tbuckley/cabot-search huggingface dataset:
Cardiac Overexpression of the Norepinephrine Transporter Uptake-1 Results in Marked Improvement of Heart Failure
Authors: GötzMünch, KaiRosport, AndreasBültmann, ChristineBaumgartner, ZhongminLi, LienLaacke, MartinUngerer
Journal: Circulation Research (2005)

A hyperadrenergic state is one of the key features of human and experimental heart failure. Decreased densities and activities of the presynaptic neuronal norepinephrine (NE) transporter uptake-1 occur both in patients and animal models. It is currently unclear to what extent the reduction of uptake-1 contributes to the deterioration of heart failure. Therefore, we investigated the effects of myocardial overexpression of uptake-1 in both nonfailing rabbit hearts and in an animal model of heart failure. Heart failure was induced in rabbits by rapid ventricular pacing. Adenoviral gene transfer was used to overexpress uptake-1 in the myocardium. Uptake-1 overexpression led to increased NE uptake capacity into the myocardium. In contrast, systemic plasma NE levels in uptake-1-overexpressing failing rabbits (uptake-1–CHF) did not differ from controls. Downregulation of SERCA-2 and β-adrenergic receptors in the failing myocardium was significantly reversed after uptake-1 overexpression. Uptake-1 overexpression ...
Serial Follow-up After Optimized Ultrasound-Guided Deployment of Palmaz-Schatz Stents
Authors: HaraldMudra, EvelynRegar, VolkerKlauss, FrankWerner, Karl-HeinzHenneke, EfthiaSbarouni, KarlTheisen
Journal: Circulation (1997)

Background The effects of ultrasound-guided high-pressure stenting on late stent and reference segment dimensions are unknown. In this study, we report about angiographic and ultrasound measurements to assess the amount and distribution of neointimal ingrowth within the stent and the changes of plaque burden and dimensions within the reference segments. Methods and Results Sixty-eight consecutive patients with 72 lesions received single or multiple Palmaz-Schatz coronary stents with a standardized protocol for stent optimization under ultrasound guidance. The residual angiographic diameter stenosis was 3±12% (reference diameter, 3.16±0.61 mm). At follow-up 4.8±2.5 months later, angiography revealed a diameter stenosis of 27±21% with a restenosis rate of 15.3% (confidence interval: 7.8% to 25.6%). Lumen renarrowing within the stent was exclusively due to neointimal ingrowth; no stent compression was observed. The neointima covered 20±20% of the stent area and was more pronounced in the midportion of the st...
Myocardial Actions of Angiotensin
Authors: Jankoch-Weser
Journal: Circulation Research (1964)

Synthetic angiotensin a has pronounced inotropic effects on isometrically contracting, isolated papillary muscles of kittens. The response increases with drug concentration over the range from 10-10 M to 10-5 M. The mean maximum increase in tension development is 120%. Contractility is raised by angiotensin through an increase in the degree of activation of the contractile elements with no significant change in the duration of their active state. Low concentrations of angiotensin have a greater inotropic action than equimolar concentrations of l-norepinephrine; but the maximum inotropic effect obtainable with l-norepinephrine is almost twice that of angiotensin. The inotropic effects of angiotensin on cat atrial muscle are slight, and the drug is inactive on frog ventricular myocardium. It has no effect on the resting length-tension relationship of mammalian atrial or ventricular muscle. The frequency of impulse formation in the SA node is not significantly changed by concentrations of angiotensin up to 1...
Abstract 20322: Extended-Duration Betrixaban Reduces the Risk of Venous Thromboembolism-Related Rehospitalization Among Acutely Ill Hospitalized Medical Patients: An APEX Trial Substudy
Authors: Gerald Chi, Tarek Nafee, Samuel Z Goldhaber, Adrian F Hernandez, Russell D Hull, Alex Gold, Serge Korjian, Yazan Daaboul, Alexander T Cohen, Robert A Harrington, C. Michael Gibson
Journal: Circulation (2017)

