tbuckley/cabot-search huggingface dataset:
Abstract 881: Identifying the context of vulnerability to MLN4924 in glioblastoma (GBM)
Authors: Leena Chaudhuri, Rita L. Bybee, Lauren K. Hartman, Sen Peng, Darren Finlay, Kristiina Vuori, Michael E. Berens, Harshil D. Dhruv
Journal: Cancer Research (2018)

Abstract Neddylation is a post-translational mechanism that marks proteins for degradation through activity of NEDD8 Activating Enzyme (NAE). NAE activates cullin-RING ligases (CRL), which ubiquitylate selected substrates and mark them for proteosomal degradation. MLN4924, or Pevonedistat, targets NAE and inhibits Neddylation and induces apoptosis in sensitive cells. To assess the preferential sensitivity of cell lines to MLN4924, we performed a 10-point drug dose response (DDR) assay on long-term established GBM cell lines. Efficacy of MLN4924 in glioma cell lines was evaluated by measuring cell viability (CellTiterGlo®) and cell cycle progression (flow cytometry with propidium iodide staining). To identify mechanism of differential response to MLN4924 treatment, cell cycle regulatory pathway and DNA damage were also examined by Western blotting. GB1 (IC50 = 0.28 μM) &amp; LN18 (IC50 = 0.19 μM) were established as sensitive and M059K (IC50 = 5.5 μM) &amp; SNU1105 (IC50 = 20.9 μM) as non-sensitive cell lines based on the IC50 values. Flow cytometry analysis of DNA content revealed significant arrest of cells in G2/M even at low doses of 100 nM of MLN4924 preferentially in GB1 and LN18. This was consistent with an increase in CRL substrates p21, p27 and WEE1 in GB1 and LN18 possibly contributing to the G2/M arrest. While CDT1 accumulation was observed starting at 2h post MLN4924 treatment in sensitive cell lines, it took upto 8h for CDT1 accumulation in the non-sensitive cell lines. Increases in CDT1 induced re-replication causing massive arrest in G2/M phase lead to increased DNA damage, validated by higher expression of γH2AX in the sensitive cell lines. Additionally, we also investigated the efficacy of MLN4924 against orthotopic glioma PDX models in vitro and in vivo to validate our findings. In a cohort of glioblastoma PDX models we discovered that GBM PDX models with lower Neddylation gene set enrichment score (GBM116, GBM59, SF7300) were markedly more vulnerable to MLN4924 than GBM PDX models with higher Neddylation gene set enrichment score (GBM91 and GBM102) in vitro and in vivo. Orthotopic PDX models of selected GBM revealed survival prolongation of GBM116, but minimal survival benefit to GBM102 tumors. Validation of the predictive markers of vulnerability to MLN4924 in additional PDX models will set the stage for prospective clinical trials of MLN4924 in glioblastoma patients. Citation Format: Leena Chaudhuri, Rita L. Bybee, Lauren K. Hartman, Sen Peng, Darren Finlay, Kristiina Vuori, Michael E. Berens, Harshil D. Dhruv. Identifying the context of vulnerability to MLN4924 in glioblastoma (GBM) [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 881.
Cold-Inducible RNA-Binding Protein Regulates Cardiac Repolarization by Targeting Transient Outward Potassium Channels
Authors: JunLi, DuanyangXie, JianHuang, FeiLv, DanShi, YiLiu, LiLin, LiGeng, YufeiWu, DandanLiang, Yi-HanChen
Journal: Circulation Research (2015)

Rationale:Cold-inducible RNA-binding protein (CIRP) is constitutively expressed at low levels across various tissues. It is rapidly upregulated by multiple stresses, underlying a general role for CIRP in organic adaptations to pathophysiological conditions. However, the role of CIRP in the heart remains unclear. Objective:To examine the biofunctions of CIRP in the mammalian heart. Methods and Results:Rats with targeted disruption of Cirp were generated using the TALEN (transcription activator-like effector nucleases)-based genome editing technique. The Cirp-knockout rats had structurally and functionally normal hearts. Resting ECG recordings revealed a short rate-corrected QT (QTc) interval in Cirp-null rats without any abnormalities in PR interval, RR interval or QRS waves as compared to wild-type animals. The shortened QTc interval from Cirp ablation was tightly linked to an abbreviated action potential duration in cardiac myocytes, which was attributable to increased transient outward potassium current...
Adiposity and Cardiovascular Disorders
Authors: HidekiKatagiri, TetsuyaYamada, YoshitomoOka
Journal: Circulation Research (2007)

