tbuckley/cabot-search huggingface dataset:
Abstract 4149: Inhibition of ribonucleotide reductase (RNR) in Ewing sarcoma cells results in suppression of protein synthesis
Authors: Stacia Koppenhafer, Kelli Goss, David Gordon
Journal: Cancer Research (2018)

Abstract Ewing sarcoma is a highly aggressive bone and soft tissue cancer that is caused by the EWS-FLI1 fusion protein. EWS-FLI1 is required for tumor growth and survival. However, directly targeting EWS-FLI1 with drugs has been challenging and an alternative therapeutic approach is to identify unique vulnerabilities incurred by the oncoprotein. In previous work, we identified that Ewing sarcoma cells are uniquely vulnerable to drugs that inhibit ribonucleotide reductase (RNR), which is the rate limiting enzyme in the synthesis of deoxyribonucleotides. Furthermore, we also showed that blocking the function of checkpoint kinase 1 (CHK1), a major regulator of the response to impaired DNA replication, using either a small molecule inhibitor or siRNA-mediated knockdown causes synergistic toxicity with gemcitabine, an irreversible inhibitor of the RRM1 subunit of RNR, in Ewing sarcoma cells. In the current work, we identifiy that inhibition of RNR in Ewing sarcoma cells in vitro and in vivo results in the suppression of protein synthesis. Moreover, we have found that the treatment of Ewing sarcoma cell lines with gemcitabine results in an increase in the active (unphosphorylated) form of 4E-BP1, which is a well-described inhibitor of protein translation. However, in contrast to the Ewing sarcoma cells, treatment of other cell types with gemcitabine did not alter 4E-BP1 phosphorylation or protein synthesis. Currently, ongoing work is focused on the in vivo testing of gemcitabine, alone and in combination with CHK1, ataxia telangiectasia and rad3-related protein (ATR), and protein synthesis inhibitors, as a novel therapeutic approach for the treatment of Ewing sarcoma. Citation Format: Stacia Koppenhafer, Kelli Goss, David Gordon. Inhibition of ribonucleotide reductase (RNR) in Ewing sarcoma cells results in suppression of protein synthesis [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 4149.
Pulmonary Hypertension Caused by Persistent Anomalous Vertical Vein Bridging the Left Subclavian Vein and Left Atrium With Hypertrophic Cardiomyopathy
Authors: SonokoMaemura, MasatoIshizuka, RyoNakata, YoshihiroMotozawa, KeisukeYamamoto, MasatakaTakizawa, HirokiUozumi, HiroshiIkenouchi
Journal: Circulation (2014)
Balloon-Protected Carotid Artery Stenting
Authors: ThiloTübler, MichaelSchlüter, OlafDirsch, HorstSievert, IlkaBösenberg, EberhardGrube, JürgenWaigand, JoachimSchofer
Journal: Circulation (2001)

Background Carotid artery stenting (CAS) has been advocated as an alternative to endarterectomy. To prevent cerebral atheroembolism during CAS, distal balloon occlusion of the target artery increasingly is employed during the procedure. A correlation of the size of captured particles with the incidence of periprocedural neurological complications (PNCs) has not been attempted. Methods and Results In a 4-center, phase-1 trial, 54 patients (46 men; age, 69±8 years) underwent 58 CAS procedures using the PercuSurge GuardWire system for distal protection. Aspirated debris was sent for histological/cytological analysis. Stent placement was successful in all cases. Mean balloon occlusion time was 10.4±4.0 minutes (range, 3.0 to 22.0 minutes). Three patients (5.2%) experienced PNCs: 1 prolonged reversible ischemic neurological deficit that resolved in ≤48 hours, 1 stroke, and 1 transient ischemic attack. Relevant particles (those with an area ≥10 000 μm2) were found in 48 aspirates (83%). The median number of par...
Heart Valve Involvement (Libman-Sacks Endocarditis) in the Antiphospholipid Syndrome
Authors: MajaHojnik, JacobGeorge, LeaZiporen, YehudaShoenfeld
Journal: Circulation (1996)

Abstract The antiphospholipid syndrome (APS) is defined by the presence of anti-phospholipid antibodies (aPLs) and venous or arterial thrombosis, recurrent pregnancy loss, or thrombocytopenia. The syndrome can be either primary or secondary to an underlying condition, most commonly systemic lupus erythematosus (SLE). Echocardiographic studies have disclosed heart valve abnormalities in about a third of patients with primary APS. SLE patients with aPLs have a higher prevalence of valvular involvement than those without these antibodies. Valvular lesions associated with aPLs occur as valve masses (nonbacterial vegetations) or thickening. These two morphological alterations can be combined and are thought to reflect the same pathological process. Both can be associated with valve dysfunction, although such association is much more common with the latter alteration. The predominant functional abnormality is regurgitation; stenosis is rare. The mitral valve is mainly affected, followed by the aortic valve. Val...
Inhibition of Catecholamine Biosynthesis in Man
Authors: Karlengelman, Albertsjoerdsma
Journal: Circulation Research (1966)

