bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 365: Increased Plasma Cholesterol Esterification by Lecithin-Cholesterol Acyltransferase Prevents Dysfunction of Red Blood Cells and Platelets and Protects from Development of Diet-Induced Atherosclerosis
Authors: Thacker Seth G , Rousset Xavier , Vaisman Boris L , Amar Marcelo J , Freeman Lita A , Esmail Safiya , Stonik John A , Remaley Alan T 
Published: July 2021

Introduction
Free cholesterol plays a vital role in maintaining cell membrane fluidity and function. Elevated levels of cholesterol in red blood cells (RBC) and platelets have been demonstrated to impair the function of these cells. In circulation, free cholesterol freely exchanges between cells and lipoproteins and lecithin-cholesterol acyltransferase (LCAT) plays a role in this exchange. The esterification of cholesterol by LCAT sequesters it in the interior of lipoprotein particles and thereby limits its movement between lipoproteins and cells. Previously, SR-B1 KO mice have been shown to have dysfunctional RBCs and platelets and this dysfunction is exacerbated by a high fat diet. These mice have a partial defect in cholesterol esterification and are susceptible to diet induced atherosclerosis.

Hypothesis
We assessed in SR-BI KO mice whether increased cholesterol esterification by LCAT would improve numbers of RBCs and platelets, as well as prevent the development of atherosclerosis.

Methods and Results
Control (C57BL/6), SR-B1 KO, SR-B1 KO x LCAT KO(DKO), and SR-B1 KO x LCAT-Trg(LCAT-Trg) mice were maintained on a western diet for 7 months. As previously observed, SR-B1 KO mice had decrease numbers of RBCs and platelets compared to control mice, and over expression of LCAT restored levels to that of wild type mice, while loss of LCAT further abrogated the decrease in cell counts(n=10). Unexpectedly, LCAT-Trg mice has the highest levels of cholesterol in plasma, but RBC and platelets showed the lowest levels of free cholesterol, as assessed by filipin staining. Atherosclerosis in western diet fed mice was assessed by Oil Red O in two ways by looking at the aortic root(n=4) and by en face analysis of the aorta(n=10). In the aortic root SRB-1KO and DKO mice showed 3x the amount of lesion size as controls, while LCAT-Trg mice had levels comparable to the controls mice. The en face analysis also showed that DKO mice had 3x the amount of lesions, while LCAT-Trg and SRB-1KO mice had levels comparable to control mice.

Conclusion
LCAT is able to modulate the movement of cholesterol between circulating cells and lipoproteins thereby protecting RBCs and platelets. Our results further demonstrate a possible benefit of LCAT on the progression of atherosclerosis.
Abstract 417: Using Self-management Support (sms) Goal Setting for Weight Control in Diabetic Patients at an Ambulatory Internal Medicine Center
Authors: Jiang Bo , Shi Qi , Jia Jihua , Tadros Sherine , Novak Gregg , Seth Jigneth , Thomas-Hemak Linda 
Published: July 2021

Introduction
Obesity is a major comorbidity that compounds the health consequences of diabetes. Effective weight control through behavior modification is an effective component for diabetic management, and can easily be counseled and implemented through primary care visits. Setting self-management Support (SMS) goals, which incorporates the needs, goals, and life experiences of patients, may improve clinical outcomes, health status, and quality of life. We hypothesized that setting SMS goals in primary care visits empowers diabetic patients to lose weight.

Methods
A chart review was conducted on a total of 205 diabetic patients. SMS goals of weight-control plan (diet and/or exercise) were incorporated into patients’ electronic medical records. A total of 115 (56%) patients included SMS goals in their treatment plan, and 90 (44%) patients did not contain SMS goals. Body weights of these patients were assessed at baseline and after 6 months of follow up.

