tbuckley/cabot-search huggingface dataset:
Abstract 3046: Evaluation of pancreatic ductal adenocarcinoma with acidoCEST MRI
Authors: Rachel A. High, Edward A. Randtke, Kyle M. Jones, Mark D. Pagel
Journal: Cancer Research (2018)

Abstract Introduction: Our goal is to evaluate the role of using extracelluar pH (pHe) as a predictor of pancreatic ductal adenocarcinoma (PDAC) development using a non-invasive, in vivo imaging technique called acidoCEST MRI, to improve early detection of pancreatic tumors. Methods: Spontaneous PDAC development was initiated by administering 14 caerulein injections over a 62 hour period to a KrasLSL.G12D/+; PdxCre mouse model. Caerulein induces pancreatitis which drives tumor development in the context of a Kras mutation. Animals were imaged with a Bruker BioSpin 7T MRI scanner with an acidoCEST MRI protocol at pre-injection, 1 hour and 48 hours post final injection of caerulein, and weekly until tumors reached a size of 200mm3. During all MR imaging, mice were anesthetized with 2.0% isofluorane, maintained at a respiration rate of 35-40 bpm, and maintained at a body temperature of 37°C. For acidoCEST MR imaging, mice were injected with 370 mg/mL iopamidol (200 μL IV bolus and 400 μL/hr IV infusion) and scanned with a 6 sec saturation time at 3.5 μT, with a 300 ms acquisition time. Pixel-wise parametric maps of pancreatic pHe values were generated via fitting the CEST spectrum with the Bloch-McConnell equations in MATLAB R2016a. Average pancreatic pHe was recorded. Results: AcidoCEST MRI was successful in acquiring in vivo pHe of normal and tumor pancreatic tissue, both with sufficient uptake of the iopamidol contrast agent. The pHe values for healthy pancreatic tissue ranged from 6.83 to 7.33 with an average of 6.96 (n=14). 1 hour after the last caerulein injection, during pancreatic inflammation, pHe ranged from 6.78 to 7.00, with an average of 6.92 (n=6). Tumors began to reach a size of 200mm3 at 5 weeks post caerulein injections. In tumor tissue, pHe was 6.59 (n=1), demonstrating tumor acidosis. Conclusions: We have demonstrated that acidoCEST MRI can be used to quantify pHe in healthy pancreatic tissue, pancreatitis, and pancreatic ductal adenocarcinoma. These pHe values will be used to determine if acidity in pancreatitis correlates with future development of PDAC and/or a more aggressive phenotype. Further pre-clinical studies using acidoCEST MRI may be performed to monitor early therapeutic response to pancreatic tumor treatment. Citation Format: Rachel A. High, Edward A. Randtke, Kyle M. Jones, Mark D. Pagel. Evaluation of pancreatic ductal adenocarcinoma with acidoCEST MRI [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 3046.
Ionic Remodeling Underlying Action Potential Changes in a Canine Model of Atrial Fibrillation
Authors: LixiaYue, JianlinFeng, RaniaGaspo, Gui-RongLi, ZhiguoWang, StanleyNattel
Journal: Circulation Research (1997)

Abstract Rapid electrical activation, as occurs during atrial fibrillation (AF), is known to cause reductions in atrial refractoriness and in adaptation to heart rate of the atrial refractory period, which promote the maintenance of AF, but the underlying ionic mechanisms are unknown. In order to determine the cellular and ionic changes caused by chronic atrial tachycardia, we studied right atrial myocytes from dogs subjected to 1, 7, or 42 days of atrial pacing at 400/min and compared them with myocytes from sham-operated dogs (pacemaker inserted but not activated). Rapid pacing led to progressive increases in the duration of AF induced by bursts of 10-Hz stimuli (from 3±2 seconds in sham-operated dogs to 3060±707 seconds in dogs after 42 days of pacing, P<.001) and reduced atrial refractoriness and adaptation to rate of the atrial refractory period. Voltage-clamp studies showed that chronic rapid pacing did not alter inward rectifier K+ current, rapid or slow components of the delayed rectifier current,...
ERK and p38 MAPK, but not NF-κB, Are Critically Involved in Reactive Oxygen Species–Mediated Induction of IL-6 by Angiotensin II in Cardiac Fibroblasts
Authors: MotoakiSano, KeiichiFukuda, ToshihikoSato, HarukoKawaguchi, MakotoSuematsu, SatoshiMatsuda, ShigeoKoyasu, HideoMatsui, KeikoYamauchi-Takihara, MasakiHarada, YoshihikoSaito, SatoshiOgawa
Journal: Circulation Research (2001)

