tbuckley/cabot-search huggingface dataset:
Abstract PR02: Mechanisms of NT5C2 activating mutations driving thiopurine resistance in relapsed lymphoblastic leukemia
Authors: Chelsea L. Dieck, Gannie Tzoneva, Farhad Forouhar, Zachary Carpenter, Marta Sanchez-Martin, Alberto Ambesi-Impiombato, Renate Kirschner-Schwabe, Scott Lew, Jayaraman Seetharaman, Liang Tong, Adolfo Ferrando
Journal: Clinical Cancer Research (2017)

Abstract Activating mutations in cytosolic 5'-nucleotidase II (NT5C2) drive resistance to 6-mercaptopurine (6-MP) in relapsed acute lymphoblastic leukemia (ALL). These gain-of function alleles encode proteins with increased nucleotidase activity, yet their specific molecular mechanisms are poorly understood. Allosteric activation of NT5C2 is primarily mediated by a marked conformational change in the helix A region, which reconfigures the catalytic center for substrate access and catalysis. Here we demonstrate that constitutively active NT5C2 mutant proteins (K359Q and L375F) adopt active helix A region structures in the absence of allosteric activator. Moreover, crystallographic, structural modeling, genetic, and functional antibody analyses identify a switch-off mechanism mediated by the dynamic mobilization of Asp407 in the tip region of the arm segment which, guided by positively charged residues located in the surface of a basic inter-monomeric cavity exposed upon allosteric activation, turns off NT5C2 by interacting with and disrupting the helical conformation of helix A. Loss of this regulatory mechanism in NT5C2 mutants involving the tip region of the arm segment and the inter-monomeric cavity drives increased nucleotidase activity and allosteric response. Finally, increased allosteric activation by the Q523X mutation results from loss of the NT5C2 C-terminal acidic tail segment, which promotes a closed inactive state in basal conditions. These results uncover dynamic mechanisms responsible for NT5C2 regulation targeted by chemotherapy resistance-driving NT5C2 mutations, with important implications for the development of NT5C2 inhibitor therapies. This abstract is also being presented as Poster 05. Citation Format: Chelsea L. Dieck, Gannie Tzoneva, Farhad Forouhar, Zachary Carpenter, Marta Sanchez-Martin, Alberto Ambesi-Impiombato, Renate Kirschner-Schwabe, Scott Lew, Jayaraman Seetharaman, Liang Tong, Adolfo Ferrando. Mechanisms of NT5C2 activating mutations driving thiopurine resistance in relapsed lymphoblastic leukemia [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr PR02.
Hypoplasia of the Small Pulmonary Arteries in Hypoplastic Left Heart Syndrome With Restrictive Atrial Septal Defect
Authors: KatsuhideMaeda, ShigeoYamaki, HideakiKado, ToshihideAsou, ArataMurakami, ShinichiTakamoto
Journal: Circulation (2004)

Background— Restrictive atrial septal defect (ASD) (including intact atrial septum [IAS]) has been reported to be a risk factor that negatively impacts survival in hypoplastic left heart syndrome (HLHS). Although lymphangiectasia and “arterialization” of the veins of the lung in HLHS with restrictive ASD have been reported, they cannot fully explain the high mortality. We have introduced a new method of evaluating the development of the pulmonary vasculature in histological sections and used it to assess patients’ lungs. We tested the hypothesis that the small pulmonary arteries (SPA), which are pulmonary arteries in a histological section whose radii are ≈25 μm to 250 μm, in HLHS with restrictive ASD are hypoplastic, but that the alveoli are not, to elucidate the mechanism underlying the poor outcome of these patients. Methods and Results— Fourteen HLHS patients between 1 day and 40 days of age were studied. In 8 cases, the ASD was restrictive [R(+) group], and in the other 6 cases it was not [R(−) group...
Lower Expression of Neutrophil Adhesion Molecule Indicates Less Vessel Wall Injury and Might Explain Lower Restenosis Rate After Cutting Balloon Angioplasty
Authors: TeruoInoue, YoshihikoSakai, KazuhiroHoshi, IsaoYaguchi, TsuneoFujito, ShigenoriMorooka
Journal: Circulation (1998)

