tbuckley/cabot-search huggingface dataset:
Abstract 338: A new investigational ATM Inhibitor, M3541, synergistically potentiates fractionated radiotherapy and chemotherapy in cancer cells and animal models
Authors: Astrid Zimmermann, Frank Zenke, Heike Dahmen, Christian Sirrenberg, Thomas Grombacher, Lyubomir T. Vassilev, Thomas Fuchss, Andree Blaukat
Journal: Cancer Research (2018)

Abstract Physical or chemical DNA damaging agents are among the most widely used classes of cancer therapeutics today. Radiotherapy and topoisomerase inhibitors induce double strand breaks (DSB) considered most dangerous if left unrepaired because they can induce growth arrest, chromosomal abnormality and/or cell death. ATM is an essential kinase which orchestrates one of the two major pathways for repair of DSBs via the high fidelity homologous recombination (HR) mechanism. In addition, ATM acts as an upstream signaling kinase, regulating cell cycle checkpoint control in the response to DSB damage. Inhibitors of ATM kinase are expected to suppress DSB DNA repair, block checkpoint controls and enhance the therapeutic effect of radiation therapy and other DSB-inducing treatment modalities. We have developed a novel, highly potent and selective inhibitor of ATM, M3541, which modifies cellular response to DSB damage leading to potentiation of radiation therapy and DSB-inducing chemotherapy. Here, we present data from the preclinical evaluation of M3541 therapeutic potential in cellular and xenograft models of cancer. ATM inhibitor sensitized multiple tumor cell lines to ionizing radiation and a topoisomerase inhibitor in vitro. Oral administration of M3541 to nude mice bearing human tumor xenografts in a clinically relevant radiation regimen strongly enhanced the antitumor activity, leading to complete tumor regression. These activities resulted from inhibition of ATM kinase activity and modulation of its downstream effects in the xenograft tissues. M3541 is currently under clinical investigation in a Phase I trial. Citation Format: Astrid Zimmermann, Frank Zenke, Heike Dahmen, Christian Sirrenberg, Thomas Grombacher, Lyubomir T. Vassilev, Thomas Fuchss, Andree Blaukat. A new investigational ATM Inhibitor, M3541, synergistically potentiates fractionated radiotherapy and chemotherapy in cancer cells and animal models [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 338.
A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human hematopoietic stem and progenitor cells
Authors: Christopher A. Vakulskas, Daniel P. Dever, Garrett R. Rettig, Rolf Turk, Ashley M. Jacobi, Michael A. Collingwood, Nicole M. Bode, Matthew S. McNeill, Shuqi Yan, Joab Camarena, Ciaran M. Lee, So Hyun Park, Volker Wiebking, Rasmus O. Bak, Natalia Gomez-Ospina, Mara Pavel-Dinu, Wenchao Sun, Gang Bao, Matthew H. Porteus, Mark A. Behlke
Journal: Nature Medicine (2018)
General practice plans need urgent overhaul and extra £2.5bn a year, says RCGP
Authors: Jacqui Wise
Journal: BMJ (2018)

The Royal College of General Practitioners (RCGP) has called for an extra £2.5bn a year for general practice services and an urgent overhaul of the General Practice Forward View , the five year plan launched two years ago by NHS England amid much fanfare.1

The college’s second annual assessment of the Forward View says that the falling number of full time equivalent GPs is a huge concern. Currently, 1000 fewer GPs work in England than when the plan was published with a target of boosting the workforce by 5000 GPs by 2020.2 “Without enough GPs, …
Abstract 5161: DARPP-32 and t-DARPP promote non-small cell lung cancer growth through regulation of IKKα-dependent cell migration and Akt/Erk-mediated cell survival
Authors: Sk. Kayum Alam, Matteo Astone, Ping Liu, Stephanie R. Hall, Abbygail M. Coyle, Erin N. Dankert, Dane K. Hoffman, Wei Zhang, Rui Kuang, Anja C. Roden, Aaron S. Mansfield, Luke H. Hoeppner
Journal: Cancer Research (2018)

