tbuckley/cabot-search huggingface dataset:
Bile Microinfarcts in Cholestasis Are Initiated by Rupture of the Apical Hepatocyte Membrane and Cause Shunting of Bile to Sinusoidal Blood
Authors: Ahmed Ghallab, Ute Hofmann, Selahaddin Sezgin, Nachiket Vartak, Reham Hassan, Ayham Zaza, Patricio Godoy, Kai Markus Schneider, Georgia Guenther, Yasser A. Ahmed, Aya A. Abbas, Verena Keitel, Lars Kuepfer, Steven Dooley, Frank Lammert, Christian Trautwein, Michael Spiteller, Dirk Drasdo, Alan F. Hofmann, Peter L.M. Jansen, Jan G. Hengstler, Raymond Reif
Journal: Hepatology (2018)

Bile duct ligation (BDL) is an experimental procedure that mimics obstructive cholestatic disease. One of the early consequences of BDL in rodents is the appearance of so‐called bile infarcts that correspond to Charcot‐Gombault necrosis in human cholestasis. The mechanisms causing bile infarcts and their pathophysiological relevance are unclear. Therefore, intravital two photon–based imaging of BDL mice was performed with fluorescent bile salts (BS) and non‐BS organic anion analogues. Key findings were followed up by matrix‐assisted laser desorption ionization imaging, clinical chemistry, immunostaining, and gene expression analyses. In the acute phase, 1‐3 days after BDL, BS concentrations in bile increased and single‐cell bile microinfarcts occurred in dispersed hepatocytes throughout the liver caused by the rupture of the apical hepatocyte membrane. This rupture occurred after loss of mitochondrial membrane potential, followed by entry of bile, cell death, and a “domino effect” of further death events of neighboring hepatocytes. Bile infarcts provided a trans‐epithelial shunt between bile canaliculi and sinusoids by which bile constituents leaked into blood. In the chronic phase, ≥21 days after BDL, uptake of BS tracers at the sinusoidal hepatocyte membrane was reduced. This contributes to elevated concentrations of BS in blood and decreased concentrations in the biliary tract. Conclusion: Bile microinfarcts occur in the acute phase after BDL in a limited number of dispersed hepatocytes followed by larger infarcts involving neighboring hepatocytes, and they allow leakage of bile from the BS‐overloaded biliary tract into blood, thereby protecting the liver from BS toxicity; in the chronic phase after BDL, reduced sinusoidal BS uptake is a dominant protective factor, and the kidney contributes to the elimination of BS until cholemic nephropathy sets in.
Abstract 156: Initial Characteristics and Outcomes of Cardiogenic Shock Due to Acute Heart Failure in Comparison with Acute Myocardial Infarction
Authors: YusukeHosokawa, TakeshiYamamoto, KenNagao, EizoTachibana, TadateruTakayama, WataruShimizu, MorimasaTakayama
Journal: Circulation (2014)

Background: Recently, the mortality of patients with cardiogenic shock (CS) secondary to acute myocardial infarction (AMI) has been improved by reperfusion therapy and mechanical circulatory support. Acute heart failure (AHF) is frequently encountered in cardiovascular emergency setting as AMI. However, the initial characteristics and outcomes of patients with CS secondary to AHF has not yet been clarified. Methods: Data from the Tokyo CCU Network registry cohort from 2010 to 2011 were analyzed. Study 1; we made a comparison of the clinical data between CS patients with AHF (group HF) and those with AMI (group MI). Study 2; we analyzed critical factors determining the prognosis of the group HF. Results: Among a total of 19316 registered patients, 6247 were AHF and 5535 were AMI. Patients with cardiac arrest were excluded from this analysis. Therefore, we analyzed 143 patients of group HF and 307 patients of group MI. Study 1; underlying cardiac disease of group HF consisted of ischemic heart disease (23%)...
Abstract 16747: Surgical Atrial Fibrillation Ablation: a Systematic Review and Meta-analysis of Randomized Controlled Trials
Authors: Graham R McClure, Emilie P Belley-Cote, Rohit K Singal, Iqbal Jaffer, Nazari Dvirnik, Kevin R An, Gabriel Fortin, Jessica Spence, Richard P Whitlock
Journal: Circulation (2016)

