tbuckley/cabot-search huggingface dataset:
Abstract 16820: CaMKIIδc Transgenic Mice Develop Spontaneous Ventricular Arrhythmias Which Can Be Suppressed by Inhibition of Late Na+ Current
Authors: MariaArolfo, LiguoChi, AliyaZeng, NesrineEl-Bizri, JoanBrown, SridharanRajamani, LuizBelardinelli, ArvinderDhalla
Journal: Circulation (2014)

Introduction: It has been shown that activated CaMKII can phosphorylate cardiac Na+ channels that leads to an enhanced late Na current (INaL). We hypothesized that enhanced INaL plays an important role in arrhythmogenesis linked to increased CaMKII activity. To test this hypothesis we determined the effect of a selective INaL inhibitor GS-967 on spontaneously occurring ventricular arrhythmias in mice overexpressing CaMKIIδc (TG). Methods: TG (n=6) and wild type (WT, n=3) mice at age 8 week (wk) were instrumented with telemetry transmitters to record ECG. ECG were recorded continuously starting 1 wk post- surgery (age 9 wk) until age 19 wk. Incidence and burden of arrhythmias were evaluated at ages 9, 11, 13, 15, 17 and 19 wks using DSI ECG Pro software. At age 17 wk, when arrhythmia burden was relatively stable, mice were treated with a single dose of GS-967 (1 mg/kg, i.p.) or vehicle. After 4 days of washout, the treatment was repeated in a cross-over manner. Arrhythmia burden was quantified over a durat...
Left Ventricle Apical Conduit to Bilateral Subclavian Artery in a Patient With Porcelain Aorta and Aortic Stenosis
Authors: Kuan-MingChiu, Tzu-YuLin, Jer-ShenChen, Shao-JungLi, Chih-YangChan, Shu-HsunChu
Journal: Circulation (2006)
PLD3 and PLD4 are single-stranded acid exonucleases that regulate endosomal nucleic-acid sensing
Authors: Amanda L. Gavin, Deli Huang, Christoph Huber, Annica Mårtensson, Virginie Tardif, Patrick D. Skog, Tanya R. Blane, Therese C. Thinnes, Kent Osborn, Hayley S. Chong, Farnaz Kargaran, Phoebe Kimm, Armen Zeitjian, Rachel L. Sielski, Megan Briggs, Sebastian R. Schulz, Alessandro Zarpellon, Benjamin Cravatt, Ee Shan Pang, John Teijaro, Juan Carlos de la Torre, Meredith O’Keeffe, Hubertus Hochrein, Markus Damme, Luc Teyton, Brian R. Lawson, David Nemazee
Journal: Nature Immunology (2018)
Mechanism of Pacemaking in IK1-Downregulated Myocytes
Authors: JonathanSilva, YoramRudy
Journal: Circulation Research (2003)

Biological pacemakers were recently created by genetic suppression of inward rectifier potassium current, IK1, in guinea pig ventricular cells. We simulated these cells by adjusting IK1 conductance in the Luo-Rudy model of the guinea pig ventricular myocyte. After 81% IK1 suppression, the simulated cell reached steady state with pacemaker period of 594 ms. Pacemaking current is carried by the Na+-Ca2+ exchanger, INaCa, which depends on the intracellular calcium concentration [Ca2+]i. This [Ca2+]i dependence suggests responsiveness (increase in rate) to β-adrenergic stimulation (βAS), as observed experimentally. Simulations of βAS demonstrate such responsiveness, which depends on INaCa expression. However, a simultaneous βAS-mediated increase in the slow delayed rectifier, IKs, limits βAS sensitivity.
Abstract 11842: Meis1 Transcriptionally Regulates the Expression of NaV1.5 Protein
Authors: NingWang, YanLu, BoYe, XiangLi, TaoYou, FaqianLi, HaodongXu
Journal: Circulation (2014)