Background—The Cutting Balloon is a novel dilatation catheter for coronary angioplasty (InterVentional Technologies Inc). It produces longitudinal, microsurgical incisions in the vessel wall before the actual dilatation. It is assumed that these controlled surgical incisions relieve hoop stress and reduce vessel wall injury and eventually restenosis. However, no clinical indicator to support the theory of reduced injury has been described. Certain clusters of differentiation (eg, CD11, CD18 on the leukocytes) are implicated in leukocyte adhesion, increased permeability, and opsonization. Therefore, they might serve as clinical indicators of the injury level of the vessels after angioplasty. Methods and Results—We randomly selected 64 patients with isolated left anterior descending coronary artery disease for either Cutting Balloon angioplasty or conventional balloon angioplasty. The expression of CD18 and CD11b on the surface of neutrophils was determined by flow cytometric analysis. Serum levels of solub...
Abstract 12868: Morphine Decreases Ticagrelor Concentrations but Not Its Effects: A Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Eva-Luise Hobl, Birgit Reiter, Thomas Stimpfl, Christian Schoergenhofer, Michael Schwameis, Ulla Derhaschnig, Bernd Jilma
Journal: Circulation (2015)

Introduction: Our recent drug interaction trial with clopidogrel showed that morphine decreases the concentrations and effects of clopidogrel, which could lead to treatment failure in susceptible individuals. This study examined possible drug-drug interactions between ticagrelor and morphine. Hypothesis: We hypothesized that the pharmacodynamic consequences of drug-drug interactions would be less between morphine and ticagrelor. Methods: Twenty-four healthy subjects received a loading dose of 180mg ticagrelor together with placebo or 5mg morphine intravenously in a randomized, double-blind, placebo-controlled, cross-over trial. Pharmacokinetics were determined by liquid chromatography tandem mass spectrometry, and ticagrelor effects were measured by platelet function tests. Results: Concomitant i.v. injection of morphine slows drug resorption of ticagrelor and its active metabolite (p&lt;0.05) by one hour and decreases plasma levels of ticagrelor and its active metabolite (by 25-31%; p &lt; 0.03) and the drug exposure (area under the curve by 22-23%; p &lt; 0.01). Importantly, however, the effects of ticagrelor on platelet aggregation in whole blood, platelet plug formation, and vasodilator-stimulated phosphoprotein (VASP) phosphorylation are not affected by morphine. Conclusions: Morphine co-administration moderately decreases ticagrelor plasma concentrations but does not inhibit ist effects. Therefore, a 180 mg loading dose of ticagrelor appears to provide consistent and reliable platelet inhibition when morphine has to be given for pain relief.
Exposure of normal human epidermal keratinocytes to ozone results in increased expression of cytochrome P450 through activation of aryl hydrocarbon receptor
Authors: Mohammad Abu Zaid, Farrukh Afaq, Naghma Khan, Ed Pelle, Mary Matsui, Daniel Maes, Hasan Mukhtar
Journal: Cancer Research (2008)

