tbuckley/cabot-search huggingface dataset:
Abstract MP02: N-Terminal Pro-B-type Natriuretic Peptide and Risk of Stroke in Those With and Without Cerebrovascular Disease: The REGARDS Cohort
Authors: Kara Landry, Suzanne Judd, Dawn Kleindorfer, George Howard, Virginia Howard, Neil Zakai, Mary Cushman
Journal: Circulation (2018)

Background: N-terminal pro-B-type natriuretic peptide (NT-pro-BNP), a commonly used marker of cardiac function, is associated with presence of stroke symptoms and is a strong risk factor for future atrial fibrillation, stroke and mortality. Little data are available on the association between NT-pro-BNP levels and stroke recurrence. Objective: We studied the relationship between NT-proBNP with the risk of future ischemic stroke across a spectrum of pre-existing cerebrovascular conditions, ranging from history of stroke symptoms, to prior transient ischemic attack (TIA), to prior stroke. Methods: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort enrolled 30 239 black and white Americans age 45 years and older in 2003-14. Among a case-cohort study sample including 1109 stroke cases and a 4311-person cohort random sample, we calculated hazard ratios of future ischemic stroke by baseline NT-proBNP stratified by presence of prior cerebrovascular conditions. Results: In the cohort sample, there were 3056 participants without any history of cerebrovascular disease, 738 with prior stroke symptoms, 196 with history of TIA and 338 with history of prior stroke. In a fully adjusted model, elevated NT-proBNP was associated with risk of stroke in participants without a pre-existing cerebrovascular condition (HR 2.32, 95% CI 1.84, 2.94), and in participants with a history of stroke symptoms (HR 1.67 95% CI 1.01, 2.78) or TIA (HR 2.66, 95% CI 1.00, 7.04), but not among those with prior stroke (HR 1.26, 95% CI 0.71, 2.21). Conclusions: These findings further support the potential for NT-proBNP testing to identify patients who are at highest risk for future stroke, although not in those with prior stroke.
Abstract 70: Trial of Ulinastatin treatment for murine model of Kawasaki Desease
Authors: Yuki Tsujita, Yoichi Kawamura, Takashi Kanai, Seiichiro Takeshita, Shigeaki Nonoyama
Journal: Circulation (2015)

Recently, we reported that the initial Ulinastatin (UTI) therapy combined with intravenous immunoglobulin (IVIG) reduced the proportion of patients with Kawasaki disease requiring additional rescue treatment and the occurrence of coronary artery lesions as compared with IVIG alone (Circulation. 2011;124(25):2822-2828.). However, there have been no reports that histologically examined the therapeutic effects of UTI., In the present study, to investigate the histological efficacy of UTI, we administered UTI in a vasculitis murine model, resembling Kawasaki disease Four-week-old male mice DBA/2 were intraperitoneally administered Candida albicans water soluble extract (CAWS) for 5 days and were treated either with UTI, IVIG, or a combination of UTI and IVIG. Further, we examined the plasma levels of neutrophil elastase andcytokinesandevaluated histopathological features.. Neutrophil elastase, TNF-α, IL-6, IP-10, and MIG significantly increased in the CAWS-treated mice. Large amount of elastase-positive neutrophils infiltrated in the coronary tissue. In addition, the infiltration of elastase-positive neutrophils was reduced in the pathological tissue of the UTI treatment group. Neutrophil elastase is strongly involved in the destruction of the elastic plate and smooth muscle layer. There is a possibility that destruction of the vascular structures can be suppressed by decreasing the elastase-positive neutrophils infiltration in the UTI treatment group.
