tbuckley/cabot-search huggingface dataset:
Abstract 1736: The combination of CXCR4 and checkpoint receptor inhibition improves survival in an orthotopic murine glioma model
Authors: Adela Wu, Pina Cardarelli, Miho Oyasu, Daniel Menezes, Paul Ponath, John Cogswell, Russell Maxwell, Andrew Luksik, Alice Hung, Eileen Kim, Zineb Belcaid, Henry Brem, Drew Pardoll, Michael Lim
Journal: Cancer Research (2018)

Abstract Introduction: Angiogenesis plays an important role in the malignancy of glioblastoma (GBM) as well as in cancer immunotherapy. In addition, PD-1 checkpoint receptors are upregulated in GBM. We investigate the treatment effects of combination immunotherapy with checkpoint inhibitor anti-PD-1 and anti-CXCR4, an antagonist of a chemokine receptor involved in immune cell homing as well as vasculature development, in a murine glioma model. Methods: C57Bl/6 mice were implanted with GL261-Luc+ glioma cells and randomized into 4 treatment arms: 1) control, 2) anti-PD-1 monotherapy, 3) anti-CXCR4 monotherapy, and 4) combination anti-PD-1 and anti-CXCR4 therapy. Overall survival and median survival were assessed. Brain samples from untreated mice were stained for CXCR4 expression on plasma membrane, and immunohistochemistry studies were conducted on human glioblastoma specimens as well. Immune cell activation and cell population changes were assessed through flow cytometry analysis. Results: Both murine and human glioma specimens demonstrated robust positive expression of CXCR4 on tumor-infiltrating immune cells and endothelial cells of vasculature specific to the tumor bed. Combination therapy with anti-PD-1 and anti-CXCR4 conferred survival benefit compared to control and both monotherapy arms. Long-term survivors that had received combination therapy demonstrate immune memory and decreased populations of immunosuppressive, tumor-promoting immune cells. For instance, the monocytic myeloid-derived suppressor cell population was decreased in the brain in mice treated with combination therapy. The pattern of change in microglia was similar in the brain compartment for the combination treatment group as well. Conclusion: Anti-CXCR4 and anti-PD-1 synergistic immunotherapy not only modulates the immune cell make-up of the glioma microenvironment but also affects vasculature within the tumor region. Dual therapy targeting both checkpoint and chemokine receptors results in improved survival rates. Citation Format: Adela Wu, Pina Cardarelli, Miho Oyasu, Daniel Menezes, Paul Ponath, John Cogswell, Russell Maxwell, Andrew Luksik, Alice Hung, Eileen Kim, Zineb Belcaid, Henry Brem, Drew Pardoll, Michael Lim. The combination of CXCR4 and checkpoint receptor inhibition improves survival in an orthotopic murine glioma model [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 1736.
Variation in Deaths From Intentional Injury and Substance Use—Reply
Authors: Laura Dwyer-Lindgren, Mohsen Naghavi, Christopher J. L. Murray
Journal: JAMA (2018)

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Abstract 10708: Impact of Age on Diastolic Function and Left Atrial Volume and Function in Normal Subjects Assessed by Two-Dimensional Speckle Tracking Echocardiography
Authors: Shintaro Abe, Masanori Kawasaki, Ryuhei Tanaka, Takatomo Watanabe, Koji Ono, Tomoko Fujii, Takashi Yoshizane, Maki Saeki, Noriyuki Onishi, Maki Nagaya, Noriaki Sato, Kazuo Amano, Masazumi Arai, Mami Iida, Toshiyuki Noda, Sachiro Watanabe, Shinya Minatoguchi
Journal: Circulation (2013)

Background: Left atrial (LA) volume (V) and function (F) is a strong predictor of cardiovascular outcomes. Using speckle tracking echocardiography (STE), attention has focused on LAV and LAF, which are affected by both age and left ventricular (LV) diastolic function (LV stiffness).However, normal reference values of LAV and LAF at each age and the impact of age on LAV and LAF have not been established. We assessed LV structure, LAV and LAF per decade in normal subjects using STE and conventional echocardiography. Methods: We used 2-dimensional STE to examine phasic LA emptying function (EF), LAV index (LAVI), peak strain and strain rate in 136 normal subjects without cardiovascular disease. We reported previously that the pulmonary capillary wedge pressure (ePCWP) is accurately estimated by the kinetics-tracking (KT) index which includes both LAEF and LAV. ePCWP was calculated as 10.7 - 12.4 x log KT index, where KT index = active LAEF / minimum LAVI. Moreover, we measured LV mass index (LVMI), ejection ...
Type 1 Diabetes in Children and Adolescents: A Position Statement by the American Diabetes Association
Authors: Jane L. Chiang, David M. Maahs, Katharine C. Garvey, Korey K. Hood, Lori M. Laffel, Stuart A. Weinzimer, Joseph I. Wolfsdorf, Desmond Schatz
Journal: Diabetes Care (2018)

