristan J. Lubinski, Rory Kirchner, Brian Dougherty, J. Carl Barrett
Journal: Cancer Research (2018)

Abstract Introduction Understanding the tumor microenvironment is challenging in situations where a tumor biopsy is unavailable. In these situations, liquid biopsies provide a less invasive alternative that can be collected at multiple timepoints throughout treatment. In particular, analyses of circulating free DNA (cfDNA) from plasma samples can distinguish genomic alterations from shed tumor DNA (ctDNA) within the cfDNA population. In this study, we aim to better understand the origin of cfDNA as well as its potential in understanding the intratumoral immune infiltration by developing and validating a strategy for identifying T cell receptor β (TCR β) rearrangements in the cfDNA from patients with solid malignancies. Methods We devised a target enrichment approach for high-throughput DNA sequencing that employs a hybridization capture strategy to bait germline variable (V) and joining (J) gene sequences in the TCR β loci. The target sequences are proximal to rearrangement sites flanking the CDR3, the principal site of contact for recognition specificity with foreign antigens presented by the major histocompatibility complex (MHC). We controlled for amplification bias by tagging DNA fragments with unique molecular indices (UMI). We validated our approach on dilutions of T cell lines in non-T cell lines, compared T cell levels determined from our method to those derived from flow cytometry, and compared data complexity at DNA input levels from 100 ng to 2 ng. Finally, we analyzed 27 pre-treatment plasma samples from cancer patients with solid malignanices, including quantification of total cfDNA concentrations, analyzing somatic genomic alterations using whole exome sequencing (WES), and employing our method for capture of TCR β rearrangements. Results Results indicate we are able to capture T cell rearrangements from cfDNA in cancer patient plasma. T cell rearrangements were identified in more than 25% of samples (7/27). Interestingly, the total cfDNA levels were not correlated to the number of T cell rearrangements detected, but all samples with detectable somatic alterations in the cfDNA (3/27) were also those with T cells identified. These preliminary results suggest a connection between apoptosis of lymphocytes and solid tumors that shed DNA into the bloodstream, and demonstrate potential utility as liquid biopsy for identifying tumor infiltrating lymphocytes. Citation Format: Lara McGrath, Elizabeth Maloney, Daniel Stetson, Tristan J. Lubinski, Rory Kirchner, Brian Dougherty, J. Carl Barrett. Capturing T cell receptor clones from circulating free DNA in cancer patients with solid malignancies [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 4582.
Outcomes for metastatic colorectal cancer (mCRC) based on microsatellite instability.
Authors: Timothy Jay Price, Christos Stelios Karapetis, Young Joanne, Amitesh Roy, Rob Padbury, Guy Maddern, James Moore, Cynthia Piantadosi, David Roder, Amanda Rose Townsend
Journal: Journal of Clinical Oncology (2018)

759 Background: Microsatellite instability (MSI) has been associated with improved survival outcomes in early stage CRC. In stage IV disease, MSI represents only 3-5% of cases and currently the prognostic implications are less clear. There is however evolving evidence that treatment pathways should include anti-PD-1 antibodies given the encouraging results in heavily pre-treated MSI mCRC patients. We undertook an analysis of the South Australian mCRC population based registry to explore the relevance of MSI status in this population based registry. Methods: The registry was analysed to assess patient characteristics and survival outcomes comparing patients with MSI or microsatellite stable (MSS) disease. K-M survival analysis was used to assess OS. Results: 4359 patients are registered on the data base. 598 (14%) patients had been tested for MSI. 62 (10.1%) of these patients had demonstrable MSI. Patient characteristics and outcomes are summarized in the table. There are statistically higher rates of right sided primary, poorly differentiated pathology and BRAF mutation in the MSI group associated with a trend to reduced survival. Chemotherapy and biological therapy received in the MSI v MSS groups was as follows; 5FU 31% v 25%, 5FU/irinotecan 17% v 12%, 5FU/oxaliplatin 52% v 58%, bevacizumab 31% v 42%, anti-EGFR 0 v 4.6%. Conclusions: The patient characteristics of MSI mCRC are in keeping with those previously reported. MSI in this population based mCRC registry is not associated with a favorable outcome as seen in earlier stage disease compared to patients with MSS disease. The trend to poorer outcomes may support routine testing and potentially an alternate treatment pathway, which may include PD-1 inhibitors.[Table: see text]
Abstract 18330: Direct Transport to a PCI Center Following Out-of-Hospital Cardiac Arrest is Associated With Improved Survival in North Carolina
Authors: Kristian Kragholm, Carolina Malta Hansen, Matthew Dupre, Ying Xian, Benjamin Strauss, Clark Tyson, Lisa Monk, Claire Corbett, Christopher B. Fordyce, David A. Pearson, Emil L. Fosbol, James G. Jollis, Benjamin Abella, Bryan McNally, Christopher B. Granger
Journal: Circulation (2015)