Reduction of catecholamine synthesis by as much as 70% has been achieved in man with the oral administration of a-methyl-para-Ltyrosine, a tyrosine hydroxylase inhibitor. Significant reduction of blood pressure and improvement of the general clinical status have been achieved in patients with pheochromocytoma. However, at the doses employed, no significant blood pressure effects were noted in patients with essential hypertension.
Abstract 3954: Anti-cancer agent P306 restores p53 pathway through PUMA
Authors: Xiaobing Tian, Amriti R. Lulla, Shengling Zhang, Avital Lev, Philip Abbosh, Rahmat Sikder, David T. Dicker, Wafik S. El-Deiry
Journal: Cancer Research (2018)

Abstract The tumor-suppressor p53 prevents cancer development via initiating cell-cycle arrest, cell death, repair, or anti-angiogenesis processes. Over 50% of human cancers harbor cancer-causing mutations in p53. p53 mutations not only abrogate its tumor-suppressor function, but also endow mutant p53 with a gain of function (GOF), creating a proto-oncogene that contributes to tumorigenesis, tumor progression, and chemo- or radiotherapy resistance. Thus, targeting mutant p53 and/or restoring a wild-type p53 signaling pathway provides an attractive strategy for cancer therapy. We previously showed that P01, a natural product, has potent anti-cancer activity against tumors with mutated p53. Based on the structure of the pharmacophore of the P01 family, we designed and synthesized new analogues. The novel synthetic analogue, P306, is potent in reducing both short-term and long-term proliferation in a broad panel of mutant p53 cell lines, including HT29, SW480, DLD-1, MDA-MB-231, MDA-MB-468, U251, FaDu, CAL-27, PANC-1, ASPC-1 and H1975, with IC50 values in the range of 33.9 to 242 nM. In this study, we have characterized a distinct mechanism of P306 that engages the apoptosis pathway by upregulating pro-apoptotic proteins including PUMA in a time-and dose-dependent manner in colorectal cancer cell lines. PUMA is necessary for the apoptotic effects of P306 in colorectal cancer cells with PUMA-mediated caspase 8 activation mediating P306-induced apoptosis. P306 not only restores p53 pathway but also depletes mutant p53 protein in various mutant p53-expressing cancer cells regardless of what kinds of mutation. P306 treatment potently downregulates c-Myc protein level, and apoptosis induced by P306 is dependent on the c-Myc-PUMA pathway. Our results provide novel mechanistic insights into the tumor cell death promoting activity of a candidate therapeutic agent for cancer. Citation Format: Xiaobing Tian, Amriti R. Lulla, Shengling Zhang, Avital Lev, Philip Abbosh, Rahmat Sikder, David T. Dicker, Wafik S. El-Deiry. Anti-cancer agent P306 restores p53 pathway through PUMA [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 3954.
Human Prostacyclin Synthase Gene and Hypertension
Authors: NaoharuIwai, TomohiroKatsuya, KazuhikoIshikawa, ToshifumiMannami, JunOgata, JitsuoHigaki, ToshioOgihara, TadashiTanabe, ShunrokuBaba
Journal: Circulation (1999)

Background—Prostacyclin (prostaglandin I2) is a strong vasodilator that inhibits the growth of vascular smooth muscle cells and is also the most potent endogenous inhibitor of platelet aggregation. Therefore, it has been considered to play an important roles in cardiovascular disease. On the basis of the hypothesis that variations of the prostacyclin synthase gene may also play an important role in human cardiovascular disease, we performed a screening for variations in the human prostacyclin synthase gene. Methods and Results—We have detected a repeat polymorphism in the promoter region of the human prostacyclin synthase gene. The number of 9-bp (CCGCCAGCC) repeats in the promoter region, which encodes a tandem repeat of Sp1 transcriptional binding sites, varied between 3 and 7 in Japanese subjects. Luciferase reporter analysis indicated that the alleles of 3 and 4 repeats (R3 and R4, respectively) had less promoter activity in cultured human umbilical vein endothelial cells. We then investigated the pos...
Aspirin, Warfarin, or the Combination for Secondary Prevention of Coronary Events in Patients With Acute Coronary Syndromes and Prior Coronary Artery Bypass Surgery
Authors: ThaoHuynh, PierreThéroux, PeterBogaty, JamesNasmith, SusanSolymoss
Journal: Circulation (2001)