Background: Surgical ablation for atrial fibrillation (AF) significantly improves maintenance of sinus rhythm and is recommended as a concomitant procedure in patients undergoing cardiac surgery. Current trials lack power to assess for patient-important outcomes such as mortality, stroke and pacemaker requirement. We performed a systematic review and meta-analysis to evaluate the efficacy and safety of surgical AF ablation. Methods: We searched Cochrane CENTRAL, MEDLINE and EMBASE from inception to May 2016 for RCTs evaluating surgical AF ablation using any lesion set versus no surgical AF ablation in adults with AF undergoing cardiac surgery. We performed screening, full-text eligibility assessment, risk of bias evaluation and data collection independently and in duplicate. We evaluated the risk of bias for individual studies with the modified Cochrane tool, overall quality of evidence with the GRADE framework and pooled data using a random effects model in Revman 5.3. Results: We identified 22 studies (...
The Value of Lung Perfused Blood Volume Computed Tomography in Selecting the Target Lesions for the Effective Treatment of Chronic Thromboembolic Pulmonary Hypertension
Authors: HirotoShimokawahara, ShunIjuuin, KoichiroSonoda, EikouSai, ErikaYamashita, KazuyukiTanoue, KiyohisaHiramine, KensakuHigashi, HidekiTanaka, NorihitoNuruki, MasahiroSonoda
Journal: Circulation (2014)
Hyperbilirubinemia, Augmentation of Endothelial Function, and Decrease in Oxidative Stress in Gilbert Syndrome
Authors: TatsuyaMaruhashi, JunkoSoga, NoritakaFujimura, NaomiIdei, ShinsukeMikami, YumikoIwamoto, MasatoKajikawa, TakeshiMatsumoto, YasukiKihara, KazuakiChayama, KensukeNoma, AyumuNakashima, HirofumiTomiyama, BonpeiTakase, AkiraYamashina, YukihitoHigashi
Journal: Circulation (2012)

Background—Patients with Gilbert syndrome have mild unconjugated hyperbilirubinemia. It has been shown that bilirubin is an endogenous antioxidant. We evaluated the role of oxidative stress in endothelial function in patients with Gilbert syndrome under normal conditions without cardiovascular risk factors. Methods and Results—A total of 108 young men with Gilbert syndrome without cardiovascular risk factors and 108 age-matched healthy men (normal controls) were enrolled in this study. Serum concentrations of bilirubin were higher in patients with Gilbert syndrome than in control subjects (29.2±11.6 versus 9.4±2.7 μmol/L; P<0.001). Serum concentrations of malondialdehyde-modified low-density lipoprotein and urinary excretion of 8-hydroxy-2′-deoxyguanosine (8-OHdG), as indices of oxidative stress, were lower in patients with Gilbert syndrome than in control subjects (61.8±24.5 versus 72.5±21.8 U/L, P=0.034; 7.8±2.4 versus 10.4±3.2 ng/mg creatinine, P=0.001, respectively). Flow-mediated vasodilation was gre...
Abstract MP65: Masked Hypertension is Associated with Cardiovascular Disease Events in African Americans: The Jackson Heart Study
Authors: John N Booth, Keith M Diaz, Samantha Seals, Mario Sims, Joseph Ravenell, Paul Muntner, Daichi Shimbo
Journal: Circulation (2016)

Introduction: Masked hypertension has been associated with increased cardiovascular disease (CVD) risk in Europeans and Asians. Hypothesis: Determine the association of masked hypertension with CVD events and all-cause mortality in African Americans (AA). Methods: The Jackson Heart Study, an exclusively AA population-based, prospective cohort study, was restricted to participants with clinic systolic/diastolic blood pressure (SBP/DBP) &lt; 140/90 mmHg and valid ambulatory blood pressure monitoring (ABPM) at the baseline exam in 2000-2004 (n=738). Masked daytime hypertension was defined as mean ambulatory daytime (10am-8pm) SBP ≥ 135 mmHg or DBP ≥ 85 mmHg. Masked nocturnal hypertension was defined as mean ambulatory nighttime (12am-6am) SBP ≥ 120 mmHg or DBP ≥ 70 mmHg. Using all ABPM measurements, masked 24-hour hypertension was defined as mean SBP ≥ 130 mmHg or DBP ≥ 80 mmHg. CVD events (nonfatal/fatal stroke, nonfatal myocardial infarction or fatal coronary heart disease) and all-cause mortality were identified and adjudicated through December 31, 2011. Results: Any masked hypertension (masked daytime, nocturnal or 24-hour hypertension) was present in 52.2% of participants; 28.2% had masked daytime hypertension, 48.2% had masked nocturnal hypertension and 31.7% had masked 24-hour hypertension. There were 51 CVD events and 44 deaths over a median follow up of 8.2 and 8.5 years, respectively. The CVD rate (95% CI) per 1,000 person years in participants with and without any masked hypertension were 13.5 (9.9-18.4) and 3.9 (2.2-7.1), respectively (Table). The multivariable adjusted hazard ratio (95% CI) between any masked hypertension and CVD was 2.49 (1.26-4.93). CVD rates for those with and without masked daytime, nocturnal and 24-hour hypertension, and the hazard ratios for CVD associated with masked daytime, nocturnal and 24-hour hypertension, were similar. Masked hypertension was not associated with all-cause mortality. Conclusion: Masked hypertension is common and associated with increased CVD risk in AAs.
Abstract 759: Preclinical evaluation of a GFRA1 targeted antibody-drug conjugate in breast cancer
Authors: Emily E. Bosco, Ronald J. Christie, Rosa Carrasco, Darrin Sabol, Jiping Zha, Karma DaCosta, Lee Brown, Sandrina Phipps, Qun Du, Binyam Bezabeh, Shannon Breen, Cui Chen, Molly Reed, MaryJane Hinrichs, Haihong Zhong, Zhan Xiao, Rakesh Dixit, Ronald Herbst, David A. Tice
Journal: Cancer Research (2018)