Obesity, a major healthcare issue, is associated with significant cardiovascular morbidities, including hypertension and atherosclerosis. Numerous intensive studies conducted this decade have revealed that adipose tissue is a major endocrine organ that secretes a variety of bioactive substances, termed adipocytokines. Adipocytokine secretion profiles are altered as obesity develops, which may increase the risk of obesity-related cardiovascular disorders. For instance, leptin is upregulated in obese subjects and plays important roles in the pathophysiology of obesity-related atherogenesis through multiple mechanisms, such as its proliferative, proinflammatory, prothrombotic, and prooxidant actions. In contrast, adiponectin, which is downregulated in obese subjects, has protective effects against cardiovascular disorders at various atherogenic stages. In addition to these factors secreted by adipose tissue, neuronal circuits involving autonomic nerves are now being recognized as an important metabolic regul...
Linear Ablation of the Isthmus Between the Inferior Vena Cava and Tricuspid Annulus for the Treatment of Atrial Flutter
Authors: ToshifumiTabuchi, KenOkumura, ToshiroMatsunaga, RyusukeTsunoda, MichihisaJougasaki, HirofumiYasue
Journal: Circulation (1995)

Background The isthmus between the inferior vena cava and the tricuspid annulus has been shown to be involved in the reentry circuit of common atrial flutter. The effects of radiofrequency catheter ablation of this isthmus were examined in the canine model of atrial flutter due to reentry around the tricuspid annulus. Methods and Results A model of atrial flutter was prepared in 11 of 14 dogs by creating intercaval and connected transverse lesions (Y-shaped lesion). Bipolar electrodes were attached at 24 atrial sites, and computer-assisted mapping was performed. Stable atrial flutter with a cycle length of 133±11 ms was repeatedly induced by rapid atrial pacing in all dogs, and atrial mapping revealed reentry around the tricuspid annulus including the isthmus. In 6 dogs, the isthmus was ligated during atrial flutter (mechanical ablation). In the other 5 dogs, a 7F large-tip electrode catheter was placed at the isthmus under a fluoroscopic control. Radiofrequency energy (25 W for 30 s) was delivered to thr...
Abstract 2074: Single-cell RNA-seq reveals heterogeneity for stem cell markers, LRG5 and CD271 to predict a subpopulation in Ewing sarcoma cells with lower levels of BRAF
Authors: Roxane Khoogar, Peter Houghton
Journal: Cancer Research (2018)

Abstract Introduction: Ewing Sarcoma (ES) is an aggressive bone and soft tissue tumor, which has a high rate of recurrence among all childhood cancers. This suggests the need for a better understanding of heterogeneous cancer populations. In many cancers, recurrence and therapy resistance has been suggested to be due to the relative state of quiescent cells. Our previous work has shown that low EWSR1-FLI1 expressing cells have a significantly lower proliferative activity, which is similar to a quiescent state. Therefore, we used cells with low EWSR1-FLI1 expression to model and predict cells with a quiescent state.Methods: Using siEWSR1 to suppress EWSR1-FLI1, we studied proliferative quiescence. The Fluidigm C1 system was used to perform SMART-Seq whole transcriptome amplification using EW8 cells. We sequenced single- cell RNA-Seq libraries prepared from 700 ES cells. We developed a computational analysis to profile single cells. Then, we used gene expression signatures derived from the quiescent population to classify parental cells with ensemble classifiers. Results: Results revealed that EW8 cells show considerable heterogeneity at the transcriptome level in control (scrambled RNAi) as well as in the quiescent populations. We identified a subpopulation of EW8 cells with a negative correlation between the expression of LGR5 and Nerve Growth Factor Receptor (NGFR/CD271). Our preliminary data from 255 single cells indicate that LGR5 (0-43.57 TPM, median 0) and CD271 (0-80.05 unique transcripts, median 6.33) were correlated (r= -0.12, P&amp;lt;0.0001) in EW8 cells. CD271 is a surface membrane protein, and a mesenchymal stem cell marker, that regulates stemness, and heterogeneity. A subpopulation of cells with low CD271 was distinguished and studied for its co-expression pattern with LRG5 and BRAF. Conclusions: Our results suggest that there are multiple subpopulations within EW8 parental (Control) cells. We can characterize them with proliferation, stemness, motility and dormancy-associated markers. Ongoing studies are aimed to determine, if EW8 cells having elevated LGR5 exhibit different sensitivity to cytotoxic agents. Data derived from this work are expected to provide insights into the extent to which CD271 contributes to dormancy, and ES heterogeneity. Whether CD271 regulates proliferation to promote a dormant state in this subpopulation is being studied. Citation Format: Roxane Khoogar, Peter Houghton. Single-cell RNA-seq reveals heterogeneity for stem cell markers, LRG5 and CD271 to predict a subpopulation in Ewing sarcoma cells with lower levels of BRAF [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 2074.
FBXW7: a critical tumor suppressor of human cancers
Authors: Chien-Hung Yeh, Marcia Bellon, Christophe Nicot
Journal: Molecular Cancer (2018)

