tbuckley/cabot-search huggingface dataset:
Abstract 15859: Fibroblast Growth Factor 23 and Myocardial Infarction in the Boston Puerto Rican Health Study
Authors: Chinedu C Ochin, Joseph Salami, Emir Veledar, Mahdi O Garelnabi, Katherine L Tucker
Journal: Circulation (2020)

Background: FGF-23 is an endocrine regulator of phosphate metabolism as well as also a potent biomarker that mediates cardiovascular remodeling, with markedly elevated plasma concentration associated with the occurrence of morbid cardiovascular events such as myocardial infarction. This association usually indicates risk of developing further adverse cardiovascular events in individuals that are already susceptible to repeat morbid cardiovascular outcomes. This cross-sectional epidemiological study aims at investigating the risk association between FGF-23 and individuals in the 8 th year cohort of the Boston Puerto Rican Health Study (BPRHS) that have self-reported clinical cardiovascular disease in the form of myocardial infarction. Methods: FGF-23 plasma concentration was measured by ELISA in 496 participants of the fourth wave of the Boston Puerto Rican Health Study (BPRHS). Multivariate logistic regressions were used to analyze the cross-sectional association of plasma FGF-23 quartile distribution with self-reported clinical diagnosis of myocardial infarction (MI). Results: The crude model for the association between FGF-23 and MI showed increased risk across the 2 nd , 3 rd and 4 th quartiles, OR (95% CI); 1.27 (0.48-3.34), 1.13 (0.42-3.04), and 3.13 (1.33-7.33), respectively. The relationship with the highest vs lowest quartile remained significant after adjusting for age, sex and BMI, OR (95% CI); 2.91 (1.15-7.36). With further adjustment for diabetes, smoking, plasma total cholesterol, HDL cholesterol and triglycerides, results were attenuated, and the latter comparison was no longer statistically significant, OR (95% CI); 2.15 (0.79-5.79). The test for trend across the quartiles yielded a p value of 0.03. Conclusion: Within this population of older Puerto Rican adults, FGF-23 was not significantly associated with increased likelihood of self-reported history of myocardial infarction. Longitudinal studies, using clinical parameters that objectively measure the progression of cardiovascular disease are needed to assess the prognostic value of FGF-23 for future cardiovascular outcomes.
Abstract 301: Aortic and Central Venous Pressure Wave Synchronization in Pseudo-Pulseless Electrical Activity
Authors: Alexander L Lindqwister, Samuel B Klein, Colin Raelson, Karen L Moodie, Kevin M Stanko, Norman A Paradis
Journal: Circulation (2020)

Introduction: Pseudo-Pulseless Electrical Activity (p-PEA) is a lifeless form of profound cardiac shock characterized by measurable cardiac mechanical activity without clinically detectable pulses. p-PEA may constitute up to 40% of reported cases of cardiac arrest and its etiologies and physiology are distinctly different from ventricular fibrillation or even true-PEA. In the normal physiologic state, there is an expected delay between the central venous (CV) and aortic (Ao) pressure waveforms corresponding to atrial kick and ventricular systole, respectively. We studied this relationship in hypoxic porcine p-PEA. Hypothesis: Development of p-PEA may be associated with changes in Ao and CV waveform synchronization. Methods: Female swine (N = 14) under intravenous anesthesia were instrumented with Ao and CV micromanometer catheters. ECG and ET-CO 2 were measured continuously. p-PEA was induced by ventilation with 6% oxygen in 94% nitrogen, and was defined as a systolic aortic pressure less than 40 mmHg. After 2 min. of p-PEA, 100% O 2 , CPR, and epinephrine were administered in a stepwise progression until ROSC was achieved. Results: One min. before the onset of hypoxia, the mean CV to Ao waveform delay was 0.161 sec. (SE ± 0.0015) across 52 experiments (n = 4797). This delay shortened during development of the p-PEA disease state (Figure 1), where the average delay decreased to 0.057 seconds (SE ± 0.0012) across 52 experiments (n = 3969, P &lt; 10-6). There were statistically significant differences (P &lt; 10-6) in waveform delays in between cohorts of animals who required more interventions to achieve ROSC, with shorter delay periods in both baseline and disease states correlating strongly with greater interventions. Conclusions: Development of the hypoxic p-PEA state may be associated with a loss of the normal CV to Ao pressure waveform delay. The degree of this loss may be associated with the severity of p-PEA disease state and predictive of the therapy required for ROSC.
Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure
Authors: John R Teerlink, Rafael Diaz, G. Michael Felker, John J.V. Mcmurray, Marco Metra, Scott D Solomon, Kirkwood F Adams, Inder Anand, Alexandra Arias-Mendoza, Tor Biering-Sørensen, Michael Böhm, Diana Bonderman, John G.F. Cleland, Ramon Corbalan, Maria G Crespo-Leiro, Ulf Dahlström, Luis E Echeverria, James C Fang, Gerasimos Filippatos, Cândida Fonseca, Eva Goncalvesova, Assen R Goudev, Jonathan G Howlett, David E Lanfear, Jing Li, Mayanna Lund, Peter Macdonald, Viacheslav Mareev, Shin-Ichi Momomura, Eileen O’meara, Alexander Parkhomenko, Piotr Ponikowski, Felix J.A. Ramires, Pranas Serpytis, Karen Sliwa, Jindrich Spinar, Thomas M Suter, Janos Tomcsanyi, Hans Vandekerckhove, Dragos Vinereanu, Adriaan A Voors, Mehmet B Yilmaz, Faiez Zannad, Lucie Sharpsten, Jason C Legg, Claire Varin, Narimon Honarpour, Siddique A Abbasi, Fady I Malik, Christopher E Kurtz
Journal: New England Journal of Medicine (2020)