Results
35 (17 %) diabetic patients were overweight and 152 (74 %) were obese in our practice. During 6 months of follow up, 64/115 (56%) patients with SMS goals documented lost weight ( ≥ 5 lb weight loss), compared to 9/31 (29 %) in patients with no SMS goal set. When comparing effect of diet only with the combination of diet and exercise, we found that 47/73 (64 %) patients with the combination SMS goal settings lost weight, while only 17/42 (40 %) of patients with the diet only SMS plans lost body weight.

Discussion
Our study highlights the importance of educating patients to maintain physical activity and healthy diet, but more importantly shows that empowering patients to agree upon and be active in goal setting is a powerful tool for disease management. Setting SMS goals may assist providers in giving patients their self-defined circle of support, so that patients can manage their conditions on a daily basis, and develop the confidence to sustain healthy behaviors for a lifetime. In addition, SMS goal-setting and progress-monitoring during each encounter help providers to assess the motivation and engagement of patients for behavior modification. Last, the dynamic physician-patient relationship during goal setting and assessment facilitates patient compliance and eventually successful weight loss.
Abstract 420: The Ratio of L-arginine to Asymmetric Dimethylarginine is Associated With Brachial-ankle Pulse Wave Velocity in Patients Undergoing Coronary Angiography
Authors: Masaki Nobuyuki , Shiraishi Yasunaga , Nakaya Yuko , Kujiraoka Takehiko , Yada Hirotaka , Hakuno Daihiko , Isoda Kikuo , Kimura Kazuo , Miyazaki Koji , Adachi Takeshi 
Published: July 2021

Background
Endothelial dysfunction decrease vasomotor function and cause vascular stiffening in addition to the structural changes. Relative L-arginine deficiency to ADMA influencing NO synthesis may increase arterial stiffness in elderly individuals. We investigated the relationship between the L-arginine / ADMA ratio and brachial ankle pulse wave velocity (baPWV) of the patients with suspected or already known coronary artery disease (CAD).

Methods and Results
The cross-sectional study enrolled 74 patients (67 ± 10 y/o) undergoing coronary angiography. There were 54 (73%) patients with CAD including 3 of coronary bypass surgery, and 11 of old myocardial infarction. Exclusion criteria were ankle brachial index (ABI) less than 0.9 in both lower extremities and hemodialysis. baPWV and ABI were obtained using an automatic waveform analyzer. Serum L-arginine, ADMA were measured by high-performance liquid chromatography. The ratio of L-arginine to ADMA was associated with baPWV (γ= -0.323, p=0.005) (Figure). Although the value of baPWV was dependent on systolic blood pressure and heart rate at measurement as reported previously, the ratio was a significant predictor of baPWV in multivariate analysis (β= -0.448, p<0.001). Additionally, serum L-arginine, and L-arginine / ADMA ratio were also independent contributing factors to baPWV in the subgroup of 46 elderly patients (>64 y/o).

Conclusion
We observed that many ageing patients with cardiovascular disease had low L-arginine / ADMA ratio accompanied with high baPWV. The findings suggested that correction of serum L-arginine level can be a therapeutic option to recover arterial compliance for the population.
Abstract 434: Insig-2a Links CREBH Signaling to Hepatic Lipogenesis and Systemic Hyperlipidemia
Authors: Wang Hai , Su Qiaozhu 
Published: July 2021

