tbuckley/cabot-search huggingface dataset:
Abstract 14127: BET Protein Inhibitor Apabetalone Suppresses Inflammatory Hyperactivation of Monocytes From Patients With Cardiovascular Disease and Type 2 Diabetes
Authors: Sylwia Wasiak, Kim Dzobo, Brooke Rakai, Yannick Kaiser, Miranda Versloot, Mahnoush Bahjat, Stephanie Stotz, Li Fu, Michael Sweeney, Jan JOHANSSON, Norman Wong, Erik Stroes, Jeffrey Kroon, Ewelina Kulikowski
Journal: Circulation (2020)

Introduction: Hyperactivation of the monocyte inflammatory response is partly controlled by epigenetic mechanisms and contributes to atherosclerotic plaque formation in patients with cardiovascular disease (CVD) and type 2 diabetes mellitus (DM2). Hypothesis: Monocyte activation in DM2+CVD is regulated by bromodomain and extraterminal (BET) epigenetic readers and can be inhibited by apabetalone - a clinical stage BET inhibitor. Methods: CD14+ monocytes from 14 DM2+CVD patients and 12 matched control subjects were treated ex vivo with 25 μM apabetalone ± 25 U/mL interferon γ (IFNγ) for 4h or 24h. Expressed genes (180) were analyzed with the Nanostring™ Innate Immunity Panel. Secreted cytokines were immunoprofiled with a Milliplex® array (42). Bioinformatics were performed with Ingenuity® Pathway Analysis (IPA®) software. Results: Unstimulated DM2+CVD monocytes had higher IL1A , IL1B and IL8 cytokine gene expression and Toll-like receptor (TLR) 2 surface abundance than control monocytes, indicating proinflammatory activation. Ex vivo apabetalone treatment reduced IL1A and IL8 mRNA (p&lt;0.001), as well as MCP-1, MCP-3, GRO-α, and IL-8 secretion (p&lt;0.01), countering the pro-inflammatory activation of DM2+CVD monocytes. Further, DM2+CVD monocytes were hyperresponsive to ex vivo stimulation with IFNγ, upregulating genes within cytokine and NF-κB pathways ( TNF , CCL7 , CCL8 , MYD88 , RELA ) &gt;30% more than controls (p&lt;0.05). Apabetalone countered IFNγ hyperresponsiveness by reducing expression of overexpressed genes by up to 30% more in DM2+CVD monocytes versus controls (p&lt;0.01). Ex vivo apabetalone treatment also countered IFNγ induced secretion of IL-1β and TNFα in DM2+CVD monocytes (p&lt;0.01). Consistently, IPA® analysis of immune gene signatures post IFNγ stimulation in both cohorts predicted a more prominent reduction of Toll-like receptor and cytokine pathways by apabetalone in the diseased state. Conclusions: Monocytes isolated from DM2+CVD patients receiving standard of care therapies are in a hyperinflammatory state and hyperactivate upon IFNγ stimulation. Apabetalone treatment diminishes this proinflammatory phenotype, providing mechanistic insight into how BET protein inhibition may reduce CVD risk in DM2 patients.
Abstract 17204: Asymmetric Patterns of Cerebral Cortical Development in Fetuses With Complex Congenital Heart Disease
Authors: Yuanchiao Lu, Kushal Kapse, Nicole Andersen, Catherine Lopez, Jessica Quistorff, Anita Krishnan, Gilbert Vezina, Mary T Donofrio, Catherine Limperopoulos
Journal: Circulation (2020)