The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown.We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes.During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups.Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016-002299-28.).
Abstract 12727: Impact of Initial Thrombocytopenia on Short and Midterm Outcomes in Patients With Acute Coronary Syndrome Who Underwent Percutaneous Coronary Intervention
Authors: Ola Abdelkarim, Mohamed Sadaka, Sherif Wagdy, Mohamed Sobhy
Journal: Circulation (2018)

Background: Patients with thrombocytopenia presenting with acute coronary syndromes (ACS) are treated by dual antiplatelet therapy in addition to percutaneous coronary interventions. Our aim was to...
The promising role of noncoding RNAs in cancer-associated fibroblasts: an overview of current status and future perspectives
Authors: Zengli Fang, Jin Xu, Bo Zhang, Wei Wang, Jiang Liu, Chen Liang, Jie Hua, Qingcai Meng, Xianjun Yu, Si Shi
Journal: Journal of Hematology & Oncology (2020)

As the most important component of the stromal cell population in the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) are crucial players in tumor initiation and progression. The interaction between CAFs and tumor cells, as well as the resulting effect, is much greater than initially expected. Numerous studies have shown that noncoding RNAs (ncRNAs) play an irreplaceable role in this interplay, and related evidence continues to emerge and advance. Under the action of ncRNAs, normal fibroblasts are directly or indirectly activated into CAFs, and their metabolic characteristics are changed; thus, CAFs can more effectively promote tumor progression. Moreover, via ncRNAs, activated CAFs can affect the gene expression and secretory characteristics of cells, alter the TME and enhance malignant biological processes in tumor cells to contribute to tumor promotion. Previously, ncRNA dysregulation was considered the main mechanism by which ncRNAs participate in the crosstalk between CAFs and tumor cells. Recently, however, exosomes containing ncRNAs have been identified as another vital mode of interaction between these two types of cells, with a more direct and clear function. Gaining an in-depth understanding of ncRNAs in CAFs and the complex regulatory network connecting CAFs with tumor cells might help us to establish more effective and safer approaches for cancer therapies targeting ncRNAs and CAFs and offer new hope for cancer patients.
The loss-of-function PCSK9Q152H variant increases ER chaperones GRP78 and GRP94 and protects against liver injury
Authors: Paul F. Lebeau, Hanny Wassef, Jae Hyun Byun, Khrystyna Platko, Brandon Ason, Simon Jackson, Joshua Dobroff, Susan Shetterly, William G. Richards, Ali A. Al-Hashimi, Kevin Doyoon Won, Majambu Mbikay, Annik Prat, An Tang, Guillaume Paré, Renata Pasqualini, Nabil G. Seidah, Wadih Arap, Michel Chrétien, Richard C. Austin
Journal: Journal of Clinical Investigation (2020)