The sterol regulatory element binding proteins (SREBPs) are master transcription factors that regulate hepatic de novo lipogenesis. Perturbation of SREBPs functionality is closely related to the onset of hyperlipidemia. The current investigation sought to advance our understanding on the activation of SREBP-1c via the interplay between the cAMP responsive element binding protein H (CREBH) and the liver specific insulin-induced gene 2a isoform (Insig-2a). Genetic depletion of CREBH specifically down regulated expression of both Insign-2a mRNA and protein levels which resulted in the hyperactivation of SREBP-1c and the subsequent hypertriglyceridemia. Challenging wild type (WT) mice with a high fat diet
(HFD) specifically stimulated expression of Insig-2a mRNA and protein in the WT mice. In contrast, HFD failed to enhance expressions of Insig-2a mRNA and protein in CREBH-null mice. No alterations were detected on the mRNA transcription of another Insig-2 isoform, Insig-2b, in the livers of WT mice and CREBH-null mice under both chow and HFD conditions. Decrease of Insig-2a caused activation of hepatic de novo lipogenesis, mainly via SREBP-1c activation, which contributed to the development of sever systemic hypertriglyceridemia and hepatic steatosis in CREBH-null mice. Consistent with the in vivo observation, forced expression of CREBH cDNA in a rat hepatoma cell line, McA cells, specifically increased expressions of both Insig-2a mRNA and protein which in turn inhibited activation of SCREBP-1c. Analyzing the gene promoter of Insig-2a, we identified a CREB binding site at the promoter of the Insig-2a and a ChIP assay further confirmed the physical association between CREBH and the Insig-2a promoter. These data identify Insig-2a as a target gene of CREBH. Modulation of Insig-2a expression by CREBH is essentially involved in regulating hepatic triglyceride metabolism. Given the role of CREBH in hepatic acute phage response signaling, this finding further reveals the cross-talk between inflammatory and insulin signal pathways in maintaining systemic lipid homeostasis and may provide rationale for pharmaceutical design to specifically target CREBH and insig-2a in the prevention and treatment of hypertriglyceridemia.
Abstract 484: Real World Experience with the Use of Dabigatran
Authors: Rajdev Archana , Bradley Jacqueline , Santos Eric , Penciu Oanal , Alexander Jonathan 
Published: July 2021

Background
The RE-LY trial in 2009 ushered in a new era in anticoagulation options for stroke prevention in atrial fibrillation.We sought to determine the safety, efficacy, and tolerability of dabigatran in a community setting.

Methods
We retrospectively reviewed demographics, bleeding rates, stroke rates, and reasons for discontinuation in patients on dabigatran for non-valvular atrial fibrillation.

Results
Of the 263 patients, mean age was 73.8 years (32 to 96) and 41.06% were female. The 150 mg BID dose was used in 93.54% of patients and 75 mg BID in 6.46%. Major bleeding was noted in 4 (1.52%), minor bleeding in 25 (9.5%), and rate of discontinuation was 22.3%. Patients who experienced major bleeding were more likely to be older, male, have higher HAS-BLED scores, and a history of gastrointestinal bleeds. All these patients were managed conservatively with no mortality.Of note, three of the four patients with major bleeds were on amiodarone in addition to dabigatran 150 mg BID.Two presented with transient ischemic attacks and had elevated PTTs suggesting compliance with dabigatran. Four patients who were admitted to the hospital with pneumonia, atrial fibrillation, and COPD exacerbation had elevated troponins without accompanying symptoms of acute coronary syndrome. In patients maintained on the 75 mg BID dose, minor bleeding was noted in two, who were also on dronedarone. No strokes or intracranial bleeds were noted in patients on either dose of dabigatran

Conclusions
This retrospective analysis demonstrates safety and efficacy of dabigatran as an oral anticoagulant in patients with non-valvular atrial fibrillation over a two-year follow-up while describing the factors associated with increased bleeding risk.It is the first study to describe experience with use of 75 mg of dabigatran. Drug interactions are a common and avoidable reason for dabigatran-associated bleeding and were noted with both amiodarone and dronedarone in our study. There was no increased incidence of myocardial infarction noted. In our study population, dabigatran is safe, effective, and convenient when there is careful patient selection with consideration of renal function and possible drug-drug interactions
Abstract 539: MicroRNA-27b Regulates Salt-Inducible Kinase 1 (SIK1) in Vascular Fibrosis
Authors: Brion Laura , Chernogubova Ekaterina , Eken Suzanne M , Jin Hong , Eriksson Per , Bertorello Alejandro , Maegdefessel Lars 
Published: July 2021