Prognostic value of CD8 + PD-1+ immune infiltrates and PDCD1 gene expression in triple negative breast cancer
Authors: Joe Yeong, Jeffrey Chun Tatt Lim, Bernett Lee, Huihua Li, Clara Chong Hui Ong, Aye Aye Thike, Wei Hseun Yeap, Yi Yang, Ansel Yi Herh Lim, Timothy Kwang Yong Tay, Jin Liu, Siew-Cheng Wong, Jinmiao Chen, Elaine Hsuen Lim, Jabed Iqbal, Rebecca Dent, Evan W. Newell, Puay Hoon Tan
Journal: Journal for ImmunoTherapy of Cancer (2019)

The role of programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) in triple negative breast cancer (TNBC) remains to be fully understood. In this study, we investigated the role of PD-1 as a prognostic marker for TNBC in an Asian cohort (<i>n</i> = 269). Samples from patients with TNBC were labeled with antibodies against PD-L1 and PD-1, and subjected to NanoString assays to measure the expression of immune-related genes. Associations between disease-free survival (DFS), overall survival (OS) and biomarker expression were investigated. Multivariate analysis showed that tumors with high PD-1<sup>+</sup> immune infiltrates harbored significantly increased DFS, and this increase was significant even after controlling for clinicopathological parameters (HR 0.95; <i>P</i> = 0.030). In addition, the density of cells expressing both CD8 and PD-1, but not the density of CD8<sup>−</sup>PD-1<sup>+</sup> immune infiltrates, was associated with improved DFS. Notably, this prognostic significance was independent of clinicopathological parameters and the densities of total CD8<sup>+</sup> cell (HR 0.43, <i>P</i> = 0.011). At the transcriptional level, high expression of <i>PDCD1</i> within the tumor was significantly associated with improved DFS (HR 0.38; <i>P</i> = 0.027). In line with these findings, high expression of <i>IFNG</i> (HR 0.38; <i>P</i> = 0.001) and IFN signaling genes (HR 0.46; <i>p</i> = 0.027) was also associated with favorable DFS. Inclusion of PD-1 immune infiltrates and <i>PDCD1</i> gene expression added significant prognostic value for DFS (ΔLRχ<sup>2</sup> = 6.35; <i>P</i> = 0.041) and OS (ΔLRχ<sup>2</sup> = 9.53; <i>P</i> = 0.008), beyond that provided by classical clinicopathological variables. Thus, PD-1 mRNA and protein expression status represent a promising, independent indicator of prognosis in TNBC.
Abstract PD1-12: Omics profiling of CDK4/6 inhibitors reveals functionally important secondary targets of abemaciclib
Authors: CE Mills, M Hafner, K Subramanian, C Chen, M Chung, SA Boswell, RA Everley, CS Walmsley, D Juric, PK Sorger
Journal: Cancer Research (2019)

Abstract The recent introduction of small molecule inhibitors of cyclin-dependent kinases (CDK) 4/6 to the clinic has improved the treatment of hormone receptor positive breast cancer, and shown promise in other malignancies. The three clinically used CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, are reported to be broadly similar although recent data suggest that abemaciclib has distinct single-agent activity in patients and a unique adverse effects profile. Key questions are: How do these drugs differ at the molecular level? Should such differences inform their use in the clinic? Can these three agents be used interchangeably or should patient stratification differ between them? We use molecular and functional profiling by mRNA sequencing, mass spectrometry-based proteomics, and GR-based dose-response assays to obtain complementary views of the mechanisms of action of CDK4/6 inhibitors. We show that abemaciclib, but not ribociclib or palbociclib, is a potent inhibitor of kinases other than CDK4/6, including CDK1/Cyclin B, which appears to cause arrest in the G2 phase of the cell cycle, and CDK2/Cyclin E/A, which is implicated in resistance to palbociclib. We show that inhibition of these additional targets is accessible in a xenograft model. Whereas ribociclib and palbociclib induce cytostasis, and cells adapt to these drugs within 2-3 days of exposure, abemaciclib induces cell death and durably blocks cell proliferation. Abemaciclib is active even in retinoblastoma protein (pRb)-deficient cells in which CDK4/6 inhibition by palbociclib or ribociclib is completely ineffective. The degree of polypharmacology of small molecule drugs is increasingly viewed as an important consideration in their design, with implications for efficacy, toxicity, and acquired resistance. In the case of CDK4/6 inhibitors, we propose that abemaciclib polypharmacology elicits unique molecular responses. More generally, we propose that multi-omic approaches are required to fully elucidate the spectrum of targets relevant to drug action in tumor cells. We expect such understanding to assist in stratifying patient populations and ordering sequential therapies when resistance arises. Citation Format: Mills CE, Hafner M, Subramanian K, Chen C, Chung M, Boswell SA, Everley RA, Walmsley CS, Juric D, Sorger PK. Omics profiling of CDK4/6 inhibitors reveals functionally important secondary targets of abemaciclib [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD1-12.