Introduction: Neurodevelopmental disabilities are common among infants with complex congenital heart disease (CHD). While hemispheric asymmetries in normal fetal brain size and shape have been reported, the effect of CHD on hemispheric development of the developing fetal brain remains unknown. Hypothesis: We hypothesized that emerging cerebral hemispheric asymmetries of the fetal CHD brain would differ compared to healthy controls using in vivo MRI tools. Methods: A total of 252 pregnant women were recruited (164 controls; 88 CHD fetuses), in which 328 fetal MRI scans were performed. Single shot fast spin echo T2-weighted images were acquired on a 1.5T GE MRI scanner. High-resolution 3D models of the fetal brain were reconstructed using slice-to-volume registration method for motion correction and Draw-EM algorithm for automatic segmentation. Volumetric analysis of brain tissues was conducted, and cortical folding measures of brain lobes were evaluated. Mixed effects regression was utilized to compare the brain features between right and left hemispheres for healthy controls and CHD fetuses. Results: The mean gestational age of all fetal MRI studies was 32.1±3.7 weeks (range: 24.0-39.4). For healthy fetuses, the volume of cortical gray matter was higher in the left hemisphere; however, this pattern was diminished in CHD fetuses. Gyrification indices were higher in the parietal and occipital lobes of the right hemisphere for controls, but not for CHD fetuses. Similarly, Gaussian curvature was higher in the right frontal lobe for controls only. Conversely, the surface area of the left occipital lobe was lower in CHD fetuses, but not in healthy fetuses. Conclusions: We report for the first time early disturbances in emerging hemispheric asymmetric patterns of the fetal brain in CHD compared to controls. The extent to which these lateralization differences reflect genetic, epigenetic and/or hemodynamic disturbances in CHD fetuses is under investigation.
Abstract 13811: The Clinical Significance of End-diastolic Forward Flow on the Prognosis After Pulmonary Valve Replacement in Patients Late After Repair of Tetralogy of Fallot
Authors: Yuji Tominaga, Masaki Taira, Tomomitsu Kanaya, Kanta Araki, Takuji Watanabe, Takayoshi Ueno, Yoshiki Sawa
Journal: Circulation (2020)

Introduction: Restrictive right ventricular physiology (r-RVP) is common in late after repair of tetralogy of Fallot (TOF) and reported to reflect diastolic dysfunction. Right ventricular (RV) diastolic dysfunction sometimes remains after pulmonary valve replacement (PVR) and is associated with arrhythmia. Pulmonary arterial end-diastolic forward flow (EDFF) is considered as a marker of r-RVP, and associated with RV volume, right atrial (RA) function, and the degree of pulmonary valve regurgitation (PR). The aim of this study is to evaluate the impact of EDFF before PVR on the clinical outcomes after PVR in patients with repaired TOF. Methods: This was a single-center, retrospective review of 46 patients who underwent PVR for moderate to severe PR between 2003 and 2019. Cases were examined EDFF before PVR and divided into two groups: with EDFF (EDFF+, n=23) and without EDFF (EDFF-, n=23). Patients with histories of atrial tachyarrhythmia underwent concomitant maze procedure. RV and RA volume were evaluated by magnetic resonance imaging. Post-PVR survival and the development of arrhythmia were assessed. Results: Age at PVR was 38±14 in EDFF+ and 35±10 years old in EDFF- (p=0.41), and the incidence of preoperative arrhythmia was not different (30% and 35%, p=1.0). RVESVI (102±24 and 86±26 ml/m 2 , p=0.048) and RAVI (84±19 and 70±20 ml/m 2 , p=0.025) before PVR, and RVEDVI (116±27 and 100±24 ml/m 2 , p=0.04) and RVESVI (71±23 and 55±16 ml/m 2 , p=0.01) at one year after PVR were greater in EDFF+. One patient in each group died due to non-cardiac disease. 5-year atrial tachyarrhythmia free rate was 62% in EDFF+ and 100% in EDFF- (Log-rank p=0.004). Multivariate Cox regression analysis revealed EDFF before PVR was a risk factor for atrial tachyarrhythmia after PVR (Hazard ratio 17 (95% CI, 2.2-406), p=0.025). Conclusions: EDFF before PVR was a significant risk factor for the development of postoperative atrial tachyarrhythmia. EDFF can complement the current indication for PVR.