595   Ozone, one of the main components of photochemical smog, represents an important source of environmental oxidative stress to which the skin is exposed, especially during smoggy and ozone alert days. The exposure of ozone has been shown to induce antioxidant depletion as well as the oxidation of lipids and proteins in mouse skin. The primary role of cytochrome P450s  (CYPs) in cutaneous tissue is to participate in biotransformation of endogenous substrates and xenobiotic materials such as environmental pollutants to which human skin is either deliberately or inadvertently exposed. For example, induction of the CYP1 family of isoforms in the skin by environmental pollutants and ultraviolet radiation has been suggested to be responsible for enhanced cutaneous carcinogenesis.  The present study was designed to determine the effect of ozone on CYP isoforms, aryl hydrocarbon receptor (AhR), epidermal growth factor receptor (EGFR) and its downstream events in normal human epidermal keratinocytes (NHEK). Western blotting and RT-PCR analyses indicated that ozone (0.3 ppm for 20 min) exposure to NHEK resulted in increased protein and mRNA expression of CYP1A1, CYP1A2 and CYP1B1, the CYP isoforms responsible for metabolic activation of environmental pollutant such as polycyclic aromatic hydrocarbons present in cigarette smoke. Because AhR induces transcription of CYP1A genes, we determined the effect of ozone on AhR. Ozone exposure resulted in increased expression of AhR protein and mRNA in NHEK. Since AhR is known to “cross-talk” with the EGFR, we next examined the phosphorylation of EGFR in ozone exposed cells. Exposure of NHEK to ozone resulted in an increased phosphorylation of EGFR. Next we determined the effect of ozone on downstream events of EGFR and found that it resulted in an increased (i) activation of PI3K, (ii) phosphorylation of AKT, and (iii) phosphorylation of ERK1/2, JNK1/2 and p38. To determine  whether ozone-induced CYPs expression is EGFR and/or AhR-dependent, we silenced NHEK by appropriate siRNAs for EGFR and AhR and then exposed them to ozone. We found that AhR silencing by siRNA abolished the capacity of these cells to increase the protein and mRNA expressions of CYP1A1, CYP1A2 and CYP1B1 upon ozone exposure. However, silencing of EGFR did not show any effect on ozone-induced protein and mRNA expression of CYPs. These data indicate that induction of CYPs by ozone is mediated through activation of AhR and not by EGFR. These studies could lead to development of novel skin care products for ameliorating ozone-induced toxic effects in the skin. Based on these results, we suggest that supplementation of skin care products with inhibitors of CYPs might be beneficial to skin damages caused by ozone especially, during smoggy and ozone alert days.
Focal Atrial Tachycardia
Authors: SatoshiHiga, Ching-TaiTai, Yenn-JiangLin, Tu-YingLiu, Pi-ChangLee, Jin-LongHuang, Ming-HsiungHsieh, YogaYuniadi, Bien-HsienHuang, Shih-HuangLee, Kwo-ChangUeng, Yu-AnDing, Shih-AnnChen
Journal: Circulation (2004)

Background— This study investigated the electrophysiologic characteristics, atrial activation pattern, and effects of radiofrequency (RF) catheter ablation guided by noncontact mapping system in patients with focal atrial tachycardia (AT). Methods and Results— In 13 patients with 14 focal ATs, noncontact mapping system was used to map and guide ablation of AT. AT origins were in the crista terminalis (n=8), right atrial (RA) free wall (n=3), Koch triangle (n=1), anterior portion of RA–inferior vena cava junction (n=1), and superior portion of tricuspid annulus (n=1); breakout sites were in the crista terminalis (n=5), RA free wall (n=5), middle cavotricuspid isthmus (n=2), and RA–superior vena cava junction (n=2). ATs arose from the focal origins (11 ATs inside or at the border of low-voltage zone), with preferential conduction, breakout, and spread to the whole atrium. After applications of RF energy on the earliest activation site or the proximal portion of preferential conduction from AT origin, 13 ATs...
Clinical Studies on Veratrum Alkaloids
Authors: Edwardmeilman, Ottokrayer
Journal: Circulation (1950)

The action of two pure veratrum alkaloids, veratridine and protoveratrine, in human hypertension is described for the first time. The vasodepressor reflex pathway involved in the response to these ester alkaloids is reviewed. Protoveratrine is found to produce a striking fall in blood pressure in both essential and renal hypertension after intravenous administration.
Prostaglandin D2 Inhibits Inducible Nitric Oxide Synthase Expression in Rat Vascular Smooth Muscle Cells
Authors: HiroshiNagoshi, YoshioUehara, FumihikoKanai, ShinMaeda, TsutomuOgura, AtsuoGoto, TeruhikoToyo-oka, HiroyasuEsumi, TakaoShimizu, MasaoOmata
Journal: Circulation Research (1998)