The ubiquitin-proteasome system (UPS) is involved in multiple aspects of cellular processes, such as cell cycle progression, cellular differentiation, and survival (Davis RJ et al., Cancer Cell 26:455-64, 2014; Skaar JR et al., Nat Rev Drug Discov 13:889-903, 2014; Nakayama KI and Nakayama K, Nat Rev Cancer 6:369-81, 2006). F-box and WD repeat domain containing 7 (FBXW7), also known as Sel10, hCDC4 or hAgo, is a member of the F-box protein family, which functions as the substrate recognition component of the SCF E3 ubiquitin ligase. FBXW7 is a critical tumor suppressor and one of the most commonly deregulated ubiquitin-proteasome system proteins in human cancer. FBXW7 controls proteasome-mediated degradation of oncoproteins such as cyclin E, c-Myc, Mcl-1, mTOR, Jun, Notch and AURKA. Consistent with the tumor suppressor role of FBXW7, it is located at chromosome 4q32, a genomic region deleted in more than 30% of all human cancers (Spruck CH et al., Cancer Res 62:4535-9, 2002). Genetic profiles of human cancers based on high-throughput sequencing have revealed that FBXW7 is frequently mutated in human cancers. In addition to genetic mutations, other mechanisms involving microRNA, long non-coding RNA, and specific oncogenic signaling pathways can inactivate FBXW7 functions in cancer cells. In the following sections, we will discuss the regulation of FBXW7, its role in oncogenesis, and the clinical implications and prognostic value of loss of function of FBXW7 in human cancers.
Abstract 15686: Coagulation-Independent Effects of Factor Xa on Protease-Activated Receptor 2 (PAR-2) in Pulmonary Hypertension
Authors: Christine Joseph, Eva M Berghausen, Arnica Behringer, Marius Vantler, Stephan Rosenkranz, Stephan Baldus
Journal: Circulation (2015)

Factor Xa (FXa) is a key molecule in the coagulation cascade. Besides, FXa exerts direct effects on cells via protease-activated receptor 2 (PAR-2), inducing proliferation and migration. Pulmonary hypertension (PH) is a fatal disease, defined by increased pulmonary vascular resistance, causing pulmonary arterial pressure elevation and finally right heart failure. Aberrant proliferation and migration of smooth muscle cells (SMCs) are crucial for underlying vascular remodeling processes in the pulmonary vasculature. We hypothesize that FXa contributes to vascular remodeling in PH via PAR-2 in pulmonary arterial SMCs (PASMCs). In vitro proliferation was assayed via BrdU incorporation, migration via modified Boyden chamber, respectively. Human PASMCs (hPASMCs), as well as murine PASMCs (mPASMCs) from WT and PAR-2-/- mice were used. FXa (0.1-1.5U/ml) and the following inhibitors were applied: Vorapaxar (PAR-1), U0126 (ERK), and SKI-178 (sphingonsine-kinase-1). Adult male WT and PAR-2-/- mice were exposed to normoxia vs. hypoxia to develop PH. After 21 days, right ventricular systolic pressure (RVSP) was measured. Right heart hypertrophy was determined by ratio of right ventricle to left ventricle plus septum (RV/(LV+S)). FXa mediated hPASMC proliferation (2.78±0.60 fold vs. ctrl, n&gt;4) via ERK and sphingosine-kinase-1. Whereas, vorapaxar did not affect FXa-mediated proliferation in hPASMCs (n=3). FXa-induced proliferation was significantly impaired in PAR-2-/- vs. WT PASMCs (1.41±0.11 vs. 1.79±0.05, n=6). FXa induced chemotaxis of hPASMCs (1.46±0.13 fold vs. ctrl, n=6). PAR-2-/- PASMCs displayed impaired basal migratory responses (1.45±0.46 cells) and decreased chemotaxis towards FXa vs. WT cells (1.37±0.81 vs. 9.958± 0.29 cells, n=3). PAR-2 deficiency protected from hypoxia-induced elevation of RVSP compared to WT mice (30.86±1.315 mm/Hg vs. 40.38±1.257 mm/Hg; n≥7). However, RV/(LV+S) was not decreased in PAR-2-/- vs. WT animals (0.392±0.026 vs. 0.413±0.0142; n≥7). Conclusively, PAR-2 plays an important role in experimental PH in mice. Additionally, we elucidated that F-Xa exerts direct mitogenic and chemotactic effects in PASMCs via PAR-2 activation, indicating a direct link between F-Xa and PAR-2 in pulmonary hypertension.
Abstract 20065: Periodontitis and Bone Metabolism in Patients With Advanced Heart Failure and After Heart Transplantation
Authors: Ulrike Schulze-Späte, Jaime Chang, Iman Mizani, Kristina Rodriguez Salaverry, Christina Wu, Meaghan Jones, Peter Kennel, Danielle Brunjes, Tse-Hwei Choo, Tomoko Kato, Donna Mancini, P. Christian Schulze
Journal: Circulation (2015)