Abstract Lung cancer is the leading cause of cancer-related death worldwide. In this study, we demonstrate that elevated expression of dopamine and cyclic adenosine monophosphate-regulated phosphoprotein, Mr 32000 (DARPP-32) and its truncated splice variant t-DARPP promotes lung tumor growth, while abrogation of DARPP-32 expression in human non-small cell lung cancer (NSCLC) cells reduces tumor growth in orthotopic mouse models. We observe a novel physical interaction between DARPP-32 and inhibitory kappa B kinase-α (IKKα) that promotes NSCLC cell migration through non-canonical nuclear factor kappa-light-chain-enhancer of activated B cells 2 (NF-κB2) signaling. Bioinformatics analysis of 513 lung adenocarcinoma patients reveals elevated t-DARPP isoform expression is associated with poor overall survival. Histopathological investigation of 62 human lung adenocarcinoma tissues also showed that t-DARPP expression is elevated with increasing tumor (T) stage. Our data suggest that DARPP-32 is a negative prognostic marker associated with increasing stages of NSCLC and may represent a novel therapeutic target. Citation Format: Sk. Kayum Alam, Matteo Astone, Ping Liu, Stephanie R. Hall, Abbygail M. Coyle, Erin N. Dankert, Dane K. Hoffman, Wei Zhang, Rui Kuang, Anja C. Roden, Aaron S. Mansfield, Luke H. Hoeppner. DARPP-32 and t-DARPP promote non-small cell lung cancer growth through regulation of IKKα-dependent cell migration and Akt/Erk-mediated cell survival [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 5161.
Anti-Inflammatory Mechanisms in the Vascular Wall
Authors: AlainTedgui, ZiadMallat
Journal: Circulation Research (2001)

Abstract—The role of vascular cells during inflammation is critical and is of particular importance in inflammatory diseases, including atherosclerosis, ischemia/reperfusion, and septic shock. Research in vascular biology has progressed remarkably in the last decade, resulting in a better understanding of the vascular cell responses to inflammatory stimuli. Most of the vascular inflammatory responses are mediated through the IκB/nuclear factor-κB system. Much recent work shows that vascular inflammation can be limited by anti-inflammatory counteregulatory mechanisms that maintain the integrity and homeostasis of the vascular wall. The anti-inflammatory mechanisms in the vascular wall involve anti-inflammatory external signals and intracellular mediators. The anti-inflammatory external signals include the anti-inflammatory cytokines, transforming growth factor-β, interleukin-10 and interleukin-1 receptor antagonist, HDL, as well as some angiogenic and growth factors. Physiological laminar shear stress is o...
Long-Term Clinical and Angiographic Follow-Up After Coronary Stent Placement in Native Coronary Arteries
Authors: TakeshiKimura, KenichiAbe, SatoshiShizuta, KeitaOdashiro, YoshinoriYoshida, KoyuSakai, KazuakiKaitani, KatsumiInoue, YoshihisaNakagawa, HiroyoshiYokoi, MasashiIwabuchi, NaoyaHamasaki, HideyukiNosaka, MasakiyoNobuyoshi
Journal: Circulation (2002)

Background— Although coronary stents have been proved effective in reducing clinical cardiac events for up to 3 to 5 years, longer term clinical and angiographic outcomes have not yet been fully clarified. Methods and Results— To evaluate longer term (7 to 11 years) outcome, clinical and angiographic follow-up information was analyzed in 405 patients with successful stenting in native coronary arteries. Primary or secondary stabilization, which was defined as freedom from death, coronary artery bypass grafting, and target lesion-percutaneous coronary intervention (TL-PCI) during the 14 months after the initial procedure or after the last TL-PCI, was achieved in 373 patients (92%) overall. Only 7 patients (1.7%) underwent TL-PCI more than twice. After the initial 14-month period, freedom from TL-PCI reached a plateau at 84.9% to 80.7% over 1 to 8 years. However, quantitative angiographic analysis in 179 lesions revealed a triphasic luminal response characterized by an early restenosis phase until 6 months,...
Abstract 13106: Improved Outcomes of Extracorporeal Cardiopulmonary Resuscitation for Out-of-hospital Cardiac Arrest - A Community-wide Evaluation
Authors: Wei-Shu Lin, Matthew Huei-Ming Ma, Nai-Kuan Chou, Mei-Fen Yang, Yu-Wen Chen, Chien-Hua Huang, Yueh-Ping Liu, Hsien-Tang Lin, Chi-Hung Lin, Allen Wen-Hsiang Chiu, Wen-Je Ko, Yih-Sharng Chen, Patrick Chow-In KO
Journal: Circulation (2015)