Introduction: Guidelines recommend implementation of regional systems of care for out-of-hospital cardiac arrest (OHCA) patients. Whether direct transport of OHCA patients to a PCI center over a non-PCI center improves outcomes is unknown. Hypothesis: Direct transport to a PCI center is associated with better outcomes. Methods: Using the Cardiac Arrest Registry to Enhance Survival, we identified OHCA patients with pre-hospital return of spontaneous circulation (ROSC) from 16 counties (population 3,143,809) in North Carolina between 2012-2014. Destination hospital was classified by PCI center status. We performed logistic regression analyses using propensity score inverse probability weights including drive time to nearest PCI center, initial rhythm and prehospital ECG information. Results: Of 1508 patients with ROSC, 1360 (90.2%) were transported to a PCI center and 148 (9.8%) to a non-PCI center (Table). The unadjusted survival rate was higher among those directly transported to a PCI center (33.5% versus 14.6%), OR 2.95 (95% CI 1.84-4.76). After accounting for potential confounding using inverse probability weights as well as adjusting for age, sex, EMS response time and clustering of county, direct transport to PCI center remained significantly associated with better survival, OR 2.47 (95% CI 2.08-2.92). Significant differences in survival remained when including patients without ST-elevation myocardial infarction only, adjusted OR 1.74 (95% CI 1.05-2.91). For patients bypassing the nearest hospital and taken directly to a PCI center with &gt;10 min of difference in drive time between nearest hospital and PCI center, adjusted OR was 2.54 (95% CI 2.01-3.23) compared to patients taken to non-PCI hospitals. Conclusions: Direct transport to a PCI center appears to be associated with improved survival in OHCA patients. This suggests that implementation of protocols to transport patients with OHCA directly to PCI centers, when feasible, may improve outcomes.
Right Gastroepiploic-to-Coronary Artery Bypass
Authors: JohnPym, PeterBrown, MaryPearson, JohnParker
Journal: Circulation (1995)

Background The right gastroepiploic artery was first used by us as a coronary artery bypass graft (CABG) in June 1984 and has become an accepted alternative conduit for myocardial revascularization. Methods and Results We have now performed this operation in 126 patients (111 of whom were men) aged 32 to 78 years. The right gastroepiploic artery was used as a pedicle graft to the right main coronary artery in 25 patients, to its posterior descending branch in 90, to a left ventricular branch in 2, to branches of the circumflex system in 6, and to the left anterior descending artery in 1. Free (aortocoronary) gastroepiploic grafts were placed to circumflex branches in 2 patients. There were 2 hospital deaths (stroke, arrhythmia), and mean±SD postoperative stay was 7.5±2.0 days. All survivors were symptomatically improved and are functionally in New York Heart Association functional class I or II. There have been 3 late deaths (at 34, 50, and 84 months) in 2 to 120 months of follow-up (mean, 41.4 months). A...
Amplitude Spectrum Area to Guide Defibrillation
Authors: Giuseppe Ristagno, Tommaso Mauri, Giancarlo Cesana, Yongqin Li, Andrea Finzi, Francesca Fumagalli, Gianpiera Rossi, Niccolò Grieco, Maurizio Migliori, Aida Andreassi, Roberto Latini, Carla Fornari, Antonio Pesenti
Journal: Circulation (2014)

Background— This study sought to validate the ability of amplitude spectrum area (AMSA) to predict defibrillation success and long-term survival in a large population of out-of-hospital cardiac arrests. Methods and Results— ECGs recorded by automated external defibrillators from different manufacturers were obtained from patients with cardiac arrests occurring in 8 city areas. A database, including 2447 defibrillations from 1050 patients, was used as the derivation group, and an additional database, including 1381 defibrillations from 567 patients, served as validation. A 2-second ECG window before defibrillation was analyzed, and AMSA was calculated. Univariable and multivariable regression analyses and area under the receiver operating characteristic curve were used for associations between AMSA and study end points: defibrillation success, sustained return of spontaneous circulation, and long-term survival. Among the 2447 defibrillations of the derivation database, 26.2% were successful. AMSA was significantly higher before a successful defibrillation than a failing one (13±5 versus 6.8±3.5 mV-Hz) and was an independent predictor of defibrillation success (odds ratio, 1.33; 95% confidence interval, 1.20–1.37) and sustained return of spontaneous circulation (odds ratio, 1.22; 95% confidence interval, 1.17–1.26). Area under the receiver operating characteristic curve for defibrillation success prediction was 0.86 (95% confidence interval, 0.85–0.88). AMSA was also significantly associated with long-term survival. The following AMSA thresholds were identified: 15.5 mV-Hz for defibrillation success and 6.5 mV-Hz for defibrillation failure. In the validation database, AMSA ≥15.5 mV-Hz had a positive predictive value of 84%, whereas AMSA ≤6.5 mV-Hz had a negative predictive value of 98%. Conclusions— In this large derivation-validation study, AMSA was validated as an accurate predictor of defibrillation success. AMSA also appeared as a predictor of long-term survival.
Recommendations of the National Heart, Lung, and Blood Institute Heart and Lung Xenotransplantation Working Group
Authors: JeffreyPlatt, VerdiDiSesa, DorothyGail, JudithMassicot-Fisher
Journal: Circulation (2002)

The National Heart, Lung, and Blood Institute (NHLBI) recently convened the Heart and Lung Xenotransplantation Working Group to identify hurdles to the clinical application of xenotransplantation, defined as the use of animal organs or tissue for transplantation, and to recommend possible solutions to these problems. The group consisted of experts in xenotransplantation from academia, industry, and federal agencies, and the discussions focused on those areas within the mission of the NHLBI. The areas covered included immunologic and physiological barriers to xenotransplantation, the limitations of the current animal models, the need for collaboration among groups, the high costs of studies using nonhuman primates and genetic engineering of pigs, and the unique problems of lung xenotransplantation. This report is a summary of those discussions.