tbuckley/cabot-search huggingface dataset:
Abstract 19778: Novel Strategy for Improved Substrate Mapping of the Atria: Omnipolar Catheter and Signal Processing Technology Assesses Electrogram Signals Along Physiologic and Anatomic Directions
Authors: D Curtis Deno, Ram Balachandran, Dennis Morgan, Stéphane Massé, Kumaraswamy Nanthakumar
Journal: Circulation (2015)

Introduction: Substrate mapping is evolving as a potential strategy for atrial fibrillation ablation. Defining scar borders and functional boundaries is typically under taken with bipolar electrodes. Catheter orientation affects electrogram (EGM) signal amplitude due to an orientation dependence of bipoles. We developed orientation independent Omnipolar Technology (OT) and compared OT EGM amplitude with traditional bipolar (Bi) methods. Methods: Four anesthetized swine were studied in 6 sessions with a 3D mapping system and a multielectrode OT ablation catheter placed in RA and LA locations in 4 rhythms. With the OT catheter in a stable location, 30 successive atrial beats were acquired. OT electrodes provided bipole (Bi) as well as OT signals along both activation (OTa) and surface normal (OTn) directions. Peak to peak amplitudes (Vpp) of OT and Bi signals were compared for magnitude and consistency. Results: As shown in the table, OT signal amplitudes over all atrial locations and rhythms were greater than traditional bipole amplitudes. The coefficients of variation for signal amplitude over successive cardiac beats were substantially less for OTa and OTn (*p &lt; 0.01 with respect to Bi) than for Bi, reflecting electrode pair orientation effects. Conclusions: Distinct electrogram signals were resolved by OT along physiologic (activation) and anatomic (surface normal) directions. Catheter orientation independent OT signal amplitudes were more self-consistent and reliable than those from orientation dependent bipolar electrode pairs. Omnipolar technology approaches may permit more accurate and specific definition of substrate and thus catheter ablation of arrhythmias.
Abstract 4370: Regulation of AGO2-KRAS interaction through epidermal growth factor receptor
Authors: Ronald F. Siebenaler, Sunita Shankar, Jean C. Tien, Vijaya L. Dommeti, Malay Mody, Chandan Kumar-Sinha, Arul M. Chinnaiyan
Journal: Cancer Research (2018)

Abstract The RAS gene family is among the most commonly mutated genes within cancer. While much research has elucidated its major functions and downstream pathways, little progress has been made in successfully targeting RAS mutations. We recently identified Argonaute 2 (AGO2) of the RNA-induced silencing complex (RISC) as a novel partner of the Switch II domain of KRAS. We have found that stable knockdown of AGO2 in KRAS-dependent cell lines lead to a decrease in KRAS protein expression with a subsequent decrease in cellular proliferation. In addition, we observed a decrease in microRNA unwinding in the presence of mutant KRAS, suggesting this interaction inhibits the endogenous RNAi function of AGO2. Despite this clear connection between KRAS and AGO2 in KRAS mediated oncogenesis, the precise function of this interaction remains unclear in both normal and cancer biology. In order to identify endogenous regulators of AGO2-RAS, we investigated the ability of EGFR signaling to modulate the AGO2-RAS interaction. We established two mouse embryonic fibroblast cell lines (NIH-3T3 and MEF) with complete knockout of AGO2. When compared to normal control cells, we found that knockout of AGO2 resulted in an increase in WT RAS-GTP activation levels, phosphorylation of Y1068-EGFR, and MAPK/ERK and PI3K/AKT signaling. Rescue of AGO2 knockout resulted in a return to normal levels of active RAS-GTP, pEGFR, and downstream signaling. Recent studies have described EGFR phosphorylation of AGO2 under hypoxic cell conditions, resulting in the inhibition of AGO2 association with RISC members. In order to better characterize the relationship between EGFR-AGO2-RAS, we found that overnight serum starvation followed by stimulation with EGF led to a decrease in AGO2-RAS co-IP in WT KRAS cells. Blocking AGO2 phosphorylation with a Y393F mutant of AGO2 prevented AGO2-RAS dissociation following EGFR stimulation. While WT KRAS cell lines displayed regulation of AGO2-RAS via EGFR, the phosphorylation of AGO2Y393 was unable to disrupt the interaction of AGO2 with mutant KRAS following stimulation with EGF. Together these results suggest a unique EGFR-AGO2-RAS signaling axis, and its dysregulation by mutant KRAS could increase oncogenic growth through promotion of AGO2-RAS interaction in cancer. Citation Format: Ronald F. Siebenaler, Sunita Shankar, Jean C. Tien, Vijaya L. Dommeti, Malay Mody, Chandan Kumar-Sinha, Arul M. Chinnaiyan. Regulation of AGO2-KRAS interaction through epidermal growth factor receptor [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 4370.
Considerable Time From the Onset of Plaque Rupture and/or Thrombi Until the Onset of Acute Myocardial Infarction in Humans
Authors: ShinsukeOjio, HisatoTakatsu, TsutomuTanaka, KatsumiUeno, KoichiYokoya, TetsuoMatsubara, TakahikoSuzuki, SachiroWatanabe, NorihikoMorita, MasanoriKawasaki, ToshihikoNagano, ItsukiNishio, KazuyoshiSakai, KazuhikoNishigaki, GenzouTakemura, ToshiyukiNoda, ShinyaMinatoguchi, HisayoshiFujiwara
Journal: Circulation (2000)