Table 1
CKIP-1 Inhibits Cardiac Hypertrophy by Regulating Class II Histone Deacetylase Phosphorylation Through Recruiting PP2A
Authors: ShukuanLing, QiaoSun, YuhengLi, LuoZhang, PengfeiZhang, XiaogangWang, ChunyanTian, QiLi, JinpingSong, HongjuLiu, GuanghanKan, HongqingCao, ZengmingHuang, JielinNie, YanqiangBai, ShanguangChen, YinghuiLi, FuchuHe, LingqiangZhang, YingxianLi
Journal: Circulation (2012)

Background—Sustained cardiac pressure overload–induced hypertrophy and pathological remodeling frequently leads to heart failure. Casein kinase-2 interacting protein-1 (CKIP-1) has been identified to be an important regulator of cell proliferation, differentiation, and apoptosis. However, the physiological role of CKIP-1 in the heart is unknown. Methods and Results—The results of echocardiography and histology demonstrate that CKIP-1–deficient mice exhibit spontaneous cardiac hypertrophy with aging and hypersensitivity to pressure overload–induced pathological cardiac hypertrophy, as well. Transgenic mice with cardiac-specific overexpression of CKIP-1 showed resistance to cardiac hypertrophy in response to pressure overload. The results of GST pull-down and coimmunoprecipitation assays showed the interaction between CKIP-1 and histone deacetylase 4 (HDAC4), through which they synergistically inhibited transcriptional activity of myocyte-specific enhancer factor 2C. By directly interacting with the catalyt...
Activin Type II Receptor Blockade for Treatment of Muscle Depletion in Chronic Obstructive Pulmonary Disease. A Randomized Trial
Authors: Michael I. Polkey, Jens Praestgaard, Amy Berwick, Frits M. E. Franssen, Dave Singh, Michael C. Steiner, Richard Casaburi, Hanns-Christian Tillmann, Estelle Lach-Trifilieff, Ronenn Roubenoff, Daniel S. Rooks
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Bimagrumab is a fully human monoclonal antibody that blocks the activin type II receptors, preventing the activity of myostatin and other negative skeletal muscle regulators.
Abstract 5547: Durable remission with nivolumab, anti-PD-1 monoclonal antibody, in a patient with advanced thymic carcinoma
Authors: Young Kwang Chae, Anderson Cho, Kyunghoon Rhee, Andrew Davis, Wade Iams, Manali Bhave, Marcelo Cruz, Lee Chun Park
Journal: Cancer Research (2018)

Abstract Thymic carcinoma is a rare neoplasm with poor prognosis that forms on the outside surface of the thymus. Due to the rarity of the disease, there are no randomized clinical trials that guide therapy. Currently, there are clinical trials under way to assess the efficacy of anti-programmed death 1 (PD-1) monoclonal antibodies for the treatment of advanced thymic carcinomas. However, the role of PD-1 inhibitors in treating thymic carcinoma remains mostly unknown. Here we present a case of a patient with thymic carcinoma who showed durable remission when treated with nivolumab. 61-year-old male was diagnosed with thymic carcinoma during an episode of COPD exacerbation in April 2015. The patient was treated with neoadjuvant chemotherapy regimen consisting of four cycles of carboplatin and paclitaxel every three weeks from June to September 2015. The mass was resected in October 2015. Margins were found to be grossly positive. The patient was deemed a poor candidate for adjuvant chemotherapy, and in February 2016 the decision was made to begin 3 mg/kg nivolumab therapy considering the poor prognosis of disease and high risk of recurrence. Close to two years after initiating therapy, he currently has no measurable disease and tolerates the medication without side effects. This is the first report demonstrating durable remission of thymic carcinoma with nivolumab treatment. Our case suggests that prospective trials evaluating the use of nivolumab in patients with thymic carcinoma are warranted. Citation Format: Young Kwang Chae, Anderson Cho, Kyunghoon Rhee, Andrew Davis, Wade Iams, Manali Bhave, Marcelo Cruz, Lee Chun Park. Durable remission with nivolumab, anti-PD-1 monoclonal antibody, in a patient with advanced thymic carcinoma [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 5547.
Abstract 11818: Post-shock Pacing With the Subcutaneous Implantable Cardioverter-Defibrillator (S-ICD): Results From the IDE Trial
Authors: Nishant Verma, Jordan M Prutkin, Kristen K Patton, Martin C Burke, Raul Weiss, Raul Weiss, Bradley P Knight
Journal: Circulation (2016)