Introduction: The patient outcome after OHCA is poor. Return to spontaneous circulation (ROSC) dramatically decreases with the duration of CPR. It has been proposed to implement extracorporeal membrane oxygenation in order to assist CPR (ECPR) in OHCA. Objective: To investigate the effects of ECPR in emergency (ED) for OHCA. Methods: A prospective 4-year observational database collected from a community-wide OHCA registry in an urban EMS was studied. The EMS ambulance staffs were capable with advanced airway, intravenous (iv) fluid skills, basic and advanced life support and AED techniques. Outcomes included 2-hour and 24-hour sustained ROSC, survival (SD) and cerebral performance category scale (CPC) at discharge. OHCA receiving ECPR were included and their pre-hospital (pre-H) and hospital (H) characteristics and outcomes were evaluated by regression analysis. Results: In the 4 years among a total of 7,220 OHCA resuscitated in ED, ECPR was used 88 times (90% male, median age 54 [IQR 44-63]), 90% non-traumatic, 58.6% arrest witnessed, 50.6% with bystander CPR, up to 72.6% initial AED rhythm showing shockable, 54% with LMA (laryngeal mask airway), 5.7% with endotracheal intubation, 18.2% with pre-H iv epinephrine, and 12.5% of them received therapeutic hypothermia. Pre-H time intervals (min:sec, median [IQR]) were 04:38 [03:30-06:08] for response, 13:00 [10:05-16:00] for scene, and 03:08 [02:09-05:00] for transport. Only 10.2% of cases presented pre-H ROSC and 9.1% got ROSC upon H arrival. Outcomes were 88.6% for 2-hr ROSC, 69.3% for 24-hr ROSC, 39.1% for SD, and 21% for good CPC 1or2 respectively. Patients with CPC 1or2 tended to be younger (median age 46.8 vs. 55.9, p=0.04) and less with LMA (29.4 vs. 61.9%, p=0.02). Conclusions: ECPR can lead to survival and good neurological outcome in selected OHCA regardless of positive ROSC at pre-H or upon H arrival after EMS resuscitation. Elder age and pre-H LMA may be adverse to neurological outcome for OHCA with ECPR.
High incidence of advanced colorectal neoplasia during endoscopic surveillance in serrated polyposis syndrome
Authors: Daniel Rodríguez-Alcalde, Sabela Carballal, Leticia Moreira, Luis Hernández, Lorena Rodríguez-Alonso, Francisco Rodríguez-Moranta, Victoria Gonzalo, Luis Bujanda, Xavier Bessa, Carmen Poves, Joaquín Cubiella, Inés Castro, Mariano González, Eloísa Moya, Susana Oquiñena, Joan Clofent, Enrique Quintero, Pilar Esteban, Virginia Piñol, Francisco Fernández, Rodrigo Jover, Lucía Cid, Esteve Saperas, María López-Cerón, Miriam Cuatrecasas, Jorge López-Vicente, Liseth Rivero-Sánchez, Gerhard Jung, María Vila-Casadesús, Ariadna Sánchez, Antoni Castells, María Pellisé, Francesc Balaguer
Journal: Endoscopy (2018)

Abstract Background Serrated polyposis syndrome (SPS) has been associated with an increased risk of colorectal cancer (CRC). Accordingly, intensive surveillance with annual colonoscopy is advised. The aim of this multicenter study was to describe the risk of advanced lesions in SPS patients undergoing surveillance, and to identify risk factors that could guide the prevention strategy. Methods From March 2013 to April 2015, 296 patients who fulfilled criteria I and/or III for SPS were retrospectively recruited at 18 centers. We selected patients in whom successful clearing colonoscopy had been performed and who underwent subsequent endoscopic surveillance. Advanced neoplasia was defined as CRC, advanced adenoma, or advanced serrated lesion that were ≥ 10 mm and/or with dysplasia. Cumulative incidence of advanced neoplasia was calculated and independent predictors of advanced neoplasia development were identified. Results In 152 SPS patients a total of 315 surveillance colonoscopies were performed (median 2, range 1 – 7). The 3-year cumulative incidence of CRC and advanced neoplasia were 3.1 % (95 % confidence interval [CI] 0 – 6.9) and 42.0 % (95 %CI 32.4 – 51.7), respectively. Fulfilling both I + III criteria and the presence of advanced serrated lesions at baseline colonoscopy were independent predictors of advanced neoplasia development (odds ratio [OR] 1.85, 95 %CI 1.03 – 3.33, P = 0.04 and OR 2.62, 95 %CI 1.18 – 5.81, P = 0.02, respectively). During follow-up, nine patients (5.9 %) were referred for surgery for invasive CRC (n = 4, 2.6 %) or because of polyp burden (n = 5, 3.3 %). After total colectomy, 17.9 % patients developed advanced neoplasia in the retained rectum. Conclusions Patients with SPS have a substantial risk of developing advanced neoplasia under endoscopic surveillance, whereas CRC incidence is low. Personalized endoscopic surveillance based on polyp burden and advanced serrated histology could help to optimize prevention in patients with SPS.
Epicardial fat in heart failure patients with mid‐range and preserved ejection fraction
Authors: Gijs van Woerden, Thomas M. Gorter, B. Daan Westenbrink, Tineke P. Willems, Dirk J. van Veldhuisen, Michiel Rienstra
Journal: European Journal of Heart Failure (2018)