Arterial fibrosis is one of the main underlying causes of vascular stiffness and various associated diseases, such as hypertension, congestive heart failure, aortic aneurysm development and renal failure. Consequently there is a growing interest in (patho)-mechanisms governing the underlying process of arterial fibrosis and successive vascular stiffness. Recently, a novel class of small noncoding RNAs, termed microRNAs (miRs), have emerged as powerful cellular regulators in disease processes. Furthermore, they have become an intriguing target for therapeutic intervention. Aim of the present study was to explore whether miRs are regulating the expression of salt-inducible kinase 1 (SIK1), which we previously identified as a crucial regulator of fibrosis in heart-/kidney- failure and arterial hypertension.
Using different bioinformatic target prediction algorithms, we identified several miRs with predicted conserved sites on the Sik1 gene, including miRs-27a/b, -130a, -148a/b and -152. By analyzing aorta, heart and kidney specimen from Sik-/- and Sik+/+ mice, we were able to detect that miR-27b was the only miR being significantly altered in all three tissues. We proceeded by treating human aortic smooth muscle cells as well as adventitial fibroblasts with TGF-β, to induce a pro-fibrotic response. Interestingly, treatment with TGF-β substantially increased miR-27b expression as well as other components of the extracellular matrix, such as collagen (Col1a1) and fibronectin (Fn1) through repression of SIK1. Overexpression of miR-27b, utilizing a pre-miR precursor, substantially decreased SIK-1 expression and further augmented the pro-fibrotic response, as indicated by raising collagen and Fn1 expressions.
The present study explores the regulatory role of miR-27b in different vascular fibrosis associated pathologies. We were able to show that miR-27b, a novel downstream-target of TGF-β signalling pathways, suppresses the expression of SIK1, which itself has been identified as a key regulator of arterial hypertension and consequential heart and kidney failure. On-going studies, utilizing inhibition of miR-27b can become an interesting novel therapeutic strategy to regulate SIK1 levels in vascular fibrosis and arterial stiffness.
Abstract 541: RAGE Regulates Cellular Migration and Adhesion Through Proteolysis of Its Ectodomain
Authors: Jules Joel , Harja Evis , Hudson Barry I 
Published: July 2021

Introduction
Enhanced expression of the Receptor for Advanced Glycation End-products (RAGE) not only plays deleterious roles in various vascular diseases but also affects many vascular properties including endothelial permeability, leukocyte adhesion and transmigration. Decreased serum level of soluble RAGE (sRAGE), which inhibits RAGE functions, has been associated with various inflammatory diseases including atherosclerosis. Notably, several studies have shown that the release of sRAGE ectodomain (ECD) occurs by proteolysis from the cell surface. However, little is known about how this process is regulated and the functional effects of RAGE ECD shedding.

Hypothesis
We hypothesize that shedding of RAGE ECD is a fundamental process regulating cell signaling pathways leading to altered cell function.

Methods & Results
Toward this end, we first demonstrated that RAGE ECD shedding is a conserved mechanism in humans and mice. Next, we showed that common activators of ECD shedding, such as the protein kinase C activator PMA; the metalloproteinase-activator APMA; and the calcium ionophore ionomycin, can induce RAGE ECD release. Furthermore, various inflammatory mediators including CRP and TNF-alpha can induce RAGE ECD shedding. Inhibition studies revealed RAGE ECD shedding could be blocked by metalloproteinase, PKC, and various MAP kinase inhibitors. Finally, utilizing a proteolytically resistant splice variant of RAGE lacking the ECD shedding site (RAGEv4), we investigated the cellular function of RAGE shedding. Compared to cell expressing RAGE or empty vector, the expression of RAGEv4 resulted in impeded cell migration. Moreover, RAGEv4 reduced cellular adhesion as compared to vector control and RAGE expressing cells. Key downstream signaling pathways affected by RAGE ECD shedding are being currently investigated.