Background—It has been thought that the thrombi and bleeding in plaques that occur after plaque rupture or endothelial damage from vessels with mild stenosis suddenly occlude the lumen and cause acute myocardial infarction (AMI). However, our hypothesis is that thrombi and bleeding may not suddenly occlude the lumen. Methods and Results—The study group consisted of 20 patients who had coronary angiograms performed within 1 week (3±3 days) before AMI and 20 control patients who had coronary angiograms performed 6 to 18 months (282±49 days) before AMI. The features of infarct-related coronary segments (IRCS) at 3 days before AMI were the presence of a significant stenosis of >50% (95% in incidence and 71±12% diameter stenosis) and Ambrose’s type II eccentric lesions (plus multiple irregularities), an indicator of plaque rupture and/or thrombi (60% [70%]), and the features at 1 year before AMI were mild stenosis of <50% (95% incidence and 30±18% diameter stenosis) with rare Ambrose’s type II eccentric lesion...
Salt-Sensitive Hypertension in Transgenic Mice Overexpressing Na+-Proton Exchanger
Authors: MakotoKuro-o, KazunoriHanaoka, YukioHiroi, TsuyoshiNoguchi, YumiFujimori, Shun-ichiTakewaki, MichikoHayasaka, HirohisaKatoh, AkiraMiyagishi, RyozoNagai, YoshioYazaki, Yo-ichiNabeshima
Journal: Circulation Research (1995)

Abstract Essential hypertension is one of the most common diseases that exacerbate the risk of cardiovascular or cerebrovascular attacks. Although the etiology of essential hypertension remains unclear, recent investigations have revealed that an enhancement of Na+-proton (Na+-H+) exchange activity is a frequently observed ion transport abnormality in hypertensive patients and animal models. To test the hypothesis that increased Na+-H+ exchange causes hypertension, we produced transgenic mice overexpressing Na+-H+ exchanger and analyzed their Na+ metabolism and blood pressure. Urinary excretion of water and Na+ was significantly decreased in transgenic mice, and systolic blood pressure was elevated after salt loading. The impaired urinary excretion of Na+ suggested that the Na+-H+ exchanger overexpressed in the renal tubules increased reabsorption of Na+, which caused a blood pressure elevation by Na+ retention after excessive salt intake. Our results demonstrate that overexpression of Na+-H+ exchanger ca...
Tumor Necrosis Factor-α Receptor 1 Is a Major Predictor of Mortality and New-Onset Heart Failure in Patients With Acute Myocardial Infarction
Authors: MarcoValgimigli, ClaudioCeconi, PatriziaMalagutti, ElisaMerli, OlgaSoukhomovskaia, GloriaFrancolini, GiordanoCicchitelli, AdrianaOlivares, GiovanniParrinello, GianfrancoPercoco, GabrieleGuardigli, DonatoMele, RobertoPirani, RobertoFerrari
Journal: Circulation (2005)

Background— Tumor necrosis factor alpha-α (TNF-α) activation is an independent prognostic indicator of mortality in patients with heart failure (HF). Despite the recognition that several TNF family cytokines are elevated during myocardial infarction, their role in predicting subsequent prognosis in these setting remains poorly understood. Methods and Results— We performed a systematic evaluation of TNF-α and its type 1 and 2 soluble receptors, together with interleukin (IL)-6, IL-1 receptor antagonist, and IL-10, in 184 patients (132 men; mean age, 64±12) consecutively admitted for myocardial infarction. We correlated their values to short- and long-term incidence of death and HF (primary outcome). In 10 patients, we also studied the presence of transcardiac gradients for TNF-α and its soluble receptors. The control group comprised 45 healthy subjects who were sex and age matched (33 men; mean age, 65±6 years) to the patients. All tested cytokines were increased in patients, and no transcardiac or systemi...
Transposition of the Great Vessels
Authors: Charlotteferencz
Journal: Circulation (1966)