Background: Heart failure (HF) is a multi-organ, pro-inflammatory syndrome that impairs bone metabolism. Proinflammatory cytokines and bone catabolism enhance periodontal disease, a local inflammatory, bacteria-induced disease that causes bone loss and periodontal soft tissue destruction. Hypothesis: Patients with advanced HF before and after heart transplantation (HTx) have more severe periodontal disease as compared to age and smoking-matched controls. Further, local inflammatory markers in the saliva and gingival crevicular fluid (GCF) can be used as markers of the local inflammatory periodontal burden in patients with HF. Methods: Medical and dental examinations were performed on patients with HF (n=41), following heart transplantation (post-HTx, n=40) and controls (n=32). Blood, saliva and GCF samples were taken to investigate markers of bone metabolism and inflammation. Results: Average New York Heart Association classification for HF was class III. Average time since HTx was 33.14 months. Overall periodontal diagnosis was more severe in patients with advanced HF and post-HTx versus controls (p&lt;0.0001). Pro-inflammatory tumor necrosis factor-alpha (TNF-α) was higher in HF and HTx patients as compared to controls (p&lt;0.05). Both, HF and HTx participants had higher levels of bone resorption marker C-terminal telopeptide and parathyroid hormone with subjects in the HF group having the highest serum levels of all groups (p≤0.05). In contrast, 25-VitD was lowest in patients with HF. The bone formation markers osteocalcin and procollagen-1 N-terminal peptide did not display differences between groups. Further, we found a significant correlation between beta-glucoronidase in saliva (r=0.4863, p&lt;0.01) and interleukin-1b in saliva (r=0.4999, p&lt;0.01) and GCF (r=0.5943, p&lt;0.001) and the severity of periodontal disease. Conclusion: Patients with advanced HF exhibit more severe periodontal disease associated with increased bone turnover markers when compared to control patients. Further, periodontal disease severity was detectable in saliva and GCF making it a potential useful tool for identifying the need for periodontal treatment in patients with advanced HF.
The Urokinase Kringle Is Required To Stabilize Binding to the Urokinase Receptor
Authors: K. Bdeir, A. Kuo, B. S. Sachais, A. H. Rux, Y. Bdeir, O. D. Liang, R. Frank, K. T. Preissner, A. Mazar, D. B. Cines
Journal: Blood (2002)
Abstract 17495: Magnesium Levels and Neurologic Outcomes in Patients Undergoing Therapeutic Hypothermia After Cardiac Arrest
Authors: William Perucki, Brett Hiendlmayr, David M O’Sullivan, Farrukh Fayyaz, Justin Lundbye, Antonio B Fernandez
Journal: Circulation (2016)

Introduction: Therapeutic hypothermia (TH) improves neurological outcomes after cardiac arrest by mitigating cerebral reperfusion injury. Plasma magnesium (Mg) inhibits glutamate release, restores ...
Super-resolution Scanning Patch Clamp Reveals Clustering of Functional Ion Channels in Adult Ventricular Myocyte
Authors: AnamikaBhargava, XianmingLin, PavelNovak, KinneriMehta, YuriKorchev, MarioDelmar, JuliaGorelik
Journal: Circulation Research (2013)