Abstract Despite recent advances in treatment, breast cancer remains the second-most common cause of cancer death among American women. A greater understanding of the molecular characteristics of individual tumors could ultimately lead to improved treatment options, particularly for subsets of breast cancer patients with unmet needs. Using an unbiased genomics approach to identify membrane-localized tumor associated antigens (TAAs), we have identified a novel breast cancer TAA that can potentially be exploited through antibody-drug conjugate (ADC) therapy. Here, we describe the development of a GFRA1-targeted ADC that demonstrates activity in GFRA1-positive cell lines and PDX tumor models. Work in non-Good Laboratory Practice (GLP) rat toxicology models revealed acceptable toxicity profiles and supports further evaluation of GFRA1-PBD in GFRA1-positive tumors. Citation Format: Emily E. Bosco, Ronald J. Christie, Rosa Carrasco, Darrin Sabol, Jiping Zha, Karma DaCosta, Lee Brown, Sandrina Phipps, Qun Du, Binyam Bezabeh, Shannon Breen, Cui Chen, Molly Reed, MaryJane Hinrichs, Haihong Zhong, Zhan Xiao, Rakesh Dixit, Ronald Herbst, David A. Tice. Preclinical evaluation of a GFRA1 targeted antibody-drug conjugate in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 759.
Abstract 295: Cardiac-Specific Gene Leucine-Rich Repeat Containing 10 (Lrrc10) is required for proper Cardiac Contractility and Responses to Biomechanical Stress
Authors: YoungsookLee, MatthewBrody, LiFeng, CourtneyReynolds, RaviBalijepalli
Journal: Circulation Research (2014)

The molecular genetic basis for early onset dilated cardiomyopathy (DCM) is largely unknown. We have identified that Lrrc10 is a cardiac-specific gene regulated by Nkx2.5 and GATA4. Lrrc10-null (Lrrc10-/-) mice exhibit prenatal systolic dysfunction followed by early onset DCM after birth. However, mechanistic roles for LRRC10 in the regulation of cardiac pathophysiology are unknown. We hypothesize that LRRC10 expression is critical for myocyte contractility and proper responses to pressure overload. Various mouse models with pathological cardiac hypertrophy showed decreased levels of Lrrc10. To test roles of LRRC10 in response to biomechanical stress, transverse aortic constriction (TAC) was performed. Lrrc10-/- mice showed significant increases in left ventricular inner diameter dimensions and drastically reduced % fractional shortening in response to 4 weeks of TAC (13%) after 4 weeks, while no significant changes occurred in WT after TAC (26% F.S.). These data indicate that pressure overload greatly ex...
Abstract 1014: Pharmacological modulation of PDAC stroma to enhance checkpoint blockade immunotherapy
Authors: Jun Zhao, Zhilan Xiao, Willem Overwijk, Chun Li
Journal: Cancer Research (2018)

