tbuckley/cabot-search huggingface dataset:
Abstract 753: Exercise Capacity, Cardiac fibrosis and Left Ventricular Remodeling in a Rat Model of Chronic Pressure Overload: Serial Echocardiography, Pressure-Volume Analysis and Gene Expression Profiling
Authors: Kyung-hee Kim, Yoonjee Park, Jae Kyeong Byun, Seung-Woon Rha
Journal: Circulation Research (2019)

Background: Pressure overload (PO) left ventricular (LV) hypertrophy is a known precursor of heart failure with preserved ejection fraction (EF). The aims of this study were to establish a reliable model of chronic PO in rats and verify the pathophysiological features of this model by evaluating cardiac function using serial echocardiography and a pressure-volume analysis. Methods: Constriction of the abdominal aorta was used to induce PO LV hypertrophy (n = 40) in rats. Twenty sham rats were compared with PO rats. Serial echo studies and exercise were performed at 2-week intervals, and invasive hemodynamic examination by a pressure-volume catheter system was performed 12 weeks after the procedure. The gene expression profiles of the left ventricle (LV) 12 weeks after the procedure were analyzed by DNA chip technology. Results: Serial echo revealed that the LV wall thickness began to increase after the PO and showed progressive increasing until the 8th week (LV septal wall thickness at 8 weeks 1.4mm±0.1mm for PO vs 0.6mm ±0.05mm for Sham, p &lt;0.01). LV dimension was comparable increased until 14 th week (LV end-systolic dimension at 14 weeks, 4.91±0.50 mm 4.71±0.25 mm for PO vs Sham; LV end-diastolic dimension, 9.02±0.42 mm vs. 8.71±0.47 mm for PO vs Sham, p&gt;0.05). The LV ejection fraction showed similar between groups until the 14th week (70.0±2.2% vs. 69.1±3.1% for PO vs. Sham). In hemodynamic analyses, the LV end-diastolic pressure and the end-diastolic pressure-volume relationship slope were greater in the PO group than sham group. When we compared LV remodeling and exercise capacity, cardiac fibrosis and exercise intolerance developed in the PO group but not in the sham group (exercise duration, 234.0 ± 80.3 vs. 597.8 ± 49.0 seconds, p &lt; 0.05, respectively). Transcriptional profiling of cardiac apical tissues revealed that gene expression related to the cardiac fibrosis, cytoskeletal pathway and G-protein signaling genes were enriched in the PO group. Conclusions: We established a small animal model of chronic PO and verified its pathophysiological features. Cardiac fibrosis and cytoskeletal pathway were important pathways in the PO group and influenced exercise capacity. This model may provide a useful tool for future research on PO heart failure.
HuC242-DM4, an antibody-maytansinoid conjugate with superior preclinical activity in human CanAg-positive tumor xenograft models in SCID mice
Authors: Robert J. Lutz, Hongsheng Xie, Wayne C. Widdison, Peter S. Wunderli, Rita M. Steeves, Victor S. Goldmacher, John M. Lambert, Ravi V. J. Chari
Journal: Cancer Research (2005)

1429  Several anti-tumor antibody-maytansinoid conjugates, commonly called TAPs (tumor-activated prodrugs) are currently under clinical evaluation. In particular, cantuzumab mertansine (huC242-DM1), has been evaluated in three Phase I clinical trials (A.W. Tolcher et al., J Clin Oncol 2003, 21:211-22; P.R. Helft et al., Clin Cancer Res 2004, 10:4363-4368) using different dosing schedules to treat patients with tumors expressing the CanAg target antigen. The immunoconjugate could be safely administered at pharmacologically meaningful doses and evidence of anti-tumor activity was seen in several patients, which led to a recommendation for broad clinical development of the agent (A.W. Tolcher et al., J Clin Oncol 2003, 21:211-22). During the clinical evaluation, further advancement in the TAP technology led to the development of TAPs with disulfide-containing linkers with increased stability under physiological conditions. One of these new TAPs that demonstrated improved pharmacokinetic behavior and superior anti-tumor activity in murine test models is huC242-DM4, which contains the same antibody as cantuzumab mertansine and targets therefore the same CanAg-expressing tumors. HuC242-DM4 caused complete regressions in several tumor xenograft models even with single i.v. administration at doses far below its maximal tolerated dose (MTD). For example, treatment of SCID mice bearing measurable N87 human gastric tumor xenografts with a single dose of 3.4 mg/kg caused complete regression of the tumors, with significant tumor regression observed at a dose below 2 mg/kg. With a MTD in SCID mice of greater than 40 mg/kg when given as a single i.v. bolus injection, a therapeutic index of over 20 was achieved. HuC42-DM 4 was also curative in mice bearing human colon tumor xenografts of HT29 and COLO 205 cells, at doses that were non-toxic. The disulfide linkage of huC242-DM4 was approximately 2-fold more stable during circulation in mice than that of cantuzumab mertansine. While the huC242-DM4 conjugate demonstrated increased stability and efficacy in vivo compared to cantuzumab mertansine, preliminary acute toxicity studies suggest that the two conjugates have similar tolerability in normal mice. The resulting increased therapeutic window for huC242-DM4 provides a preclinical rationale for its clinical evaluation in patients with CanAg-positive tumors, such as colorectal, pancreatic, gastric, and esophageal carcinomas.
Abstract 861: Inner Mitochondrial Collapsing in Response to Acute Overstretch of Rat Ventricular Papillary Muscles
Authors: Naritomo Nishioka, Yoichiro Kusakari, Jun Tanihata, Susumu Minamisawa
Journal: Circulation Research (2019)