Background: The impact of extended thromboprophylaxis with betrixaban on the risk of rehospitalization related to venous thromboembolism (VTE) has not been studied. Methods: In the APEX trial, 7,51...
Abstract LB-177: Quantification of cell signaling proteins by immuno-MALDI
Authors: Robert Popp, René P. Zahedi, André LeBlanc, Yassene Mohammed, Adriana Aguilar-Mahecha, Oliver Pötz, Mark Basik, Gerald Batist, Christoph H. Borchers
Journal: Cancer Research (2018)

Abstract Introduction. To improve cancer patient stratification and overcome the drawbacks of currently used approaches to assess signaling pathway proteins, we set out to develop immuno-matrix assisted laser ionization/desorption (iMALDI) assays combined with a phosphatase-based phosphopeptide quantitation (PPQ) approach to measure PI3K/AKT/mTOR pathway activity. Specifically, we targeted the C-terminal tryptic peptides of AKT1 and AKT2 due to their involvement in full kinase activation. Methods. Following trypsin digestion of cell lysate, stable isotope-labeled standard (SIS) peptides are added. After splitting the solution, one aliquot is treated with phosphatase. Bead-coupled antibodies enrich the non-phosphorylated target peptides, which are washed and spotted onto a MALDI plate, and acidic MALDI matrix elutes the peptides. The resulting light/heavy ratios of both aliquots allow the calculation of protein expression levels and peptide phosphorylation stoichiometry. Results. The iMALDI assays were validated for linear range and accuracy, as well as interference screening, requiring only ~50 µg of total cell or tissue lysate protein to quantify both AKT1 and AKT2 expression levels and phosphorylation stoichiometry. CVs of technical replicates were found to consistently be below 10%. We were able to quantify AKT1 and AKT2 from various cell lines and fresh frozen tumor samples, including SW480 and HCT116 colon cancer cell lines, MDA-MB-231 breast cancer cells, and colon cancer and breast cancer tumor lysates. Further, a direct comparison of matched fresh frozen and formalin-fixed paraffin-embedded (FFPE) tissues showed that the expression levels and phosphorylation stoichiometry quantified differ depending on the tissue preservation method, and that phosphorylation stoichiometries above 30% occur in only a small subset of samples. A direct comparison of four pairs of normal and adjacent tumor tissues showed elevated AKT1 phosphorylation stoichiometry of ~40% in a colorectal cancer liver metastasis, and significantly elevated AKT1 (3.6-fold) and AKT2 (2.2-fold) expression levels in a surgical breast tumor sample. Future directions. In a next step, patient-derived mouse xenograft tissue samples, collected after specific drug treatment, will be analyzed, and the AKT results will be correlated to genomic data to answer the hypothesis whether the AKT expression levels and phosphorylation stoichiometries correlate with response to treatment. Citation Format: Robert Popp, René P. Zahedi, André LeBlanc, Yassene Mohammed, Adriana Aguilar-Mahecha, Oliver Pötz, Mark Basik, Gerald Batist, Christoph H. Borchers. Quantification of cell signaling proteins by immuno-MALDI [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 LB-177.
Calcineurin Inhibition Attenuates Mineralocorticoid-Induced Cardiac Hypertrophy
Authors: YoshiyuTakeda, TakashiYoneda, MasashiDemura, MikiyaUsukura, HiroshiMabuchi
Journal: Circulation (2002)

Background— It remains unclear how mineralocorticoids induce cardiac hypertrophy and fibrosis. Recently, activation of the calcium-dependent phosphatase, calcineurin, has been shown to induce cardiac hypertrophy. In the present study, we examine the role of calcineurin in mineralocorticoid-induced cardiac hypertrophy and fibrosis. Methods and Results— Uninephrectomized Wistar-Kyoto rats were placed on a 1.0% NaCl diet and treated with aldosterone (0.75 μg · h−1) for 6 weeks with or without the calcineurin inhibitors, FK506 (0.5 mg · kg−1 · d−1) or cyclosporine A (10 mg · kg−1 · d−1). The effect of the angiotensin II type 1 receptor antagonist, losartan (10 mg · kg−1 · d−1)on aldosterone-induced cardiac hypertrophy was also studied. Treatment with aldosterone increased the heart weight/body weight ratio, cardiomyocyte size, and collagen amount. The expression of mRNA of both type-III collagen and atrial natriuretic peptide in the heart were increased by aldosterone administration. Both calcineurin activity...
ARID5B regulates metabolic programming in human adaptive NK cells
Authors: Frank Cichocki, Cheng-Ying Wu, Bin Zhang, Martin Felices, Bianca Tesi, Katie Tuininga, Phillip Dougherty, Emily Taras, Peter Hinderlie, Bruce R. Blazar, Yenan T. Bryceson, Jeffrey S. Miller
Journal: The Journal of Experimental Medicine (2018)