Introduction: Genome-wide association studies have identified loci associated with cardiac conduct system (CCS) function, including Meis1. Meis1, a transcription factor, plays a critical role in the regulation of cardiac differentiation and proliferation. Mechanisms of Meis1 linked to CCS function are unknown. Hypothesis: We hypothesized that Meis1 regulates NaV1.5 expression by affecting SCN5a promoter activity and plays important roles in the regulation of CCS function and development of arrhythmias in myocardial infarction (MI). Methods: In silico promoter analysis was performed to determine if SCN5a promoter harbors Meis1 conservative binding sites. Luciferase reporter assay was done to determine effects of Meis1 on SCN5a promoter activity in HeLa cells infected with adenovirus-Meis1 or transfected with siRNA targeting Meis1. qRT-PCR and Western blot were employed to determine effects of Meis1 on NaV1.5 or H2O2 on Meis1 expression, and they were used to determine NaV1.5 and Meis1 levels in peri-infarc...
Abstract 1895: Landmark development of PI3K delta specific inhibitors for hematologic cancer therapeutics by data-driven drug design
Authors: Suji Hong, Jong Woo Kim, Chi Woo Lee
Journal: Cancer Research (2018)

Abstract PI3K δ is hyper activated primarily in B cell malignancy and plays a central role in the malignant cell retention in proliferation, survival and homing at the lymphoid tissue and bone marrow in a variety of signaling pathways. Our BW compounds(BW-101, BW-108) are highly potent and selective PI3K δ inhibitors with marked selectivity over the other PI3K isoforms(α, β, γ). BW compounds are designed for the purpose of advancing the PI3K δ inhibition activity and overcoming the toxicities in which are hepatotoxicity and immunotoxicity due to small ratio of PI3K γ/PI3K δ. BW compounds are proven to be best-in-class in PI3K δ inhibition activity and to possess a bigger ratio of PI3K γ/PI3K δ related to the immunotoxicity than that of Idelalisib As small molecules, they inhibit PI3Kδ in the way of competing with ATP strongly at PI3Kδ binding site that issues in apoptosis of malignant B and T cell through blocking AKT down pathway. BW compounds have shown the good PK profiles in rat so that their in vivo efficacies were superior to those of Idelalisib in xenograft studies. Such a result demonstrated the therapeutic potential of these compounds in acute leukemia mediated via the PI3Kδpathway. In the side of toxicity, BW compounds also are showing desirable properties. Citation Format: Suji Hong, Jong Woo Kim, Chi Woo Lee. Landmark development of PI3K delta specific inhibitors for hematologic cancer therapeutics by data-driven drug design [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 1895.
Enhanced Functional Gap Junction Neoformation by Protein Kinase A–Dependent and Epac-Dependent Signals Downstream of cAMP in Cardiac Myocytes
Authors: SatoshiSomekawa, ShigetomoFukuhara, YoshikazuNakaoka, HisakazuFujita, YoshihikoSaito, NaokiMochizuki
Journal: Circulation Research (2005)

Gap junctions (GJs) constituted by neighboring cardiac myocytes are essential for gating ions and small molecules to coordinate cardiac contractions. cAMP is suggested to be a potent stimulus for enhancement of GJ function. However, it remains elusive how cAMP potentiates the GJ of cardiomyocytes. Here we demonstrated that the gating function of GJ is enhanced by the protein kinase A (PKA)–dependent signal, and that the accumulation of connexin43 (Cx43), the most abundant Cx in myocytes, is enhanced by an exchange protein directly activated by cAMP (Epac) (Rap1 activator)–dependent signal. The gating function of GJs was analyzed by microinjected dye transfer method. The accumulation of Cx43 was analyzed by quantitative immunostaining. Using the PKA-specific activator N6-benzoyladenosine-3′,5′-cyclic monophosphate (6Bnz) and Epac-specific activator 8-(4-chlorophenylthio)-2′-O-methyladenosine-3′,5′-cyclic monophosphate (8CPT), we could delineate the two important downstream signals of cAMP for enhanced GJ n...
Abstract IA16: PapGene, PapSEEK, and PapDREAming for early detection of ovarian cancer
Authors: Ie-Ming Shih
Journal: Clinical Cancer Research (2018)