Background—Patients with a non–ST-elevation acute coronary syndrome and prior CABG are at high risk of a recurrent ischemic event despite aspirin therapy. This trial investigated the potential benefit of secondary prevention with warfarin. Methods and Results—In a double-blind randomized trial, 135 patients with unstable angina or non–ST-segment elevation myocardial infarction, with prior CABG, and who were poor candidates for a revascularization procedure received therapy with aspirin and placebo+warfarin, warfarin and placebo+aspirin, or aspirin and warfarin for 12 months. Warfarin was titrated to an international normalized ratio of 2.0 to 2.5. The primary end point (death or myocardial infarction or unstable angina requiring hospitalization 1 year after randomization) occurred in 14.6% of the patients in the warfarin-alone group, in 11.5% of patients in the aspirin-alone group, and in 11.3% of patients randomized to the combination therapy (P=0.76). Subgroup analyses by risk features provided no indic...
Plasma Activity and Insertion/Deletion Polymorphism of Angiotensin I–Converting Enzyme
Authors: FlavioRibichini, GiuseppeSteffenino, AntonioDellavalle, GiuseppeMatullo, ElenaColajanni, TerenzioCamilla, AntonelloVado, GabriellaBenetton, EugenioUslenghi, AlbertoPiazza
Journal: Circulation (1998)

Background—Tissue proliferation is almost invariably observed in recurrent lesions within stents, and ACE, a factor of smooth muscle cell proliferation, may play an important role. Plasma ACE level is largely controlled by the insertion/deletion (I/D) polymorphism of the enzyme gene. The association among restenosis within coronary stents, plasma ACE level, and the I/D polymorphism is analyzed in the present prospective study. Methods and Results—One hundred seventy-six consecutive patients with successful, high-pressure, elective stenting of de novo lesions in the native coronary vessels were considered. At follow-up angiography, recurrence was observed in 35 patients (19.9%). Baseline clinical and demographic variables, plasma glucose and serum fibrinogen levels, lipid profile, descriptive and quantitative angiographic data, and procedural variables were not significantly different in patients with and without restenosis; mean plasma ACE levels (±SEM) were 40.8±3.5 and 20.7±1.0 U/L, respectively (P<.000...
East Asian Variant of Aldehyde Dehydrogenase 2 Is Associated With Coronary Spastic Angina
Authors: YujiMizuno, EisakuHarada, SumioMorita, KenjiKinoshita, MarikoHayashida, MakotoShono, YoshinobuMorikawa, ToyoakiMurohara, MasafumiNakayama, MichihiroYoshimura, HirofumiYasue
Journal: Circulation (2015)

Background—Coronary spastic angina (CSA) is a common disease among East Asians, including Japanese. The prevalence of alcohol flushing syndrome associated with deficient activity of the variant aldehyde dehydrogenase 2 (ALDH2*2) genotype is prevalent among East Asians. We examined whether CSA is associated with the ALDH2*2 genotype in Japanese. Methods and Results—The study subjects consisted of 202 patients in whom intracoronary injection of acetylcholine was performed by angiography on suspicion of CSA (119 men and 83 women; mean age, 66.2±11.4 years). They were divided into CSA (112 patients) and control groups (90 patients). ALDH2 genotyping was performed by the direct application of the TaqMan polymerase chain reaction system on dried whole blood. Clinical and laboratory data were examined using conventional methods. The frequencies of male sex, ALDH2*2 genotype carriers, alcohol flushing syndrome, tobacco smoking, and the plasma level of uric acid were higher (P<0.001, P<0.001, P<0.001, P<0.001, and...
Abstract 2477: Exosomal RNA mediates transformation of nontumorigenic human bronchial lung epithelial cells
Authors: Sarunya Kitdumrongthum, Sean Humphrey, Hana Kubo, Feng Tian, Sarah Allen, Nadia Atallah, Humna Hasan, Andrea L. Kasinski
Journal: Cancer Research (2018)