Natural killer (NK) cells with adaptive immunological properties expand and persist in response to human cytomegalovirus. Here, we explored the metabolic processes unique to these cells. Adaptive CD3-CD56dimCD57+NKG2C+ NK cells exhibited metabolic hallmarks of lymphocyte memory, including increased oxidative mitochondrial respiration, mitochondrial membrane potential, and spare respiratory capacity. Mechanistically, we found that a short isoform of the chromatin-modifying transcriptional regulator, AT-rich interaction domain 5B (ARID5B), was selectively induced through DNA hypomethylation in adaptive NK cells. Knockdown and overexpression studies demonstrated that ARID5B played a direct role in promoting mitochondrial membrane potential, expression of genes encoding electron transport chain components, oxidative metabolism, survival, and IFN-γ production. Collectively, our data demonstrate that ARID5B is a key regulator of metabolism in human adaptive NK cells, which, if targeted, may be of therapeutic value.
Active specific immunotherapy for lethal canine hemangiosarcoma: A model system for the treatment of angiosarcoma with curative intent.
Authors: William Karl Decker, Laurel Douglass, Matthew M Halpert, Vanaja Konduri, Yunyu Chen, Dan Liang, Jonathan M Levitt, Brittany Neal, Caleb Hudson, Heidi Hottinger, Sindy Piscoya, Nicola Wilson, Lisa DiBernardi, Shonda Stallings, Zharkyn Omarbekov, Lori Seelhoff, Oscar Ramirez, Qizhi Cathy Yao, Ratan D Bhardwaj, Vinod Ravi
Journal: Journal of Clinical Oncology (2017)

e14539 Background: Angiosarcoma is a deadly malignant neoplasm of the vascular endothelium. Metastases are often present at diagnosis, and 5-year survival is only 10-30%. Though it comprises only 1% all soft tissue sarcoma diagnoses, it is a major killer among companion canines, responsible for an estimated 120,000 deaths per year in the US. The canine disease (termed HSA) closely mimics the human disease in both pathology and genetics. It frequently presents in the dog as acute hemoabdomen secondary to splenic rupture. Even if life-saving splenectomy is performed, median OS is only 48 days, and 1 year OS hovers at 0%. Given the accelerated timeline of the canine disease, the outbred dog is an ideal system in which to translate novel therapeutic approaches. Here we report an analysis of a phase I multi-site, open-label veterinary trial of chemo-immunotherapy performed on consecutively-presenting splenectomized companion canines with histopathologically-verified HSA. Methods: Subjects were administered two cycles of 20 mg/m 2 (low-dose) doxorubicinand an autologous cell-therapy reported to generate durable CD8 + memory similar to that of physiologic viral infection. Vaccine was generated from mobilized peripheral blood and cryopreserved tumor antigen and was administered with type I interferon. Disease burden was monitored monthly by abdominal ultrasound, chest x-ray, and echocardiogram. Results: At the time of submission, median OS had not been reached in the per protocol population, with 75% of animals alive and healthy (NED or ongoing PR) at up to 1 year post-splenectomy (p &lt; 0.0002). Ultrasound documented resolution of local mesenteric disease in one animal, sternal lymphadenopathy in another, and hepatic metastases in a third. In the intent-to-treat population, median OS was 109 days with 43% of animals alive and healthy at up to 1 year post-splenectomy. Conclusions: Administration of autologous cell therapy with low-dose doxorubicin is feasible, safe, and highly efficacious in the companion canines. If subjects survived long enough to begin treatment, prognosis became favorable. The results suggest that additional clinical studies in both canines and humans are warranted.
Genomic Organization of the KCNQ1 K+ Channel Gene and Identification of C-Terminal Mutations in the Long-QT Syndrome
Authors: NathalieNeyroud, PascaleRichard, NicolasVignier, ClaireDonger, IsabelleDenjoy, LaurenceDemay, MariaShkolnikova, RicardoPesce, PhilippeChevalier, BernardHainque, PhilippeCoumel, KettySchwartz, PascaleGuicheney
Journal: Circulation Research (1999)