Introduction: The effect of acute ventricular volume overload on organelles such as myofibrils and mitochondria are incompletely understood. Purpose: We performed acute overstretch on cardiac papillary muscle to investigate the functional and morphological changes. Methods: We used male SD-rats (10-12 weeks old) and dissected papillary muscles from the right ventricle. A papillary muscle preparation was stretched to Lmax. We overstretched it within 2 seconds up to 110% of Lmax (110%Overstretch; 110%OS) or 120% of Lmax (120%OS), and stimulated it (1Hz, 36°C) with tension measurement, compared with Lmax group. After the measurement of tension, we analyzed the morphological changes in muscle fibers and organelles using a Transmission electron microscopy (TEM). Results: The active tension after overstretch was immediately decreased to 67.8±3.8% in 110%OS, and to 17.3±4.0% in 120%OS. In TEM study, muscle fibers kept their well-organized structures and the sarcomere length was stretched to 2.4 μm in 110%OS, and to 2.6 μm in 120%OS. In contrast, in 110%OS, inner mitochondrial density was lower than that in Lmax, indicating swelled mitochondria. In 120%OS, inner mitochondrial empty space with vacuolation was found in the large area of myocardium, indicating that inner mitochondria cristae were susceptible to mechanical stress-induced deterioration. Conclusions: Acute overstretch of rat papillary muscles causes inner mitochondrial collapsing with preserved the sarcomere structure. It could account for the mechanisms of acute volume-overloaded heart failure.
Significant Prognostic Impact of [18F]Fluorodeoxyglucose-PET Scan Performed During and At the End of Treatment with R-CHOP in High-Tumor Mass Follicular Lymphoma Patients: A GELA-GOELAMS Study
Authors: Jehan Dupuis, Michel Meignan, Anne Julian, Christelle Tychyj-Pinel, Alina Berriolo-Riedinger, Pauline Brice, Herve Tilly, Nicolas Mounier, Andrea Gallamini, Nathalie Berenger, Guy Laurent, Corinne Haioun, Gilles Andre Salles
Journal: Blood (2011)
Abstract 804: Elimination of Cells Expressing Senescence Associated Glycoprotein Attenuates Theatherosclerotic Diseases
Authors: Masayoshi Suda, Ippei Shimizu, Yohko Yoshida, Goro Katsuumi, Yuka Hayashi, Ryutaro Ikegami, Ayako Nagasawa, Masaaki Nakao, Ryo Fruuchi, Takuya Ozawa, Tohru Minamino
Journal: Circulation Research (2019)