Abstract Exosomes are nanovesicles with a diameter between 30-150 nm. Exosomes are produced and released by all cell types into body fluids and, thus, play a major role in cell-cell communication through the transfer of proteins, lipids, and nucleic acids into recipient cells. Uptake of bioactive cargo into recipient cells can impart physiologic and biologic changes in the recipient cell. Especially in cancer, exosome released from cancer cells can reprogram cells, driving various hallmarks of cancer, such as proliferation, migration, invasion, and angiogenesis. In this study we evaluated the effects of exosomes, isolated from non-small cell lung cancer (NSCLC) cells, on nontumorigenic human bronchial epithelial cells (HBECs). Firstly, we determined that cancer cells generate more exosomes than nontumorigenic cells and that cancer cell-derived exosomes are readily taken up by nontumorigenic cells. The nontumorigenic cells exposed to NSCLC-derived exosomes gained the ability to migration and invade. In parallel, we observed that NSCLC-derived exosomes promoted changes in epithelial-to-mesenchymal gene profiles, supporting the conclusion that HBECs were becoming transformed. Exosomes were also capable of permeablizing a monolayer of human endothelial cells, suggesting that NSCLC-derived exosomes may disrupt the vasculature enhancing metastatic capabilities. Importantly, the transformative effects of the exosomes were mediated mostly by exosomal RNA. Comparing the RNA profile from a panel of cancerous exosomes to RNAs contained inside of exosomes isolated from nontumorigenic, one long noncoding RNA (lncRNA) was highly elevated. Knockout of this lncRNA greatly diminished the capability of the cancerous exosomes to promote the observed hallmarks of cancer, suggesting that a single lncRNA is responsible for the majority of the tumorigenic capacity of the exosomes. In vivo mouse modeling and patient-based evidence are currently under way to support these cell-based findings. Citation Format: Sarunya Kitdumrongthum, Sean Humphrey, Hana Kubo, Feng Tian, Sarah Allen, Nadia Atallah, Humna Hasan, Andrea L. Kasinski. Exosomal RNA mediates transformation of nontumorigenic human bronchial lung epithelial 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 2477.
Incomplete Stent Apposition and Very Late Stent Thrombosis After Drug-Eluting Stent Implantation
Authors: StéphaneCook, PeterWenaweser, MarioTogni, MichaelBillinger, CyrillMorger, ChristianSeiler, RolfVogel, OttoHess, BernhardMeier, StephanWindecker
Journal: Circulation (2007)

Background— Stent thrombosis may occur late after drug-eluting stent (DES) implantation, and its cause remains unknown. The present study investigated differences of the stented segment between patients with and without very late stent thrombosis with the use of intravascular ultrasound. Methods and Results— Since January 2004, patients presenting with very late stent thrombosis (>1 year) after DES implantation underwent intravascular ultrasound. Findings in patients with very late stent thrombosis were compared with intravascular ultrasound routinely obtained 8 months after DES implantation in 144 control patients, who did not experience stent thrombosis for ≥2 years. Very late stent thrombosis was encountered in 13 patients at a mean of 630±166 days after DES implantation. Compared with DES controls, patients with very late stent thrombosis had longer lesions (23.9±16.0 versus 13.3±7.9 mm; P<0.001) and stents (34.6±22.4 versus 18.6±9.5 mm; P<0.001), more stents per lesion (1.6±0.9 versus 1.1±0.4; P<0.00...
Abstract 700: Characterization of new AML PDX models: Engraftment kinetics and mutational profile
Authors: Pali Kaur, Victoria Sachs, Amanda L. Christie, David M. Weinstock, James G. Keck
Journal: Cancer Research (2018)

Abstract Acute myeloid leukemia (AML) is a genetically heterogeneous cancer of progenitor cells in myeloid hematopoiesis. Due to heterogeneity, most of AMLs are not responsive to targeted therapy. In addition, treatment outcome varies greatly depending upon patient age, disease etiology and mutational status. Previously, a large repository of well-characterized patient-derived- xenografts (PDXs) of hematologic malignancies was established (Townsend et al., 2016). This repository was generated by injecting primary bone marrow and blood samples from patients with leukemia into NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mice. An average success rate of 23.2% engraftment was observed in first passage (P0). In this study, we have characterized ten AML PDX models in NSG-SGM3 mice by serial transplantation. NSG-SGM3 (NOD.Cg-Prkdcscid Il2rgtm1Wjl Tg(CMV-IL3,CSF2,KITLG)1Eav/MloySzJ) mice have been found to have increased proliferation and survival of engrafted AML cells along with decreased disease latency (Wunderlich et al., 2010). Leukemic engraftment in these models was confirmed by flow analysis for hCD45+ hCD33+ in the peripheral blood, bone marrow and spleen of engrafted mice. Kinetics of engraftment varied from one model to another; and ranged from 10% - 80% of hCD33+ in peripheral blood 8 week post AML cell injection (1X106 cells/mouse). Four models displayed positive response to Cytarabine (Ara-C) treatment with reduction in levels of human CD33+ cells following a 5-day treatment cycle. Data will be presented on model characterization to show distinct engraftment kinetics, correlation with disease mutations and response to AML standard of care drug Cytarabine. These models have varying mutational profiles and treatment histories. Mutations include FLT3, FLT3-ITD, NPM1, TP53, DNMT3A and CUX1 alone or in combination. Treatment phases at the time of collection varied from untreated to relapse post-chemotherapy. These AML PDX models are useful tools for testing new experimental therapeutics. Diversity of these AML PDX models will facilitate focus on specific AML targets, thus providing an invaluable tool set to support drug discovery. Citation Format: Pali Kaur, Victoria Sachs, Amanda L. Christie, David M. Weinstock, James G. Keck. Characterization of new AML PDX models: Engraftment kinetics and mutational profile [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 700.
Abstract 2981: Clonal deletion of tumor-specific T cells by combination checkpoint blockade compromises antitumor efficacy in low tumor burden states
Authors: Chien-Chun Steven Pai, Xiaoqing Lu, Donald Simons, Michel DuPage, Kole T. Roybal, Mingyi Chen, Serena Kwek, Amy-Jo Casbon, Gillian A. Kinsbury, Lawrence Fong
Journal: Cancer Research (2018)