Abstract Advances in genomic technologies are revolutionizing how we understand pathogenesis in ovarian cancer. These technologies are critical in developing innovative strategies to diagnose cancer earlier by detecting rare mutant alleles or aberrant methylation marks among a pool of normal DNA. Studies integrating these technologies provide the fundamental scientific underpinning for designing future standards of care to reduce the burden of ovarian cancer through early detection and prevention. This presentation will focus on two related topics. One is to summarize the recent research findings from the Johns Hopkins Ovarian Cancer Early Detection (JHOCD) group in deciphering the major molecular alterations involving in ovarian cancer in situ lesions (serous tubal intraepithelial carcinoma, STIC) and its precursors (including serous tubal intraepithelial lesion, STIL and so-called “p53” signatures) in fallopian tubes. The clinicopathologic and molecular studies we have done have helped define the precursor lesions in many high-grade serous carcinomas (HGSC) of the ovary, the most common and aggressive type of ovarian epithelial cancer. The other focus is to discuss the promise and challenges in applying genetic and epigenetic methods to detect ovarian HGSC. In an effort to replicate the success of cervical cancer screening, several approaches for the early detection of ovarian cancers have been proposed. JHOCD team has first reported the feasibility of using cervical cytology samples to detect ovarian carcinomas. We have extended this original study by determining whether different sample collection methods including cervical cytology specimens, uterine lavage/brush, and blood, alone or in combination with each other or serum CA-125 levels, can achieve a better sensitivity and specificity. The objective of JHOCD is to facilitate the proposed clinical studies to assess the clinical benefit in applying the aforementioned molecular diagnostics for early ovarian cancer diagnosis in high-risk women (including those carrying BRCA mutations). Citation Format: Ie-Ming Shih. PapGene, PapSEEK, and PapDREAming for early detection of ovarian cancer. [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 IA16.
In Situ Akt Phosphorylation in the Nucleus Tractus Solitarii Is Involved in Central Control of Blood Pressure and Heart Rate
Authors: Hsiao-NingHuang, Pei-JungLu, Wan-ChenLo, Chia-HuiLin, MichaelHsiao, Ching-JiunnTseng
Journal: Circulation (2004)

Background— Previously, we have shown that nitric oxide (NO) plays a significant role in central cardiovascular regulation and modulates the baroreflex in the nucleus tractus solitarii (NTS) of rats. NO production is mediated by activation of NO synthase (NOS). Insulin signaling was involved in controlling peripheral blood pressure via the activation of endothelial NOS. Here, we investigated whether the insulin signal transduction pathway is involved in controlling central cardiovascular effects. Methods and Results— Insulin was injected into NTS of urethane-anesthetized male Wistar-Kyoto (WKY) rats. Unilateral microinjection (60 nL) of insulin (100 IU/mL) into the NTS produced prominent depressor and bradycardic effects in 8- and 16-week-old WKY rats. In addition, pretreatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and the NOS inhibitor L-NAME into the NTS caused attenuation of the cardiovascular response evoked by insulin in either 8- or 16-week-old WKY rats. Western blot analy...
Abstract 3993: Efficacy of SHP2 phosphatase inhibition in cancers with nucleotide-cycling oncogenic RAS, NF1 loss and RAS-GTP-dependent oncogenic BRAF
Authors: Trever G. Bivona, Robert Nichols, Franziska Haderk, Carlos Stahlhut, Christopher Schulze, Golzar Hemmati, David Wildes
Journal: Cancer Research (2018)

Abstract Oncogenic alterations in the RAS-RAF-MEK-ERK pathway, including mutant forms of KRAS, BRAF, and loss of the tumor suppressor and RAS GTPase-activating protein (GAP) NF1, drive the growth of a wide spectrum of cancers. While BRAF and MEK inhibitors are efficacious against BRAFV600E-driven cancers, effective targeted therapies are lacking for most cancers driven by other pathway alterations, including oncogenic KRAS, NF1 loss, and non-V600E oncogenic BRAF. Here, we show that targeting the PTPN11/SHP2 phosphatase with a novel small molecule allosteric inhibitor is effective in human cancer models bearing nucleotide-cycling oncogenic RAS (e.g. KRASG12C), NF1 loss, or RAS-GTP dependent oncogenic BRAF (e.g. class 3 BRAF mutants). SHP2 inhibitor treatment decreases oncogenic RAS-RAF-MEK-ERK signaling and cancer growth by disrupting SOS1-mediated RAS-GTP loading. Our findings illuminate a critical function for SHP2 in promoting oncogenic RAS activation and downstream signaling in cancers with nucleotide-cycling oncogenic RAS, RAS-GTP dependent oncogenic BRAF, and NF1 loss. SHP2 inhibition is a promising molecular therapeutic strategy for patients with cancers bearing these oncogenic drivers. Citation Format: Trever G. Bivona, Robert Nichols, Franziska Haderk, Carlos Stahlhut,Christopher Schulze, Golzar Hemmati, David Wildes. Efficacy of SHP2 phosphatase inhibition in cancers with nucleotide-cycling oncogenic RAS, NF1 loss and RAS-GTP-dependent oncogenic BRAF [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 3993.
Abstract 3547: Properties of lipid rafts in two epigenetically distinct subtypes of the oncogenic cell-line SW13
Authors: Luis Espejo, Kathryn J. Leyva, Elizabeth E. Hull
Journal: Cancer Research (2018)