FACTORS ASSOCIATED WITH BLEEDING EVENTS IN PATIENTS ON RIVAROXABAN FOR NON-VALVULAR ATRIAL FIBRILLATION: A REAL WORLD EXPERIENCE
Authors: Tauseef Akhtar, Jishanth Mattumpuram, Setri Fugar, Sagar Ranka, Juan Del Cid Fratti, Hashim Mann, Alok Uprety, Aakash Putta, Yasmeen Golzar
Journal: Journal of the American College of Cardiology (2019)
PREDICTORS OF MORTALITY IN PATIENTS UNDERGOING MITRACLIP FOR SEVERE MITRAL REGURGITATION
Authors: Mikhail Narezkin, Brian Karahalios, Miguel A. Chavez, Anya Narezkina, Jiken Bhatt, Ashrith Guha, Colin Barker, Neal Kleiman
Journal: Journal of the American College of Cardiology (2019)
Analysis of the Multiple Myeloma HLA Peptidome Identifies a Naturally Presented Bcma-Derived Peptide As an Immunogenic T-Cell Epitope for Immunotherapeutic Approaches
Authors: Tatjana Bilich, Simon D. Walz, Annika Nelde, Helmut R. Salih, Ana Marcu, Daniel Johannes Kowalewski, Katja Weisel, Lothar Kanz, Hans-Georg Rammensee, Stefan Stevanovic, Juliane S. Walz
Journal: Blood (2018)
The Role of Transcription Factor and Signaling Gene Mutations in the Clonal Evolution of MDS to Secondary AML
Authors: Andrew E Menssen, Christopher A Miller, Ajay J Khanna, Gue Su Chang, Jin J Shao, Sridhar Nonavinkere Srivatsan, Joshua Robinson, Kimberly J Brendel, Sharon E Heath, Eric J. Duncavage, Matthew J. Walter
Journal: Blood (2018)
COMPARING ANTI-COAGULATION STRATEGIES IN PATIENTS UNDERGOING WATCHMAN IMPLANTATION: INCIDENCE OF PERIPROCEDURAL AND 45-DAY THROMBOSIS AND BLEEDING
Authors: Nachiket Madhav Apte, Michael Pierpoline, Aman Patel, Lance Longmore, Tawseef Dar, Alexander Robinson, Ahsan Khan, Aaron Timins, Karan Gupta, Kimberly Wilson, Daniel Jipescu, Anand Subramanian, Som Aftabizadeh, Senthil Thambidorai, Madhu Reddy
Journal: Journal of the American College of Cardiology (2019)
IMPACT OF HOSPITAL VOLUME ON IN-HOSPITAL AND NINETY-DAY OUTCOMES FOLLOWING TRANSCATHETER MITRAL VALVE REPAIR USING MITRACLIP: NATIONAL READMISSION DATABASE ANALYSIS
Authors: Ilhwan Yeo, Luke Kim, Shinobu Itagaki, Joanna Chikwe, Jim Cheung, Shing-Chiu Wong, Natalia Egorova
Journal: Journal of the American College of Cardiology (2019)
DISTINCT MYOCARDIAL DISEASE PATTERNS DETECTED ON FREE-BREATHING MOTION-CORRECTED LATE GADOLINIUM ENHANCEMENT ASSOCIATE WITH BASELINE DISEASE SEVERITY AND INCIDENT OUTCOMES IN A LARGE CLINICAL POPULATION
Authors: Hongyang Pi, Fredrika Fröjdh, Eric Olausson, Aatif Sayeed, Maren Maanja, Louise Niklasson, Timothy C. Wong, Martin Ugander, Hui Xue, Peter Kellman, Erik Schelbert
Journal: Journal of the American College of Cardiology (2019)
MACHINE LEARNING IDENTIFIES SITES WHERE ABLATION TERMINATES PERSISTENT ATRIAL FIBRILLATION
Authors: Mahmood Alhusseini, Firas Abuzaid, Paul Clopton, Albert Rogers, Miguel Rodrigo, Tina Baykaner, Paul Wang, Wouter-Jan Rappel, Sanjiv Narayan
Journal: Journal of the American College of Cardiology (2019)
Abstract 102: An Internal Pool of b-Adrenergic Receptors Activates PLC-mediated PI4P Hydrolysis in Cardiac Myocytes
Authors: Alan V Smrcka, Craig A Nash, Wenhui Wei
Journal: Circulation Research (2018)

Cardiac hypertrophy and subsequent heart failure is a leading cause of morbidity and mortality in the USA. Previously, our laboratory identified a prohypertrophic pathway where PLCε, scaffolded to mAKAPβ at the nuclear envelope, hydrolyzes phosphatidylinositol 4-phosphate (PI4P) at the Golgi to locally generate DAG and drive hypertrophic gene expression. This pathway is activated by multiple upstream signals including the Epac-selective cAMP analogue, cpTOME. However, stimulation of β-adrenergic receptors with Isoproterenol (Iso) does not activate this pathway despite strongly raising cAMP. We were able to uncover Iso stimulated PI4P hydrolysis only in the presence of a cAMP phosphodiesterase 3 inhibitor. To determine if internal β-adrenergic receptors can stimulate