Although accumulation of senescent vascular endothelial cells impairs the vessel homeostasis and promote atherosclerotic diseases, underlying mechanisms are largely unknown. We found that Senescence associated glycoprotein (SAGP) expression was significantly increased in human endothelial cells undergoing replicative senescence. SAGP expression in aorta was significantly increased in Apo-E knockout mice. Furthermore, mean SAGP expression was significantly higher in the leukocytes of the patients with atherosclerotic diseases.These data suggest that SAGP would become the novel cellular senescence and/or atherosclerotic disease marker. The genetic deletion of SAGP resulted in high level of mitochondrial reactive oxygen species (ROS) and promoted premature senescence in human endothelial cells. And this associated with suppression of mitochondrial autophagy, mitophagy, suggesting that SAGP protect cells from ROS by inducing mitophagy. Thus, wegenerated ApoE-KO / SAGP gain-of-function transgenic mice and found that atherosclerotic plaque burden was attenuated in these transgenic mice. In contrast, in SAGP / ApoE double knockout mice atherosclerosis were impaired. These data suggest that modulation of SAGPwould become a new therapeutic target for atherosclerotic diseases.Recently, it is reported that elimination of senescent cells (senolysis) reversibly improved pathological aging phenotypes. We generated SAGP-DTR (diphtheria toxin receptor) transgenic mice,inducible elimination of SAGP positive senescent cells upon administration of diphtheria toxin. Elimination of SAGP expressing cells significantly reduced the atherosclerotic plaque burden. Furthermore, we developed a cytotoxic vaccine targeting SAGP. Administration of SAGP vaccine to ApoE-KO mice significantly reduced atherogenesis. These data indicate that targeting SAGP-positive cells could be a strategy for senolytic therapy.
Abstract 628: Diabetes-Mediated Vascular Calcification is RAGE-Dependent
Authors: Amber M Kay, James A Stewart
Journal: Circulation Research (2019)

Type II diabetes mellitus (DM) is characterized by chronic hyperglycemia, and medial vascular calcification is a common cardiovascular complication of DM. This leads to aortic stiffening, which can leave patients at an increased risk for heart attack or stroke. Advanced Glycation End-Products (AGEs)/Receptor for AGEs (RAGE) signaling cascade has been implicated as a potentiator of diabetes-mediated vascular calcification, but it is not well understood. AGE/RAGE signaling influences both cellular and systemic responses to increase bone matrix proteins in hyperglycemic and calcification conditions and has also been shown to increase oxidative stress by promoting diabetes-mediated vascular calcification. This causes a phenotypic switch of vascular smooth muscle cells (VSMCs) to osteoblast-like cells and the hypothesized activation of adventitial fibroblasts (AFBs) to a myofibroblast phenotype. The purpose of this research is to understand AGE/RAGE mediated vascular calcification as a complication of diabetes. Calcification was induced for 7 days in primary mouse VSMCs and AFBs of non-diabetic, diabetic, non-diabetic RAGE knockout (RKO), and diabetic RKO, and then treated with AGEs to activate RAGE. Alizarin Red S staining was utilized to visualize calcification. Intracellular calcium levels were quantified and normalized to cell number (DAPI). Pronounced calcification was observed in non-diabetic VSMCs and the loss of RAGE resulted in decreased calcification in the non-diabetic RKO VSMCs. AFBs were exposed to the same experimental conditions as the VSMCs and calcification was increased in the diabetic AFBs while calcification was significantly decreased in the diabetic RKO AFBs. These data demonstrated that diabetes-mediated vascular calcification was RAGE-dependent in both cell types. Literature has cited the VSMC as the primary mediator for vascular calcification, but we have shown that the AFBs in the outer layer of the aorta have the ability to calcify and this is mediated by RAGE signaling, which elucidates a role for RAGE in diabetes-mediated vascular calcification. Understanding the role of AGE/RAGE signaling in diabetes-mediated vascular calcification will allow for possible targets for pharmacological intervention.
Implementation of standardized workflows to reduce inpatient length of stay for medical oncology patients.
Authors: Joseph Hooley, Heather Koniarczyk, Cheryl M. Carrino, Kimberly Primm, Curt Westrick, Michelle Brusio, Chad W. Cummings
Journal: Journal of Clinical Oncology (2019)

80 Background: Reducing length of stay (LOS) is an important initiative for hospitals for both clinical and financial reasons. Patients who are hospitalized for extended lengths of time may be more susceptible to hospital-acquired infections and other complications. Reducing LOS can also decrease cost of care and allow for more streamlined patient throughput. Our institution sought to evaluate opportunities to reduce LOS for our medical oncology patient population. Methods: Several interventions were implemented to streamline discharge planning. The structure of rounding was evaluated and standardized on each inpatient oncology unit to ensure that it was multidisciplinary and occurred each day at an established time. A process was established for Advanced Practice Providers (APPs) to write prescriptions the day before discharge (delivered directly to the bedside), and for APPs to begin discharge of patients early the following morning with use of a new discharge checklist. Standardized workflow was also created for instances where prior authorizations were required for prescriptions. We partnered with our Home Care providers to streamline the process for patients anticipated to be discharged to that service. Partnership was also established with physical therapy (PT) to avoid ordering low-value consults and to provide enhanced education to nursing staff about early patient mobility. Another project is being piloted to move lab draws six hours earlier the night prior to discharge. This provides the medical team additional time to assess and treat based on lab results if the patient required blood product transfusions or electrolyte replacement prior to discharge. Results: Implementation of interventions began throughout the first several months of 2019. Each of the first four months of 2019 saw consecutive improvements in both observed average LOS and LOS observed-to-expected ratios. Overall, a 2% decrease was seen in both of these metrics when comparing January to April 2019 to the 2018 baseline. Conclusions: Implementing several interventions to streamline workflows and processes leading up to a patient’s discharge can be effective in reducing both overall LOS and LOS observed-to-expected ratios.
Abstract 890: Vascular MicroRNA-204 Promotes Diabetes-Associated Endothelial Dysfunction
Authors: Ravinder R Gaddam, Young-Rae Kim, Mohanad Gabani, Jannik Proff, Julia S Jacobs, Kaikobad Irani, Ajit Vikram
Journal: Circulation Research (2019)