Individuals harboring the loss-of-function (LOF) proprotein convertase subtilisin/kexin type 9 Gln152His variation (PCSK9Q152H) have low circulating low-density lipoprotein cholesterol levels and are therefore protected against cardiovascular disease (CVD). This uncleavable form of proPCSK9, however, is retained in the endoplasmic reticulum (ER) of liver hepatocytes, where it would be expected to contribute to ER storage disease (ERSD), a heritable condition known to cause systemic ER stress and liver injury. Here, we examined liver function in members of several French-Canadian families known to carry the PCSK9Q152H variation. We report that PCSK9Q152H carriers exhibited marked hypocholesterolemia and normal liver function despite their lifelong state of ER PCSK9 retention. Mechanistically, hepatic overexpression of PCSK9Q152H using adeno-associated viruses in male mice greatly increased the stability of key ER stress-response chaperones in liver hepatocytes and unexpectedly protected against ER stress and liver injury rather than inducing them. Our findings show that ER retention of PCSK9 not only reduced CVD risk in patients but may also protect against ERSD and other ER stress-driven conditions of the liver. In summary, we have uncovered a cochaperone function for PCSK9Q152H that explains its hepatoprotective effects and generated a translational mouse model for further mechanistic insights into this clinically relevant LOF PCSK9 variant.
Abstract 14890: Diagnosing Duchenne Muscular Dystrophy-Associated Cardiomyopathy: Echocardiogram Shoots, Cardiac Magnetic Resonance Imaging Scores
Authors: Rahul Sheth, Claudio Ramaciotti, Faris G Araj, Daniel Cheeran, Alpesh A Amin, Mark H Drazner, Ronald M Peshock, Pradeep P Mammen
Journal: Circulation (2020)

Background: Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder characterized by progressive muscle degeneration. The leading cause of death is complications from the development of DMD-associated cardiomyopathy. The majority of DMD patients have skeletal abnormalities that limit the quality of echocardiograms (ECHO). Although cardiac magnetic resonance imaging (cMRI) is the gold standard cardiac imaging tool, the vast majority of DMD patients are evaluated by ECHO rather than cMRI. We hypothesized that when compared to ECHO, cMRI more accurately assesses cardiac function and provides more valuable data for the diagnosis of DMD-associated cardiomyopathy. Methods: We undertook a retrospective study of 20 DMD patients referred to the UT Southwestern Adult Neuromuscular Cardiomyopathy Clinic who had undergone both an ECHO and cMRI within 15 months of each other. We assessed the proportion of studies demonstrating reduced left ventricular (LV) function [cMRI LVEF&lt;62%, ECHO fractional shortening (FS)&lt;25%] and that were technically difficult by both techniques. In addition, we assessed the proportion of cMRIs with late gadolinium enhancement (LGE), a marker of myocardial fibrosis and associated with increased mortality. Results: Amongst these patients, 10% of cMRIs and 85% of ECHOs were technically difficult. By cMRI, 30% of the studies were normal (LVEF 64±2 %), while 70% showed reduced function (LVEF: 44±12%). By ECHO, 75% of the studies were normal (FS 32±5), while 25% showed reduced function (FS: 15±8). Of the patients with truly reduced function by cMRI, 64% were considered normal by ECHO. Finally, 61% of cMRI studies showed LGE (50% with normal LVEF and 67% with reduced LVEF). Conclusions: In summary, cMRI is superior to ECHO in assessing cardiac function in DMD. ECHO underestimates left ventricular dysfunction, likely due to the poor quality of studies obtained in this patient population. In addition, cMRI identifies LGE, a marker associated with increased mortality, irrespective of cardiac function. Earlier utilization of cMRI will expedite the diagnosis of DMD-associated cardiomyopathy and enable the cardiologist to initiate aggressive guideline-directed medical therapy at an earlier age.
Sialic acid-engineered mesoporous polydopamine nanoparticles loaded with SPIO and Fe3+ as a novel theranostic agent for T1/T2 dual-mode MRI-guided combined chemo-photothermal treatment of hepatic cancer
Authors: Gaofeng Shu, Minjiang Chen, Jingjing Song, Xiaoling Xu, Chenying Lu, Yuyin Du, Min Xu, Zhongwei Zhao, Minxia Zhu, Kai Fan, Xiaoxi Fan, Shiji Fang, Bufu Tang, Yiyang Dai, Yongzhong Du, Jiansong Ji
Journal: Bioactive Materials (2020)

