tbuckley/cabot-search huggingface dataset:
Abstract 4327: The epigenetic effects of benzo[a]pyrene exposure
Authors: Francesca Galea, Paul A. White, Volker M. Arlt, Paolo Vineis, James M. Flanagan
Journal: Cancer Research (2018)

Abstract Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental carcinogens formed from the incomplete combustion of organic materials. Exposure to PAHs can be linked to at least 9 different cancer types, including lung and breast cancer. PAH are genotoxic and can form DNA adducts which can either be repaired or lead to mutations. DNA repair can lead to aberrant DNA methylation, however, few studies have investigated the link between PAH exposure and DNA methylation modifications. Here, we have used a mouse model to investigate the epigenetic consequences of PAH exposure. Mice (n=3/group) were treated by oral gavage with 0, 25, 50 and 75 mg/kg bodyweight/day of benzo[a]pyrene (BaP) for 28 days. Lung DNA from these mice was used to prepare Reduced Representation Bisulphite Sequencing (RRBS) libraries which were then sequenced using Illumina HiSeq2500to an average depth of 25x. For each mouse, DNA methylation was averaged over 500 bp tiled windows and differentially methylated regions (DMRs) were identified by comparing the controls (untreated) with all BaP-exposed mice (treated) irrespective of dose. In the treated vs untreated we identified 1815 windows (&amp;gt;25% methylation difference, p&amp;lt;0.05). Of these, we found that DMRs were under-represented in 5' untranslated regions (UTR), promoter, long interspersed nuclear elements (LINEs) regions and CpG islands compared with the genomic distribution of windows. DMRs were found to occur significantly more frequently in transcription termination regions. In addition, we found significantly more hypomethylation events in exon, intergenic, intronic and promoter regions, long terminal repeats (LTR) and short interspersed nuclear elements (SINE) and more hypermethylation in LINEs. Pyrosequencing validation on a selection of these DMRs is ongoing, using DNA from the same mice used in RRBS, plus mice exposed to BaP and other PAHs in lung and other tissues. In summary, these results show that PAHs have an effect on DNA methylation, and that these changes happen mostly within the gene body or intergenically, with significantly less differences observed at traditional gene expression regulators such as promoters. This implies that the DNA methylation changes effected by BaP exposure may serve another purpose other than gene expression regulation. Citation Format: Francesca Galea, Paul A. White, Volker M. Arlt, Paolo Vineis, James M. Flanagan. The epigenetic effects of benzo[a]pyrene exposure [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 4327.
Electroanatomic Substrate of Idiopathic Left Ventricular Tachycardia
Authors: FeifanOuyang, RiccardoCappato, SabineErnst, MasahikoGoya, MariusVolkmer, JoachimHebe, MatthiasAntz, ThomasVogtmann, AnselmSchaumann, ParwisFotuhi, MartinHoffmann-Riem, Karl-HeinzKuck
Journal: Circulation (2002)

Background— An abnormal potential (retroPP) from the left posterior Purkinje network has been demonstrated during sinus rhythm (SR) in some patients with idiopathic left ventricular tachycardia (ILVT). We hypothesized that this potential can specifically be identified and be a critical substrate for ILVT. Methods and Results— In 9 patients with ILVT and 6 control patients who underwent mapping of the left ventricle during SR using 3-dimensional electroanatomic mapping, an area with retroPP was found within the posterior Purkinje fiber network only in patients with ILVT. The earliest and latest retroPP was 185.4±57.4 and 465.2±37.3 ms after Purkinje potential; in the other patient with ILVT, an entire left ventricle mapping demonstrated a slow conduction area and passive retrograde activation along the posterior fascicle during ILVT. ILVT was noninducible in 3 patients after SR mapping. Diastolic potentials critical for ILVT during ILVT coincided with the earliest retroPP during SR in 7 patients. Mechanica...
Abstract 18483: Therapeutic Administration of IL-2/ Anti-IL-2 Monoclonal Antibody Complexes Enhances Healing After Experimental Myocardial Infarction in Mice
Authors: JohannesWeirather, UlrichHofmann, NiklasBeyersdorf, ThomasKerkau, StefanFrantz
Journal: Circulation (2014)