Background: The failure to achieve a decline in blood pressure at rest in type 2 diabetes (T2D) patients is believed to reflect endothelial dysfunction, and it increases the risk of coronary artery disease. Previously we discovered that the intestinal microbes govern vascular endothelial function through microRNA-204 (miR-204). The objective of this study was to investigate whether miR-204 contributes to diabetes-associated vascular endothelial dysfunction. Methods: To test miR-204's role in diabetes we generated leptin receptor mutant genetically diabetic mice lacking miR-204 (db/db-miR-204 -/- ). The vascular function was assessed by determining the vessel relaxation of phenylephrine-induced precontracted aortic rings. To ascertain the vascular miR-204 role in endothelial function ex-vivo experiments were performed, on aorta isolated from db/db mice, using miR-204 inhibitor. The miR-204 expression and localization were done using quantitative real-time PCR (qRT-PCR) and In-situ hybridization (ISH) assays. Results: A significant increase in the vascular miR-204 expression was observed in the thoracic aorta of db/db mice compared to the age-matched control (208.80 ± 45.60 vs. 80.65 ± 13.11; p&lt;0.05). The genetic deletion of miR-204 rescues endothelial function (improved vascular relaxation; 36.17 ± 7.42 vs. 76.56 ± 4.43; p&lt;0.001). The db/db-miR-204 -/- mice develop obesity but are protected against diabetes (as evidenced by better glycemic control). Ex-vivo inhibition of miR-204 rescues diabetes-associated impairment of endothelium-dependent vasorelaxation (18.10 ± 2.16 vs. 50.64 ± 7.66; p&lt;0.01). Next, we plan to identify the molecular mediator of miR-204 effects on the vascular endothelial function using Argonaute 2-crosslinked immunoprecipitation (Ago2-CLIP) assay. Conclusions: Type 2 diabetes upregulates vascular miR-204, and genetic deletion of miR-204 rescues diabetes-associated impairment in endothelial function.
Determining the influence of patient-perceived curability on advance care planning in patients with cancer.
Authors: Cameron Pywell, Aidan Gilbert, Rachel Charles, Star Ye, Gabrielle Betty Rocque
Journal: Journal of Clinical Oncology (2019)

198 Background: Advance Care Planning (ACP) allows patients to express their wishes regarding medical interventions when they are no longer able to make decisions. We hypothesized that among cancer patients treated at the University of Alabama at Birmingham (UAB), those who perceived their disease to be incurable were more likely to have an ACP. Methods: This cross-sectional study utilized data from patient reported outcome (PRO) surveys administered at the UAB outpatient oncology clinic. PRO responses included Eastern Cooperative Oncology Group (ECOG) performance status, perceived curability, and ACP status. Clinical and demographic information abstracted from the electronic health record included sex, stage, disease progression, phase of care (treatment: diagnosis to 1 year; survivorship: 1 year to 6 months before death; end of life: 6 months prior to death), diagnosis date, race, and marital status. The association between perceived curability and ACP was evaluated using likelihood ratios (LR) and 95% confidence intervals (CI) from generalized linear models with a log link and Poisson distribution with robust variance estimates adjusting for sex, race, stage, phase of care, ECOG, and marital status. Results: We analyzed PRO responses from 818 patients with a variety of different cancers. The majority of patients were female (68%), white (74%), were married (61%), had an early stage (0/I/II/III) cancer with no progression (56%), and had an ECOG of 0 or 1 (74%). Gynecologic (30%) and hematologic (28%) were the most common malignancies. The majority of patients were in the treatment (46%) or survivorship (48%) phase of care. Most patients did not have an ACP (59%). The majority of patients believed that their cancer was curable (61%). In adjusted models, there was no difference in ACP status between those believing their cancer was curable versus incurable (LR: 0.97, CI: 0.77-1.23). Conclusions: The absence of difference in ACP with respect to perceived curability suggests that patients’ completion of ACP depends on other factors, which may be more patient-specific rather than disease-specific. Our data reinforce the importance of addressing ACP for all patients.
Abstract 14676: Adverse Pregnancy Outcomes Are Associated With Reduced Coronary Flow Reserve in Women With Signs and Symptoms of Ischemia Without Obstructive Coronary Disease
Authors: Ki Park, Odayme Quesada, Galen Cook-Wiens, Janet Wei, Margo Minissian, Eileen M Handberg, C. Noel Bairey Merz, Carl J Pepine
Journal: Circulation (2017)