A microscopic study of the lungs of 106 patients with transposition of the great vessels has revealed early and severe hypertensive alterations in the pulmonary arteries. These striking changes, associated in almost all instances with normal pulmonary veins, indicate a state of high resistance of the arterial bed. Pulmonary arterial damage was, in general, most advanced in the patients with a large ventricular septal defect, but in spite of this these were the patients who lived longest. It seemed obvious, therefore, that their relatively favorable course was due to a greater beneficial than damaging effect of the ventricular septal defect. Consideration of these findings in the light of known physiologic data has led to a clarification of the physiologic variations of the transposition circulation. Using the recognized physiologic definitions of flows and shunts the transposition circulation is characterized by a diminished effective flow and a bidirectional but predominantly left-to-right shunt. The eff...
Therapeutic Ablation of Gain-of-Function Mutant p53 in Colorectal Cancer Inhibits Stat3-Mediated Tumor Growth and Invasion
Authors: Ramona Schulz-Heddergott, Nadine Stark, Shelley J. Edmunds, Jinyu Li, Lena-Christin Conradi, Hanibal Bohnenberger, Fatih Ceteci, Florian R. Greten, Matthias Dobbelstein, Ute M. Moll
Journal: Cancer Cell (2018)
Abstract 5400: A comprehensive analysis of the interactome of miR-21, an established oncomir, by Argonaute-CLIP analysis identifies novel conserved and species-specific targets of miR-21 in human liver and hepatocellular carcinoma
Authors: Aaron B. Koenig, Juan M. Barajas, Kalpana Ghoshal
Journal: Cancer Research (2018)

Abstract MicroRNAs are ~22 nucleotide RNAs that regulate gene expression at the post-transcriptional level by binding messenger RNA transcripts. MicroRNA (miR)-21 participates in carcinogenesis in hepatocellular carcinoma (HCC) and other malignancies. Here we analyze the miR-21 interactome in HCC by high-throughput sequencing of RNA isolated by Argonaute cross-linking immunoprecipitation (Argonaute-CLIP) in nine HCC cases with matched livers. Argonaute-CLIP identified miR-21 bound to 580 target sites on coding transcripts, of which 332 were located in the coding sequences, 214 in the 3'-untranslated region, and 34 in the 5'-untranslated region, introns or downstream sequences. Overall, 403 target sites (69.5%) enriched for miR-21 in HCCs relative to liver. We compared expression of miR-21 targets in 377 patients with liver cancer registered in The Cancer Genome Atlas. Ago-CLIP miR-21 enrichment score in HCC distinguished expression of miR-21 targets by their correlation with miR-21 expression. Comparison of the miR-21 interactome in mouse and human livers identified common and species-specific targets. Among targets of miR-21, 27.6% were downregulated in HCC. The miR-21 interactome was predicted to regulate tumor metabolism by inhibiting PPAR alpha/RXR alpha and LXR/RXR signaling. To identify targets of miR-21, we matched Ago-CLIP targets to genes previously reported as aberrantly expressed after anti-miR-21 overexpression in HCC. RMND5A, encoding an E3 ubiquitin ligase, was identified as a potential target of miR-21 regulation and was variably expressed in HCC. Three predicted miR-21 targets, CAMSAP1, DDX1 and MARCKSL1, correlated with HCC patient survival. Collectively, our analysis biochemically identified novel targets of miR-21 likely to play a causal role in hepatocarcinogenesis. Citation Format: Aaron B. Koenig, Juan M. Barajas, Kalpana Ghoshal. A comprehensive analysis of the interactome of miR-21, an established oncomir, by Argonaute-CLIP analysis identifies novel conserved and species-specific targets of miR-21 in human liver and hepatocellular carcinoma [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 5400.
Simplified Determination of Arterial Insufficiency
Authors: Traviswinsor
Journal: Circulation (1951)