Halting the FGF/FGFR axis leads to antitumor activity in Waldenström macroglobulinemia by silencing MYD88
Authors: Antonio Sacco, Cinzia Federico, Arianna Giacomini, Cinzia Caprio, Federica Maccarinelli, Katia Todoerti, Vanessa Favasuli, Antonella Anastasia, Marina Motta, Domenico Russo, Giuseppe Rossi, Nicole Bozza, Riccardo Castelli, Antonino Neri, Roberto Ronca, Chiara Cattaneo, Alessandra Tucci, Marco Mor, Marco Presta, Aldo M. Roccaro
Journal: Blood (2020)
Abstract PO-061: The role of Cathepsin E expression in pancreatic ductal adenocarcinoma tumorigenesis
Authors: Ericka Velez-Bonet, Sabrina Kaul, Corbin Pontious, Marcus Hong, Kelly Dubai, Zobeida Cruz-Monserrate
Journal: Cancer Research (2020)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal 5-year survival rate of 10% due to a lack of early detection and effective treatments. Aspartic protease Cathepsin E (CTSE) expression is increased early in PDAC, but its role in tumorigenesis is unknown. We hypothesize that high CTSE expression promotes proliferation, invasion, inhibition of apoptosis, and the secretion of cancer-associated cytokines in PDAC. Methods: Human PDAC cell lines (Mpanc96, Panc-1, and Miapaca2) were engineered to express high levels of CTSE. Cell proliferation, invasion, and apoptosis were analyzed and compared to control cell lines expressing low levels of CTSE. Cells were treated with aspartic protease inhibitors (Pepstatin A and Ritonavir) and monitored for proliferation (24 - 72 hours) and invasion (48 hours). Apoptosis was measured using propidium iodide and analyzed via flow cytometry. Conditioned media from cells was collected (72 hours) after treatment to assess differential secretion of cancer-associated cytokines using a cytokine array. Results: Proliferation was not affected by the overexpression of CTSE; however, inhibition of CTSE slowed proliferation in the Panc-1 and MiaPaca2, but not Mpanc96 cells. CTSE inhibitors promoted invasion of Mpanc96 and Panc-1, but not Miapaca2 cells, regardless of CTSE levels. Apoptosis was not significantly different between the cell lines treated with the aspartic protease inhibitors compared to controls. Increased expression of CTSE induced the secretion of various cytokines such as epithelial neutrophil-activating protein 78 (ENA-78), a chemokine expressed in inflammatory pancreatic disorders. Treatment with the inhibitor Pepstatin A decreased ENA-78 secretion. Conclusions: CTSE levels does not appear to affect proliferation or apoptosis; however, inhibition of CTSE increased cell invasion and resulted in altered cytokine secretion. Further studies examining how CTSE influences invasiveness, and cytokine secretion may create new opportunities for developing effective therapies for PDAC. Citation Format: Ericka Velez-Bonet, Sabrina Kaul, Corbin Pontious, Marcus Hong, Kelly Dubai, Zobeida Cruz-Monserrate. The role of Cathepsin E expression in pancreatic ductal adenocarcinoma tumorigenesis [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-061.
Enhancing Community Engagement by Schools and Programs of Public Health in the United States
Authors: Mindi B. Levin, Janice V. Bowie, Steven K. Ragsdale, Amy L. Gawad, Lisa A. Cooper, Joshua M. Sharfstein
Journal: Annual Review of Public Health (2020)