Background: The role of innate immunity in healing and remodeling after myocardial infarction (MI) has been studied in great detail. Recently, we demonstrated that Foxp3+CD4+ regulatory T cells (Treg cells) facilitate wound healing post-MI. We therefore pursued a strategy to activate Treg cells in a therapeutic fashion by employing a treatment modality with clinical potential, i.e. by administration of interleukin (IL)-2/ anti-IL-2 monoclonal antibody (IL-2 mAB) complexes. Methods and results: Mice were subjected to experimental MI and treated with IL-2/ IL-2 mAB complexes beginning on day 1 after infarction. IL-2 and anti-IL-2 mAB (clone JES5-1) were mixed at a molar ratio of 1:2 and each mouse was treated on three consecutive days receiving a dose of 6 μg IL-2/ IL-2 mAB complexes per injection corresponding to approximately 5000 IU IL-2 per day. Mice were monitored for up to 7 days. IL-2/ IL-2 mAB complex treatment attenuated left-ventricular remodeling by trend and preserved cardiac function compared t...
Characterization of Reentrant Circuits in Left Atrial Macroreentrant Tachycardia
Authors: FeifanOuyang, SabineErnst, ThomasVogtmann, MasahikoGoya, MariusVolkmer, AnselmSchaumann, DietmarBänsch, MatthiasAntz, Karl-HeinzKuck
Journal: Circulation (2002)

Background— Left atrial macroreentrant tachycardia (LAMRT) has not been characterized in detail. Methods and Results— Twenty-eight patients with LAMRT, including 4 patients with ablated typical atrial flutter (AFL), underwent electroanatomic mapping of the left atrium (LA) between February 1999 and October 2001. LA maps were performed during LAMRT in 26 patients and during sinus rhythm in 2 patients. Electrically silent areas or continuous lines of double potentials were identified as acquired anatomic barriers in all patients. In 23 of 26 patients with LAMRT mapping, 42 reentry circuits with a protected isthmus were identified. The isthmus was 11.8±5.9 mm wide, with the maximal amplitude of 0.07 to 3.61 mV. Radiofrequency pulses terminated all LAMRTs in 23 patients and resulted in conduction block across the isthmus in 20 patients. In 2 patients with sinus mapping, all identified isthmuses were ablated. Additionally, AFL was induced and ablated in 6 patients. Atrial tachycardia recurred in 4 patients: 3 ...
Abstract 20613: Highly Accurate Cardiac 3d Printing is Feasible and Helpful in High-Risk Patients With Complex Congenital Heart Disease
Authors: Shafkat Anwar, Gautam K Singh, Monica Sharma, Katie Mowers, Jacob R Miller, Joseph J Billadello, Pirooz Eghtesady, Pamela K Woodard
Journal: Circulation (2017)

Introduction: Three-dimensional (3D) printing is a transformational technology for congenital heart disease (CHD) patients. We present the experience from a tertiary care heart center in pediatric ...
Meta-analysis to Evaluate High-Dose Therapy Followed by Stem Cell Transplant in Patients With Multiple Myeloma
Authors: Brian Claggett, Lu Tian, Lee-Jen Wei
Journal: JAMA Oncology (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Abstract 16394: Effect of Brief Repetitive Ischemia/Reperfusion on Myocardial Electrical Activity Visualized and Quantified by 3D Endocardial Electroanatomical Mapping
Authors: Mariann Gyongyosi, Noemi Pavo, Katrin Zlabinger, Inna Sabdyusheva, Zsolt Petrasi, Ors Petnehazy, Peter Ferdinandy, Gerald Maurer
Journal: Circulation (2013)

Introduction: Brief repetitive ischemia/reperfusion (R-IR) confers cardioprotection against subsequent prolonged ischemia, referred to ischemic preconditioning (IP). Hypothesis: In this study we in...
Multiple Roles for Neutrophils in Atherosclerosis
Authors: OliverSoehnlein
Journal: Circulation Research (2012)

Because of their rare detection in atherosclerotic lesions, the involvement of neutrophils in the pathophysiology of atherosclerosis has been largely denied. However, over the past couple of years, studies have provided convincing evidence for the presence of neutrophils in atherosclerotic plaques and further revealed the causal contribution of neutrophils during various stages of atherosclerosis. This review describes mechanisms underlying hyperlipidemia-mediated neutrophilia and how neutrophils may enter atherosclerotic lesions. It also highlights possible mechanisms of neutrophil-driven atherogenesis and plaque destabilization. Knowledge of the contribution of neutrophils to atherosclerosis will allow for exploration of new avenues in the treatment of atherogenesis and atherothrombosis.
Upregulation of Cardiac Angiotensin II AT1 Receptors in Congenital Cardiomyopathic Hamsters
Authors: ChantalLambert, YoletteMassillon, SylvainMeloche
Journal: Circulation Research (1995)