Rationale:Compartmentation of ion channels on the cardiomyocyte surface is important for electric propagation and electromechanical coupling. The specialized T-tubule and costameric structures facilitate spatial coupling of various ion channels and receptors. Existing methods such as immunofluorescence and patch clamp techniques are limited in their ability to localize functional ion channels. As such, a correlation between channel protein location and channel function remains incomplete. Objective:To validate a method that permits routine imaging of the topography of a live cardiomyocyte and study clustering of functional ion channels from a specific microdomain. Methods and Results:We used scanning ion conductance microscopy and conventional cell-attached patch clamp with a software modification that allows controlled increase of pipette tip diameter. The sharp nanopipette used for topography scan was modified into a larger patch pipette that could be positioned with nanoscale precision to a specific si...
Circulating Cardiac Troponin I in Severe Congestive Heart Failure
Authors: EmileMissov, CharlesCalzolari, BernardPau
Journal: Circulation (1997)

Background Spontaneous progression of severe congestive heart failure is structurally characterized by cellular degeneration and multiple foci of myocardial cell death. The cardiac muscle isoform of troponin I is uniquely expressed in the adult human myocardium, and an increase in its circulating levels is highly indicative of myocardial injury. Accordingly, we addressed the usefulness of cardiac troponin I as a sensitive and specific molecular marker of congestive heart failure in patients with severely reduced left ventricular performance. Methods and Results A new generation single-step immunoenzymoluminometric assay with high analytical sensitivity was used to assess cardiac troponin I in patients with severe congestive heart failure, healthy blood donors, and hospitalized control subjects without known cardiac disease. The cardiac troponin I concentration (mean±SEM) was 72.1±15.8 pg/mL in heart failure patients and 20.4±3.2 and 36.5±5.5 pg/mL in healthy and hospitalized control subjects, respectively...
Abstract 14966: Rate Responsive Pacing is Associated With Lower Mortality in Dual-chamber Pacemaker Patients
Authors: Vinod Sharma, Barry A Borlaug, Athula Abeyratne, Yong Cho, Eugene S Chung
Journal: Circulation (2017)

Introduction: Rate Responsive Pacing (RRP) pacing is a feature in most modern devices that provides heart rate support in response to increased patient activity. The clinical impact of RRP on patie...
Abstract 2846: Extracellular ATP induces different types of drug resistances in cancer cells through ATP internalization-mediated intracellular ATP level increase
Authors: Xiaozhuo Chen, Xuan Wang, Haiyun Zhang, Yanrong Qian, Yunsheng Li, Yanyang Cao, Pratik Shriwas
Journal: Cancer Research (2018)

Abstract Cancer cells are able to uptake extracellular ATP (eATP) via macropinocytosis to elevate intracellular ATP (iATP) levels, enhancing their survival from drug treatment (1). However, the involved drug resistance mechanisms are unknown. Here we investigated the roles of eATP as either an energy or a phosphorylating molecule in general drug resistance mediated by ATP internalization and iATP elevation. We report that eATP increased iATP levels and promoted drug resistance to various tyrosine kinase inhibitors (TKIs) and chemo-drugs in human cancer cell lines of five cancer types, including non-small cell lung cancer, breast cancer, colon, liver cancer, and pancreatic cancer (2). In A549 lung cancer cells, the resistance was downregulated by macropinocytosis inhibition or siRNA knockdown of PAK1, an essential macropinocytosis enzyme, strongly suggesting that the resistance is mediated at least in part by micropinocytosis (and therefore ATP internalization) (2). The elevated iATP upregulated the efflux activity of ABC transporters in A549 and SK-Hep-1 cells, as well as phosphorylation of PDGFRα and proteins in the PDGFR-mediated Akt-mTOR and Raf-MEK signaling pathways in A549 cells, increasing cell cycle progression and decreasing drug-induced apoptosis. Similar phosphorylation upregulations were found in A549 tumors. The resistance was not significantly affected by purinergic receptor-mediated signaling. These results demonstrate, for the first time, that eATP induces different types of drug resistance by eATP internalization and iATP elevation, implicating the ATP-rich tumor microenvironment in cancer drug resistance, expanding our understanding of the roles of eATP in the Warburg effect and offering new anticancer drug resistance targets. References 1.Qian, Y. et al. Mol Cancer Res 14(11); 1087-1096 (2016) 2.Wang, X. et al. Oncotarget 8, 87860-87877 (2017). Citation Format: Xiaozhuo Chen, Xuan Wang, Haiyun Zhang, Yanrong Qian, Yunsheng Li, Yanyang Cao, Pratik Shriwas. Extracellular ATP induces different types of drug resistances in cancer cells through ATP internalization-mediated intracellular ATP level increase [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 2846.