The US Centers for Disease Control and Prevention define community engagement as "the process of working collaboratively with and through groups of people" in order to improve their health and well-being. Central to the field of public health, community engagement should also be at the core of the work of schools and programs of public health. This article reviews best practices and emerging innovations in community engagement for education, for research, and for practice, including critical service-learning, community-based participatory research, and collective impact. Leadership, infrastructure, and culture are key institutional facilitators of successful academic efforts. Major challenges to overcome include mistrust by community members, imbalance of power, and unequal sharing of credit. Success in this work will advance equity and improve health in communities all around the world.
Phase 3 Trial of Interleukin-1 Trap Rilonacept in Recurrent Pericarditis
Authors: Allan L. Klein, Massimo Imazio, Paul Cremer, Antonio Brucato, Antonio Abbate, Fang Fang, Antonella Insalaco, Martin LeWinter, Basil S. Lewis, David Lin, Sushil A. Luis, Stephen J. Nicholls, Arian Pano, Alistair Wheeler, John F. Paolini
Journal: New England Journal of Medicine (2020)

Interleukin-1 has been implicated as a mediator of recurrent pericarditis. The efficacy and safety of rilonacept, an interleukin-1α and interleukin-1β cytokine trap, were studied previously in a phase 2 trial involving patients with recurrent pericarditis.We conducted a phase 3 multicenter, double-blind, event-driven, randomized-withdrawal trial of rilonacept in patients with acute symptoms of recurrent pericarditis (as assessed on a patient-reported scale) and systemic inflammation (as shown by an elevated C-reactive protein [CRP] level). Patients presenting with pericarditis recurrence while receiving standard therapy were enrolled in a 12-week run-in period, during which rilonacept was initiated and background medications were discontinued. Patients who had a clinical response (i.e., met prespecified response criteria) were randomly assigned in a 1:1 ratio to receive continued rilonacept monotherapy or placebo, administered subcutaneously once weekly. The primary efficacy end point, assessed with a Cox proportional-hazards model, was the time to the first pericarditis recurrence. Safety was also assessed.A total of 86 patients with pericarditis pain and an elevated CRP level were enrolled in the run-in period. During the run-in period, the median time to resolution or near-resolution of pain was 5 days, and the median time to normalization of the CRP level was 7 days. A total of 61 patients underwent randomization. During the randomized-withdrawal period, there were too few recurrence events in the rilonacept group to allow for the median time to the first adjudicated recurrence to be calculated; the median time to the first adjudicated recurrence in the placebo group was 8.6 weeks (95% confidence interval [CI], 4.0 to 11.7; hazard ratio in a Cox proportional-hazards model, 0.04; 95% CI, 0.01 to 0.18; P<0.001 by the log-rank test). During this period, 2 of 30 patients (7%) in the rilonacept group had a pericarditis recurrence, as compared with 23 of 31 patients (74%) in the placebo group. In the run-in period, 4 patients had adverse events leading to the discontinuation of rilonacept therapy. The most common adverse events with rilonacept were injection-site reactions and upper respiratory tract infections.Among patients with recurrent pericarditis, rilonacept led to rapid resolution of recurrent pericarditis episodes and to a significantly lower risk of pericarditis recurrence than placebo. (Funded by Kiniksa Pharmaceuticals; RHAPSODY ClinicalTrials.gov number, NCT03737110.).
ST18 affects cell–cell adhesion in pemphigus vulgaris in a tumour necrosis factor‐α‐dependent fashion*
Authors: S. Assaf, L. Malki, T. Mayer, J. Mohamad, A. Peled, M. Pavlovsky, K. Malovitski, O. Sarig, D. Vodo, E. Sprecher
Journal: British Journal of Dermatology (2020)

Pemphigus vulgaris (PV) is a life-threatening mucocutaneous autoimmune blistering disease. We previously showed that genetic variants within the ST18 gene promoter area confer a sixfold increase in the propensity to develop PV. ST18, a transcription factor, was found to be overexpressed in the epidermis of patients with PV. In addition, it was found to promote autoantibody-mediated abnormal epidermal cell-cell adhesion and secretion of proinflammatory mediators by keratinocytes.To delineate the mechanism through which ST18 contributes to destabilization of cell-cell adhesion.We used quantitative reverse-transcriptase polymerase chain reaction, immunofluorescence microscopy, a luciferase reporter system, site-directed mutagenesis, chromatin immunoprecipitation (ChIP) and the dispase dissociation assay.The ChIP and luciferase reporter assays showed that ST18 directly binds and activates the TNF promoter. Accordingly, increased ST18 expression contributes to PV pathogenesis by destabilizing cell-cell adhesion in a tumour necrosis factor (TNF)-α-dependent fashion. In addition, dual immunofluorescence staining showed increased expression of both ST18 and TNF-α in the skin of patients with PV carrying an ST18-associated PV risk variant, which was found to be associated with a more extensive PV phenotype.Our findings suggest a role for TNF-α in mediating the deleterious effect of increased ST18 expression in PV skin.
Photoacoustic spectroscopic studies of ovarian tissue in different pathological conditions: Classification using cluster analysis
Authors: Rani A. Bhat, K. K. Mahato, Sudha D. Kamath, Satadru Ray, V. B. Kartha
Journal: Cancer Research (2006)