Abstract The epithelial SW13 cancer cell line has two naturally occurring well-defined cell subtypes. The SW13(Vim-) has a phenotype that resembles typical epithelial tumors, displaying increased growth and proliferation with a low level of invasiveness. The SW13(Vim+) subtype has a mesenchymal-like phenotype, commonly associated with more invasive and metastatic states of epithelial cancers. SW13(Vim-) can be converted to a pseudo SW13(Vim+) phenotype when treated with histone deacetylase inhibitors (HDACi). This model is used to study the epigenetic phenotypic differences between tumor-like cancer cells and cells that display a more metastatic phenotype. Gene chip data obtained from the SW13 treated and untreated cells displays differential expression in many genes, specifically genes for cellular membrane proteins and genes involved in cholesterol, sphingolipid, and GPI-anchored protein metabolism; all of which are essential components of lipid rafts. Additionally, recent improved outcomes noted in patients using statin drugs further implicates that cholesterol plays a role in cancer progression, although the mechanism for this improvement is not well understood. This suggests lipid rafts are a candidate for a physical structure that manifests the differential effect of cholesterol perturbations in cancer phenotypes. We hypothesize that lipid raft protein composition is distinctly different between the two SW13 cell subtypes, and that the differences in the composition of lipid rafts may play a role in the unique oncogenic phenotypes of the two subtypes. Utilizing low-temperature detergent-resistant lipid raft isolation techniques, western blotting, and mass spectrometry we investigate protein composition differences between the two SW13 cell subtypes. Cholesterol assays are applied to assess the distribution and total cholesterol content of each SW13 subtype, this also provides translational confirmation of the gene chip data obtained from the subtypes. Cholesterol depletion techniques utilizing cyclodextrin for acute disruption and simvastatin for chronic disruption are being implemented to perturb lipid rafts and observe their role in the oncogenic phenotypes of the SW13 cell subtypes. Specifically, metastatic qualities are measured after lipid raft and cholesterol perturbations. Initial findings support differential cholesterol representation in the two SW13 cell subtypes. Potential findings may explain a mechanism in which cholesterol perturbations are capable of decreasing metastasis and improving the outcome of patients with epithelial cancers. Citation Format: Luis Espejo, Kathryn J. Leyva, Elizabeth E. Hull. Properties of lipid rafts in two epigenetically distinct subtypes of the oncogenic cell-line SW13 [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 3547.
Alterations of Cardiac Structure in Patients With Isolated Office, Ambulatory, or Home Hypertension
Authors: RobertoSega, GiuseppeTrocino, ArturoLanzarotti, StefanoCarugo, GiancarloCesana, RiccardoSchiavina, FrancoValagussa, MicheleBombelli, CristinaGiannattasio, AlbertoZanchetti, GiuseppeMancia
Journal: Circulation (2001)

Background— The prevalence and clinical significance of isolated office (or white coat) hypertension is controversial, and population data are limited. We studied the prevalence of this condition and its association with echocardiographic left ventricular mass in the general population of the PAMELA (Pressione Arteriose Monitorate E Loro Associazioni) Study. Methods and Results— The study involved a large, randomized sample (n=3200) representative of the Monza (Milan) population, 25 to 74 years of age. Participants in the study (64% of the sample) underwent measurements of office, home, 24-hour ambulatory blood pressure, and echocardiography. Isolated office hypertension was defined as systolic or diastolic values ≥140 mm Hg or ≥90 mm Hg, respectively. Home and ambulatory normotension were defined according to criteria previously established from the PAMELA Study, for example, <132/83 mm Hg (systolic/diastolic) for home and 125/79 mm Hg for 24-hour average blood pressure. Treated hypertensive subjects wer...
Calcitonin Gene-Related Peptide Mediates Acetylcholine-Induced Endothelium-Independent Vasodilation in Mesenteric Resistance Blood Vessels of the Rat
Authors: MakotoTakenaga, HiromuKawasaki, AkihikoWada, TanenaoEto
Journal: Circulation Research (1995)