PI4P hydrolysis, we treated NRVMs with the membrane permeable β-adrenergic agonist, dobutamine. In contrast to the membrane impermeable Iso, dobutamine induced rapid and sustained PI4P hydrolysis that was at least partially blocked by the cell permeable β-adrenergic antagonist, metoprolol. The cell impermeable βAR antagonist, sotalol could not block dobutamine effects, suggesting that a pool of internal β-adrenergic receptors can induce PI4P hydrolysis. Over expression of the RA1 domain of PLCε, which competes PLCε away from the mAKAPβ scaffold, also inhibited dobutamine stimulation of PI4P hydrolysis. These data suggest that β-adrenergic stimulation in internal membranes, potentially at the Golgi apparatus or nuclear envelope, can stimulate PI4P hydrolysis. These observations demonstrate a novel mechanism for PLC activation through an internal GPCR, which may participate in development of cardiac hypertrophy and heart failure. Targeting internal β-adrenergic receptors may allow for the development of selective therapies to treat heart failure.
ACUTE CORONARY SYNDROME IN FIRST TRIMESTER OF PREGNANCY: TO STENT, BYPASS, OR LEAVE ALONE?
Authors: Prasanna Manjini Sengodan, Ashwin Durairaj, Christy M. Isler, Kerianne Crockett, Mohamed Fadol Osman, Ashesh N. Buch
Journal: Journal of the American College of Cardiology (2019)
Abstract 475: Human Cardiac Progenitor Cells Derived Exosomes Stimulate Cardiomyocytes Proliferation by MicroRNA-Hippo Pathway
Authors: Sudhish Sharma, Grace Bigham, Chetan Ambastha, Muthukumar Gunasekaran, Phillip Z Brohawn, Sotirios Karathanasis, Sunjay Kaushal
Journal: Circulation Research (2018)

Background: We identified that human neonatal cardiac progenitor cells (CPCs) improve cardiac function and attenuate adverse left ventricular remodeling after myocardial infarction through their exosomes (nEXOs). RNAseq analysis of nEXOs identified miRs which may be responsible for modulation of Hippo signaling, thereby promoting cardiomyocytes proliferation. Hypothesis: nEXOs effectively stimulate endogenous cardiomyocyte (CM) proliferation by targeting the Hippo pathway to restore cardiac function in an injured heart. Methods and results: nCPCs were conditioned for 48 hours in serum free nutrition mix (Ham’sF12) and nEXOs were purified from supernatant using size exclusion chromatography (SEC; CL2B) coupled with ultracentrifugation. nEXOs were quantified by Nanosight (NS300) and characterized by transmission electron microscopy and flow cytometry for the presence of CD63 and CD9. Our results show recovery of cardiac function (ejection fraction = 63.4% vs 40.5%, n=10, p&lt;0.001)) and generation of myocardial mass in a rodent MI model following nEXOs’ intra-myocardial injection. We further show that nEXOs are preferentially acquired by CMs in the border zone of the infarction (m-cherry-Alix labeled EXOs). Using deep RNAseq (sequencing depth: 25 million reads) coupled with literature based in silico analysis, we identified a candidate panel of miRNAs, predicted to promote CM proliferation by targeting the Hippo Pathway. Our In vitro experiments show that miR-528-3p and miR-7641 (25nM) are the most effective miRs to induce proliferation of quiescent cardiomyocytes (40.1% and 48.8%, respectively, n=3). Increased miR-7641 expression led to a profound increase in quiescent CMs proliferation, in part through repression of the Hippo signal transduction pathway (increased YAP/pYAP ratio). By immunoblotting we show that LATs1/2 (a protein in the Hippo pathway) is directly targeted by miR-7641. nEXOs enriched with miR 7641 promote CM proliferation by 3 folds as compared to non-enriched nEXOs. Conclusion: Our data for the first time demonstrates the ability of EXOs derived micro-RNA based therapeutic approaches to improve cardiac function through the activation of cardiomyocyte proliferation.