Abstract A myriad of combination immunotherapies is being developed as cancer treatments with the goal of enhancing antitumor immunity. We found that depending on the disease setting, combined immune checkpoint blockade may not always lead to synergistic antitumor effects. While combined anti-CTLA-4 and anti-PD-1 improves control of established tumors, this combination can paradoxically compromise antitumor immunity in the low tumor burden state in preclinical models as well as in melanoma patients. This paradoxical outcome results from treatment-induced apoptosis of tumor-specific T cells. These changes further alter the overall T-cell receptor repertoire. Activated tumor-specific T cells express higher levels of IFN-γ receptor and are more susceptible to apoptosis. Deficiency of IFN-γ receptor on immune cells rescues this phenotype and restores antitumor activity. Additionally, tumor-specific T cells lacking the IFN-γ receptor demonstrate a significant survival advantage compared to their wild-type counterparts in tumor-bearing mice receiving combination therapy. Finally, combination therapy induces significantly higher levels of IFN-γ in the low versus high tumor burden state on a per cell basis, reflecting their less exhausted immune status. Thus, the optimal immunotherapy strategy may depend on disease context, and may not always favor more potent combination immunotherapies. Citation Format: Chien-Chun Steven Pai, Xiaoqing Lu, Donald Simons, Michel DuPage, Kole T. Roybal, Mingyi Chen, Serena Kwek, Amy-Jo Casbon, Gillian A. Kinsbury, Lawrence Fong. Clonal deletion of tumor-specific T cells by combination checkpoint blockade compromises antitumor efficacy in low tumor burden states [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 2981.
Vascular Endothelial Growth Factor Receptor-1 Regulates Postnatal Angiogenesis Through Inhibition of the Excessive Activation of Akt
Authors: Jun-ichiroNishi, TohruMinamino, HideyukiMiyauchi, AikaNojima, KaoruTateno, ShoOkada, MasayukiOrimo, JunjiMoriya, Guo-HuaFong, KenjiSunagawa, MasabumiShibuya, IsseiKomuro
Journal: Circulation Research (2008)

Vascular endothelial growth factor (VEGF) binds both VEGF receptor-1 (VEGFR-1) and VEGF receptor-2 (VEGFR-2). Activation of VEGFR-2 is thought to play a major role in the regulation of endothelial function by VEGF. Recently, specific ligands for VEGFR-1 have been reported to have beneficial effects when used to treat ischemic diseases. However, the role of VEGFR-1 in angiogenesis is not fully understood. In this study, we showed that VEGFR-1 performs “fine tuning” of VEGF signaling to induce neovascularization. We examined the effects of retroviral vectors expressing a small interference RNA that targeted either the VEGFR-1 gene or the VEGFR-2 gene. Deletion of either VEGFR-1 or VEGFR-2 reduced the ability of endothelial cells to form capillaries. Deletion of VEGFR-1 markedly reduced endothelial cell proliferation and induced premature senescence of endothelial cells. In contrast, deletion of VEGFR-2 significantly impaired endothelial cell survival. When VEGFR-1 expression was blocked, VEGF constitutively...
Adjuvant immunotoxin therapy with anti-B4-blocked ricin after autologous bone marrow transplantation for patients with B-cell non- Hodgkin's lymphoma
Authors: ML Grossbard, JG Gribben, AS Freedman, JM Lambert, J Kinsella, SN Rabinowe, L Eliseo, JA Taylor, WA Blattler, CL Epstein
Journal: Blood (1993)