tbuckley/cabot-search huggingface dataset:
Abstract 14745: The Histone Reader PHF7 Cooperates With the SWI/SNF Complex at Cardiac Super Enhancers to Promote Direct Cardiac Reprogramming
Authors: Glynnis A Garry, Svetlana Bezprozvannaya, Kenian Chen, Huanyu Zhou, Hisayuki Hashimoto, Maria G Morales, Ning Liu, Rhonda S Bassel-Duby, Eric N Olson
Journal: Circulation (2020)

Direct cardiac reprogramming of fibroblasts to cardiomyocytes presents an attractive therapeutic strategy to restore cardiac function following injury. Cardiac reprogramming was initially achieved through the overexpression of the transcription factors Gata4, Mef2c, and Tbx5 (GMT), and later, Hand2 (GHMT) and Akt1 (AGHMT) were found to further enhance this process. Yet, staunch epigenetic barriers severely limit the ability of these cocktails to reprogram adult fibroblasts. We undertook a screen of mammalian gene regulatory factors to discover novel regulators of cardiac reprogramming in adult fibroblasts and identified the histone reader PHF7 as the most potent activating factor. Mechanistically, PHF7 localizes to cardiac super enhancers in fibroblasts, and through cooperation with the SWI/SNF complex, increases chromatin accessibility and transcription factor binding at these sites. Further, PHF7 recruits cardiac transcription factors to activate a core regulatory circuit in reprogramming. Importantly, PHF7 is the first epigenetic factor shown to achieve efficient reprogramming in the absence of Gata4. Here, we highlight the underexplored necessity of cardiac epigenetic modifiers, such as PHF7, in harnessing chromatin remodeling and transcriptional complexes to overcome critical barriers to direct cardiac reprogramming.
High titers and low fucosylation of early human anti–SARS-CoV-2 IgG promote inflammation by alveolar macrophages
Authors: Willianne Hoepel, Hung-Jen Chen, Chiara E. Geyer, Sona Allahverdiyeva, Xue D. Manz, Steven W. de Taeye, Jurjan Aman, Lynn Mes, Maurice Steenhuis, Guillermo R. Griffith, Peter I. Bonta, Philip J.M. Brouwer, Tom G. Caniels, Karlijn van der Straten, Korneliusz Golebski, René E. Jonkers, Mads D. Larsen, Federica Linty, Jan Nouta, Cindy P.A.A. van Roomen, Frank E.H.P. van Baarle, Cornelis M. van Drunen, Gertjan Wolbink, Alexander P.J. Vlaar, Godelieve J. de Bree, Rogier W. Sanders, Lisa Willemsen, Annette E. Neele, Diederik van de Beek, Theo Rispens, Manfred Wuhrer, Harm Jan Bogaard, Marit J. van Gils, Gestur Vidarsson, Menno de Winther, Jeroen den Dunnen
Journal: Science Translational Medicine (2021)

Patients diagnosed with coronavirus disease 2019 (COVID-19) become critically ill primarily around the time of activation of the adaptive immune response. Here, we provide evidence that antibodies play a role in the worsening of disease at the time of seroconversion. We show that early-phase severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific immunoglobulin G (IgG) in serum of critically ill COVID-19 patients induces excessive inflammatory responses by human alveolar macrophages. We identified that this excessive inflammatory response is dependent on two antibody features that are specific for patients with severe COVID-19. First, inflammation is driven by high titers of anti-spike IgG, a hallmark of severe disease. Second, we found that anti-spike IgG from patients with severe COVID-19 is intrinsically more proinflammatory because of different glycosylation, particularly low fucosylation, of the antibody Fc tail. Low fucosylation of anti-spike IgG was normalized in a few weeks after initial infection with SARS-CoV-2, indicating that the increased antibody-dependent inflammation mainly occurs at the time of seroconversion. We identified Fcγ receptor (FcγR) IIa and FcγRIII as the two primary IgG receptors that are responsible for the induction of key COVID-19-associated cytokines such as interleukin-6 and tumor necrosis factor. In addition, we show that anti-spike IgG-activated human macrophages can subsequently break pulmonary endothelial barrier integrity and induce microvascular thrombosis in vitro. Last, we demonstrate that the inflammatory response induced by anti-spike IgG can be specifically counteracted by fostamatinib, an FDA- and EMA-approved therapeutic small-molecule inhibitor of Syk kinase.
Abstract 12926: Prescription of Direct Oral Anticoagulant Affects Activated Clotting Time During Percutaneous Coronary Intervention and Clinical Outcomes
Authors: Suguru Ebihara, Kentaro Jujo, Kazuho Kamishima, Kensuke Shimazaki, Tetsu Moriyama, Natsuko Shiozaki, Keiko Inagaki, Yuji Iwanami, Issei Ishida, Kazuhito Suzuki, Katsumi Saito, Nobuhisa Hagiwara
Journal: Circulation (2018)