Abstract Angiotensin II (Ang II) is a growth factor that stimulates protein synthesis and induces cellular hypertrophy in cardiac myocytes. To gain insight into the role of Ang II in cardiac hypertrophy, we examined the expression and subtype distribution of Ang II receptors in the ventricles of embryonic and of 25- to 350-day-old inbred control and cardiomyopathic (CHF 146) hamsters. Studies were also performed with heterozygous (cardiomyopathic×control) animals. Compared with the control hamsters, cardiomyopathic hamsters presented decreased body weights and increased ratios of ventricular weight to body weight in every adult group studied. Typical histological lesions appeared in the left ventricle of cardiomyopathic animals around 70 to 75 days, and their severity increased with time. Radioligand binding studies with cardiac ventricular membranes indicated that iodinated [Sar1,Ile8]Ang II (sarile) binds to a homogeneous population of sites in membranes derived from adult normal and cardiomyopathic ani...
Abstract P322: Soda Consumption is Associated With Carotid Intima-Media Thickness Among Middle-Aged Mexican Women
Authors: MarielArvizu, AdrianaMonge, MarthaThamez, EduardoOrtiz-Panozo, ElsaYunes, AndresCatzín-Kuhlmann, CarlosCantu-Brito, RuyLópez-Ridaura, MartinLajous
Journal: Circulation (2015)

Introduction: Soda intake is associated with cardiovascular disease. Other sweetened drinks often considered healthy alternatives to sodas could have a similar impact on cardiovascular risk. Hypothesis: Sugar-sweetened beverages commonly consumed by Hispanics have a negative influence on cardiovascular risk. Methods: We evaluated the cross-sectional relationship of sweetened beverages and common carotid intima-media thickness (CIMT) in 1,054 disease-free women without diabetes, high cholesterol, history of stroke and/or myocardial infarction, from the Mexican Teachers’ Cohort. Beverage intake was estimated from a validated food-frequency questionnaire in 2008 and 4 years later, CIMT measurements were performed by neurologists. We defined subclinical atherosclerosis as CIMT ≥0.8mm or presence of plaque and beverage intake was categorized in quartiles of servings/day. Results: Mean (±SD) soda intake was 0.5 ± 0.7 servings/day among 45.2 ± 4.7 year old women and atherosclerosis prevalence was 8.7%. After adj...
AB0208 Cyclophosphamide may induce remission of relapsing polychondritis refractory to corticosteroids
Authors: N Kyriazis, J Dais, E Archontis, H Exarhou, A Koumaditis
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Relapsing polychondritis (RP) is so rare that controlled therapy trials have not been carried out. Therefore, strategies for the treatment of RP refractory to moderate- or high-dose corticosteroids (CS) have not been established. <h3>Objectives</h3> To report a severe case of RP, refractory to CS, in which complete remission was induced by cyclophosphamide (CP) therapy. <h3>Methods</h3> Retrospective clinical and laboratory analysis of one patient. <h3>Results</h3> A 55-year-old Caucasian woman developed ear and nose cartilage inflammation, for the first time, when she was 31. At that time a biopsy of auricular cartilage confirmed the clinical diagnosis of RP. The disease responded to an initial short-term CS therapy (20 mg prednisolone/day), but a maintenance dose of 5–10 mg prednisolone/day was required to control symptoms and prevent relapses ever since. Meanwhile, she developed diabetes mellitus and cataract. Additionally, she had chronic anaemia due to thalassemia minor. Sixteen months ago, after strenuous physical exercise, a severe relapse of the disease occurred suddenly. The patient presented with acute arthritis of the knees and wrists, chondritis of the auricular, nasal, and laryngotracheal cartilages, as well as symptoms of eye inflammation. She complained of severe arthralgias, hoarseness, cough, eye irritation, tinitus, and vertigo. Physical examination revealed fever (38°C), tenderness of thyroid cartilage and the anterior trachea, bilateral episcleritis and cataract, cochlear and vestibular dysfunction, and effusion of both knees. Laboratory investigation showed an erythrocyte sedimentation rate of 41 mm, C-reactive protein 15.5 mg/dl (normal &lt;0.9 mg/dl), glucose 216 mg/dl, hematocrit 35%, haemoglobin concentration 10.3 g/dl, white blood cell count 10,540/μl with 71% polymorphs, platelet count 477,000/μl, negative rheumatoid factor, microscopic hematuria, and inflammatory synovial fluid, containing 15,800 white cells/μl (95% polymorphs, 5% lymphocytes), but no crystals or microorganisms. The manifestations of laryngotracheal, ocular, and inner ear inflammation were refractory to 60 mg prednisolone/day for four weeks. Then, oral CP (1.5 mg/Kg/day) was added and a quick improvement ensued. Within four months of CP therapy complete clinical remission of the disease and normalisation of laboratory tests was observed. Subsequently, CP was discontinued and prednisolone was gradually tapered off over the next six months. Eventually, five months after stopping CS, the disease still remains quiescent without therapy. <h3>Conclusion</h3> Although RP may have a remitting course, the remission in our patient has most likely been induced by CP in combination with prednisolone. Our observation suggests that CP is an effective therapy for severe cases of RP refractory to CS alone. Moreover, CP seems capable of inducing sustained remission of this disease.
Abstract 1380: Towards peptidomimetics to target DOT1L recruitment in MLL-AF9 leukemia
Authors: Sierrah Marie Grigsby, Jennifer Chase, Bridget Waas, Ann Friedman, Lei Du, Aihong Yao, James Ropa, Justin Serio, Andrew Muntean, Ivan Maillard, Haying Sun, Zaneta Nikolovska-Coleska
Journal: Cancer Research (2018)