Hepatic cancer is a serious disease with high morbidity and mortality. Theranostic agents with effective diagnostic and therapeutic capability are highly needed for the treatment of hepatic cancer. Herein, we aimed to develop a novel mesoporous polydopamine (MPDA)-based theranostic agent for T1/T2 dual magnetic resonance imaging (MRI)-guided cancer chemo-photothermal therapy. Superparamagnetic iron oxide (SPIO)-loaded MPDA NPs ([email protected]) was firstly prepared, followed by modifying with a targeted molecule of sialic acid (SA) and chelating with Fe3+ ([email protected]/Fe3+ NPs). After that, doxorubicin (DOX)-loaded [email protected]/Fe3+ NPs ([email protected]/DOX/Fe3+) was prepared for tumor theranostics. The prepared [email protected]/Fe3+ NPs were water-dispersible and biocompatible as evidenced by MTT assay. In vitro photothermal and relaxivity property suggested that the novel theranostic agent possessed excellent photothermal conversion capability and photostability, with relaxivity of being r1 = 4.29 mM−1s−1 and r2 = 105.53 mM−1s−1, respectively. [email protected]/Fe3+ NPs could effectively encapsulate the DOX, showing dual pH- and thermal-triggered drug release behavior. In vitro and in vivo studies revealed that [email protected]/DOX/Fe3+ NPs could effectively target to the hepatic tumor tissue, which was possibly due to the specific interaction between SA and the overexpressed E-selectin. This behavior also endowed [email protected]/DOX/Fe3+ NPs with a more precise T1-T2 dual mode contrast imaging effect than the one without SA modification. In addition, [email protected]/DOX/Fe3+ NPs displayed a superior therapeutic effect, which was due to its active targeting ability and combined effects of chemotherapy and photothermal therapy. These results demonstrated that [email protected]/DOX/Fe3+ NPs is an effective targeted nanoplatform for tumor theranostics, having potential value in the effective treatment of hepatic cancer.
Abstract 12981: Association of Serum Growth Differentiation Factor-15 With Egfr, Hemoglobin and Sarcopenia in Healthy Community-dwelling Older Females
Authors: Taira Fukuda, Shigeru Toyoda, Shichiro Abe, Teruo Inoue, Toshiaki Nakajima
Journal: Circulation (2020)

Introduction: Anemia and sarcopenia with renal dysfunction caused by cytokine imbalance can contribute to decreased quality of life for older individuals. Several studies showed that serum GDF-15 level, a member of the TGF-β cytokine superfamily, was negatively correlated with eGFR. In this study, we examined the association of GDF-15 with eGFR, hemoglobin (Hb) and sarcopenia in healthy community-dwelling older females. Methods: A total of 66 healthy older community-dwelling females (age: 75.8 ± 6.2 years) were enrolled for this study. Skeletal muscle mass index (SMI) by bioelectrical impedance analysis, hand-grip strength and walking speed were assessed, and sarcopenia was evaluated. Serum GDF-15 concentration was determined by enzyme-linked immunosorbent assay. Hb, serum iron (Fe), serum albumin (Alb) and high-sensitive C reactive protein (hsCRP) levels were measured and estimated glomerular filtration rate (eGFR) was evaluated. Multiple linear regression analyses with serum GDF-15 concentration, eGFR and Hb as the dependent variable were performed to identify influencing independent factors. Results: Among the study subjects, 4 (6%) had sarcopenia. The serum GDF-15 level was positively correlated with age (r = 0.486, p &lt; 0.001) and negatively correlated with walking speed (r = -0.363, p = 0.003), but there was no correlation between GDF-15 level and hand-grip strength or SMI. Serum GDF-15 level was also negatively correlated with eGFR (r = -0.535, p &lt; 0.001) and serum Fe level, but had no correlation with hsCRP, Hb or Alb levels. In multiple regression analysis, eGFR and Hb were independent variables to predict serum GDF-15 level, even after adjusting for age and body mass index (eGFR: β = -0.423, p &lt;0.001; Hb: β = -0.363, p=0.004). Serum GDF-15 level was an independent variable to predict eGFR and Hb. Conclusions: Serum GDF-15 level was negatively correlated with eGFR, although it had no correlation with muscle strength or mass. Both Hb and eGFR were predictors for serum GDF-15 concentration in healthy older females. In these community-dwelling older females, renal dysfunction via GDF-15 might be accompanied by anemia, but not sarcopenia.
Abstract PO-045: Interleukin 1 receptor accessory protein (IL1RAP) in novel targetable pathway in pancreatic cancer
Authors: Yang Zhang, Xiaoyi Chen, Shanisha Gordon-Mitchell, Kith Pradhan, Gaurav Choudhary, Tushar D. Bhagat, Beamon Agarwal, Ulrich Steidl, Anirban Maitra, Amit Verma
Journal: Cancer Research (2020)

Abstract Interleukin-1 Receptor Accessory Protein (IL1RAP) is a surface molecule that mediates activation of pro-inflammatory IL-1 associated signaling pathways. It is overexpressed in myeloid leukemias and is associated with worse prognosis. We aimed to evaluate IL1RAP as a target for therapy in pancreatic adenocarcinoma (PDAC). Immunohistochemistry demonstrated overexpression of IL1RAP in PDAC specimens from K-Ras/p53/Cre (KPC) mice when compared to controls. Evaluation of human PDAC tissue microarrays containing 262 samples also revealed overexpression of IL1RAP in 81% of the samples. Single cell RNA-Seq analysis of human primary pre-neoplastic lesions and frank adenocarcinoma specimens indicated that overexpression occurs on malignant EPCAM positive cells during carcinogenesis. IL1RAP knockdown via siRNA on the A6L PDAC cell line significantly reduced cell viability, invasiveness, and ability to form colonies. IL1RAP knockdown cells showed significant arrest in the G1/G0 phase of the cell cycle on flow cytometry and showed reduced phospho-ERK proliferative signaling on Western blot. RNA sequencing of IL1RAP knockdown cells indicated downregulation of several groups of genes involved in cell cycle progression, including CDK1 and TOP2A, whose reduced expression was confirmed on Western blot. Inhibition of the downstream signaling molecule IRAK4 (interleukin-1 receptor-associated kinase 4) using two pharmacologic inhibitors, CA-4948 and PF06650833, resulted in significantly reduced growth in pancreatic cancer cell lines and reduced proliferative phospho-ERK signaling on Western blot. Preliminary in vivo data in NSG mice showed a reduction in tumor size with oral treatments of these two IRAK4 inhibitors. Overall, our studies indicate IL1RAP is overexpressed in PDAC, and reducing IL1RAP and inhibiting downstream IRAK4 result in lowered tumor proliferation in vitro and in vivo, potentially via cell cycle arrest and reduced proliferative signaling. Citation Format: Yang Zhang, Xiaoyi Chen, Shanisha Gordon-Mitchell, Kith Pradhan, Gaurav Choudhary, Tushar D. Bhagat, Beamon Agarwal, Ulrich Steidl, Anirban Maitra, Amit Verma. Interleukin 1 receptor accessory protein (IL1RAP) in novel targetable pathway in pancreatic cancer [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-045.
Engineered Microsystems for Spheroid and Organoid Studies
Authors: Sung‐Min Kang, Daehan Kim, Ji‐Hoon Lee, Shuichi Takayama, Joong Yull Park
Journal: Advanced Healthcare Materials (2020)

3D in vitro model systems such as spheroids and organoids provide an opportunity to extend the physiological understanding using recapitulated tissues that mimic physiological characteristics of in vivo microenvironments. Unlike 2D systems, 3D in vitro systems can bridge the gap between inadequate 2D cultures and the in vivo environments, providing novel insights on complex physiological mechanisms at various scales of organization, ranging from the cellular, tissue-, to organ-levels. To satisfy the ever-increasing need for highly complex and sophisticated systems, many 3D in vitro models with advanced microengineering techniques have been developed to answer diverse physiological questions. This review summarizes recent advances in engineered microsystems for the development of 3D in vitro model systems. The relationship between the underlying physics behind the microengineering techniques, and their ability to recapitulate distinct 3D cellular structures and functions of diverse types of tissues and organs are highlighted and discussed in detail. A number of 3D in vitro models and their engineering principles are also introduced. Finally, current limitations are summarized, and perspectives for future directions in guiding the development of 3D in vitro model systems using microengineering techniques are provided.