tbuckley/cabot-search huggingface dataset:
Cleaved N-terminal histone tails distinguish between NADPH oxidase (NOX)-dependent and NOX-independent pathways of neutrophil extracellular trap formation
Authors: Elmar Pieterse, Nils Rother, Cansu Yanginlar, Jelle Gerretsen, Sebastian Boeltz, Luis Enrique Munoz, Martin Herrmann, Peter Pickkers, Luuk B Hilbrands, Johan van der Vlag
Journal: Annals of the Rheumatic Diseases (2018)

Objectives Neutrophil extracellular traps (NETs) act in various rheumatic diseases. Although NET formation was originally described as a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-dependent pathway, it appears that there are also NOX-independent pathways of NET release. Currently, no tools are available that can discriminate between both NET-forming pathways. We aimed to develop a serological method allowing the discrimination between NETs generated through NOX-dependent or NOX-independent pathways. Methods Histones from in vitro generated NOX-dependent and NOX-independent NETs were characterised with a panel of lupus-derived antibodies against N-terminal histone tails using immunofluorescence microscopy, western blot and ELISA. NETs in patients with NET-associated diseases, that is, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriatic arthritis (PsA) and sepsis, were characterised in sandwich ELISAs employing antibodies against myeloperoxidase (MPO) and N-terminal histone tails as detecting and capturing antibodies, respectively. Functional responses of endothelial cells to NOX-dependent and NOX-independent NETs were assessed as well. Results Neutrophil elastase cleaves the N-terminal tails of core histones during NOX-dependent, but not during NOX-independent NET formation. Consequently, the detection of MPO–histone complexes with antibodies against N-terminal histone tails allows discrimination between NETs formed through a NOX-dependent or NOX-independent manner. Characterisation of in vivo circulating NETs revealed the presence of NOX-independent NETs in RA, SLE and sepsis, but NOX-dependent NETs in PsA. NOX-independent NETs displayed an increased capacity to activate endothelial cells when compared with NOX-dependent NETs. Conclusions These results indicate heterogeneity in NET-forming pathways in vivo and highlight the need for disease-specific strategies to prevent NET-mediated pathology.
Statins Activate Peroxisome Proliferator-Activated Receptor γ Through Extracellular Signal-Regulated Kinase 1/2 and p38 Mitogen-Activated Protein Kinase–Dependent Cyclooxygenase-2 Expression in Macrophages
Authors: MiyukiYano, TakeshiMatsumura, TakafumiSenokuchi, NorioIshii, YusukeMurata, KayoTaketa, HiroyukiMotoshima, TetsuyaTaguchi, KazuhiroSonoda, DaisukeKukidome, YohTakuwa, TeruoKawada, MichaelBrownlee, TakeshiNishikawa, EiichiAraki
Journal: Circulation Research (2007)

Both statins and peroxisome proliferator-activated receptor (PPAR)γ ligands have been reported to protect against the progression of atherosclerosis. In the present study, we investigated the effects of statins on PPARγ activation in macrophages. Statins increased PPARγ activity, which was inhibited by mevalonate, farnesylpyrophosphate, or geranylgeranylpyrophosphate. Furthermore, a farnesyl transferase inhibitor and a geranylgeranyl transferase inhibitor mimicked the effects of statins. Statins inhibited the membrane translocations of Ras, RhoA, Rac, and Cdc42, and overexpression of dominant-negative mutants of RhoA (DN-RhoA) and Cdc42 (DN-Cdc42), but not of Ras or Rac, increased PPARγ activity. Statins induced extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) activation. However, DN-RhoA and DN-Cdc42 activated p38 MAPK, but not ERK1/2. ERK1/2- or p38 MAPK–specific inhibitors abrogated statin-induced PPARγ activation. Statins induced cyclooxygenase (COX)-2 exp...
Abstract 4869: Discovery and characterization of highly potent and selective USP7 inhibitors and benchmarking against clinical MDM2 antagonists
Authors: Gerald Gavory, Colin O'Dowd, Elias Arkoudis, Oliver Barker, Eamon Cassidy, Anthony Dossang, Jakub Flasz, Matt Helm, Caroline Hughes, Keeva McClelland, Hugues Miel, Ewa Odrzywol, Natalie Page, Tim Harrison
Journal: Cancer Research (2018)