We recently reported that angiotensin II (Ang II) induced IL-6 mRNA expression in cardiac fibroblasts, which played an important role in Ang II–induced cardiac hypertrophy in paracrine fashion. The present study investigated the regulatory mechanism of Ang II–induced IL-6 gene expression, focusing especially on reactive oxygen species (ROS)-mediated signaling in cardiac fibroblasts. Ang II increased intracellular ROS in cardiac fibroblasts, and the increase was completely inhibited by the AT-1 blocker candesartan and the NADH/NADPH oxidase inhibitor diphenyleneiodonium (DPI). We first confirmed that antioxidant N-acetylcysteine, superoxide scavenger Tiron, and DPI suppressed Ang II–induced IL-6 expression. Because we observed that exogenous H2O2 also increased IL-6 mRNA, the signaling pathways downstream of Ang II and exogenous H2O2 were compared. Ang II, as well as exogenous H2O2, activated ERK, p38 MAPK, and JNK, which were significantly inhibited by N-acetylcysteine and DPI. In contrast with exogenous ...
The Role of Auscultation in the Differentiation of Fallot's Tetralogy from Severe Pulmonary Stenosis with Intact Ventricular Septum and Right-to-Left Interatrial Shunt
Authors: Louisvogelpoel, Velvaschrire
Journal: Circulation (1955)

A clinical and phonocardiographic study has been made of the murmurs and heart sounds in the differentiation of Fallot's tetralogy from severe pulmonary stenosis with intact septum and right-to-left interatrial shunt. A striking difference in the behaviour of the systolic murmur was found in the two conditions and this affords a new, simple bedside method of diagnosis. Important differences in the behaviour of the heart sounds were also found, but these are usually more difficult to evaluate clinically and may require special study.
Effects of MCI-154, a Calcium Sensitizer, on Left Ventricular Systolic and Diastolic Function in Pacing-Induced Heart Failure in the Dog
Authors: ShinobuTeramura, TetsuYamakado, MitsuguMaeda, TakeshiNakano
Journal: Circulation (1997)

Background MCI-154 is a positive inotropic agent that increases the myofilament response to Ca2+. Whether MCI-154 has beneficial effects on left ventricular dysfunction in chronic heart failure is not known. We examined the effects of MCI-154 on left ventricular systolic and diastolic function in pacing-induced heart failure in dogs. Methods and Results We studied eight anesthetized dogs before and 2 to 4 weeks after rapid right ventricular pacing. Left cineventriculograms with simultaneous left ventricular pressures (tip manometer) were obtained before and during intravenous administration of MCI-154 (1.0 μg·kg−1·min−1 for 15 minutes) in the control and heart-failure states. Left ventricular volume dynamics was derived from frame-by-frame (20-ms) analyses of left ventricular angiograms. In heart failure, left ventricular contractility as assessed by shifts of the end-systolic pressure-volume ratio, evaluated by inferior vena cava occlusion, was improved by MCI-154 (+1.94 mm Hg/mL, P<.05) to an extent sim...
Risk of Assessing Mortality Risk in Elective Cardiac Operations
Authors: MarcoRanucci, SerenellaCastelvecchio, LorenzoMenicanti, AlessandroFrigiola, GabrielePelissero
Journal: Circulation (2009)

Background— Several mortality risk scores exist in cardiac surgery. All include a considerable number of independent risk factors. In elective cardiac surgery patients, the operative mortality is low, the number of events recorded per year is limited, and the risk model may be overfitted. The present study aims to develop and validate an operative mortality risk score for elective patients based on a limited number of factors. Methods and Results— The development series included 4557 adult patients who had undergone an elective cardiac operation at our institution from 2001 to 2003; the validation series includes the 4091 patients who subsequently underwent an operation. Three independent factors were included in the mortality risk model: age, creatinine, and left ventricular ejection fraction (ACEF). The ACEF score was computed as follows: age (years)/ejection fraction (%)+1 (if serum creatinine value was >2 mg/dL). The ACEF score was compared with 5 other risk scores in the validation series. Discrimina...
Abstract 12195: Novel Magnetic Resonance Imaging Marker of Myocardial Fibrosis: Validation in a Model of Hypertensive Heart Disease
Authors: Otavio R Coelho-Filho, Richard Mitchell, Francois-Pierre Mongeon, Heitor Moreno, Raymond Y Kwong, Michael Jerosch-Herold
Journal: Circulation (2011)