Abstract—Vascular smooth muscle cells (VSMCs) as well as macrophages have been shown to generate a substantial amount of NO in inflammatory vascular lesions. Prostaglandin (PG) D2 (PGD2) is produced by inflammatory cells, including mast cells and macrophages. We investigated whether PGD2 modulates NO metabolism in rat VSMCs. PGD2 at a concentration of 10–7 mol/L or greater dose-dependently inhibited nitrite accumulation in the medium of cultured VSMCs stimulated with interleukin 1β (IL-1β). In a dose-response analysis of IL-1β and nitrite accumulation, PGD2 was seen to decrease the maximal ability of VSMCs to generate NO, arguing against competition by PGD2 at cytokine receptors. Northern analysis showed that PGD2 suppresses induction of inducible NO synthase (iNOS) mRNA in IL-1β–stimulated VSMCs, with consequent inhibition of iNOS protein expression in Western analysis. A thromboxane A2 (TXA2) analogue, U46619 (10–5 mol/L), produced less inhibition of NO generation than did PGD2. Neither the PGI2 analog ...
Abstract 4948: MDM2 antagonism overcomes resistance to CDK4/6 inhibition in melanoma
Authors: Anna E. Vilgelm, Nabil Saleh, Kelsie Riemenschneider, Lauren Slesur, Sheau-Chian Chen, Gregory D. Ayers, Rondi M. Kauffman, Mark C. Kelley, Douglas B. Johnson, Ann Richmond
Journal: Cancer Research (2018)

Abstract Metastatic melanoma is an aggressive disease characterized by resistance to conventional cancer treatments such as radiation and chemotherapy. While immune checkpoint blockade and BRAF inhibitor therapies are effective in many melanoma cases, a significant proportion of patients are resistant to these standard of care treatments and thus require new therapeutic approaches. We hypothesized that targeting CDK4/6 may offer hope to melanoma patients refractory to immunotherapy and BRAF inhibition, based on CDK4 being a key oncogene activated by mutations or deletions of CDKN2A gene, which are very common in melanoma (&amp;gt;50% of cases). However, in vivo studies using our extensive collection of melanoma patient-derived xenografts (PDX) showed that the majority of melanoma tumors are intrinsically resistant to CDK4/6 inhibition. We identified the mechanism of this resistance which was driven by cooperative activities of other CDKs expressed by tumor cells that compensated for the loss of CDK4/6 function to allow cell cycle progression through G1 and S phases. In order to overcome compensatory activation of other CDKs, we used small molecule antagonists of MDM2-p53 interaction, that stabilize p53 protein, which, in turn, upregulates an endogenous pan-CDK inhibitor, p21. Notably, combined MDM2 and CDK4/6 antagonism resulted in greater inhibition of tumor growth than either inhibitor individually. This synergistic effect was observed in multiple melanoma PDX models and in immunocompetent mice bearing mouse melanoma tumors. In summary, our preclinical data suggest that combining CDK4/6 inhibitors with MDM2 antagonists is a promising strategy for the treatment of metastatic melanoma, which should be further tested by a clinical study. Citation Format: Anna E. Vilgelm, Nabil Saleh, Kelsie Riemenschneider, Lauren Slesur, Sheau-Chian Chen, Gregory D. Ayers, Rondi M. Kauffman, Mark C. Kelley, Douglas B. Johnson, Ann Richmond. MDM2 antagonism overcomes resistance to CDK4/6 inhibition in melanoma [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 4948.
Safety and Efficacy of Exenatide Once Weekly Plus Dapagliflozin Once Daily Versus Exenatide or Dapagliflozin Alone in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Monotherapy: 52-Week Results of the DURATION-8 Randomized Controlled Trial
Authors: Serge A. Jabbour, Juan P. Frías, Elise Hardy, Azazuddin Ahmed, Hui Wang, Peter Öhman, Cristian Guja
Journal: Diabetes Care (2018)