Abstract—The voltage-gated K+ channel KVLQT1 is essential for the repolarization phase of the cardiac action potential and for K+ homeostasis in the inner ear. Mutations in the human KCNQ1 gene encoding the α subunit of the KVLQT1 channel cause the long-QT syndrome (LQTS). The autosomal dominant form of this cardiac disease, the Romano-Ward syndrome, is characterized by a prolongation of the QT interval, ventricular arrhythmias, and sudden death. The autosomal recessive form, the Jervell and Lange-Nielsen syndrome, also includes bilateral deafness. In the present study, we report the entire genomic structure of KCNQ1, which consists of 19 exons spanning 400 kb on chromosome 11p15.5. We describe the sequences of exon-intron boundaries and oligonucleotide primers that allow polymerase chain reaction (PCR) amplification of exons from genomic DNA. Two new (CA)n repeat microsatellites were found in introns 10 and 14. The present study provides helpful tools for the linkage analysis and mutation screening of th...
Abstract 2430: Targeting Nrf2 in esophageal adenocarcinoma sensitizes cancer cells to cisplatin treatment
Authors: Dunfa Peng, Tianling Hu, Shoumin Zhu, Wael El-Rifai
Journal: Cancer Research (2018)

Abstract Background: The incidence rate of the esophageal adenocarcinoma (EAC) has increased rapidly among men since 1976 in the USA. EAC is considered to originate from premalignant Barrett's esophagus (BE) which results from chronic gastroesophageal reflux disease (GERD). It has been reported that oxidative stress is steadily increased in GERD-BE-EAC progression cascade. NFE2-related factor 2 (Nrf2) is a major regulator of cellular anti-oxidant properties that maintains cell viability and cellular homeostasis. Methods and Results: Using Western blot analysis, we detected overexpression of Nrf2 protein in several EAC cell lines, as compared to BE cell lines (CPA, BAR10T) and normal esophageal squamous cell lines. Nrf2 overexpression was also confirmed in primary EAC samples, using immunohistochemistry on a tissue microarray that contained 76 EACs. Knockdown of Nrf2 by siRNA or CRISPR/CAS9 in EAC cells (FLO1 and OE33), that have constitutive high levels of Nrf2, enhanced the sensitivity of cancer cells to cisplatin (CDDP). We confirmed these results by using a Nrf2 specific inhibitor (Brusatol). Further studies demonstrated that dysfunction of Nrf2, either through knockdown of Nrf2 expression or using its specific inhibitor, depleted several Nrf2 target genes such as GR, HO-1, GSTM2, GPX3 and GPX4, which have anti-oxidative properties, leading to a significant increase in cellular ROS levels. The excessive ROS levels resulted in an increase in oxidative DNA damage (measured by 8-oxoguanine) and double strand breaks (measured by p-H2AX) which were further increased by treatment with CDDP with subsequent increase in cancer cell death. Conclusion: These results indicate that constitutive overexpression of Nrf2 in EAC cells protects tumor cells from high level of ROS and favors tumor cell survival and drug resistance. Targeting Nrf2 through its specific inhibitor may have a therapeutic window in EAC. Additional studies are ongoing to determine the molecular mechanisms underlying NRF2 overexpression in EACs. Citation Format: Dunfa Peng, Tianling Hu, Shoumin Zhu, Wael El-Rifai. Targeting Nrf2 in esophageal adenocarcinoma sensitizes cancer cells to cisplatin treatment [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 2430.
Online Myocardial Viability Assessment in the Catheterization Laboratory via NOGA Electroanatomic Mapping
Authors: MariannGyöngyösi, HeinzSochor, AliashgarKhorsand, LiorGepstein, DietmarGlogar
Journal: Circulation (2001)