Introduction: In the subcutaneous implantable cardioverter-defibrillator (S-ICD) system, post-shock pacing (PSP) is a programmable feature allowing the delivery of 200 mA of transthoracic demand ventricular pacing at 50 bpm for up to 30 seconds post-shock. The need for and efficacy of PSP with the S-ICD is unknown. Methods: The S-ICD Investigational Device Exemption (IDE) trial enrolled 330 patients, 314 of whom underwent successful S-ICD implantation. At the time of implant, VT/VF was induced with a transthoracic 50Hz burst during testing and again ≥150 days later if the patient was also enrolled in a chronic conversion testing study. PSP was enabled at the discretion of the investigator. Regardless of the vector selected for VT/VF sensing, PSP sensing is based on the vector between the parasternal electrodes rather than a vector including the generator as it is part of the pacing bipole and unable to sense. Capture was defined as the presence of a QRS complex immediately after the pacing stimuli. Results: PSP was enabled for 728 of the 733 VT/VF episodes during conversion testing. Of these, 654 were at initial implant and 74 at chronic conversion testing. In 544 episodes (74.8%), PSP was appropriately inhibited as the heart rate was &gt;50 bpm. In 184 episodes (25.2%) there was at least one paced beat post-shock. In one episode, a single impulse of PSP was inappropriately delivered when an ectopic beat was undersensed. PSP occurred with equal frequency at acute (25.4%) and chronic (24.3%) conversion testing. In all episodes, capture was achieved when pacing was delivered. There were no pacing-induced arrhythmias, undersensing of VT/VF recurrence despite the change in sensing vector or other harm associated with PSP. Conclusion: Transthoracic demand ventricular PSP is safely and effectively delivered by the S-ICD for up to 30 seconds in approximately one quarter of subjects for a heart rate ≤ 50 bpm immediately after an effective shock for induced VT/VF. Since shocks were delivered in the presence of deep sedation or general anesthesia, how this correlates with the need for pacing and its tolerability after shocks for spontaneous events remains unknown.
Bromodomain-Containing Protein 4
Authors: JolyaneMeloche, FrançoisPotus, MylèneVaillancourt, AliceBourgeois, IanJohnson, LaureDeschamps, SophieChabot, GrégoireRuffenach, SarahHenry, SandraBreuils-Bonnet, ÈveTremblay, ValérieNadeau, CarolineLambert, RenéeParadis, SteeveProvencher, SébastienBonnet
Journal: Circulation Research (2015)

Rationale:Pulmonary arterial hypertension (PAH) is a vasculopathy characterized by enhanced pulmonary artery (PA) smooth muscle cell (PASMC) proliferation and suppressed apoptosis. Decreased expression of microRNA-204 has been associated to this phenotype. By a still elusive mechanism, microRNA-204 downregulation promotes the expression of oncogenes, including nuclear factor of activated T cells, B-cell lymphoma 2, and Survivin. In cancer, increased expression of the epigenetic reader bromodomain-containing protein 4 (BRD4) sustains cell survival and proliferation. Interestingly, BRD4 is a predicted target of microRNA-204 and has binding sites on the nuclear factor of activated T cells promoter region. Objective:To investigate the role of BRD4 in PAH pathogenesis. Methods and Results:BRD4 is upregulated in lungs, distal PAs, and PASMCs of patients with PAH compared with controls. With mechanistic in vitro experiments, we demonstrated that BRD4 expression in PAH is microRNA-204 dependent. We further studie...
Abstract 4109: Multi-modality imaging to interrogate lipidome changes during melanoma progression in zebrafish
Authors: Fiona Henderson, Hannah Johnston, Emrys Jones, Duncan Foster, Raghavendar T. Nagaraju, Michael Green, Michael Fairclough, Irene Barinaga-Rementeria Ramirez, Shuning He, B.Ewa Snaar-Jagalska, Katherine A. Hollywood, Warwick Dunn, Herman P. Spaink, Paul Lorigan, Emmanuelle Claude, Kaye Williams, Adam Hurlstone, Adam McMahon
Journal: Cancer Research (2018)