3584  Introduction: Laser photoacoustic spectroscopy can provide information on both spectroscopic as well as acoustic transmission properties of materials in a single measurement. The technique can thus be used for the dual purpose of optical pathology and optical imaging of physiological systems. Imaging techniques like x-rays, positron emission tomography, nuclear magnetic resonance and scintigraphy have disadvantages like exposure to radioactive material, insufficient resolution, inability to provide information on biochemical composition etc. Whereas, optical methods have advantages like very high sensitivity, non-invasive probing, possibility of repeat testing and also providing biochemical information. Experimental: In the present work, pulsed laser-induced photoacoustic spectroscopic studies on pathologically certified normal, benign and malignant ovarian tissues were carried out at 325nm excitation. Spectra were recorded in time domain using transient digitizer, and were Fourier transformed to frequency domain by MATLAB®. MATLAB® is a high-performance language for technical computing. It integrates computation, visualization, and programming in an easy-to-use environment. Spectral analysis and classification for discrimination among normal, malignant, and benign classes was performed using Principal Component Analysis (PCA)/cluster analysis. Results and Conclusion: Typical pulsed laser-induced photoacoustic signal of normal, benign and malignant ovarian tissues at 325 nm excitation and the corresponding Fourier Transform spectra are shown in the illustration. The photoacoustic signal spectra were recorded keeping the tissue in a 2mm wide cuvette, moist in saline, exciting it from the top and detecting the signal using PZT detector. The signal, in the time domain, was recorded using transient digitizer. For classification, principal component analysis was performed on the feature space to reduce its dimensionality. We have shown that feature vector of length 6 could be reduced to 2 components using PCA technique. It can be concluded that the PAS technique is a suitable method for discrimination of normal and malignant ovarian tissues.
Abstract 15446: In-hospital Mortality Outcomes Between Urban and Rural Hospitals for Patients Undergoing Percutaneous Coronary Intervention
Authors: Katie Chang, Nicholas Chiu, Rahul Aggarwal
Journal: Circulation (2020)

Introduction: Percutaneous Coronary Intervention (PCI) is among the most common procedures in cardiology. However, in-hospital mortality for patients undergoing PCI procedures based on hospital location and teaching status needs evaluation. Understanding this relationship is necessary for identifying disparities in patient outcomes for PCI procedures. Hypothesis: To evaluate whether urban teaching hospitals have lower in-hospital mortality rates for PCI procedures than urban non-teaching and rural hospitals. Methods: We used data from the 2016 National Inpatient Sample (NIS) database to identify inpatient PCI hospitalizations. Hospitals were categorized as rural, urban teaching, and urban non-teaching. We used multivariable logistic regression to evaluate in-hospital mortality for PCI by hospital location and teaching status. We controlled for age, sex, race, length of stay, and comorbidities. Analyses accounted for the survey weighting design. Results: We identified 80,793 unweighted inpatient hospitalizations for PCI, representing 390,070 admissions when accounting for the survey weighting design. Of the 390,090 admissions, there were 21,020 (5.4%) from rural hospitals and 369,070 from urban hospitals (94.6%). Within the urban hospitals, there were 267,365 (72.4%) admissions from teaching hospitals and 101,705 (27.6%) admissions from non-teaching hospitals. There were no significant differences for in-hospital mortality between urban (6885 +/- 224.2 deaths) and rural hospitals (355 +/- 52.6 deaths, p= 0.6351). In-hospital mortality was found to be lower at urban teaching hospitals (4895 +/- 187.1 deaths) than at urban non-teaching hospitals (1990 +/- 123.5 deaths, p= 0.0096). Conclusions: In-hospital mortality for inpatient PCI procedures was not associated with hospital location, but rather with hospital teaching status. Urban teaching hospitals had lower rates of in-hospital mortality for PCI procedures than urban non-teaching hospitals. Further investigation to identify causes for this discrepancy is necessary.
Abstract 14569: Efficacy and Tolerability of Elamipretide in Patients With Barth Syndrome: Results From Tazpower, a Randomized, Double-Blind, Placebo-Controlled, Crossover and Open-Label Extension Trial
Authors: Hilary J Vernon, WIlliam R Thompson, Anthony Aiudi, John J Jones, Jim Carr, Brittany DeCroes Hornby
Journal: Circulation (2019)

Introduction: Barth syndrome (BTHS) is a rare, X-linked infantile-onset disease caused by defects in the TAZ gene that encodes tafazzin, a critical enzyme for cardiolipin (CL) maturation, the essen...
Antibody tests have higher sensitivity at ≥15 days after symptom onset and 99% specificity for detecting SARS-CoV-2
Authors: Alexander Lawandi, Robert L. Danner
Journal: Annals of Internal Medicine (2020)

Source CitationDeeks JJ, Dinnes J, Takwoingi Y, et al. Antibody tests for identification of current and past infection with SARS-CoV-2. Cochrane Database Syst Rev. 2020;6:CD013652. https://pubmed.ncbi.nlm.nih.gov/32584464/AbstractClinical Impact RatingsGIM/FP/GP: Hospitalists: Infectious Disease: