tbuckley/cabot-search huggingface dataset:
Abstract 2367: Identification of p-AKT as a PD marker for MER kinase in human G361 cells
Authors: Yaoyu Chen
Journal: Cancer Research (2018)

Abstract Abnormalities in receptor tyrosine kinases (RTKs) have been shown to be involved in a wide range of important biological activities in cancer, including cell proliferation, differentiation and drug resistance. The TAM family of RTKs includes three family members: TYRO3, AXL, and MER. Binding of ligands to the these receptors was reported to lead to activation of the TAM kinases, as well as PI3K/AKT, RAS/RAF/MAPK and JAK/STAT signaling pathways in human cancer cells. Among these three TAM kinases, the MER signaling pathway represents an attractive target for the treatment of human cancers. MER phosphorylation is dependent on the ligand GAS6, however, ligand activated phospho-MER is often not stable and is very difficult to detect without pervanadate pretreatment in human cancer cells and this has been a hurdle for developing a selective MER kinase inhibitor. Therefore, it is important to identify a specific pharmacodynamic marker to monitor MER kinase activity in human cancer cells. Here, we report the development of a phospho-AKT assay for characterization of MER kinase inhibitors in human G361 cells. We profiled the expression of MER among multiple human cancer cells and demonstrated that MER and TYRO3, but not AXL show high levels of protein expression in human G361 melanoma cells. In G361 cells, phospho-AKT is induced by GAS6 treatment and the induction of phospho-AKT can be reversed by AXL/MER tool compounds. To determine the role MER and TYRO3 play in the activation of phospho-AKT, either MER or TYRO3 was selectively depleted by siRNA knockdown. We demonstrate that GAS6 induced phospho-AKT is only dependent on MER kinase, but not TYRO3 in human G361 melanoma cells. In addition, using phospho-AKT as readout, a high-throughput cell-based assay was established in the G361 human melanoma cells for evaluation of compound potency in inhibiting MER pathway activation. Further, we observed a correlation in compound potency between inhibition of phospho-AKT in G-361 cells and phospho-MER in MER-overexpressing BAF3 cells. In summary, we have demonstrated that GAS6 induced phospho-AKT can be a potential pharmacodynamic marker for inhibition of MER kinase and have successfully developed a cell-based functional assay for screening small molecule inhibitors of MER kinase for potential therapeutic utility in treating GAS6/MER-deregulated human cancers. Citation Format: Yaoyu Chen. Identification of p-AKT as a PD marker for MER kinase in human G361 cells [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 2367.
Expression of Coxsackievirus and Adenovirus Receptor in Hearts of Rats With Experimental Autoimmune Myocarditis
Authors: MasahiroIto, MakotoKodama, MasayoshiMasuko, MasayukiYamaura, KoichiFuse, YumikoUesugi, SatoruHirono, YujiOkura, KiminoriKato, YukoHotta, TakaoHonda, RyozoKuwano, YoshifusaAizawa
Journal: Circulation Research (2000)

Abstract—The expression of coxsackievirus and adenovirus receptor (CAR) was dominant in the brains and hearts of mice until the newborn phase. There is no detailed information concerning the relation between the expression of CAR and development of hearts. It is also uncertain whether CAR is able to be induced in adult hearts after cardiac injury. We demonstrated that CAR was abundant in the hearts of newborn rats but was barely detectable in the hearts of adult rats. The expression of CAR in rat hearts with experimental autoimmune myocarditis, which was induced by immunization of purified cardiac myosin, was serially investigated. Active myocarditis was observed from day 15 after immunization. By immunohistochemistry, cardiomyocytes were strongly stained for CAR antibody from days 24 to 42. CAR mRNA was also detected from days 18 to 30 by using reverse transcription–polymerase chain reaction. In the next experiment, the induction of CAR on isolated cardiomyocytes was investigated. CAR was barely detectab...
Abstract 19375: Rapamycin Treatment Regulates miRNAs Associated With Mitochodrial and Endoplasmic Reticulum Functions in a Pig Model of Miocardial Ischemia-reperfusion Injury
Authors: Cesario Bianchi, Paulo S Oliveira, Antonio D Lassaletta, Frank W Sellke, Kleber G Franchini, Christoph Schorl
Journal: Circulation (2015)

Introduction: Previously(Lassaletta et al,PMC3943541)we showed that Rapamycin treatment of normal pigs subjected to an acute myocardial ischemia-reperfusion injury (IRI) was associated with increase myocardial necrosis and refractory left ventricle (LV) defibrillations. In an effort to better understand rapamycin effects we applied a non-bias genomic analysis to determine if microRNAs were modified by rapamycin treatment in this pre-clinical animal model of IRI. Hypothesis: We hypothesized that microRNA expression were modified by rapamycin-treated and would identify novel and meaningful pharmacological mechanisms related to its detrimental effects on reperfusion injury. Methods: Young male Yorkshire swine (16-19 kg) received either no drug (controls, n=5) or were given 4mg of oral rapamycin daily (n=5). After two weeks of treatment, all animals underwent median sternotomy and the mid-LAD was occluded for 60 minutes followed by 120 minutes of reperfusion. RNA was extracted from LV non-ischemic and ischemic areas from each group and processed (according to the manufacture′s specifications at Brown University Genomic Core facility) for microRNA (miRNA) expression analysis using a Affymetrix GeneChip miRNA3.0 Array containing over 25,000 probe sets of which 257 miRNA probes of domestic pigs. Data were processed using MetaCore version 5.0 (GeneGo, St Joseph, MI) for both statistical (FDR: p&lt;0.05) and pathway analysis. Results: miRNA regulated in 5 animals per group were annotated for human orthologs. A total of 23 miRNAs were differentially expressed. Interestingly, all miRNAs were down-regulated in the rapamycin-treated animals. Of those, nine had human orthologs: miR 181c-3p was highly represented followed by miR323a-5p, miR1245b-3p, miR4324, miR331-5p, miR491-5p and miR490-3p. Conclusions: Recent studies show that miRNA 181c regulates myocardial mitochondrial function through cytochrome c oxidase and complex IV gene expressions (PMCID: PMC4014556)and regulates Glucose-regulated protein (GRP78)/BiP [an endoplasmic reticulum stress (ER) chaperone](PMID: 24696166). Hence It is likely that rapamycin effects (detrimental or not) are associated with mitochondrial function and ER stress response.
Autologous Bone-Marrow Mononuclear Cell Implantation Improves Endothelium-Dependent Vasodilation in Patients With Limb Ischemia
Authors: YukihitoHigashi, MasashiKimura, KeikoHara, KensukeNoma, DaisukeJitsuiki, KeigoNakagawa, TetsuyaOshima, KazuakiChayama, TaijiroSueda, ChikaraGoto, HiroakiMatsubara, ToyoakiMurohara, MasaoYoshizumi
Journal: Circulation (2004)

Background— Patients with limb ischemia were associated with endothelial dysfunction. The purpose of this study was to determine whether autologous bone-marrow mononuclear cell (BM-MNC) implantation improves endothelial dysfunction in patients with limb ischemia. Methods and Results— We evaluated the leg blood flow (LBF) response to acetylcholine (ACh), an endothelium-dependent vasodilator, and sodium nitroprusside (SNP), an endothelium-independent vasodilator, before and after BM-MNC implantation in 7 patients with limb ischemia. LBF was measured with a mercury-filled Silastic strain-gauge plethysmograph. The number of BM-MNCs implanted into ischemic limbs was 1.6×109±0.3×109. The number of CD34+ cells included in the implanted BM-MNCs was 3.8×107±1.6×107. BM-MNC implantation improved the ankle-brachial pressure index (0.33±0.21 to 0.39±0.17, P=0.06), transcutaneous oxygen pressure (28.4±11.5 to 36.6±5.2 mm Hg, P=0.03), and pain-free walking time (0.8±0.6 to 2.9±2.2 minutes, P=0.02). After BM-MNC implant...
Abstract 5334: Spg20 (Spartin) promoter methylation identifies tumor B lymphocytes
Authors: Raffaele Frazzi, Tonia De Simone, Mariaelena Pistoni, Francesco Merli
Journal: Cancer Research (2018)

Abstract Introductory sentence. The layer of regulation represented by gene promoter methylation is being investigated in Non-Hodgkin lymphoma (NHL) cell lines, primary B lymphocytes and peripheral blood mononuclear cells (PBMCs). The aim is to assess whether the panel of differentially methylated genes we previously identified is able to distinguish normal B lymphocytes from lymphoma cells. Experimental procedures. Quantitative, gene-specific methylation assays. Immunosorting of human B lymphocytes. Proliferation assays. 5-azacytidine treatment. NHL-derived cell lines. New data. Here we show that NHL-derived cell lines display a characteristic profile of promoter methylation on specific tumor suppressors and target genes. A panel of 9 target promoters was selected previously and assessed on a series of healthy and tumor primary B lymphocytes. 4 out of 5 NHL-cell lines show a highly methylated profile on KLF4, DAPK1 and SPG20, at variance with normal B lymphocytes (lymph-node derived) and PBMCs where these targets are completely unmethylated. Interestingly, PBMCs from healthy donors display the same methylation pattern as the one shown by B lymphocytes immunologically sorted from follicular hyperplasias. Spartin (SPG20) emerges here as a differentially methylated gene associated to lymphocyte malignancy, at variance with other tumor suppressors in our panel that show variability among different cell lines. SPG20 is completely or highly methylated in all the tested NHL-cell lines. According to this observation, SPG20 results not methylated in PBMCs as well as sorted non-tumor B lymphocytes. On the contrary, the methylation status of three different BCL6 CpG islands (assessed with the same technique) may vary among different cell lines. In order to investigate what's the functional role of these specific promoters methylation, we treated Toledo and NU-DUL-1 cell lines with the demethylating agent 5-azacytidine (5AZA). We observe that the dose-dependent inhibition of proliferation upon 5AZA is accompanied by a small but reproducible decrease in SPG20 and MZB1 promoter methylation. Experiments aimed at assessing any involvement of DNA methyltransferases DNMT1 and DNMT3a are currently ongoing. Conclusions. Our data show a consistent methylation profile of 9 gene promoters on 5 different NHL-derived cell lines. Spartin emerges as a completely methylated promoter in the tested tumor cells. PBMCs show a consistent unmethylated profile of Spartin and of all the target genes. The epigenetic regulation of these genes in B-derived lymphomas warrants further investigation. Citation Format: Raffaele Frazzi, Tonia De Simone, Mariaelena Pistoni, Francesco Merli. Spg20 (Spartin) promoter methylation identifies tumor B lymphocytes [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 5334.
Abstract 10950: Direct Renin Inhibition Improved Cardiac Remodeling and Survival in Mouse Model of Dilated Cardiomyopathy
Authors: Kenichi Hongo, Satoshi Morimoto, Yoichiro Kusakari, Kimiaki Komukai, Makoto Kawai, Michihiro Yoshimura, Satoshi Kurihara
Journal: Circulation (2011)

Introduction: The renin-angiotensin system (RAS) is important during the pathogenesis of heart failure. Among inhibitors of RAS, direct renin inhibitors (DRIs) are promising for the treatment of heart failure, although little evidence has been reported. Hypothesis: DRIs are effective for the treatment of heart failure due to dilated cardiomyopathy (DCM). Methods: We used a knock-in mouse with a deletion mutant of cardiac troponin T (ΔK210), which causes human DCM (DCM mouse). Echocardiography was used to estimate the cardiac function in vivo. Histological examinations were performed to evaluate cardiac fibrosis using Masson's trichrome staining. To evaluate the intracellular Ca2+ transient (CaT) and tension, the aequorin method was applied to papillary muscle preparations. Results: The DCM mice died within a few months after birth and a DRI (aliskiren, 50 mg/kg/day) significantly improved the survival (p<0.001, log rank test). The left ventricular chamber size was enlarged and the fractional shortening wa...
Abstract 14903: Activating Transcription Factor 3 Regulates High-Fat Diet-Induced Adipocytes Hypertrophy and Lipid Metabolism in Mice
Authors: Ching-FengCheng, Hui-ChenKu, Tzu-LingTseng, Pei-FangLai, HengLin
Journal: Circulation (2014)

Obesity is a severe and complicated health issue related to lifestyle and dietary modifications, and is highly associated with cardiovascular diseases. Activating transcription factor 3 (ATF3) is a member of the ATF/cAMP-response element-binding protein family of transcriptional factors. It can be induced by stress condition in a variety of tissues, including adipocytes. Here we demonstrated that ATF3 can regulate lipid metabolism in high-fat-diet (HFD)-induced obesity in mice. ATF3-/- mice (KO) were given HFD for 16 weeks, with body weights significantly increased as compared to B6 wild-type (WT) littermate mice (KO: 41.3±0.98 gm vs. WT: 34.3±0.9 gm, p<0.05, n=6). The obese ATF3-/- mice then received AAV8-mediated gene transfer of ATF3 (AAV8-ATF3) at 16 weeks, in which decrease body weights were observed in the AAV8-ATF3 mice as compared to ATF3-/- mice receiving AAV8-GFP (AAV8-ATF3: 36.5±0.7 gm, p<0.05, n=6). Histology demonstrated increased adipocyte cell diameter in ATF3-/- mice, in which such enlarge...
Phosphatase-Mediated Enhancement of Cardiac cAMP-Activated Cl− Conductance by a Cl− Channel Blocker, Anthracene-9-Carboxylate
Authors: Shi-ShengZhou, AkiraTakai, MakotoTominaga, YasunobuOkada
Journal: Circulation Research (1997)

Abstract An aromatic carboxylate, anthracene-9-carboxylic acid (9-AC), is known as a Cl− channel blocker. However, variable 9-AC effects have hitherto been reported on the cardiac cAMP-activated Cl− conductance, when applied extracellularly. We have reexamined the 9-AC effect on the Cl− conductance activated by isoproterenol or forskolin in guinea pig ventricular myocytes under whole-cell patch-clamp conditions. The inward current was blocked by 9-AC at ≥0.5 mmol/L, but in contrast, the outward current was enhanced at much lower concentrations (ED50, ≈13 μmol/L). 9-AC applied by the intracellular perfusion technique increased both the inward and outward currents. In the presence of intracellular 9-AC, deactivation of the conductance after washout of isoproterenol or forskolin was largely prevented. 9-AC produced an enhancing effect, even after inhibiting the deactivation process by okadaic acid (OA), whereas it failed to produce additional effects in the presence of orthovanadate. Intracellular applicatio...
Abstract 1361: Micro RNA-200C is one of the important Fanconi Anemia (FA) pathway downstream regulators in lung cancer
Authors: Wenrui Duan, Shirley Tang, Li Gao, Kathleen Dotts, Andrew Fink, Arjun Kalvala, Brittany Aguila, Miguel A. Villalona-Calero
Journal: Cancer Research (2018)

Abstract The Fanconi Anemia (FA) pathway is essential for human cells to maintain integrity following DNA damage. This pathway is involved in the endogenous repair of double stranded DNA breaks and homologous recombination as well as repair of DNA cross-linking caused by exogenous agents. Cancers with defective FA pathway are expected to be more sensitive to cross-link based therapy, or to treatments in which additional repair mechanisms are targeted. We have recently reported the detection of 22% of NSCLC to be FA functionally inactive by Fanconi Anemia Triple Staining Immunofluorescence (FATSI) test. Studies have shown involvement of certain micro RNA (miRNA) as regulatory elements in the development of lung cancer. We set out to evaluate potential involvement of miRNAs in the regulation of the Fanconi Anemia (FA) pathway. Using Nanostring counter miRNA array we screened 734 different miRNA expression in two FA defective lung cancer cells and matched control cells along with two FA pathway deficient lung tumors and matched non-tumor lung tissue samples. Selected miRNA expression were validated with real-time PCR analysis. miRNA target gene expression was analyzed through AmpliSeq RNA gene expression analysis. Among 734 different miRNAs, a cluster of microRNAs were found to be up-regulated including an important cancer related micro RNA, miR-200C. Nanostring data showed that miR-200C was increased 7.5 fold on average in the FA defective lung cancer cells as compared to control cell. An average of 22 fold increase in miR-200C was detected in the FA defective lung tumor tissues comparing to matching non-tumor tissues. AmpliSeq analysis showed the ZEB1(zinc finger E-box binding homeobox 1) mRNA expression was down regulated in10 out 10 lung tumors (100%) comparing to non-tumor tissues, and 9 out of 10 samples (90%) showed reduction in ZEB2 expression. MiRNA-200C has been reported as a negative regulator of epithelial-mesenchymal transition (EMT) and inhibiting cell migration and invasion by promoting the upregulation of E-cadherin through targeting ZEB1 and ZEB2 transcription factors. Our findings indicate that the FA pathway regulates downstream genes through regulation of miRNAs in lung cancer. MiR-200C appears to be one of the most important FA downstream regulators in lung cancer. Validation with a larger sample size will be needed to confirm our findings. Citation Format: Wenrui Duan, Shirley Tang, Li Gao, Kathleen Dotts, Andrew Fink, Arjun Kalvala, Brittany Aguila, Miguel A. Villalona-Calero. Micro RNA-200C is one of the important Fanconi Anemia (FA) pathway downstream regulators in lung 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 1361.
Diatom Silica for Biomedical Applications: Recent Progress and Advances
Authors: Shaheer Maher, Tushar Kumeria, Moom Sin Aw, Dusan Losic
Journal: Advanced Healthcare Materials (2018)