Suguru EBIHARA1,2, Kentaro JUJO1,3, Kazuho KAMISHIMA2, Kensuke SHIMAZAKI3, Tetsu MORIYAMA3, Natsuko SHIOZAKI3, Keiko INAGAKI2, Yuji IWANAMI3, Issei ISHIDA1,3, Kazuhito SUZUKI2, Katsumi SAITO3, Nobu...
Abstract 16850: Machine Learning Based Estimation of Systolic and Diastolic Arterial Blood Pressure From the Electrocardiogram and Oxygen Saturation Waveforms
Authors: Rahul Kumar Sevakula, Mohamad Kassab, Sandeep Chandra Bollepalli, Eric M Isselbacher, Antonis Armoundas
Journal: Circulation (2020)

Introduction: Accurate, continuous blood pressure (BP) monitoring requires invasive equipment. We investigate the utility of a machine learning algorithm (ML) to estimate the systolic (sys) and diastolic (dia) BP from the electrocardiogram (ECG) and oxygen saturation (SpO2) signals. Methods: We identified over 2,000 hours (~9.2 M heart-beats), of 4 lead ECG, arterial BP, and SpO2 waveforms, from 82 random ICU patients, with various diagnoses. The ECG, BP and SpO2 waveforms were delineated using a wavelet-transform-based algorithm. Features extracted from the ECG and SpO2 signals were used as input to the ML model, while the sys/dia BP values of the corresponding BP signal (range: 0-250 mmHg), served as the gold standard. Using these features, we trained two independent Random Forest (RF) models to estimate the sys/dia BP values, and measured their performance over five-fold cross-validation. To identify the optimal window-length (# heart beats) in estimating sys/dia BP values, the entire process of extracting features and training/testing of RF models was performed for window-lengths of {1,5,6,7,8,9,10,11,12,13,14,15,20,30,50} heart-beats. Results: The root-mean-square error (RMSE) at each window-length is shown in the Figure. The lowest RMSE for both estimated sys/dia BP, 5.81±4.61 mmHg and 3.73±3.26 mmHg, respectively, was achieved at 14 heart-beats. The corresponding RMSE values using a one-beat length-window were 7.73±5.93 mmHg and 5.28±4.42 mmHg, respectively. This result indicates the ability to estimate the instantaneous BP values even on a beat-to-beat basis, with low-error. Conclusions: In comparison to prior studies, our novel ML model, to the best of our knowledge, has been trained over the largest amount of data. Our ML model can accurately estimate the sys/dia values of the arterial BP. Figure: RMSE values obtained while estimating the mean sys/dia BP, across different window-lengths.
Abstract P090: Does The Increasing Prevalence Of Obesity Explain The Decrease In Blood Pressure Control Among Us Adults With Hypertension?
Authors: Kathryn Foti, Shakia T Hardy, Alexander Chang, Elizabeth Selvin, Josef Coresh, Paul Muntner
Journal: Circulation (2021)