Conclusions
RAGE ECD shedding is a conserved and tightly regulated mechanism involving distinct signaling pathways. Shedding of RAGE regulates key cellular properties including adhesion and migration. Our data suggest that proteolysis of RAGE is a major regulatory process and may emerge as a novel therapeutic target for cardiovascular diseases.
Abstract 550: Differential Regulation of CD39 Expression by Il-1ß in Leukocytes and Endothelial Cells
Authors: Sutton Nadia R , Petrovic-Djergovic Danica , Baek Amy , Kanthi Yogen , Liao Hui , Visovatti Scott H , Pinsky David J 
Published: July 2021

Background
CD39 (ENTPD-1) is a membrane-spanning ectonucleotidase that is responsible for the phosphohydrolysis of ATP to ADP and ADP to AMP. CD39 levels are modulated in multiple conditions, including pulmonary hypertension, cardiac, liver and renal injury, cancer, and autoimmune diseases. However, little is known about the upstream regulation of this molecule, or whether modulation of CD39 represents a response to inflammatory cytokines or is integral to the pathological process. Elevated levels of cytokine IL-1β are a hallmark of many inflammatory states.

Objectives
Objectives were to measure CD39 expression after stimulation with the IL-1β. CD39 is expressed on leukocytes and endothelial cells; therefore, CD39 expression was evaluated in these cell types.

Methods
Human umbilical vein endothelial cells (HUVECs) were treated with either 10 pg/ml or 1 ng/ml IL-1β for 12 hours. Cells were harvested and CD39 mRNA expression was measured using qPCR. CD39 protein expression was measured using Western Blot. Mononuclear leukocytes were isolated from whole blood of healthy humans via density gradient cell separation (n=3). Leukocytes were cultured for 12 hours with or without the addition of IL-1β (1ng/ml). Leukocytes were then assessed for expression of CD39, CD73, CD14, CD19, CD4, CD8, and CD25 by flow cytometry.

Findings
IL-1β (1 ng/ml) treatment resulted in decreased CD39 mRNA expression in HUVECs (1.1 vs. 3.9, p<0.01). IL-1β treatment also resulted in decreased CD39 protein expression in HUVECs (untreated, 1.56, 10pg/ml, 0.96, 1ng/ml, 0.48, untreated vs. 10pg/ml, p<0.01). IL-1β increased the percentage of T-reg CD4+CD25+ expressing CD39+ cells (treated vs untreated, 3.94 vs. 2.73%, p=0.013). There was a trend toward an increased percentage of CD4+ T cells expressing CD39+ with IL-1β treatment (13.85% vs.11.83%, p=0.25).

Conclusions
This is the first report of modulation of CD39 expression in response to the inflammatory cytokine IL-1β. Interestingly, IL-1β downregulated CD39 expression in HUVECs, but resulted in increased CD39 expression on a T-reg population positive for CD4 and CD25. CD39 could be differentially regulated depending on the inflammatory stimulus and target cell type.
Abstract 557: Human S100/calgranulin Accelerates Ectopic Cardiac Calcification and Promotes Cardiac Hypertrophy in Transgenic Mice with Chronic Kidney Disease in a RAGE Dependent Manner
Authors: Hofmann Bowman Marion , Yan Ling , Mathew Liby , Chellan Bijoy , Gardner Brandon , Earley Judy , Puri Tipu S. 
Published: July 2021

Purpose
Chronic kidney disease (CKD) is associated with accelerated cardiovascular disease. Elevated serum S100A12 predicts cardiovascular mortality in patients with end stage renal disease. We test the hypothesis that human S100/calgranulin transgenic mice exposed to the metabolic changes of CKD would develop accelerated cardiovascular disease.