Abstract Leukemias harboring rearrangements of mixed-lineage leukemia gene (MLL1) are associated with poor clinical outcomes, and new therapeutic approaches are needed. Rearrangement of the MLL1 gene generates fusion oncoproteins which drive the high expression of the clustered homeobox (HOX) genes and induce leukemic transformation. Genome-wide histone methylation studies have revealed that the abnormal expression of MLL1 fusion target genes is associated with high levels of histone H3 lysine 79 (H3K79) methylation. Recruitment of DOT1L (disruptor of telomeric silencing 1-like), a unique histone methyltransferase that catalyzes methylation of H3K79, proved to be essential for the transforming activity of multiple MLL fusion proteins. We have mapped the binding site to a short segment of 10 amino acids in DOT1L and shown that DOT1L mutants lacking these residues did not support transformation by MLL-AF9. We hypothesized that by targeting the AF9-DOT1L protein-protein interactions (PPIs), we would selectively kill MLL-AF9 cells without effecting DOT1L role in normal hematopoiesis. Using established DOT1Lf/f MLL-AF9 with reintroduced WT-DOT1L, DOT1L missing 10aa AF9-binding domain (D10), DOT1L with a point mutation in the AF9-binding domain (I867A) and enzymatically inactive DOT1L (RCR), we were able to demonstrate that by disrupting the AF9-DOT1L PPIs, although we can inhibit leukemogenesis similarly to enzymatic inhibition, this interaction is not essential for normal hematopoiesis. Based on our initial studies to map the DOT1L interaction site and in conjunction with utilizing reported NMR structures of the AF9-DOT1L complex, we investigated the nature of the interactions and the minimum length of the peptide. Using different natural and unnatural amino acids, we successfully designed a 7mer peptide with KD of 10 nM and 25 nM against AF9 and ENL, respectively, showing similar potency as the originally identified and validated 10mer peptide. These results lay the groundwork for further optimization of the 7mer peptide towards developing DOT1L peptidomimetics with improved potency and cellular activity, to further validate the PPIs between DOT1L and MLL-fusion proteins as a potential therapeutic target for MLL rearranged leukemia. Citation Format: Sierrah Marie Grigsby, Jennifer Chase, Bridget Waas, Ann Friedman, Lei Du, Aihong Yao, James Ropa, Justin Serio, Andrew Muntean, Ivan Maillard, Haying Sun, Zaneta Nikolovska-Coleska. Towards peptidomimetics to target DOT1L recruitment in MLL-AF9 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 1380.
Chronic Endothelin Receptor Blockade Attenuates Progressive Ventricular Dilation and Improves Cardiac Function in Rats With Myocardial Infarction
Authors: DanielaFraccarollo, KaiHu, PaoloGaluppo, PeterGaudron, GeorgErtl
Journal: Circulation (1997)