Introduction: Adverse pregnancy outcomes (APOs) are associated with increased risk for future adverse cardiovascular events. Abnormalities in vascular function may play a role. Whether a history of...
Abstract 147: Screening for Developmental and Injury-Induced Genes That Facilitate Heart Regeneration
Authors: Akansha M Shah, Miao Cui, Zhaoning Wang, Wei Tan, Ning Liu, Rhonda Bassel-Duby, Eric N Olson
Journal: Circulation Research (2019)

The adult mammalian heart has a limited capacity to regenerate upon injury, such as myocardial infarction (MI). MI in adult mouse hearts results in a reduced cardiac function, due to extensive loss of cardiomyocytes and formation of scar tissue by activated fibroblasts. In contrast, the newborn postnatal day 1 (P1) mouse heart is able to regenerate and restore its cardiac function following injury. However, this regenerative ability dramatically declines after P7. The molecular properties and mechanisms that facilitate neonatal heart regeneration remain unknown. To gain further insight into the realm of cardiac regeneration, our lab performed transcriptome analysis by bulk and single cell RNA-seq on P1 and P8 hearts at various time points following MI surgery. We also performed enhancer profiling by H3K27ac ChIP-seq. Coupling of both these approaches has uncovered two different gene sets that that may promote the regenerative ability of neonatal hearts: developmental genes and injury-induced genes. Amongst the neonatal-specific developmental genes, Igf2bp3, a RNA-binding protein, and Hic2, a transcriptional regulator, have been shown to promote neonatal rat ventricular cardiomyocyte (NRVM) proliferation and are currently being characterized for their involvement in neonatal heart regeneration by using gain-of-function and loss-of-function in vivo approaches. Amongst the injury-induced genes, we identified mitogens secreted from macrophages that promote NRVM proliferation. This is in line with the differential immune response elicited by P1 hearts upon MI-injury. We have also shown that an epicardial secreted factor in P1 hearts can enhance human umbilical vein endothelial cell tube formation, indicative of its role in angiogenesis. In summary, by using a multi-layered genomic analysis, we identified various genes that are involved in different cellular responses during neonatal heart regeneration. This comprehensive analysis of the neonatal regenerative response provides insights into the molecular basis of neonatal heart regeneration, and can potentially identify genes that can be modulated to facilitate adult heart regeneration.
Abstract 265: Thyrotoxic Pericarditis in a Mouse Model of Graves' Disease
Authors: Fengyi Zhao, Liping Wu, Bingyin Shi
Journal: Circulation Research (2019)

Objectives: To investigate the cardiac pathological changes of hyperthyroid heart disease in mice. Methods: A transient model for human Graves’ disease was successfully established in mice using three immunizations with recombinant adenovirus expressing the extracellular A subunit of the human thyrotropin receptor (Ad-TSHR). We induced the hyperthyroid heart mouse model by prolonging the regular injections of Graves’ disease mouse model to nine months. Heart tissues were weighed and stained with hematoxylin-eosin (HE) and MASSON Trichrome staining to check and define the pathological changes. Results: We observed that mice in the Graves’ disease hyperthyroid heart group (GH) showed enhanced cardiac hypertrophy and fibrosis. The HW/BW (ratio of heart weight to body weight) of GH group (5.528±0.4014, n=6) was significantly higher than control group (4.343±0.03913, n=6) (P&lt;0.05). In GH group, 2 of 6 hearts showed typical cor villosum (Image 1). The MASSON Trichrome staining exhibited aggravated cardiac fibrosis on the surface of the heart in GH group. Conclusions: Pericarditis as a complication of thyrotoxicosis has been reported several times in clinical work. This is the first reported case of pericarditis in the mouse model of Graves’ disease, suggesting a possible link between pericarditis and thyrotoxicosis.