Reactive hyperemia following 15 minute arterial occlusion at the ankle was studied in plethysmographic tracings using the venous occlusion technic. The resulting curves present an essentially different pattern in normal subjects and patients with various types of peripheral arterial disease. Several characteristic features can be distinguished, notably the level of highest blood flow after release of arterial occlusion, the time required until the highest blood flow is reached, and the degree of secondary vasoconstriction. Evaluation of these factors permits an estimate of the therapeutic value of lumbar sympathectomy.
Abstract 4556: Phagocytosis response of macrophage to CD47 expression of tumor cells in anti-CD47 therapy
Authors: Huajun Yang, Zhongliang Li, Phillip Wang, Beibei Tang, Qinyun Ma, Frank Xing, Qian Shi
Journal: Cancer Research (2018)

Abstract Macrophage as an important surveillance system is escaped by human cancer cells expressing CD47. To reinstate macrophage functionality in clearing tumor cells targeting CD47 and thereby blocking phagocytosis inhibitory CD47-SIRPalpha interaction has been an important strategy in immune-oncology therapy. We profiled a large panel of tumor cell lines, Crown's proprietary PDX models and clinical lung cancer tumors for CD47 expression. Although it has been reported as a ubiquitously expressed immune-escape marker in cancer cells, the expression levels of CD47 vary among different tumor cell lines and models when the cells were examined by flow cytometry. It is of interest that a portion of tumor cells in fact do not present CD47. To tackle the cause for the loss of CD47 expression, whole-exome sequencing was performed to examine the intactness of the gene in the CD47 loss models. The results will be presented. We next established a robust and reproducible in vitro assay platform to support anti-CD47 drug research. We applied a macrophage differentiation system using isolated CD14+ monocytes as starting material, and were able to achieve &amp;gt;80% of M1 and M2 populations, respectively, through the 6-day differentiation. Differentiated macrophage was co-cultured with target tumor cells labeled for flow cytometry analysis. In the presence of blocking anti-CD47 antibody BRICK126, steady and specific phagocytosis effect was observed when target tumor cells express high level of CD47 markers. BRIC126 antibody blocks the CD47-SIRPalpha interaction. In contrast, aCD274 antibody did not yield more than background phagocytosis effect in the same assay. To prove the CD47-specific effect, we constructed isogenic cell models from a couple of parental cell models in that CD47 gene is knocked out in one sub-cell line and overexpressed in another sub-cell line. The isogenic systems were then subject to the CD47 biology assay and more profound changes in phagocytosis responses were observed. Furthermore, the in vitro findings were validated in in vivo setting. Citation Format: Huajun Yang, Zhongliang Li, Phillip Wang, Beibei Tang, Qinyun Ma, Frank Xing, Qian Shi. Phagocytosis response of macrophage to CD47 expression of tumor cells in anti-CD47 therapy [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 4556.
Matrix Metalloproteinases as Novel Disease Markers in Takayasu Arteritis
Authors: AkifumiMatsuyama, NaohikoSakai, MasatoIshigami, HisatoyoHiraoka, SusumuKashine, AyumuHirata, TadashiNakamura, ShizuyaYamashita, YujiMatsuzawa
Journal: Circulation (2003)

Background— Takayasu arteritis (TA) is a chronic vasculitis that primarily affects large elastic arteries. Monitoring of disease activity is crucial because the disease tends to progress despite treatment with glucocorticoid and/or immunosuppressive agents. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) have generally been used as disease activity markers, but these are nonspecific inflammatory markers and lack the sensitivity and specificity to accurately monitor the disease status. Given the histological findings characterized by destruction of elastic fibers, we hypothesized that matrix metalloproteinases (MMPs) could be useful as markers of disease activity in TA. Methods and Results— A consecutive series of 25 patients with TA were enrolled in this study. According to the National Institutes of Health criteria of disease activity, 11 were in an active phase and the remaining 14 were in remission. Circulating levels of MMP-2, MMP-3, and MMP-9 were determined by ELISA in all patients...
Abstract P060: Reduction of Cardiovascular Mortality in the United States Population, 1988-2004: A Larger Contribution of Declining Exposures to Cadmium and Lead Compared to Traditional Cardiovascular Risk Factors
Authors: AdrianRuiz-Hernandez, AnaNavas-Acien, RobertoPastor-Barriuso, JosepRedon, EliseoGuallar, MariaTellez-Plaza
Journal: Circulation (2016)