Abstract Sonic hedgehog signaling pathway is an important regulator during the initiation and progression of pancreatic cancer, and sustained activation of this pathway contributes to excessive deposition of tumor stroma and maintenance of tumor-initiating cells. Cyclopamine (CPA) is a potent inhibitor of the SHH pathway. In this work, we encapsulated both paclitaxel (PTX) and CPA in a long-circulating polymeric micelles to obtain M-CPA/PTX. In a genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC) (KPC model), systemic administration of M-CPA/PTX significantly prolonged the median survival of mice with well-established tumors from 23 days with nab-paclitaxel or gemcitabine to 58 days post-enrollment (p&amp;lt;0.0001). Further studies indicated that M-CPA/PTX modulated PDAC stroma by softening extracellular matrix, increasing blood perfusion, and alleviating hypoxia without depletion of α-smooth muscle actin-positive tumor-associated fibroblasts. Significantly, combination of M-CPA/PTX and anti-PD-1 immunotherapy significantly prolonged the survival of PDAC-bearing KPC mice compare with monotherapies (p&amp;lt;0.01). In an immune-competent, orthotopic PDAC model bearing established murine PDAC, treatments with combined M-CPA/PTX and anti-PD-1 enhanced tumor infiltration of CD8+ T cells and IFNγ expression. Neutralization of either CD8 T cells or INFγ nullified the therapeutic gain achieved with combination therapy. Thus, M-CPA/PTX enhanced checkpoint blockade immunotherapy through modulation of PDAC stroma and enhanced tumor infiltration of effector immune cells. Citation Format: Jun Zhao, Zhilan Xiao, Willem Overwijk, Chun Li. Pharmacological modulation of PDAC stroma to enhance checkpoint blockade immunotherapy [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 1014.
Novel Modulator for Endothelial Adhesion Molecules
Authors: NoriyukiOuchi, ShinjiKihara, YukioArita, KazuhisaMaeda, HiroshiKuriyama, YoshihisaOkamoto, KikukoHotta, MakotoNishida, MasahikoTakahashi, TadashiNakamura, ShizuyaYamashita, TohruFunahashi, YujiMatsuzawa
Journal: Circulation (1999)

Background—Among the many adipocyte-derived endocrine factors, we recently found an adipocyte-specific secretory protein, adiponectin, which was decreased in obesity. Although obesity is associated with increased cardiovascular mortality and morbidity, the molecular basis for the link between obesity and vascular disease has not been fully clarified. The present study investigated whether adiponectin could modulate endothelial function and relate to coronary disease. Methods and Results—For the in vitro study, human aortic endothelial cells (HAECs) were preincubated for 18 hours with the indicated amount of adiponectin, then exposed to tumor necrosis factor-α (TNF-α) (10 U/mL) or vehicle for the times indicated. The adhesion of human monocytic cell line THP-1 cells to HAECs was determined by adhesion assay. The surface expression of vascular cell adhesion molecule-1 (VCAM-1), endothelial-leukocyte adhesion molecule-1 (E-selectin), and intracellular adhesion molecule-1 (ICAM-1) was measured by cell ELISA. ...
Glycemic Variation and Cardiovascular Risk in the Veterans Affairs Diabetes Trial
Authors: Jin J. Zhou, Dawn C. Schwenke, Gideon Bahn, Peter Reaven
Journal: Diabetes Care (2018)

OBJECTIVE There is uncertainty about the importance of glycemic variability in cardiovascular complications in patients with type 2 diabetes. Using the Veterans Affairs Diabetes Trial (VADT), we investigated the association between variation in fasting glucose and glycated hemoglobin (HbA1c) over time and the incidence of cardiovascular disease (CVD) and assessed whether this is influenced by intensive or standard glycemic control. RESEARCH DESIGN AND METHODS During the VADT, fasting glucose and HbA1c were measured every 3 months for up to 84 months in 1,791 individuals. Variability measures included coefficient of variation (CV) and average real variability (ARV) for fasting glucose and HbA1c. Overall mean glucose and HbA1c measures as well as their maximum and the most recent measurement were also examined. RESULTS Variability measures (CV and ARV) of fasting glucose were significantly associated with CVD even after adjusting for other risk factors, including mean fasting glucose. When considering separately groups receiving intensive and standard glycemic control, this relationship was evident in the intensive treatment group but not in the standard group. Additional adjustment for severe hypoglycemic episodes did not alter the relationship between fasting glucose variability and CVD. Interestingly, no HbA1c measures were associated with CVD after adjusting for multiple baseline risk factors. CONCLUSIONS Our analysis indicates that in the VADT, variability of fasting glucose plays a role in the development of CVD complications beyond the influence of standard fasting glucose measures. The adverse consequences of fasting glucose variability on CVD appear greatest in those receiving intensive glucose control.
Abstract 2249: PWS: An integrated web service platform enabling precision medicine
Authors: Zhenyu Duan
Journal: Cancer Research (2018)