Abstract Lipids play diverse roles in the body, including cell structure, cell signalling, and energy production; all of which are altered in cancer. Lipid metabolism is therefore a potential therapeutic target, and here has been investigated using a transgenic zebrafish model. This study combines transcriptome and lipidomic analyses for the first time, with in-vivo positron emission tomography (PET) and ex-vivo desorption electrospray ionisation-mass spectrometry (DESI-MS), to investigate lipid metabolism changes in melanoma. Most lipids are made of fatty acids, and the methods by which tumours acquire fatty acids can be altered compared to normal tissue. Here, the PET tracer [18F]-FTHA (a fatty acid analogue) has been used to demonstrate free fatty acid uptake in melanoma tumours in-vivo. Additionally, the excellent spatial resolution of mass spectrometry imaging has been utilised by imaging the FTHA ex-vivo by DESI-MS, allowing more precise spatial correlation with the histology, and revealing the heterogeneous nature of this fatty acid uptake. These imaging data complement the findings of the transcriptome analyses which show upregulation of genes associated with fatty acid uptake. Integrating transcriptome and lipidome data analyses revealed dysregulation of glycerophospholipid pathways, and was supported by DESI-MS data, which revealed heterogeneous changes in lipid metabolism. Citation Format: Fiona Henderson, Hannah Johnston, Emrys Jones, Duncan Foster, Raghavendar T. Nagaraju, Michael Green, Michael Fairclough, Irene Barinaga-Rementeria Ramirez, Shuning He, B.Ewa Snaar-Jagalska, Katherine A. Hollywood, Warwick Dunn, Herman P. Spaink, Paul Lorigan, Emmanuelle Claude, Kaye Williams, Adam Hurlstone, Adam McMahon. Multi-modality imaging to interrogate lipidome changes during melanoma progression in zebrafish [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 4109.
Destabilization of AT1 Receptor mRNA by Calreticulin
Authors: GeorgNickenig, FrankMichaelsen, CorneliusMüller, AnjaBerger, ThomasVogel, AgapiosSachinidis, HansVetter, MichaelBöhm
Journal: Circulation Research (2002)

AT1 receptor activation leads to vasoconstriction, blood pressure increase, free radical release, and cell growth. AT1 receptor regulation contributes to the adaptation of the renin-angiotensin system to long-term stimulation and serves as explanation for the involvement of the AT1 receptor in the pathogenesis of cardiovascular disease. The molecular mechanisms involved in AT1 receptor regulation are poorly understood. Here, we report that angiotensin II accelerates AT1 receptor mRNA decay in vascular smooth muscle cells. A cognate mRNA region within the 3′ untranslated region at bases 2175 to 2195 governs the inducible decay of the AT1 receptor mRNA. Sequential protein purifications led to the discovery of a novel mRNA binding protein, calreticulin, which mediates destabilization of the AT1 receptor mRNA. Angiotensin II–caused phosphorylation of calreticulin enables binding of calreticulin to the AT1 receptor mRNA at bases 2175 to 2195 and propagates calreticulin-induced acceleration of AT1 receptor mRNA...
Endocarditis Pathogen Promotes Vegetation Formation by Inducing Intravascular Neutrophil Extracellular Traps Through Activated Platelets
Authors: Chiau-JingJung, Chiou-YuehYeh, Ron-BinHsu, Chii-MingLee, Chia-TungShun, Jean-SanChia
Journal: Circulation (2015)

Background—Endocarditis-inducing streptococci form multilayered biofilms in complex with aggregated platelets on injured heart valves, but the host factors that interconnect and entrap these bacteria-platelet aggregates to promote vegetation formation were unclear. Methods and Results—In a Streptococcus mutans endocarditis rat model, we identified layers of neutrophil extracellular traps interconnecting and entrapping bacteria-platelet aggregates inside vegetation that could be reduced significantly in size along with diminished colonizing bacteria by prophylaxis with intravascular DNase I alone. The combination of activated platelets and specific immunoglobulin G–adsorbed bacteria are required to induce the formation of neutrophil extracellular traps through multiple activation pathways. Bacteria play key roles in coordinating the signaling through spleen tyrosine kinase, Src family kinases, phosphatidylinositol-3-kinase, and p38 mitogen-activated protein kinase pathways to upregulate the expression of P...
Abstract 16287: The Calibration of Oxygen Uptake, Delivery, and Utilization is Influenced by Heart Failure With Preserved versus Reduced Ejection Fraction During Exercise
Authors: Erik HVan Iterson, Barry ABorlaug, Bruce DJohnson, Thomas POlson
Journal: Circulation (2016)