OBJECTIVE Among patients with type 2 diabetes uncontrolled with metformin, exenatide once weekly (QW) plus dapagliflozin combination produced greater reductions in glycemia, weight, and systolic blood pressure (SBP) at 28 weeks than exenatide QW or dapagliflozin alone (DURATION-8). Here, we investigated the safety and maintenance of efficacy at 52 weeks, after a 24-week extension. RESEARCH DESIGN AND METHODS This phase 3, multicenter, double-blind study randomized adults with type 2 diabetes (with glycated hemoglobin [HbA1c] 8.0–12.0% [64–108 mmol/mol] and on metformin ≥1,500 mg/day) to exenatide QW (2-mg subcutaneous injection) plus once-daily dapagliflozin (10-mg oral tablet), exenatide QW plus oral placebo, or dapagliflozin plus injected placebo. Extension-period P values were nominal. RESULTS Of 1,375 patients screened, 695 were randomized (mean baseline HbA1c 9.3% [78 mmol/mol]); 81.2% completed the study, and 75.3% completed treatment. At 52 weeks, HbA1c reductions were greater with exenatide QW plus dapagliflozin (least squares mean change −1.75% [−19.1 mmol/mol]) versus exenatide QW (−1.38% [−15.1 mmol/mol]; P = 0.006) or dapagliflozin (−1.23% [−13.4 mmol/mol]; P &amp;lt; 0.001); mean HbA1c values were 6.9% (52 mmol/mol), 7.2% (55 mmol/mol), and 7.4% (57 mmol/mol), respectively. Weight and SBP reductions were greater with exenatide QW plus dapagliflozin (−3.31 kg and −4.5 mmHg) versus exenatide QW (−1.51 kg and −0.7 mmHg; both P &amp;lt; 0.001) but similar to those with dapagliflozin (−2.28 kg and −2.7 mmHg; P = 0.057 and P = 0.100, respectively). The exenatide QW plus dapagliflozin regimen was well tolerated with no unexpected safety findings; more patients treated with exenatide QW experienced gastrointestinal and injection site–related adverse events. No major hypoglycemia occurred. CONCLUSIONS Among patients with type 2 diabetes uncontrolled with metformin, exenatide QW plus dapagliflozin provided sustained improvements in glycemia, weight, and SBP over 52 weeks, with no unexpected safety findings.
Cellular Basis for the ECG Features of the LQT1 Form of the Long-QT Syndrome
Authors: WataruShimizu, CharlesAntzelevitch
Journal: Circulation (1998)

Background—This study examines the cellular basis for the phenotypic appearance of broad-based T waves, increased transmural dispersion of repolarization (TDR), and torsade de pointes (TdP) induced by β-adrenergic agonists under conditions mimicking the LQT1 form of the congenital long-QT syndrome. Methods and Results—A transmural ECG and transmembrane action potentials from epicardial, M, and endocardial cells were recorded simultaneously from an arterially perfused wedge of canine left ventricle. Chromanol 293B, a specific IKs blocker, dose-dependently (1 to 100 μmol/L) prolonged the QT interval and action potential duration (APD90) of the 3 cell types but did not widen the T wave, increase TDR, or induce TdP. Isoproterenol 10 to 100 nmol/L in the continued presence of chromanol 293B 30 μmol/L abbreviated the APD90 of epicardial and endocardial cells but not that of the M cell, resulting in widening of the T wave and a dramatic accentuation of TDR. Spontaneous as well as programmed electrical stimulatio...
Thyroid Hormone Activation in Human Vascular Smooth Muscle Cells
Authors: HaruoMizuma, MasamiMurakami, MasatomoMori
Journal: Circulation Research (2001)