BACKGROUND The relative distribution volume of gadolinium measured by post-contrast CMR T1 imaging, closely correlates with the myocardial extracellular volume fraction (MECVF). MECVF may be a novel marker of diffuse interstitial fibrosis, not quantifiable by late gadolinium enhancement imaging. We hypothesized that MECVF correlates with the connective tissue volume fraction (CTVF) in a rodent model of hypertensive heart disease created by chronic inhibition of nitric oxide biosynthesis with Nω-nitro-L-arginine-metyl-ester (L-NAME). METHODS L-NAME (40mg/Kg/day) or placebo were administered respectively to 22 (body weight 36.9±2.3g) and 15 (body weight 37.6±2.5g) wild-type mice. 4.7T CMR studies were done at baseline and 7 weeks after treatment. The myocardial partition coefficient was measured by before and after Gd-DPTA (0.5 mmol/kg) T1 quantification by Look-Locker gradient-echo cine and adjusted to hematocrit to measure MECVF. CTVF was obtained by Masson's trichrome staining. The heart of L-NAME-treate...
Noninvasive Electrocardiographic Imaging of Arrhythmogenic Substrates in Humans
Authors: YoramRudy
Journal: Circulation Research (2013)

Cardiac excitation is determined by interactions between the source of electric activation (membrane depolarization) and the load that cardiac tissue presents. This relationship is altered in pathology by remodeling processes that often create a substrate favoring the development of cardiac arrhythmias. Most studies of arrhythmia mechanisms and arrhythmogenic substrates have been conducted in animal models, which may differ in important ways from the human pathologies they are designed to represent. Electrocardiographic imaging is a noninvasive method for mapping the electric activity of the heart in humans in real-world conditions. This review summarizes results from electrocardiographic imaging studies of arrhythmogenic substrates associated with human clinical arrhythmias. Examples include heart failure, myocardial infarction scar, atrial fibrillation, and abnormal ventricular repolarization.
Abstract MP06: Sport Club Participation During Adolescence and Sports-Related Physical Activity During Adulthood in Relation to Mortality From Cardiovascular Disease: The JACC Study
Authors: KrisztinaGero, HiroyasuIso, AkihikoKitamura, KazumasaYamagishi, HiroshiYatsuya, AkikoTamakoshi
Journal: Circulation (2015)

Background and Purpose: Taking part in cultural or sport club activities during Junior and Senior high school years is an integral part of Japanese culture. This study examines potential effects of sport club participation during Junior and Senior High School and sports-related physical activity during adulthood on mortality from cardiovascular disease (CVD). Methods: Between 1988 and 1990, as part of the Japan Collaborative Cohort (JACC) Study, 29 526 men and 41 044 women aged 40 to 79 years with no history of coronary heart disease (CHD), cerebrovascular disease, or cancer responded to a questionnaire, which included questions regarding the frequency of sports participation at baseline and sport club participation during Junior and Senior high school. A follow-up study was conducted until the end of 2009, and 4230 cardiovascular deaths (870 CHD and 1859 stroke) were identified. Cox proportional-hazard regression model was used to estimate hazard ratios first separately, and then combined for sports part...
Abstract 4884: OXPHOS: A novel target for cancer therapy in oncogene addicted tumor
Authors: Jayshree L. Hirpara, Jie Eu Qing, Andrea Wong, Naoto Ohi, Tsunoda Takeshi, Boon Cher Goh, Shazib Pervaiz
Journal: Cancer Research (2018)