ASSOCIATION OF SUBCLINICAL ATRIAL FIBRILLATION WITH RISK OF STROKE: RESULTS FROM A META-ANALYSIS
Authors: Sanghamitra Mohanty, Prasant Mohanty, Veronica Natale, Chintan Trivedi, Domenico Della Rocca, Qiong Chen, Omer Gedikli, Alfredo C. Tapia, Joanna Assadourian, Luigi di Biase, Andrea Natale
Journal: Journal of the American College of Cardiology (2019)
A phase II study of loratidine (L) and naproxen (N) to prevent pegfilgrastim-induced pain (PIP).
Authors: Jeffrey J. Kirshner, Charles E Heckler, Carol Reichel, Gary R. Morrow
Journal: Journal of Clinical Oncology (2012)

e19510 Background: We have previously demonstrated the efficacy of N in terms of preventing the incidence, severity and duration of PIP (ASCO 2010; JCO, in press). Last year at ASCO, we reported the results of a pilot study of L, using similar methodology. The present pilot study was designed to determine the safety and efficacy of the combination of N + L , used to prevent PIP. Methods: Using identical eligibility criteria to the aforementioned studies, 41 pts were treated with N 500 mg po bid and L 10 mg po qd beginning on the morning of their initial dose of P and continuing for 5-8 days. Pain at any time was recorded by pts in diaries using a 0-10 scale. Unexpected adverse events were promptly reported. Similar methodology and statistical analyses were used, with the primary endpoint being AUC for the severity and duration of pain. Results: Six pts either did not take the pills or return questionnaires. 35 evaluable pts were treated (27F;8M). Cancers included 24 breast, 7 lung and 4 others. AUC was 7.10. At any time during the 5 days after administration of P, 10 pts experienced no pain, 17 had some mild pain and 8 had some severe pain. No unexpected adverse events were reported. Comparison to our prior studies is tabulated (see table below). Conclusions: The combination of N + L does not appear to be unsafe when used to prevent PIP, but in these small pilot studies, the regimen does not appear to be any more efficacious than either drug when used alone. A larger study is needed to specifically evaluate efficacy and toxicity. [Table: see text]
Abstract 9809: Does Blood Transfusion Deteriorate the Prognosis in Targeted Temperature Management After Cardiac Arrest?
Authors: Eisuke Kagawa, Keigo Dote, Masaya Kato, Shota Sasaki, Yasuki Kihara
Journal: Circulation (2015)

Introduction: It is well known that blood transfusion can worsen outcomes in patients with acute coronary syndrome without cardiac arrest. However, little is known regarding patients receiving blood transfusion after cardiac arrest in the current era of targeted temperature management (TTM) and coronary reperfusion. Hypothesis: We assessed the hypothesis that blood transfusion worsen the prognosis of patients after cardiac arrest. Methods: Adult comatose survivors of cardiac arrest treated with TTM were enrolled in this study. We assessed the association between blood transfusion and 90-day survival. We constructed 90-day survival curves using the Kaplan-Meier method to assess the impact of blood transfusion after cardiac arrest. Cox proportional hazards regression was utilized to adjust for the association of blood transfusion and 90-day survival. A P &lt; 0.05 was defined as statistically significant. Results: Among all study patients (N = 253), the median age was 62 years (interquartile range, 52 - 72 years), 75% were men, 51% had shockable initial rhythms, and the time interval from collapse to return of spontaneous circulation was 37 min (21 - 57 min). After hospital arrival, 60% of the study patients underwent immediate coronary angiography, 31% underwent subsequent coronary revascularization, and 99 patients (39%) received blood transfusions. The prevalence of blood transfusion were significantly higher in the patients underwent coronary revascularization (57% vs. 31%, P &lt; 0.001). The 90-day survival curves are shown in the figure. Blood transfusion was independently associated with reduced 90-day survival (hazard ratio 0.68 [95% confidence interval, 0.47 - 0.98], P = 0.04). Conclusions: Blood transfusion may worsen survival in patients not treated with coronary revascularization, but not in patients treated with coronary revascularization after cardiac arrest in the current TTM era.