Introduction: The proportion of US adults with hypertension who had controlled blood pressure (BP) decreased from 2013-2018. The rising prevalence of obesity has been implicated as a reason for this decline. We investigated trends in BP control from 2013-2018 among US adults with hypertension, overall and among those taking antihypertensive medication, by body mass index (BMI) category. Methods: We used National Health and Nutrition Examination Survey data from 2013-2014, 2015-2016, and 2017-2018 for US adults aged ≥18 with hypertension (N=5,580). We examined the BMI distribution [normal (BMI &lt;25 kg/m 2 ), overweight (BMI 25-&lt;30 kg/m 2 ), class 1 obesity (BMI 30-&lt;35 kg/m 2 ), class 2 or 3 obesity (BMI ≥35 kg/m 2 )] in each survey cycle. We calculated the age-adjusted prevalence of BP control (&lt;140/90 mmHg) overall and among those taking antihypertensive medication in each survey cycle by BMI category. We examined trends in BP control within BMI category adjusted for age and other sociodemographic and clinical characteristics; we tested differences in trends by BMI category using interaction terms. Results: The prevalence of overweight and obesity among US adults with hypertension did not change from 2013-2018 ( Table ). The overall proportion of adults with hypertension who had controlled BP was higher among those with overweight or obesity than those with normal BMI. BP control among those taking antihypertensive medication was similar among those with overweight or obesity and those with normal BMI. BP control overall decreased over time with no evidence of a difference by BMI category. Among those taking antihypertensive medication, BP control decreased in those who were overweight or had class 1 obesity but not in those with normal BMI or class 2 or 3 obesity. Conclusions: Among US adults with hypertension, there was no increase in the prevalence of overweight and obesity from 2013-2018 and BP control decreased in all subgroups. These findings suggest the obesity epidemic is not driving the decrease in BP control in the US population.
From Systemic Inflammation to Myocardial Fibrosis
Authors: Walter J. Paulus, Michael R. Zile
Journal: Circulation Research (2021)

In accordance with the comorbidity-inflammation paradigm, comorbidities and especially metabolic comorbidities are presumed to drive development and severity of heart failure with preserved ejection fraction through a cascade of events ranging from systemic inflammation to myocardial fibrosis. Recently, novel experimental and clinical evidence emerged, which strengthens the validity of the inflammatory/profibrotic paradigm. This evidence consists among others of (1) myocardial infiltration by immunocompetent cells not only because of an obesity-induced metabolic load but also because of an arterial hypertension-induced hemodynamic load. The latter is sensed by components of the extracellular matrix like basal laminin, which also interact with cardiomyocyte titin; (2) expression in cardiomyocytes of inducible nitric oxide synthase because of circulating proinflammatory cytokines. This results in myocardial accumulation of degraded proteins because of a failing unfolded protein response; (3) definition by machine learning algorithms of phenogroups of patients with heart failure with preserved ejection fraction with a distinct inflammatory/profibrotic signature; (4) direct coupling in mediation analysis between comorbidities, inflammatory biomarkers, and deranged myocardial structure/function with endothelial expression of adhesion molecules already apparent in early preclinical heart failure with preserved ejection fraction (HF stage A, B). This new evidence paves the road for future heart failure with preserved ejection fraction treatments such as biologicals directed against inflammatory cytokines, stimulation of protein ubiquitylation with phosphodiesterase 1 inhibitors, correction of titin stiffness through natriuretic peptide-particulate guanylyl cyclase-PDE9 (phosphodiesterase 9) signaling and molecular/cellular regulatory mechanisms that control myocardial fibrosis.
Self-assembly of protein-polymer conjugates for drug delivery
Authors: Corey. A. Stevens, Kuljeet Kaur, Harm-Anton Klok
Journal: Advanced Drug Delivery Reviews (2021)

Protein-polymer conjugates are a class of molecules that combine the stability of polymers with the diversity, specificity, and functionality of biomolecules. These bioconjugates can result in hybrid materials that display properties not found in their individual components and can be particularly relevant for drug delivery applications. Engineering amphiphilicity into these bioconjugate materials can lead to phase separation and the assembly of high-order structures. The assembly, termed self-assembly, of these hierarchical structures entails multiple levels of organization: at each level, new properties emerge, which are, in turn, influenced by lower levels. Here, we provide a critical review of protein-polymer conjugate self-assembly and how these materials can be used for therapeutic applications and drug delivery. In addition, we discuss central bioconjugate design questions and propose future perspectives for the field of protein-polymer conjugate self-assembly.
3D Bioprinting: Fast Stereolithography Printing of Large‐Scale Biocompatible Hydrogel Models (Adv. Healthcare Mater. 10/2021)
Authors: Nanditha Anandakrishnan, Hang Ye, Zipeng Guo, Zhaowei Chen, Kyle I. Mentkowski, Jennifer K. Lang, Nika Rajabian, Stelios T. Andreadis, Zhen Ma, Joseph A. Spernyak, Jonathan F. Lovell, Depeng Wang, Jun Xia, Chi Zhou, Ruogang Zhao
Journal: Advanced Healthcare Materials (2021)

In article number 2002103, Ruogang Zhao, Chi Zhou, and co-workers, present the development of fast hydrogel stereolithography technology (FLOAT) for the fabrication of large-sized biocompatible hydrogel models. The high printing speed of the FLOAT significantly reduces environmental stress-induced cellular injuries. The perfusable vessel networks enabled by the multiscale printing capability allows maintenance of high cellular viability and metabolic functions in the core of the large-sized models.
Abstract 13402: FHL-1 Contributes to and Colocalizes With Titin in Cardiac Hypertrophy
Authors: Nesrine El-Bizri, Jing Liu, Rachel Matt, Rugmani P Iyer, Girija Raman, Keith Q Tanis, Heather Zhou, Thomas W Rosahl, Payal Sheth, Gayathri Swaminath
Journal: Circulation (2020)

Increased myocardial stiffness is a hallmark of impaired diastole in heart failure (HF). Hypo-phosphorylation of the N2B unique sequence (N2Bus) of titin (TTN), a giant myofilament protein, increases passive tension leading to diastolic dysfunction in HF. Enhancing the altered N2Bus phosphorylation improves cardiac stiffness and function. FHL-1, an interacting protein potentially modulating N2Bus phosphorylation is increased in HF. FHL-1 knockout mice display blunted cardiac hypertrophy and improved diastolic compliance in response to pressure-overload by transverse aortic constriction, TAC. FHL-1 also regulates skeletal muscle hypertrophy. We hypothesize that FHL-1 contributes to cardiac hypertrophy and colocalizes/interacts with TTN in heart failure. In house IHC data showed site-specific N2Bus hypo-phosphorylation at S4099, S4010 and S4185 in human HCM and/or DCM tissue samples. Longitudinal in-vivo studies showed that FHL-1 and cardiac hypertrophy markers genes were increased in left ventricles (LV) of TAC mice using RNA-seq. A persistently enhanced FHL-1 protein expression by immunoblotting and mass spectrometry strongly correlated with LV hypertrophy at 1, 4, and 6 weeks post-TAC. In addition, LV hypertrophy correlated negatively with function (fractional shortening). Increases in FHL-1 and hypertrophy markers mRNA levels were confirmed by RT-qPCR in neonatal rat ventricular myocytes (NRVM) under phenylephrine (PE) and endothelin-1 (ET-1) induced hypertrophy. Under similar conditions, FHL-1 protein levels were increased by immunofluorescence (IF) in cytoplasmic, perinuclear and nuclear regions of NRVM. Colocalization of phospho-TTN and FHL-1 was observed in NRVM and was enhanced under PE- and ET-1 induced hypertrophy. IF studies in human skeletal myotubes showed that FHL-1 expression was increased during myoblast differentiation and IGF1-E3R induced hypertrophy. Preliminary data using Microscale Thermophoresis showed binding affinity between N2Bus and FHL-1 proteins. Our studies show that FHL-1 contributes to hypertrophy in addition to N2B hypo-phosphorylation status contributing to diastolic dysfunction in HF. Targeting FHL-1 and TTN can be a potential strategy to improve diastolic compliance in HF.
Abstract 040: Bedscales: Non-Contact Home Health Monitor For Longitudinal Characterization Of Periodic Breathing In Chronic Heart Failure
Authors: Claire Zhang, Nicholas Harrington, Robert L Owens, Kevin R King
Journal: Circulation (2021)

Periodic breathing (PB), including its subtype Cheyne-Stokes respiration, is a pattern of sleep-disordered breathing marked by cyclic modulations in tidal volume and respiratory rate. PB is commonly identified in patients with chronic heart failure (CHF), and portends a worse prognosis. Due to the impracticality of existing monitoring methods, no longitudinal data exist on whether individual patients may experience prognostically significant fluctuations in PB. Here, we present a novel tool enabling long-term in-home investigation of PB. By passively capturing respirations during sleep via mechanical sensors placed under the legs of a bed, the need for patient compliance is circumvented. PB events were identified by computing an amplitude modulation index, and features including respiratory rate, cycle length, and hyperpnea duration were extracted. To demonstrate viability for longitudinal studies, devices were installed in the homes of 25 CHF patients to continuously record respirations, 9 of whom were found to exhibit PB. In an illustrative case, ~15,000 cycles of PB were captured over 3 months in a patient discharged after hospitalization for heart failure with reduced ejection fraction. Bedscales documented the patient’s worsening tachypnea accompanied by changes in PB parameters (shortened cycle and hyperpnea durations). A chest X-ray showed evidence of pneumonia and antibiotics were prescribed, after which tachypnea improved and trends of PB parameters reversed. This case highlights the potential utility of Bedscales in detecting subtle deviations from an individual’s baseline respiratory signatures; future work is needed to assess the predictive power of these parameters. Taken together, these results demonstrate the feasibility of Bedscales as a low-cost, scalable tool for longitudinal population-level studies of PB in relation to chronic diseases such as CHF. Future research could examine whether such data might predict exacerbations and direct early intervention to prevent rehospitalization.
Effect of a Digital Intervention on Depressive Symptoms in Patients With Comorbid Hypertension or Diabetes in Brazil and Peru
Authors: Ricardo Araya, Paulo Rossi Menezes, Heloísa Garcia Claro, Lena R. Brandt, Kate L. Daley, Julieta Quayle, Francisco Diez-Canseco, Tim J. Peters, Daniela Vera Cruz, Mauricio Toyama, Suzana Aschar, Liliana Hidalgo-Padilla, Hellen Martins, Victoria Cavero, Thais Rocha, George Scotton, Ivan F. de Almeida Lopes, Mark Begale, David C. Mohr, J. Jaime Miranda
Journal: JAMA (2021)

Depression is a leading contributor to disease burden globally. Digital mental health interventions can address the treatment gap in low- and middle-income countries, but the effectiveness in these countries is unknown.
Pharmacological inhibition of noncanonical EED-EZH2 signaling overcomes chemoresistance in prostate cancer
Authors: Xin Li, Lajos Gera, Shumin Zhang, Yanhua Chen, Lei Lou, Lauren Marie Wilson, Zhong-Ru Xie, Giuseppe Sautto, Degang Liu, Alira Danaher, Kenza Mamouni, Yang Yang, Yuhong Du, Haian Fu, Omer Kucuk, Adeboye O Osunkoya, Jia Zhou, Daqing Wu
Journal: Theranostics (2021)

Chemoresistance is a major obstacle in prostate cancer (PCa) treatment. We sought to understand the underlying mechanism of PCa chemoresistance and discover new treatments to overcome docetaxel resistance.
Abstract 15362: “FFR at Rest”: Characterizing Patients With Severe Coronary Stenosis and Maximal Vasodilation at Rest
Authors: Srikanth Vallurupalli, Shivkumar Agarwal, Rimsha Hasan, Mohammed Eid Madmani, Aisha Siraj, Rahil Rafeedheen, Mohamed Ayan, Negar Salehi, Malek Al-Hawwas, Abdul Hakeem, Barry F Uretsky
Journal: Circulation (2019)

Introduction: Patients with severe obstructive coronary disease may have exhausted their vasodilatory reserve in the resting state. The incidence and clinical implications of this phenomenon have n...
Abstract 17255: Premature Atrial Stimulation Reveals Increased Conduction Slowing and Block in Cardiac Surgery Patients That Develop Postoperative Atrial Fibrillation
Authors: Muhammad S Khan, Vikas Sharma, Ravi Ranjan, Jason P Glotzbach, Craig Selzman, Derek J DOSDALL
Journal: Circulation (2020)

Introduction: Postoperative atrial fibrillation (POAF) is a common cardiac surgery complication that is highly associated with increased morbidity and mortality. The relation of presurgical left atrial (LA) conduction abnormalities and POAF during intraoperative premature atrial stimulation (S1S2) pacing is investigated and reported. Hypothesis: Intraoperative premature atrial stimulation reveals increased areas of slowed or blocked conduction in patients that develop POAF. Methods: High-density intraoperative epicardial mapping was conducted in 20 cardiac surgery patients with no history of preoperative atrial fibrillation (AF) both in sinus rhythm (SR) and during S1S2 pacing. A flexible array comprised of 240 electrodes was placed on the posterior LA wall in between the pulmonary veins. For each patient, the area of conduction block (CB), conduction delay (CD) and combined conduction delay and block (CDCB) for conduction velocity &lt;0.1 m/s, 0.1 - 0.2 m/s and &lt;0.2 m/s, respectively were quantified. Results: In 20 patients, 6 (30%) developed POAF. As shown in the Figure, conduction maps revealed the presence of significantly higher areas of CD (13.2±6.6% vs. 6.1±4.2%, p=0.03) and CDCB (17.5±8.7% vs. 7.4±6.4%, p=0.03), and a trend toward larger CB (4.2±3.8% vs. 1.3±2.9%, p=0.09) in patients that developed POAF for premature atrial beat S2 compared to patients that remained in SR after cardiac surgery. S1 paced beats and SR did not show significant differences in abnormal conduction percentages between patients with and without POAF. Conclusions: Premature atrial stimulation accentuates conduction abnormalities in cardiac surgery patients that develop POAF, revealing a pre-surgical substrate that may indicate greater risk for post-surgical atrial arrhythmias.
Panaxadiol arrests cell cycle at G1/S phase by elevating p21WAF1/CIP1
Authors: Joonseok Choi, Ying Hua Jin, Soona Shin, Kwangyoul Lee, Jeong Hill Park, Seung Ki Lee
Journal: Cancer Research (2004)

852  We show that panaxadiol (PD), a ginseng saponin with a dammarane skeleton, selectively interferes with the cell cycle in human cancer cell lines. PD inhibited DNA synthesis in a dose-dependent manner with IC50 values ranging from 0.8 μM-1.2 μM in SK-HEP-1 cells and HeLa cells. PD-treated cells were arrested at G1/S phase, which coincided well with decreases in Cyclin A-cdk2 activity, but not in Cyclin E-cdk2 and Cdc2 activities. The intracellular levels of p21WAF1/CIP1 were significantly and selectively elevated in a dose- and time-dependent manners in PD-treated HeLa cells. Similarly, levels of the p21WAF1/CIP1 protein that is associated with the Cyclin A–Cdk2 complex increased, and these increases correlated well with the down-regulation of Cyclin A-cdk2 activity. And these increased level of p21WAF1/CIP1 in PD-treated HeLa cells were restored by PD-withdrawal. Thus, PD selectively elevates p21WAF1/CIP1 levels and thereby arrests the cell cycle at G1/S phase by down-regulating Cyclin A-Cdk2 activity.