Aims Adipose tissue and inflammation may play a role in the pathophysiology of patients with heart failure (HF) with mildly reduced or preserved ejection fraction. We therefore investigated epicardial fat in patients with HF with preserved (HFpEF) and mid‐range ejection fraction (HFmrEF), and related this to co‐morbidities, plasma biomarkers and cardiac structure. Methods and results A total of 64 HF patients with left ventricular ejection fraction &gt;40% and 20 controls underwent routine cardiac magnetic resonance examination. Epicardial fat volume was quantified on short‐axis cine stacks covering the entire epicardium and was related to clinical correlates, biomarkers associated with inflammation and myocardial injury, and cardiac function and contractility on cardiac magnetic resonance. HF patients and controls were of comparable age, sex and body mass index. Total epicardial fat volume was significantly higher in HF patients compared to controls (107 mL/m 2 vs. 77 mL/m 2 , P &lt;0.0001). HF patients with atrial fibrillation and/or type 2 diabetes mellitus had more epicardial fat than HF patients without these co‐morbidities (116 vs. 100 mL/m 2 , P =0.03, and 120 vs. 97 mL/m 2 , P =0.001, respectively). Creatine kinase‐MB, troponin T and glycated haemoglobin in patients with HF were positively correlated with epicardial fat volume (R =0.37, P =0.006; R =0.35, P =0.01; and R =0.42, P =0.002, respectively). Conclusion Heart failure patients had more epicardial fat compared to controls, despite similar body mass index. Epicardial fat volume was associated with the presence of atrial fibrillation and type 2 diabetes mellitus and with biomarkers related to myocardial injury. The clinical implications of these findings are unclear, but warrant further investigation.
Abstract MP61: Dietary Fiber Intake and Mortality Among Myocardial Infarction Survivors
Authors: ShanshanLi, AlanFlint, JenniferPai, JohnForman, FrankHu, WalterWillett, KathrynRexrode, KennethMukamal, EricRimm
Journal: Circulation (2014)

Background: Dietary fiber is associated with lower risk of coronary heart disease in healthy populations. It is unclear whether higher consumption of dietary fiber after myocardial infarction (MI) is associated with lower mortality. Objective: To evaluate the associations of dietary fiber post-MI and changes from pre- to post- with all-cause and cardiovascular mortality. Design: The Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS) are two large prospective cohort studies of US women and men with repeated dietary measurements. We included 2,258 women and 1,840 men who were free of cardiovascular disease, stroke or cancer at enrollment, survived a first MI during follow up, were free of stroke at the time of initial MI onset, and provided both pre-MI and at least one post-MI food frequency questionnaire. We evaluated the associations of dietary fiber post-MI and changes from pre- to post- with all-cause and cardiovascular mortality using Cox proportional hazards models, adjusti...
Acidosis-Induced Coronary Arteriolar Dilation Is Mediated by ATP-Sensitive Potassium Channels in Vascular Smooth Muscle
Authors: HiroshiIshizaka, LihKuo
Journal: Circulation Research (1996)

Abstract Although a decrease in extravascular pH has been suggested to be involved in coronary flow regulation during hypoxia, ischemia, and increased metabolic demand of the heart, its vasomotor control mechanism has not been elucidated. To examine the effect of acidosis on vasomotor tone, porcine coronary arterioles (40 to 110 μm) were isolated, cannulated, and pressurized to 60 cm H2O intraluminal pressure without flow for in vitro study. Acidosis (pH 7.4 to 7.0) was produced by adding HCl to the extravascular solution. The involvement of potassium channels in the vasomotor response to acidosis was evaluated by using BaCl2 (100 μmol/L, nonspecific potassium channel inhibitor), glibenclamide (5 μmol/L, ATP-sensitive potassium channel inhibitor), and iberiotoxin (100 nmol/L, calcium-activated potassium channel inhibitor). To determine whether endothelial hyperpolarization contributes to the acidosis-induced dilation, the pH-diameter relation of the vessel was examined under a high intraluminal concentrat...
Abstract 3280: Utah somatic variant calling pipeline featuring multi-sample joint calling, variant-graph based accurate allele frequency estimation and subclone analysis
Authors: Yi Qiao, Xiaomeng Huang, Dillon Lee, Andrew Farrell, Thomas Nicholas, Brent Pederson, Aaron Quinlan, Gabor Marth
Journal: Cancer Research (2018)