Abstract The role of calcitonin gene-related peptide (CGRP)–containing vasodilator nerves in acetylcholine chloride (ACh)–induced vasodilation was studied in the perfused mesenteric vascular bed isolated from the rat. Bolus infusions of ACh at smaller doses (0.1 and 1 nmol) produced rapid and short-lived vasodilation. However, larger doses (10 and 100 nmol) of ACh caused a rapid and subsequent long-lasting vasodilator response in which the duration of vasodilation was prolonged in a concentration-dependent manner. Pretreatment with capsaicin (1 μmol/L for 20 minutes) significantly shortened the duration of vasodilator response to ACh but did not affect the initial rapid phase of ACh-induced vasodilation. Chemical removal of the vascular endothelium by perfusion with sodium deoxycholate (1.75 to 1.80 mg/mL) for 30 seconds and subsequent treatment with Nω-nitro-l-arginine (100 μmol/L) to inhibit nitric oxide synthesis abolished the initial rapid vasodilator action of ACh at any given concentration. However,...
Abstract 828: Targeting theMEToncogene by concomitant inhibition of receptor and ligand by an antibody-‘decoy' strategy
Authors: Cristina Basilico, Chiara Modica, Federica Maione, Elisa Vigna, Paolo M. Comoglio
Journal: Cancer Research (2018)

Abstract Background: MET, a master gene sustaining ‘invasive growth', is a relevant target for cancer precision therapy. In a limited number of cases, a MET genetic lesion drives the malignant phenotype in ligand-independent manner (oncogene ‘addiction'). In the vast majority of tumors, however, wild-type MET behaves as a ‘stress-response' gene and relies on the ligand (HGF) to sustain cell ‘scattering', invasive growth and apoptosis protection (oncogene ‘expedience'). In this context -i.e. ligand-dependent MET activation- concomitant targeting of MET and HGF could be crucial to reach effective inhibition. Methods: To test this hypothesis we combined an anti-MET antibody (MvDN30), characterized by the property of inducing ‘shedding' (i.e. removal of MET from the cell surface), with a ‘decoy' (i.e. the soluble extracellular domain of the MET receptor) endowed with HGF-sequestering ability. To avoid antibody/decoy interaction -and subsequent neutralization- we identified by site directed mutagenesis a single aminoacid in the extracellular domain of MET -lysine 842- that is critical for MvDN30 binding, and engineered the corresponding recombinant decoyMET (K842E). The effect of MvDN30 and decoyMETK842E in combination on the inhibition of MET phosphorylation and on the impairment of different MET driven biological responses (motility, invasion, cell proliferation, apoptosis and anchorage independent cell growth) was evaluated on a panel of cancer cells (lines and patient derived-primary cultures) expressing wild-type MET sensitive to HGF stimulation. Therapeutic efficacy was assessed in an orthotopic model of pancreatic cancer generated in SCID mice engineered to express human HGF. Results: The decoyMETK842E retains the ability to bind HGF with high affinity and inhibits HGF-induced MET phosphorylation. In HGF-dependent cellular models, MvDN30 antibody and decoyMETK842E used in combination cooperate in restraining invasive growth, and synergize in blocking cancer cell ‘scattering'. The antibody and the decoy unbridle apoptosis of colon cancer stem cells grown in vitro as spheroids. In the preclinical model of MET ‘expedience' concomitant treatment with antibody and decoy significantly reduces metastatic spread. Conclusions: The data reported indicate that vertical targeting of the MET/HGF axis results in powerful inhibition of ligand-dependent MET activation, providing proof of concept in favor of combined targeted therapy of MET ‘expedience'. Citation Format: Cristina Basilico, Chiara Modica, Federica Maione, Elisa Vigna, Paolo M. Comoglio. Targeting the MET oncogene by concomitant inhibition of receptor and ligand by an antibody-‘decoy' strategy [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 828.
Deck the Halls With Diverse Portraits
Authors: Caroline Wellbery, Ranit Mishori
Journal: JAMA (2018)

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