Mortality Associated With Development of Squamous Cell Cancer in Patients With Inflammatory Bowel Diseases Receiving Treatment With Thiopurines
Authors: Nabeel Khan, Helen Lee, Chinmay Trivedi, Himanshu Kavani, Elina Medvedeva, Dawei Xie, James D. Lewis, Yu-Xiao Yang
Journal: Clinical Gastroenterology and Hepatology (2019)
INCIDENCE AND PREDICTORS OF LONG TERM CARDIOTOXICITY IN ANTRACYCLINE BASED CHEMOTHERAPY IN BREAST CANCER PATIENTS
Authors: Rebeca Mata Caballero, J.M. Serrano Antolin, I.A. Gonzalez Garcia, J.M. Muniz Garcia, A. Curcio Ruigomez, C. Gutierrez Landaluce, S. Del Castillo Arrojo, C. Graupner Abad, C. Cristobal Varela, D. Galan Gil, M.J. Espinosa Pascual, B. Izquierdo Coronel, P. Talavera Calle, V. Gonzalez Pastor, R.M. Jimenez Hernandez, J.J. Alonso Martin
Journal: Journal of the American College of Cardiology (2019)
Abstract 14116: Effects of Statin Intensity and Low-density Lipoprotein Cholesterol Lowering in Korean Patients With Chronic Ischemic Heart Disease and Very Low Low-density Lipoprotein Cholesterol
Authors: Soo Youn Lee, Jong-Chan Youn, Sungha Park, Seok-Min Kang, Donghoon Choi, Seung Jin Oh, Eung Ju Kim, Sang-Hak Lee
Journal: Circulation (2015)

Introduction: Current guidelines on lipid management emphasize LDL-C lowering &gt;50% of baseline levels with intensive statin regimens in patients with coronary artery disease. However, whether this strategy is beneficial also in patients with very low LDL-C has not been proven. Furthermore, controversy remains on the optimal statin intensity for Asians in whom outcome data of lipid therapy are highly limited. Methods and Results: Totally, 3867 patients with chronic ischemic heart disease were initially screened. Among them, 393 subjects(age: 66 years; males: 68%) who showed baseline LDL-C &lt;80 mg/dL without lipid lowering medications were finally included. Patients were retrospectively classified to 4 groups according to statin intensity they received : no (n=35), Moderate-low (atorvastatin 10mg or similar, n=135), moderate-high (atorvastatin 20 mg or similar, n=177), or high (atorvastatin 40-80 mg or similar, n=46) intensity. Patients took blood tests every 3-6 months and were clinically followed-up for major adverse cardiac events (MACE). During the mean follow-up of 3.8 years, 41 patients (10.4%) experienced MACE. The event-free survival was higher in patients receiving higher dose statins (Figure, p=0.03). In the univariate analysis, age (p=0.05), the % change of LDL-C (p=0.01), and the statin intensity (p=0.03) were associated with MACE. In the multivariate analysis, the statin intensity was found to be an only independent predictor of clinical outcome (p=0.05). Interestingly, the beneficial effect of statins became significant at the moderate-high dose. The predictive value of the % change of LDL-C was not significant after controlling other variables. Conclusions: Our study demonstrated that higher dose statins (at least moderate-high intensity) were more beneficial in Asian patients with chronic ischemic heart disease even if their LDL-C is &lt;80 mg/dL. This effect was independent of % change of LDL-C.