Introduction:Lead and cadmium exposures have markedly declined in the US following the banning of lead in gasoline and the implementation of tobacco control, air pollution reduction, and hazardous waste remediation policies since the mid 1970s. While lead and cadmium have been proposed as cardiovascular disease risk factors, little is known about their potential contribution to the decline in cardiovascular mortality in US adults. Hypothesis: We assessed the hypothesis that lead and cadmium exposure reductions partly explain the decreasing trend in cardiovascular mortality that occurred in the US from 1988-1994 to 1999-2004, after controlling for traditional cardiovascular risk factors including smoking, obesity, physical inactivity, hypertension, diabetes, chronic kidney disease, and dyslipidemia. Methods: Cohort study of 15,421 men and women ≥40 years old participating in the National Health and Nutrition Examination Survey (NHANES) 1988-1994 and 1999-2004. We implemented a mediation approach with addit...
Acute toxicity in African American and Caucasian patients with adjuvant/neoadjuvant chemotherapy for breast cancer.
Authors: Mansoor Ul Haq, Namratha Vontela, Pranitha Naini, Jessica N. Snider, Mark S. Walker, Lee Steven Schwartzberg
Journal: Journal of Clinical Oncology (2014)

1059 Background: The incidence of breast cancer is higher in Caucasian (C) compared to African American (AA) patients (pts), however the mortality is higher in AA. This disparity has been explained by a higher stage at diagnosis, triple negative tumors, high nuclear grade, and decreased access to health care among the AA women pts. This difference still persists when these factors are controlled. We hypothesized that AA pts have reduced dose intensity of chemotherapy due to treatment delays and dose reductions as a result of increased acute toxicity leading to inferior outcomes. Methods: Data was collected by retrospective chart review on 100 consecutive C and 100 AA pts with early stage breast cancer who received adjuvant or neoadjuvant chemotherapy during 2009 to 2011 at a community cancer center. Data collected included pt demographics, comorbidities, disease characteristics, treatment received, acute toxicities, and pt reported symptom burden as assessed by a validated electronic survey. Results: Mean age of C and AA pts was 56.1 vs. 51.5, respectively (p = .0049). All pts had ECOG performance status of 0-1, with no race differences. AA pts had higher rates of diabetes (17.0% vs. 11.9%) and hypertension (49.0% vs. 36.6%). The mean Charlson Comorbidity Index score was 3.1 for C and 3.4 for AA (p = .064). 44% of C presented at stage II and III as compared to 61% of AA patients (p = .028). AA had higher tumor grade (p = .005) . For chemotherapy AA got numerically more dose dense AC-paclitaxel, similar docetaxel-cyclophosphamide and less cyclophosphamide-methotrexate-5FU as compared to C. Most common side effects for C and AA respectively were, anemia: 50.5% vs. 68%, neutropenia: 14.9% vs. 12%, nausea: 27% vs. 15%, diarrhea: 13.9% vs. 11%, infection: 13.9% vs. 14% and neuropathy: 16.8% vs. 13%. Treatment delays and dose reductions did not differ between race groups. Patient reported symptom burden also did not differ among race groups. Conclusions: Despite difference in comorbidities and stage at presentation, no significant difference was observed in acute toxicities due to chemotherapy, in pt reported symptoms or the rates of chemotherapy delay and dose reduction between C and AA pts with early stage breast cancer.
Aspirin Increases Ferritin Synthesis in Endothelial Cells
Authors: StefanieOberle, TobiasPolte, AidaAbate, Hans-PeterPodhaisky, HenningSchröder
Journal: Circulation Research (1998)

Abstract—Aspirin has recently been shown to increase endothelial resistance to oxidative damage. However, the mechanism underlying aspirin-induced cytoprotection is still unknown. Using cultured cells, the present study investigates the effect of aspirin on the expression of ferritin, a cytoprotective protein that sequesters free cytosolic iron, the main catalyst of oxygen radical formation. In bovine pulmonary artery endothelial cells, aspirin at low antithrombotic concentrations (0.03 to 0.3 mmol/L) induced the synthesis of ferritin protein in a time- and concentration-dependent fashion up to 5-fold over basal levels, whereas ferritin H (heavy chain) mRNA remained unaltered. Aspirin-induced cytoprotection from hydrogen peroxide toxicity was mimicked by exogenous iron-free apoferritin but not iron-loaded ferritin, demonstrating the antioxidant function of newly synthesized ferritin under these conditions. Ferritin induction by aspirin was specific in that other nonsteroidal anti-inflammatory drugs such a...