Introduction: Patients with heart failure with preserved (HFpEF) or reduced (HFrEF) ejection fraction demonstrate low oxygen uptake (VO2) and cardiac output (Q) during cardiopulmonary exercise testing (CPET). Relationships between VO2 and Q with both O2 delivery (DO2) and O2 utilization remain unclear across the HF spectrum. We hypothesized that compared to HFpEF, HFrEF patients demonstrate impaired mechanisms of O2 uptake, delivery, and utilization during submaximal exercise at matched external workload (20W). Methods: HFpEF and HFrEF [N = 30 vs 21; EF; 61 ± 3 vs 22 ± 4 %; males: 17 vs 20; age: 71 ± 4 vs 56 ± 4 yrs; BSA: 2.14 ± 0.1 vs 2.06 ± 0.12 m2; means ± 95% CL] performed CPET. VO2 was measured breath-by-breath. Q indexed to BSA (QI) was measured via the direct Fick method. We calculated arterial oxygen content, CaO2 = (1.34 x Hb x SaO2) + (0.0031 x PaO2); DO2 = (CaO2 x QI x 10); VO2 index, VO2I = AVO2 x QI x 10; O2 utilization coefficient (OUC) = VO2I/DO2. Between group comparisons were adjusted for...
Abstract 1471: Genomic drivers differ across 33 tumor types, but factors regulating hallmarks of cancer are similar
Authors: Christopher L. Plaisier
Journal: Cancer Research (2018)

Abstract The unique complement of genes expressed in a given cell type modifies the response to a specific somatic mutation. Thus, each tumor type would present with a different set of mutations that modulate the activity of common factors regulating genes which influence the cancer phenotypes (e.g. the hallmarks of cancer). We assessed the validity of this hypothesis by applying the SYstems Genetics Network AnaLysis (SYGNAL) pipeline to the ~10,000 multi-omic profiles across 33 tumor types from The Cancer Genome Atlas (TCGA). The SYGNAL pipeline synthesizes correlative approaches with mechanistic knowledge to construct a gene regulatory network. A basis of the SYGNAL approach is the discovery of biclusters: gene modules that are both co-expressed and co-regulated over subsets of tumors, by specific transcription factors (TFs) and miRNAs. On top of the biclusters we discover potential mechanistic influences of somatic mutations modulating the activity of these regulators. We discovered 284 somatically mutated genes modulating the activity of 187 transcriptional regulators (175 TFs and 12 miRNAs) which regulated 7,786 significantly co-expressed biclusters that were significantly associated with patient survival. The discovery of 1.5 fold more somatic mutations than transcriptional regulators is consistent with our hypothesis that mutations will be unique to tumor types while the regulation of the genes involved in the hallmarks of cancer will be common across tumor types. We also find that only 15% of causal flows (mutation-&amp;gt;regulator-&amp;gt;gene) are observed across multiple tumor types. We observed only four causal flows across three tumor types (NFE2L2-&amp;gt;BCL6B-&amp;gt;HSPG2 for BLCA, ESCA, and HNSC tumor types; TP53-&amp;gt;ERG-&amp;gt;MTX1 for BRCA, LUAD, and STAD tumor types; TP53-&amp;gt;ZNF511-&amp;gt;NAA38 for LUAD, PRAD, and READ tumor types; and TP53-&amp;gt;AEBP2-&amp;gt;THOC6 for COAD, KICH, and READ tumor types). There were no causal flows observed across more than three tumor types. Using our top-down systems approach we are able to catalog the impact of somatic mutations on the transcriptional regulatory network across 33 tumor types. We are working to replicate the co-expression and survival relationships we discovered in independent cohorts for each tumor type. In addition, we are working to identify potential therapeutic targets at both the regulator and gene level. Future studies will use predictive models based on our detailed transcriptional regulatory networks to identify transcriptional regulators driving cancer phenotypes that won't have general toxicity in normal cells. Citation Format: Christopher L. Plaisier. Genomic drivers differ across 33 tumor types, but factors regulating hallmarks of cancer are similar [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 1471.