Abstract Cancer cells are highly dependent on glycolysis over oxidative phosphorylation (OXPHOS). However, there is emerging evidence that (a) dysfunctional OXPHOS may be a major factor driving oncogene addiction and (b) feedback activation of the transcription factor STAT3 is a common surrogate survival pathway in oncogene addicted cancer cells. As such, invasive cancers exhibit enhanced oxidative phosphorylation, mitochondrial biogenesis and mitochondrial oxygen consumption rate. Therefore, inhibiting OXPHOS and STAT3 activity could have potential therapeutic implications for oncogene addicted and OXPHOS-dependent cancers. Here we report that oncogene addicted non-small cell lung carcinoma (NSCLC) cell line HCC827 and its gefitinib resistant clone and malignant melanoma cell line A375 and its vemurafanib resistant clone have significantly higher OXPHOS activity. In addition, these cells express higher level of the mitochondrial electron transport chain complex I protein (NDUFA9) and increased complex I activity as well as higher mitochondrial DNA copy number. Of note, significantly increased activity of STAT3 is detected in oncogene addicted cancer cells, and the increased mitochondrial oxygen consumption and complex I activity could be significantly inhibited by a novel small molecule inhibitor of STAT3, OPB-51602. The latter is shown to be an effect that might be independent of the STAT3 inhibitory activity of the small molecule compound. Most importantly, the novel STAT3 inhibitor showed strong activity in three different murine models of carcinogenesis as well as in patients treated with the STAT3 inhibitor. These data provide evidence that oncogene addicted cancer cells switch to OXPHOS over glycolysis and serve as proof of principle for identifying targeted new OXPHOS inhibitor in recalcitrant cancers. Citation Format: Jayshree L. Hirpara, Jie Eu Qing, Andrea Wong, Naoto Ohi, Tsunoda Takeshi, Boon Cher Goh, Shazib Pervaiz. OXPHOS: A novel target for cancer therapy in oncogene addicted tumor [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 4884.
Ultrasonic Tissue Characterization Predicts Myocardial Viability in Early Stage of Reperfused Acute Myocardial Infarction
Authors: ShinTakiuchi, HiroshiIto, KatsuomiIwakura, YoshiakiTaniyama, NagahiroNishikawa, TohruMasuyama, MasatsuguHori, YorihikoHigashino, KenshiFujii, TakazoMinamino
Journal: Circulation (1998)

Background—The aim of the present study was to characterize temporal changes in cyclic variation of ultrasonic integrated backscatter (IBS), which reflects intrinsic contractile performance, in patients with reperfused acute myocardial infarction (AMI) and to elucidate the clinical value of tissue characterization in predicting myocardial viability. Methods and Results—We recorded short-axis IBS images before and 3, 7, and 21 days after reperfusion in 26 patients with AMI and obtained the cyclic variation of IBS in the normal and infarct zones. When cyclic variation showed synchrony and asynchrony, we expressed its magnitude as positive and negative values, respectively, called the phase-corrected magnitude. We also measured average wall motion score (dyskinesis, 4; normal, 0) of the infarct segments. The phase-corrected magnitude was lower in the infarct zone than in the normal zone before reperfusion (0.3±2.5 versus 5.2±1.7 dB, P<.05). At day 3, the phase-corrected magnitude increased by 2.1±2.6 dB desp...
Abstract 4865: BI 907828: A highly potent MDM2 inhibitor with low human dose estimation, designed for high-dose intermittent schedules in the clinic
Authors: Joerg Rinnenthal, Dorothea Rudolph, Sophia Blake, Andreas Gollner, Andreas Wernitznig, Ulrike Weyer-Czernilofsky, Christian Haslinger, Pilar Garin-Chesa, Jürgen Moll, Norbert Kraut, Darryl McConnell, Jens Quant
Journal: Cancer Research (2018)

Abstract MDM2 inhibitors block the interaction between the Tumor Protein p53 (TP53) and MDM2, its key negative regulator, and represent a new therapeutic concept for cancer therapy. MDM2 inhibitors are designed to restore p53 activity in TP53 wild-type tumors. Several MDM2 inhibitors are currently being evaluated in early clinical development with mainly daily dosing regimens. However, recent clinical data suggest myelosuppression as an on-target, dose-limiting toxicity for this class of inhibitors. Particularly thrombocytopenia could limit the clinical utility of MDM2 inhibitors. Hence there is a need to mitigate these side effects and to improve the therapeutic window. One approach is less frequent dosing to allow bone marrow recovery while still maintaining efficacious exposure levels and clinical activity. Here we present pharmacokinetic data on BI 907828, a novel and potent MDM2 inhibitor with optimized drug-like properties. Due to its high permeability, good physiological solubility and low systemic clearance, the compound shows a high bioavailability in mice, rats, dogs and minipigs. BI 907828 is not absorption-limited, even at multiples of the efficacious dose, and shows a reliable, dose-linear PK with low variability in AUC and Cmax across species. Based on a good PK-PD correlation with efficacy in preclinical models and a robust human PK prediction based on in vivo PK data across species, a low human efficacious dose is predicted. The PK properties of BI 907828 enable a variety of different clinical dosing schedules with the potential to improve the therapeutic index with respect to on-target safety. In summary, BI 907828 is a novel, potent, orally available MDM2 inhibitor with excellent PK properties and low estimated human dose suitable for high-dose intermittent dose schedules in the clinic. Citation Format: Joerg Rinnenthal, Dorothea Rudolph, Sophia Blake, Andreas Gollner, Andreas Wernitznig, Ulrike Weyer-Czernilofsky, Christian Haslinger, Pilar Garin-Chesa, Jürgen Moll, Norbert Kraut, Darryl McConnell, Jens Quant. BI 907828: A highly potent MDM2 inhibitor with low human dose estimation, designed for high-dose intermittent schedules in the clinic [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 4865.
Genome-Wide Scan for Japanese Familial Intracranial Aneurysms
Authors: ShigekiYamada, MakiUtsunomiya, KayokoInoue, KazuhikoNozaki, SumikoInoue, KatsunobuTakenaka, NobuoHashimoto, AkioKoizumi
Journal: Circulation (2004)