Abstract Given the importance of USP7 in known oncogenic pathways and its emerging role in immuno-oncology, the identification of USP7 inhibitors has attracted considerable interest in the scientific community. However, despite substantial efforts over the past 15 years, the development of genuine deubiquitinase (DUB) inhibitors, which exhibit both drug-like properties and a well-defined mechanism of action, has proven particularly challenging. In this study, we report the application of UbiPlexTM, our purpose-built DUB drug discovery platform, to USP7. In particular, we detail the identification, optimization and detailed characterization of a new class of non-covalent and highly potent USP7 inhibitors (IC50 &amp;lt; 10 nM). In addition, these inhibitors have shown exquisite selectivity for USP7 over other DUBs and proteases. We also disclose high-resolution co-crystal structures of USP7 in complex with these inhibitors that reveal an allosteric mode of binding. Further profiling in cells demonstrated potent target engagement with endogenous USP7 (EC50 &amp;lt;20 nM). In line with the known biology of USP7, this effect induced the proteasomal degradation of MDM2, concomitant stabilization of p53 and induction of p21 in multiple cell lines. The identification and parallel profiling of inactive enantiomers further validated the on-target effect of our lead molecules. Finally, we report the identification of cell lines hyper-sensitive (EC50 &amp;lt; 30 nM) to USP7 inhibitors in both haematological and solid cancer cell line settings and demonstrate equal or superior activity when compared to clinically relevant MDM2 antagonists. In summary, this work exemplifies the tractability and druggability of USP7 as a cancer target and provides new insights and directions for the potential clinical development of USP7 inhibitors. Citation Format: Gerald Gavory, Colin O'Dowd, Elias Arkoudis, Oliver Barker, Eamon Cassidy, Anthony Dossang, Jakub Flasz, Matt Helm, Caroline Hughes, Keeva McClelland, Hugues Miel, Ewa Odrzywol, Natalie Page, Tim Harrison. Discovery and characterization of highly potent and selective USP7 inhibitors and benchmarking against clinical MDM2 antagonists [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 4869.
"Color Vectorcardiogram" Recorded with a Specially Designed Apparatus for Spatial Representation By Coloring
Authors: Shinjikinoshita, Tadashikobayashi
Journal: Circulation (1971)

Using a vectorcardiogram only in the horizontal plane, spots of the vector loop were colored according to a specially designed apparatus, so that changes in height of the spots could be indicated by differences in those colors. Consequently, the spatial vectorcardiogram was represented by a single, colored graph, i.e. a color vectorcardiogram. By the use of this graph, an attempt was made to facilitate the understanding of vectorcardiography for common clinicians. The colors corresponding to the heights of the deflections in the Y axis were chosen as follows: in a level of the origin or zero point of the vector loop, yellow; above the origin, reddish colors; and below the origin, bluish colors.
Relationship of Socioeconomic Status to the Incidence and Prehospital, 28-Day, and 1-Year Mortality Rates of Acute Coronary Events in the FINMONICA Myocardial Infarction Register Study
Authors: VeikkoSalomaa, MattiNiemelä, HeikkiMiettinen, MattiKetonen, PirjoImmonen-Räihä, SeppoKoskinen, MarkkuMähönen, SeppoLehto, TapioVuorenmaa, PerttiPalomäki, HarriMustaniemi, EskoKaarsalo, MattiArstila, JormaTorppa, KariKuulasmaa, PekkaPuska, KaleviPyörälä, JaakkoTuomilehto
Journal: Circulation (2000)

Background—Low socioeconomic status (SES) is associated with increased coronary heart disease mortality rates. There are, however, very little data on the relation of SES to the incidence, recurrence, and prognosis of myocardial infarction (MI) events. Methods and Results—The FINMONICA MI Register recorded detailed information on all MI events among men and women aged 35 to 64 years in 3 areas of Finland during the period of 1983 to 1992. We carried out a record linkage of the MI register data with files of Statistics Finland to obtain information on indicators of SES, such as taxable income and education, for each individual who is registered. In the analyses, income was grouped into 3 categories (low, middle, and high), and education was grouped into 2 categories (basic and secondary or higher). Among men with their first MI event (n=6485), the adjusted incidence rate ratios were 1.67 (95% CI 1.57 to 1.78) and 1.84 (95% CI 1.73 to 1.95) in the low- and middle-income categories compared with the high-inc...
Quantitative Studies of Triglyceride Lipolysis after Heparin Administration
Authors: Hymanengelberg
Journal: Circulation Research (1958)