Abstract—Thyroid hormone has been reported to have significant effects on the peripheral vascular system, including relaxation of vascular smooth muscle cells and antiatherosclerotic effects. To exert its biological activity, thyroxine, which is a major secretory product of thyroid gland, needs to be converted to 3,5,3′-triiodothyronine (T3) by iodothyronine deiodinase. Type I iodothyronine deiodinase (DI) is widely distributed and maintains circulating T3 level, whereas type II iodothyronine deiodinase (DII) is present in a limited number of tissues to provide local intracellular T3. In the present study, we have identified iodothyronine deiodinase in cultured human coronary artery smooth muscle cells (hCASMCs) and human aortic smooth muscle cells (hASMCs). All of the characteristics of the deiodinating activity in hCASMCs and hASMCs were compatible with DII. Northern analysis demonstrated that DII mRNA was expressed in both hCASMCs and hASMCs, and DII mRNA levels as well as DII activities were rapidly i...
Response to Letter Regarding Article, “Role of Left Ventricular Stiffness in Heart Failure With Normal Ejection Fraction”
Authors: DirkWestermann, MarioKasner, FrankSpillmann, AlexanderRiad, WolfgangPoller, MatthiasPauschinger, Heinz-PeterSchultheiss, CarstenTschöpe, PaulSteendijk, KerstinWeitmann, WolfgangHoffmann
Journal: Circulation (2009)
Abstract 2561: Fully human immunoglobulin heavy chain only-derived CD33 CAR for the treatment of acute myeloid leukemia
Authors: Dina Schneider, Ying Xiong, Weizao Chen, Zhongyu Zhu, Darong Wu, Jennifer Hwang, Dimiter S. Dimitrov, Boro Dropulic, Rimas J. Orentas
Journal: Cancer Research (2018)

Abstract CD33 antigen is a promising target expressed on non-solid cancers, including acute myeloid leukemia (AML). Present investigative approaches to treatment of CD33-positive AML include antibody drug conjugates (My96, Mylotarg®) and CART cells incorporating CD33-targeting domains derived from a humanized scFv. Here, we designed a chimeric antigen receptor utilizing targeting domain derived from a fully human CD33 fragment variable heavy chain sequence, termed CAR33VH, and examined its in vitro and in vivo potency against AML. Primary human CD4+ CD8+ T cells derived from three healthy donors were transduced with lentiviral constructs (LV) encoding CAR33VH, or control CAR construct based on scFv My96 (My96CAR). Flow cytometric analysis revealed expression of CAR33VH at 32%-45%, and expression of My96CAR at 77% - 86%. When challenged with CD33+ AML tumor lines HL60 and MOLM-14 in vitro, both constructs demonstrated efficient target killing. CD33- tumor lines K562 and Reh were not sensitive to CAR killing, underscoring CAR specificity to CD33 antigen. Pro-inflammatory cytokines IFN gamma, TNF alpha and IL-2 in culture supernatants of CART cells incubated with CD33+ HL-60 and MOLM-14 tumors, but not with CD33- K562 cells overnight, were induced, as measured by ELISA. Long-term co-incubation assay of CART cells with HL-60 leukemia at E:T ratios 1:5 to 1: 0.04, suggested similar killing potency and persistence of CAR33VH to the positive control scFv-based CAR. In in vivo AML model, NSG mice engrafted with MOLM-14 cells stably expressing firefly luciferase, both CAR33VH, and My96CAR control were equally efficient in tumor elimination. In conclusion, CAR33VH, comprised of a fully human heavy-chain variable fragment only antigen binding domain, was efficient in tumor killing in vitro and in vivo, and may be used clinically for treatment of CD33+ hematologic malignancies. To our knowledge, this is one of the first instances demonstrating the feasibility of employing heavy chain only binder sequence in CART design. Citation Format: Dina Schneider, Ying Xiong, Weizao Chen, Zhongyu Zhu, Darong Wu, Jennifer Hwang, Dimiter S. Dimitrov, Boro Dropulic, Rimas J. Orentas. Fully human immunoglobulin heavy chain only-derived CD33 CAR for the treatment of acute myeloid leukemia [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 2561.