Background Left ventricular dilatation after myocardial infarction is associated with impaired ventricular function and heart failure and has important implications for survival. The purpose of this study was to investigate the role of endothelin-1 (ET-1) in ventricular dilatation and the effects of chronic endothelin receptor blockade by a mixed ETA and ETB receptor blocker (bosentan) on the circulating and cardiac endothelin systems. Methods and Results Three hours after coronary ligation or sham operation, bosentan (100 mg · kg body wt−1 · d−1) or placebo was given by gavage. Seven days and 8 weeks after surgery, hemodynamic and left ventricular volume studies were performed. Acute bosentan treatment (7 days) had no effects on hemodynamic parameters and early left ventricular dilatation. In the rats with large infarcts, chronic bosentan treatment (8 weeks) versus placebo reduced left ventricular systolic pressure (116±2 versus 125±3 mm Hg, P<.05) and arterial pressure (93±2 versus 103±3 mm Hg, P<.05), ...
Abstract 4880: Novel nano-molar small-molecule STAT3 inhibitor series with antitumor activities against human breast cancer
Authors: Peibin Yue, Francisco Lopez-Tapia, Christine Brotherton-Pleiss, Casie Kubota, Jasmine Chen, Marcus Tius, James Turkson
Journal: Cancer Research (2018)

Abstract Constitutively-active Signal transducer and activator of transcription (STAT) 3 has been well validated as a significant mechanistic underpinning of many human cancers and a target for anticancer therapy. To date, no small molecule STAT3 inhibitor has been successfully developed for clinical application as a therapeutic agent, despite the discovery of many molecular entities that inhibit the protein. To advance the therapeutic development of small molecule STAT3 inhibitors, we focused on the existing lead compounds, BP-1-102, SH4-54, and SH5-07 (all three showing IC50 of 4-7 μM). All three leads are based on an N-methylglycinamide scaffold, with its two amine groups condensed with three different functionalities. Intensive medicinal chemistry campaign was directed towards understanding and optimizing the molecular determinants critical for enhanced STAT3-inhibitory potency and strong antitumor effects. We report the development of nanomolar potent inhibitors of STAT3 DNA-binding activity. Most notably, the analogs H127, H145, H171, H174, H181, and H182 preferentially inhibit STAT3 activity in DNA-binding assay in vitro, with IC50 of 300 - 800 nM, compared to little or no observed effect on STAT1 and STAT5 DNA-binding activity at concentrations up to 20 μM. Treatment of human breast cancer MDA-MB-231 and MDA-MB-468 cells with H171, H174 or H182 inhibited constitutive STAT3 DNA-binding activity and phosphorylation at Tyr705 in both time- and dose-dependent manner. H171, H174 or H182 further blocked the growth and viability, colony formation, and oncogenic transformation of the human breast cancer cells that harbor persistently active STAT3, with IC50 of 1.0 - 1.9 μM, compared to the IC50 of 3.8 - 8.1 μM against the viability of the immortalized breast epithelial cells that do not harbor persistently active STAT3. These compounds represent some of the first nanomolar potent small molecules observed to directly inhibit STAT3 activity, with potent antitumor cell effects. Citation Format: Peibin Yue, Francisco Lopez-Tapia, Christine Brotherton-Pleiss, Casie Kubota, Jasmine Chen, Marcus Tius, James Turkson. Novel nano-molar small-molecule STAT3 inhibitor series with antitumor activities against human breast 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 4880.
“No deal” Brexit could be catastrophic for NHS, warns BMA
Authors: Abi Rimmer
Journal: BMJ (2018)

The NHS could be crippled by a lack of staff and would offer worse patient care if the UK leaves the European Union without a deal, the BMA has warned.

In the foreword to a briefing paper published on 16 August, Chaand Nagpaul, chair of the BMA Council, said that the union had a duty to “set out the consequences of leaving the EU with no future deal in place.”1

The association warned that the uncertainty created by a “no deal” Brexit …