The extent of triglyceride lipolysis by postheparin lipemia clearing factor (lipoprotein lipase) was studied in vitro in 8 atherosclerotic individuals. Varying doses of heparin were injected intravenously and subcutaneously and blood was drawn at stated time intervals for analysis. The rate of splitting of human low density lipoproteins was then determined by measurement of the rate of release of unesterified fatty acids upon incubation of postheparin plasma plus lipoproteins in vitro at 37 C. The data obtained gives a range of the minimum in vivo removal of alimentary neutral fat following an injection of heparin.
Increased Expression of Integrin-Linked Kinase Attenuates Left Ventricular Remodeling and Improves Cardiac Function After Myocardial Infarction
Authors: LiangDing, LiDong, XinChen, LujieZhang, XiaoyuXu, AlbertFerro, BiaoXu
Journal: Circulation (2009)

Background— Left ventricular (LV) remodeling is associated with the development of heart failure after myocardial infarction. Here we investigated whether integrin-linked kinase (ILK) may regulate LV remodeling and function after myocardial infarction. Methods and Results— Adenoviral vector expressing ILK (n=25) or empty adeno-null (n=25) was injected into rat peri-infarct myocardium after left anterior descending coronary artery ligation. ILK expression was confirmed by Western blotting and immunofluorescence. Echocardiographic and hemodynamic analyses demonstrated relatively preserved cardiac function in adeno-ILK animals. ILK treatment was associated with reduced infarct scar size, increased scar thinning ratio, and preserved LV diameter, wall thickness, cardiomyocyte size, and myofilament density. Enhanced angiogenesis and reduced fibrosis were observed in the adeno-ILK group, along with reduced apoptosis as demonstrated by terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling analysis...
Differential Effects of Nifedipine and Co-Amilozide on the Progression of Early Carotid Wall Changes
Authors: AlainSimon, JéromeGariépy, DominiqueMoyse, JaimeLevenson
Journal: Circulation (2001)

Background—Common carotid artery intima-media thickness (IMT) progression was compared between 4 years of treatment with nifedipine and diuretic. Methods and Results—This study, ancillary to the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT), involved nifedipine 30 mg or co-amilozide (hydrochlorothiazide 25 mg and amiloride 2.5 mg) with optional subsequent titration. Among 439 randomized hypertensive patients, 324 had ≥1 year of follow-up (intent-to-treat group), and 242 completed follow-up (until-end-of-study group). Ultrasonography was performed at baseline, 4 months later, and then every year. Central computerized reading provided far-wall IMT, diameter, and cross-sectional area IMT (CSA-IMT). The primary outcome was IMT progression rate (slope of IMT-time regression). Secondary outcomes were changes from baseline (Δ) in IMT, diameter, and CSA-IMT. In the until-end-of-study population, between-treatment differences existed in IMT progression rate (P=0.00...
Abstract 1669: Identification of mutant KRas-Raf-1 binding disruptors
Authors: Rajanikanth Vangipurapu, Liwei Chen, Perry Kennedy, Karen C. Morrison, Paul J. Hergenrother, Said M. Sebti
Journal: Cancer Research (2018)

Abstract Mutant KRas is a major driver of human cancer, yet currently no clinically approved therapies that directly target mutant KRas are available. In order to identify novel drugs that bind either mutant KRas or its effector Raf-1, we used alpha-screen and GST-pull down assays to identify disruptors of KRas G12D binding to the Ras-binding domain of Raf-1. From a novel, natural product-inspired chemical library called Complexity To Diversity (CTD), we have identified a series of 5 hits that belong to a family of gibberellic acid-derived compounds and 2 hits from a family of pleuromutilin-derived compounds. At present we are using Differential Scanning Fluorimeter (DSF) and Isothermal calorimetry (ITC) assays to determine whether these hits bind to KRas G12D or Raf-1 RBD. These studies may lead to identifying chemical probes that can be developed to target mutant KRas-driven cancers. Citation Format: Rajanikanth Vangipurapu, Liwei Chen, Perry Kennedy, Karen C. Morrison, Paul J. Hergenrother, Said M. Sebti. Identification of mutant KRas-Raf-1 binding disruptors [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 1669.
Abstract 12597: Incorporation of Myocardial Contrast Echocardiography into a Clinical Stress Echocardiography Service is Feasible and Improves the Diagnostic Accuracy Beyond that Provided by Wall Motion Assessment Only
Authors: Benoy N Shah, Navtej S Chahal, Sanjeev Bhattacharyya, Wei Li, Isabelle Roussin, Rajdeep S Khattar, Roxy Senior
Journal: Circulation (2012)