Methods
A novel humanized mouse with transgenic expression of human S100/calgranulin (hBAC-S100) was generated by expression of a bacterial artificial chromosome of the human S100/calgranulin gene cluster containing genes and regulatory elements for S1008/9 and S100A12 (60kb) in C57BL6/J mice. The hBAC-S100 mice were crossed with the RAGE KO mice (same C57BL6/J strain, gift from Ann Marie Schmidt, NYU) and F4 animals were used for the experiment. CKD was induced in hBAC-S100 and wild type (WT) littermate mice with intact or lacking RAGE signaling by surgical ligation of the ureters. The heart and aorta were analyzed after 10 weeks of elevated blood urea nitrogen.

Results
hBAC-S100 mice express human S100A12 in circulating myeloid cells and S100A12 was present in the serum of hBAC-S100 mice (25 ng/ml serum), but was not detected in WT mice. Importantly, serum hS100A12 was increased in hBAC-S100 mice with CKD compared to sham operated hBAC-S100 mice (42±17 ng/ml and 25±7 ng/ml, p=0.04). Moreover, hBAC-S100 mice with CKD exhibited ectopic cardiac calcification in fibroblast-rich annulus of the mitral and aortic valves upon Alizarin Red staining. In vivo ECHO showed abnormal mitral valve doppler flow with reduced ratio of early (E) to atrial (A) filling in hBAC-S100 mice with CKD compared to WT-CKD mice (1.17 ±0.1 vs 1.35 ±0.1, p=0.003), indicating diastolic dysfunction. Notably, hBAC-S100 mice with CKD develop cardiac hypertrophy as evidenced by increased heart weight/ body weight ratio and elevated gene expression of hypertrophic and fibrotic markers, such as ANP, β-MHC, TGF-β, CTGF, and Col 1a1. This phenotype was not observed in hBAC-S100 mice lacking RAGE, despite exposure to the same degree of CKD.

Conclusion
Circulating myeloid derived human S100/calgranulin is associated with the development of ectopic cardiac calcification and cardiac hypertrophy in chronic kidney disease in a RAGE dependent manner.
Abstract 76: MicroRNA-144 Regulates Hepatic ABCA1 and Plasma HDL Following Activation of the Nuclear Receptor FXR
Authors: Vallim Thomas , Tarling Elizabeth , Kim Tammy , Civelek Mete , Baldan Angel , Esau Christine , Edwards Peter A 
Published: July 2021

Rationale
The bile acid receptor Farnesoid-X-Receptor (FXR) regulates many aspects of lipid metabolism by various complex and not fully understood molecular mechanisms. We set out to investigate the molecular mechanisms for FXR-dependent regulation of lipid and lipoprotein metabolism.

Objective
To identify FXR-regulated microRNAs that were subsequently involved in regulating lipid metabolism.

Methods and Results
ATP binding cassette transporter A1 (ABCA1) is a major determinant of plasma High Density Lipoprotein (HDL)-cholesterol levels. Here we show that activation of the nuclear receptor FXR in vivo increases hepatic levels of miR-144, which in turn lower hepatic ABCA1 and plasma HDL levels. We identified two complementary sequences to miR-144 in the 3’ untranslated region (UTR) of ABCA1 mRNA that are necessary for miR-144-dependent regulation. Overexpression of miR-144 in vitro decreased both cellular ABCA1 protein and cholesterol efflux to lipid-poor apolipoprotein A-I (ApoA-I) protein, whilst overexpression in vivo reduced hepatic ABCA1 protein and plasma HDL- cholesterol. Conversely, silencing miR-144 in mice increased hepatic ABCA1 protein and HDL- cholesterol. In addition, we utilized tissue-specific FXR deficient mice to show that induction of miR-144 and FXR-dependent hypolipidemia requires hepatic, but not intestinal FXR. Finally, we identified functional FXR response elements (FXREs) upstream of the miR-144 locus, consistent with direct FXR regulation.

Conclusion
In conclusion, we have identified a pathway involving FXR, miR-144 and ABCA1 that together regulate plasma HDL cholesterol. This pathway may be therapeutically targeted in the future in order to increase HDL levels.