Diatoms are unicellular photosynthetic algae enclosed in porous 3D nanopatterned silica enclosures called "frustules." The diatom frustules are made from biosilica self-assembled into intricate porous shells that feature unique properties including high specific surface area, biocompatibility, tailorable surface chemistry, thermal stability, and high mechanical and chemical resistance. The ability to cultivate diatoms in artificial environments and their abundant availability of diatom frustules as mineable fossilized mineral deposits (diatomite or diatomaceous earth; DE) make diatom silica a promising natural alternative to synthetic porous silica for a broad range of biomedical, environmental, agricultural, and energy applications. This review article provides a comprehensive and current account of the use of natural DE silica materials in biomedical applications focused mainly on drug delivery with some highlights on biosensing, tissue engineering, and clotting agents. The article also covers some basic physical and chemical aspects of DE material such as purification, surface chemical functionalization, biocompatibility, and cellular uptake that are critical for the development of an efficient drug carrier.
Abstract 16468: Results of Research Genetic Testing in Pediatric Cardiomyopathy Patients Justify Broader Clinical Genetic Testing
Authors: Stephanie M Ware, Steven E Lipshultz, Steven D Colan, Ling Shi, Charles E Canter, Daphne T Hsu, Debra A Dodd, Melanie D Everitt, Paul F Kantor, Linda J Addonizio, John L Jefferies, Joseph Rossano, Elfriede Pahl, Paolo Rusconi, Jeffrey Schubert, Teresa Lee, Erin Miller, Muhammad Tariq, James D Wilkinson, Jeffrey A Towbin
Journal: Circulation (2015)

Introduction: Pediatric cardiomyopathies are genetically heterogeneous diseases with high risk of death or cardiac transplant. Despite progress in identifying causes, the majority of cases remain idiopathic. Currrently, genetic testing is not performed in all children with cardiomyopathy. Gene identification leads to better individual risk stratification and has the potential to stimulate the development of therapies based on the underlying mutation. The aim of this study is to identify genetic mutations in pediatric cardiomyopathy patients using whole exome sequencing. Hypothesis: Sarcomeric mutations are under-diagnosed causes of all forms of cardiomyopathy in children. Methods: Probands with cardiomyopathy were recruited from 11 institutions. Results of clinical genetic testing prior to enrollment were collected. Whole exome sequencing was performed and mutations were identified in 35 genes currently available on clinical genetic testing panels. Results: The initial 154 probands subjected to exome included 78 patients with DCM, 43 with HCM, 14 with RCM, and 19 with LVNC, mixed, or unknown types. Familial disease was present in 38% and the remainder were idiopathic. Twenty-seven percent had positive clinical genetic testing prior to enrollment. Exome testing identified mutations in 38 subjects who had not had clinical testing, increasing the cohort positive testing rate to 55% (DCM, 34.6%; HCM, 74.4%; RCM, 71.4%). Forty-five percent of subjects with no family history of disease had an identifiable mutation. Conclusions: Pediatric cardiomyopathy patients have a high incidence of mutations that can be identified by clinically available genetic testing. Lack of a family history of cardiomyopathy was not predictive of normal genetic testing. These results support the broader use of genetic testing in pediatric patients with all functional phenotypes of cardiomyopathy to identify disease causation allowing better family risk stratification.
Abstract 20285: Relationship Between INR and Outcomes in Modern Trials With Warfarin Controls
Authors: Tzu-Yun McDowell, John Lawrence, Jeffry Florian, Mary Ross Southworth, Stephen Grant, Norman Stockbridge
Journal: Circulation (2017)

Introduction: A target INR of 2-3 has been recommended for patients with atrial fibrillation (AF) and risk factors for thromboembolism. This recommendation is largely based on evidence from observational studies a decade ago. Our study utilized collective data from modern trials with warfarin controls to examine the longitudinal relationship between warfarin anticoagulation, as assessed by INR, on the clinical outcome events of interest. Methods: We obtained subject-level data for warfarin-treated patients from three large clinical studies supporting the approval of dabigatran (Pradax®), apixaban (Eliquis®) and edoxaban (SAVAYSA®). Ischemic stroke, intracranial hemorrhagic (ICH) and all-cause mortality were selected as the outcome events of interest. We performed multivariate Cox regression modeling to examine the association between time-dependent INR and each outcome event. Benefit-Risk analysis was assessed by summing estimated annual event rate for both ischemic stroke and ICH. Results: A total of 21,...
Screening for Atrial Fibrillation With Electrocardiography
Authors: Jill Jin
Journal: JAMA (2018)

Daniel E. Jonas, MD, MPH; Leila C. Kahwati, MD, MPH; Jonathan D. Y. Yun, MD; Jennifer Cook Middleton, PhD; Manny Coker-Schwimmer, MPH; Gary N. Asher, MD, MPH