INTRODUCTION Myocardial contrast echocardiography (MCE) has been shown in clinical trials to improve the diagnostic accuracy of stress echocardiography (SE). However, the feasibility and value of MCE incorporated into a clinical SE service in a ‘real-world’ setting is unknown. HYPOTHESIS We hypothesized that evaluation of myocardial perfusion - as well as wall motion - is feasible and improves the diagnostic accuracy of the clinical SE service in our center. METHODS We performed MCE during SE in all patients undergoing pharmacological stress and patients undergoing treadmill exercise whom we suspected may not attain a high workload or target heart rate. We documented prospectively demographic variables, reason for referral, stress modality, amount of contrast used and value of MCE, which was assigned to one of four pre-determined categories: incremental benefit over wall motion (WM) analysis, more confidence with WM analysis, no benefit over WM analysis or other (e.g. uninterpretable MCE images). All MCE ...
Abstract 5707: On-treatment changes in CRP as a surrogate for overall survival for atezolizumab benefit in 2nd line NSCLC
Authors: Namrata Patil, Wei Zou, Simonetta Mocci, Vinita Gupta, Luciana Molinero, Alan Sandler, Marcus Ballinger, Susan Flynn, Marcin Kowanetz, Priti Hegde
Journal: Cancer Research (2018)

Abstract Background: Overall survival (OS) is an optimal endpoint for evaluation of checkpoint inhibitors (CPI). Identification of early surrogates of OS is important to inform early clinical signals and treatment decisions. We evaluated C-reactive protein (CRP) in clinical trials with atezolizumab (anti-PD-L1 antibody). CRP is elevated in different inflammatory and malignant conditions and is often considered to be a marker of poor prognosis. Materials and Methods: Serum from patients enrolled in the 2L+ NSCLC studies POPLAR and OAK (randomized phase 2 and phase 3 controlled trials of patients with non-small cell lung cancer (NSCLC) who progressed on post-platinum chemotherapy) was analyzed for CRP levels over time. Patients were binned by changes in CRP at 6 weeks post-treatment (C3D1; Cycle 3 Day 1) as compared to pre-treatment levels, by either greater than 1.5 fold, less than 1.5 fold or unchanged (within +1.5 fold). Results: C3D1 decreases in serum CRP were associated with RECIST1.1 based responses to atezolizumab but not with docetaxel in the POPLAR study, and these findings were further validated in the OAK study. Patients with RECIST based disease progression (PD) demonstrated an increase in serum CRP as early as Cycle 2 (3 weeks post atezolizumab therapy). Notably, decrease in CRP levels was strongly associated with improved PFS and OS. Results from OAK are shown below (table). Furthermore, in patients with RECIST PD or stable disease (SD), decrease in on-treatment CRP also predicted long overall survival. Conclusion: CRP is a soluble biomarker that is modulated post-atezolizumab treatment. This simple lab test may provide utility in informing OS benefit for CPIs and combinations. C3D1 CRP fold change relative to pre-treatmentHRCIp valueHRCIp valueITT0.750.62-0.910.0040.740.6-0.910.0053CRP &amp;lt;1.5 FC0.480.33-0.690.0000950.490.32-0.750.0011CRP +1.5 FC0.850.62-1.150.280.610.43-0.860.0049CRP&amp;gt;=1.5 FC0.960.69-1.340.811.250.86-1.810.25 Citation Format: Namrata Patil, Wei Zou, Simonetta Mocci, Vinita Gupta, Luciana Molinero, Alan Sandler, Marcus Ballinger, Susan Flynn, Marcin Kowanetz, Priti Hegde. On-treatment changes in CRP as a surrogate for overall survival for atezolizumab benefit in 2nd line NSCLC [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 5707.
Abstract 1999: Study of CD44 variant 6 (CD44v6) in prostate cancer chemo-/radio resistance in vivo
Authors: Jie Ni, Paul Cozzi, Julia Beretov, Joseph Bucci, Peter Graham, Yong Li
Journal: Cancer Research (2018)