Background— Genetic factors have an important role in the pathogenesis of intracranial aneurysm (IA). The results of previous studies have suggested several loci. Methods and Results— From 29 IA families with ≥3 individuals affected by IA, we used nonparametric (model-free) methods for linkage analyses, using GENEHUNTER and Merlin software. Genome-wide linkage analyses revealed 3 regions on chromosomes 17cen (maximum nonparametric logarithm of the odds score [MNS] = 3.00, nominal P=0.001), 19q13 (MNS=2.15, nominal P=0.020), and Xp22 (MNS=2.16, nominal P=0.019). We tested 4 candidate genes in these regions: the microfibril-associated protein 4 gene (MFAP4) and the promoter polymorphism of the inducible nitric oxide synthase gene (NOS2A) on chromosome 17cen, the epsilon genotypes of the apolipoprotein E gene (APOE) on chromosome 19q13, and the angiotensin I converting enzyme 2 gene (ACE2) on chromosome Xp22. Associations of their polymorphisms with IA were evaluated by a case-control study (100 cases: 29 pr...
Involvement of Src Family Protein Tyrosine Kinases in Ca2+ Sensitization of Coronary Artery Contraction Mediated by a Sphingosylphosphorylcholine-Rho-Kinase Pathway
Authors: FumiakiNakao, SeiKobayashi, KimikoMogami, YoichiMizukami, SatoshiShirao, SaoriMiwa, NatsukoTodoroki-Ikeda, MasaakiIto, MasunoriMatsuzaki
Journal: Circulation Research (2002)

We recently reported that sphingosylphosphorylcholine (SPC) is a novel messenger for Rho-kinase–mediated Ca2+ sensitization of vascular smooth muscle (VSM) contraction. Subcellular localization and kinase activity of Src family protein kinases (SrcPTKs), except for c-Src, is controlled by a reversible S-palmitoylation, an event inhibited by eicosapentaenoic acid (EPA). We examined the possible involvement of SrcPTKs in SPC-induced Ca2+ sensitization and effects of EPA. We used porcine coronary VSM and rat aortic VSM cells (VSMCs) in primary culture. An SrcPTKs inhibitor, PP1, and EPA inhibited SPC-induced contraction, concentration-dependently, without affecting [Ca2+]i levels and the Ca2+-dependent contraction induced by high K+ depolarization. A digitized immunocytochemical analysis in VSMCs revealed that SPC induced translocation of Fyn, but not of c-Src, from the cytosol to the cell membrane, an event abolished by EPA. Translocation of Rho-kinase from the cytosol to the cell membrane by SPC was also i...
Myocardial Cell Death in Human Diabetes
Authors: AndreaFrustaci, JanKajstura, CristinaChimenti, IgorJakoniuk, AnnarosaLeri, AttilioMaseri, BernardoNadal-Ginard, PieroAnversa
Journal: Circulation Research (2000)

Abstract—The renin-angiotensin system is upregulated with diabetes, and this may contribute to the development of a dilated myopathy. Angiotensin II (Ang II) locally may lead to oxidative damage, activating cardiac cell death. Moreover, diabetes and hypertension could synergistically impair myocardial structure and function. Therefore, apoptosis and necrosis were measured in ventricular myocardial biopsies obtained from diabetic and diabetic-hypertensive patients. Accumulation of a marker of oxidative stress, nitrotyrosine, and Ang II labeling were evaluated quantitatively. The diabetic heart showed cardiac hypertrophy, cavitary dilation, and depressed ventricular performance. These alterations were more severe with diabetes and hypertension. Diabetes was characterized by an 85-fold, 61-fold, and 26-fold increase in apoptosis of myocytes, endothelial cells, and fibroblasts, respectively. Apoptosis in cardiac cells did not increase additionally with diabetes and hypertension. Diabetes increased necrosis by...