Abstract Current tumor variant detection software tools are focused on the identification of somatic mutations in a single tumor sample (e.g. the primary tumor) compared to normal control tissue, and are not adequate for studies where multiple samples from the same patient, either at consecutive time points or at different metastatic sites are collected. Here we present a software framework that facilitates simultaneous analysis of such multi-sample datasets. Our framework utilizes our FreeBayes variant caller for jointly calling all tumor samples and normal controls from the patient. This ensures that even very low frequency mutations are called because read evidence is aggregated across all samples; and that allele frequency information for a called somatic variant is provided uniformly for all samples. Short and medium-length INDELs, and structural variants are identified by our RUFUS software, a new reference-free mutation calling algorithm for both germline and somatic mutation detection, with extremely high sensitivity and specificity. We use our Graphite tool, a graph-genome based read realignment algorithm, to eliminate false positive somatic calls i.e. inherited variants masquerading as somatic mutations, and to substantially increase accuracy of allele frequency estimation of the true somatic calls, a feature critical for downstream subclone analysis. In addition, we use the FACETS package for CNV and LOH analysis, also critical for downstream subclone analysis. Finally, we utilize SubcloneSeeker, our algorithm to reconstruct the evolution of the cancer at the subclonal level from the somatic variant allele frequencies, to understand how the tumor evolved over time, in response to multiple courses of treatment, or over space, across multiple metastatic sites. We demonstrate the use of this pipeline in published and ongoing studies involving longitudinal and multi-site tumor sample datasets. Citation Format: Yi Qiao, Xiaomeng Huang, Dillon Lee, Andrew Farrell, Thomas Nicholas, Brent Pederson, Aaron Quinlan, Gabor Marth. Utah somatic variant calling pipeline featuring multi-sample joint calling, variant-graph based accurate allele frequency estimation and subclone analysis [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 3280.
Abstract 15580: Cerebral Microbleeds Are Associated With High Systolic Arterial Blood Pressure, but Not Arterial Stiffness in Patients With Cardiovascular Disease
Authors: Yohei Yamauchi, Yumiko Kanzaki, Yuki Wada, Hideaki Shima, Nobukazu Ishizaka
Journal: Circulation (2016)

Background: Gradient-echo T2*-weighted magnetic resonance imaging (MRI) is highly sensitive for detecting cerebral microbleeds (CMBs). The presence of CMBs is thought to correlate with anticoagulan...
Abstract 2590: Race-specific differential expression of CCL25 and CCR9 in triple-negative breast cancer
Authors: Jeronay King, Neeraj Kapur, Hina Mir, Dominique N. Gales, James W. Lillard, Shailesh Singh
Journal: Cancer Research (2018)

Abstract Breast cancer (BrCa) is the second leading cause of cancer-related deaths among women. Therapeutic intervention of the disease is impeded due to the heterogeneity contributed by inter- and intra-tumoral diversity, as well as difference among cancer-bearing individuals. Triple-negative breast cancer (TNBC) is a hormone-independent and highly aggressive subtype that disproportionally affects African-American (AA) women. However, the molecular basis of racial disparity in therapeutic response and clinical outcome in AA and Caucasian (CA) patients is still obscure. Our group was the first to show the involvement of CCR9 and its natural ligand, CCL25 in cancer progression and therapeutic response, including breast cancer. In this study, we have shown the association of CCR9 and CCL25 with TNBC. Both CCR9 and CCL25 are highly expressed in TNBC cells (MDA-MB-468 and MDA-MB-231) compared to other BrCa subtypes (MCF-7, MDA-MB-361, SKBr-3). Expression of this receptor-ligand pair was significantly elevated in TNBC cells derived from AA compared to those derived from CA patients. RNA-Seq based transcriptome data obtained from The Cancer Genome Atlas (TCGA) confirmed these results. Further, phospho-proteomic profiling of cancer signaling molecules showed race specific hyper-activation of GSK-3α, GSK-3β and NF-κB in AA derived cells. These molecules are known to provide the survival advantage to cancer cells. These findings, therefore, highlight significance of CCR9 and its association with the disparity in observed in TNBC. Hence, CCR9 targeted approach to address the disparity in the therapeutic outcome of TNBC seems to be promising. Citation Format: Jeronay King, Neeraj Kapur, Hina Mir, Dominique N. Gales, James W. Lillard, Shailesh Singh. Race-specific differential expression of CCL25 and CCR9 in triple-negative 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 2590.