Abstract Background: Chemo-/radio-resistance is an important reason for prostate cancer (CaP) progression and metastasis. CD44 is a well-documented cancer stem cell (CSC) biomarker, and one of its variants, CD44 variant 6 (CD44v6) is closely associated with aggressive behaviour and correlates with poor prognosis in a variety of human cancers. Our previous study has demonstrated increased expressions of CD44v6 in metastatic CaP cell lines and human CaP tissues, which was associated with CaP progression and chemo-/radio-resistance in vitro. However, the role of CD44v6 in CaP progression and therapeutic resistance in vivo is still uncertain. Aim: The aim of this study was to investigate the role of CD44v6 in CaP development and chemo-/radioresistance as well as underlying pathways in vivo, and find whether it is a suitable therapeutic target for CaP therapy. Methods: CD44v6 gene was knocked down (KD) in PC-3M CaP cell line using short hairpin RNA (shRNA). Subcutaneous (s.c.) and orthotopic CaP animal models were established using PC-3M-CD44v6-KD and PC-3M-CD44v6-scramble (scr) control cells, to assess the effect of CD44v6 on CaP tumourigenesis, chemotherapy (docetaxel) response and radiation response. Signal transduction proteins in PI3K/Akt/mTOR pathway (Akt, p-Akt, mTOR and p-mTOR) as well as proliferation and apoptosis makers were assessed by immunohistochemistry in xenografts from both animal models. Results: Both s.c. and orthotopic xenografts from PC-3M-CD44v6-KD cells displayed supressed tumour growth and increased responsiveness to docetaxel (40mg/kg) and radiation (2Gy/day for 4 consecutive days) compared to control xenografts from PC-3M-CD44v6-scr cells in NOD/SCID male mice. Down-regulation of the PI3K/Akt/mTOR pathway proteins (p-Akt and p-mTOR), proliferation marker (Ki-67) and angiogenesis marker (CD31), as well as up-regulation of apoptotic responses (cleaved Caspase-3) to chemotherapy, DNA damage responses (γ-H2AX) to radiation were found in PC-3M-CD44v6-KD s.c. xenografts, respectively. Conclusions: CD44v6 is actively involved in CaP tumorigenesis and treatment responses to chemo-/radio-therapy via PI3K/Akt/mTOR signalling pathway in in vivo mouse models and holds promise as a therapeutic target for the treatment of CaP. Key words: CD44v6, prostate cancer, chemo-/radio-resistance, animal model, metastasis Citation Format: Jie Ni, Paul Cozzi, Julia Beretov, Joseph Bucci, Peter Graham, Yong Li. Study of CD44 variant 6 (CD44v6) in prostate cancer chemo-/radio resistance in vivo [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 1999.
Vesicular Trafficking of Tyrosine Kinase Receptors and Associated Proteins in the Regulation of Signaling and Vascular Function
Authors: SanchitaMukherjee, MathewosTessema, AngelaWandinger-Ness
Journal: Circulation Research (2006)

Receptor tyrosine kinases (RTKs) play a pivotal role in the development and function of the cardiovascular system. Ligand-activated RTKs promote numerous downstream signal transduction pathways that lead to vascular permeability, as well as proliferation, migration, and differentiation of vascular endothelia and smooth muscle cells. Ligand binding also promotes internalization of the activated receptors either to downregulate the signaling via degradation of the ligand/receptor complex or to signal from endosomes. However, the outcomes of receptor internalization via clathrin-dependent or caveolar pathways and trafficking mechanisms are incompletely clarified in vascular systems. Activity modulation through endocytosis and vesicular trafficking significantly impacts downstream targets of RTKs such as endothelial nitric oxide synthase (eNOS) and VE-cadherin. RTKs and their associated targets are also transported to the nucleus, where they may directly impact nuclear signaling. Although the nuclear transpor...
Stent Placement Versus Balloon Angioplasty for the Treatment of Obstructive Lesions of the Popliteal Artery
Authors: AljoschaRastan, HansKrankenberg, IrisBaumgartner, ErwinBlessing, StefanMüller-Hülsbeck, ErnstPilger, DierkScheinert, JohannesLammer, MartinGißler, EliasNoory, Franz-JosefNeumann, ThomasZeller
Journal: Circulation (2013)

Background—Stenting has been shown to improve patency after femoral artery revascularization compared with balloon angioplasty. Limited data are available evaluating endovascular treatment for obstructive lesions of the popliteal artery. Methods and Results—This prospective, randomized, multicenter trial compared primary nitinol stent placement to percutaneous transluminal balloon angioplasty in patients with peripheral artery disease Rutherford-Becker class 2 to 5 who had a de novo lesion in the popliteal artery. The primary study end point was 1-year primary patency, defined as freedom from target-lesion restenosis (luminal narrowing of ≥50%) as detected by duplex ultrasound. Secondary end points included target-lesion revascularization rate and changes in Rutherford-Becker class. Provisional stent placement was considered target-lesion revascularization and loss of primary patency. Two hundred forty-six patients were included in this trial. The mean target-lesion length was 42.3 mm. One hundred ninety-...