Background The aim of this prospective study was to investigate the concordance between quantitative resting 201Tl uptake as an established myocardial viability index and the electrical activity of the heart, determined by NOGA nonfluoroscopic electroanatomic mapping. Methods and Results The myocardial resting and late resting thallium uptakes of 384 myocardial segments from 32 patients (27 males aged 65±8 years) with previous myocardial infarction and chronic stable angina were compared with unipolar voltage potentials and local shortening of the left ventricle as assessed by electroanatomic mapping. The quantitative thallium uptake data were analyzed by polar map analysis by division into 12 comparable myocardial segments, as represented in electroanatomic mapping images. Unipolar voltage potentials exhibited a significant logarithmic correlation with both resting and late resting thallium uptake (attenuation corrected: r=0.660 and r=0.744; non-attenuation corrected: r=0.623 and r=0.721). Receiver opera...
Abstract B57: Adhesion and beyond: CD44 in ovarian cancer spheroids
Authors: Joelle D. Sacks, Hilal Gurler Main, Goda G. Muralidhar, Osama Elfituri, Hao-Liang Xu, Andre A. Kajdacsy-Balla, Maria V. Barbolina
Journal: Clinical Cancer Research (2018)

Abstract Epithelial ovarian carcinoma (EOC) metastasis is characterized by the shedding of malignant cells from the surface of the primary tumor and their implantation onto the peritoneal surface lining the abdominal cavity in addition to more distant sites. This shedding of malignant cells from the primary site results as either single cells or free-floating multicellular aggregates, known as spheroids, in the ascites. Although single cells and spheroids may potentially seed metastases, considerable evidence now suggests that the aggregation of cells is important for anchorage-independent cell survival and growth, and spheroid formation may represent an important intermediate survival mechanism to facilitate EOC dissemination. Recent studies have uncovered human transmembrane cell adhesion molecule CD44 standard (CD44s) isoform expression correlating with high-grade and advanced-stage ovarian carcinoma. Moreover, it has also been suggested that CD44s may be an important mediator of ovarian cancer cell implantation in the peritoneal cavity, enhancing the metastatic potential of ovarian cancer cells. Thus, we investigated the functional significance of CD44 standard by means of in vitro culture experiments with ovarian cancer spheroids. After characterizing 8 EOC cell lines, a spectrum of CD44 expression was observed and two cell lines with high CD44s (ES-2 and SKOV-3) and two cell lines low in CD44s (OVCAR-4 and OVSAHO) were chosen for further testing. Interestingly, the high CD44s-expressing cell lines formed larger spheroids that adhered significantly faster to a monolayer of primary mesothelial cells. Stable knockdown of CD44 using CRISPR/Cas9 in these 2 cell lines reduced spheroid formation, suggesting that differential expression of CD44 standard plays a role in cell-cell adhesion. When ES-2 CD44-/- cells were injected i.p. into athymic nude mice, decreased ascites production and mesentery tumor burden were observed as well as increased overall survival. However, CD44 knockdown also significantly increased metastasis to the lung, suggesting a suppressive role for CD44 in EOC metastasis as well. These in vivo data imply that CD44 enhances the metastatic potential in ovarian cancer spheroids influencing peritoneal tumor growth while suppressing metastasis to lung tissue. Citation Format: Joelle D. Sacks, Hilal Gurler Main, Goda G. Muralidhar, Osama Elfituri, Hao-Liang Xu, Andre A. Kajdacsy-Balla, Maria V. Barbolina. Adhesion and beyond: CD44 in ovarian cancer spheroids. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B57.
Response to ’Correspondence to viewpoint ’Defining refractory rheumatoid arthritis' by Buch' by Roodenrijs <i>et al</i>
Authors: Maya H Buch
Journal: Annals of the Rheumatic Diseases (2018)

I would like to thank Roodenrijs et al 1 for their thoughtful comments on my viewpoint ‘Defining refractory rheumatoid arthritis’2 and appreciate their acknowledgement of this important subgroup of patients with unmet clinical needs.

The authors highlight their description and recent review of ‘difficult to treat RA’3 that in contrast to my viewpoint includes refractory rheumatoid arthritis (RA) in the presence of persistent inflammation and in its absence. I acknowledge this approach is more inclusive in encompassing the breadth of reasons that contribute to challenging RA treatment decision making in real-world practice and …