Abstract Aiming at providing an integrated platform to accelerate global drug development with personalized medicine, Predicine Web Service (PWS) is built to enable real time project status report, interpretation of clinical impact for genomic aberrations, and novel biomarker discovery with data mining algorithms and analytics. A large-scale Predicine database is built with KnowledgeBase layer and dynamically growing genomics data layer. The KnowledBase layer integrates genome annotations, ontologies, computed variant impacts, and curated clinical implications. The dynamic genomic data layer is designed to be scalable so that both Predicine patient genomic profiles and public domain genomics data can be imported with standardized data models. A wide range of curated databases and public domain genomics profiles are integrated, including COSMIC, ClinVar, dbSNP, 1000 Genomes, ExAC, CIViC, GeneDrug KnowledgeBase, MSK IMPACT, and TCGA. Data mining algorithm and analytics are developed to enable data driven interpretation and biomarker discovery. An intuitive web interface is developed for users to select patient space with clinical and genomics criteria, to generate patient reports with ability to drill down to multi-level variant data, and to discover biomarkers leading to hypothesis of novel targets, drug response association, and combination therapy. The project management module securely communicates the status of projects and samples for pharmaceutical companies and other clients. On PWS, private domain patient data can be combined with comprehensive public domain data for comparative and comprehensive global analysis to enable precision medicine. Citation Format: Zhenyu Duan. PWS: An integrated web service platform enabling precision medicine [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 2249.
Predictive Power of Increased QT Dispersion in Ventricular Extrasystoles and in Sinus Beats for Risk Stratification After Myocardial Infarction
Authors: AndrzejDąbrowski, ElżbietaKramarz, RyszardPiotrowicz, LeszekKubik
Journal: Circulation (2000)

Background—QT dispersion, commonly measured in sinus beats (QTd-S), can also be calculated in premature ventricular beats (QTd-V). To date, no studies have addressed the relation between these 2 variables. Methods and Results—In 148 patients with remote myocardial infarction and premature ventricular beats on a routine ECG, QT dispersion, defined as the difference between the maximum and the minimum QT interval across the 12-lead ECG, was calculated separately for the ventricular extrasystole and the preceding sinus beat. In the total group of patients, QTd-V was greater than QTd-S (83±33 versus 74±34 ms, respectively; P=0.001). During a follow-up period of 35±17 months, arrhythmic events (sustained ventricular tachycardia, ventricular fibrillation, or sudden death) were noted in 30 patients. A QTd-V of ≥100 ms was a stronger univariate marker of arrhythmic events than was a QTd-S of ≥100 ms, and multivariate analysis selected only prolonged QTd-V (hazard ratio 3.81, 95% CI 2.2 to 11.2) and low ejection f...
Abstract 3214: FePt nanoparticles overcoming radiotherapy resistance in hCtr-1 high expression cells via mitochondria targeting
Authors: Tsung-Lin Tsai, Macus Tien Kuo, Jen-Ya Wang, Wan-Li Shin, Helen H. W. Chen, Wu-Chou Su
Journal: Cancer Research (2018)

Abstract The glutathione (GSH) overexpression small-cell-lung-cancer cell lines, SR3A-13 and SR3A-14, transfected with recombinant DNA encoding γ-glutamylcysteine synthetase (γ-GCSh), are radiation resistant. However, they are more sensitive to cisplatin treatment, compared with parental cell (SR3A)1. In addition to be a copper transporter, the hCtr-1 is also a transporter for platinum (Pt)-based agents. Therefore, the cellular uptake of cisplatin is enhanced by the upregulation of human copper transporter 1 (hCtr-1) at the cell membrane. We have synthesized an alloy FePt nanoparticles (FePt NPs) that generated excellent contrast effects in both CT and MRI images2. Interestingly, the uptake of FePt NPs by SR3A-13 and -14 cells was 3-3.5 fold higher than that of SR3A cells, measured with inductively coupled plasma optical emission spectrometry (ICP-OES) and transmission electron microscopy (TEM). Because intracellular NPs have been shown to generate reactive oxygen species (ROS) and overproduction of ROS may enhance the efficacy of radiotherapy, we sought to explore whether treatment with the alloy FePt NPs can reverse the radiation resistance in SR3A-13 and -14 cells. We found co-treatment with the alloy FePt NPs and radiation effectively reduce the survivals of these 2 cells. Furthermore, we found an alternation in mitochondrial appearance accompanied with low signal of Tetramethylrhodamine, methyl ester (TMRM), indicating a malfunction is induced in mitochondria. We conclude that FePt NPs are able to overcome radiation resistance in hCtr-1 high expression cells via mitochondria targeting. Citation Format: Tsung-Lin Tsai, Macus Tien Kuo, Jen-Ya Wang, Wan-Li Shin, Helen H. W. Chen, Wu-Chou Su. FePt nanoparticles overcoming radiotherapy resistance in hCtr-1 high expression cells via mitochondria targeting [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 3214.