tbuckley/cabot-search huggingface dataset:
Abstract 16715: Anatomical Data Defined by 64-Slice CT Angiography Predicts Prognosis of Coronary Artery by-Pass Patients More Accurately That Clinical Risk Predictors
Authors: Gary R Small, Yeung Yam, Li Chen, Osman Ahmed, Mouaz Al-Mallah, Daniel S Berman, Victor Y Cheng, Kavitha Chinnaiyan, Gilbert L Raff, Todd C Villines, Stephan Achenbach, Matthew J Budoff, Filippo Cademartiri, Tracy Q Callister, Hyuk-Jae Chang, Augustin Delago, Allison Dunning, Martin Hadamitzky, Jörg Hausleiter, Philipp Kaufmann, Fay Y Lin, Erica Maffei, James K Min, Leslee J Shaw, Benjamin J Chow
Journal: Circulation (2011)

Objective: We sought to determine the incremental prognostic value of 64 multi-slice coronary computed tomography angiography (CCTA) in coronary artery bypass (CABG) patients. Background: Prognostication in CABG patients can be difficult. Anatomical assessment of native coronary artery disease and graft patency may provide useful information, but the utility of CCTA in the assessment of CABG patients is unknown. Methods: 657 CABG patients with all cause mortality follow up were identified from a multicenter CCTA registry, of 10,628 patients from 5 CCTA centres. Clinical risk was profiled with modified logistic and additive EuroSCOREs. CCTA defined coronary anatomy. Patients were classified by unprotected coronary territory (UCT), or a summary of native vessel disease and graft patency: the coronary artery protection score (CAPS). Results: 76.6% of patients were male and the median age was 68 years. 44 deaths occurred over 48 months follow-up. LVEF, creatinine, age, severity of native vessel disease, UCT, CAPS and EuroSCOREs were univariate predictors of mortality (p&lt;0.001). In multivariate analysis using additive EuroSCORE, UCT (p=0.004) and CAPS were predictive of events (p&lt;0.001). In comparison to additive EuroSCORE, CAPS score was associated with a 27% net reclassification index. Conclusions: CCTA provides incremental anatomical data to clinical risk assessment to better determine the prognosis of symptomatic patients post CABG. CAPS evaluation using CCTA may help determine those patients at highest risk.
Abstract 16654: Sizing Strategy is a Major Determinant for Postoperative Pressure Gradients in Commonly Implanted Stented Tissue Valves
Authors: Mahmoud A Diab, Jack Peter, Gloria Faerber, Wolfgang Bothe, Susanne Lemke, Martin Breuer, Martin Breuer, Torsten Doenst
Journal: Circulation (2011)

Background Heated debates revolve around hemodynamic performance of stented tissue valves. We and others reported differences in valve size nomenclature confusing direct comparisons. Relative valve opening has been suggested to be improved by designing pericardial valves with stents on the outside (Perimount), or the inside (Mitroflow) of the valve, but the sizing strategies and sizer dimensions are also different. We reviewed hemodynamics of our patients having received aortic valve replacement (AVR) with the the Edwards Perimount or the Sorin Mitroflow, both valves, where size selection was based on intra-annular sizing. We speculated that differences in sizing strategy may be more important than differences in valve design. Methods We analyzed discharge echos (performed by the same examiner) from all patients having received a Perimount (n=521) or a Mitroflow (n=157) between 01/2007 and 11/2010. We obtained valve outer diameters from the manufacturers, and measured sizer dimensions with a calliper. We compared mean gradients (ΔP) and maximum velocity across the valve (Vmax) based on size label, outer diameter, or selected size based on suggested sizing strategy. Results The majority of implanted valves were size 23 (n=259). Their outer diameters were 31mm for Perimount, and 26mm for Mitroflow. Despite the smaller outer diameter, the lowest gradients were found in the Mitroflow: ΔP 11.72±4.18 mmHg (Vmax 2.31±0.38 m/s) vs Perimount: ΔP 12.85±4.29 mmHg (Vmax 2.41± 0.34 m/s) p&lt;0.05, suggesting a design advantage. However, the 23 Mitroflow sizer was 25mm and the 21sizer was 23mm. In contrast, the 23 Perimount sizer was indeed 23mm. Thus, an intrannular sizing strategy for a patient with a 23 mm annulus will result in the selection of a 21 Mitroflow but a 23 Perimount. Hemodynamic comparison of the 21 Mitroflow with the 23 Perimount eliminated the above described differences (21 Mitroflow: ΔP 13.5 ± 5.4 mmHg (Vmax 2.52 ± 0.25 m/s). Conclusion The potential hemodynamic advantage of the Mitroflow may be lost due to a “defensive” sizing strategy. The results underscore the importance of sizing strategy and surgical technique and supports the provision of replica sizers with the new generation valves.
Abstract 16695: <i>O</i> -GlcNAc Cycling Enzymes and Myofilaments in Diabetic Cardiomyopathy: An Increased Association Leading to Myofilament Ca <sup>2+</sup> Desensitization
Authors: Genaro Ramirez, Chad Slawson, Quira Zeidan, Wengang Ding, Xiaoxu Shen, Wei D Gao, Viviane Caceres, Nazareno Paolocci, Gerald W Hart, Anne M Murphy
Journal: Circulation (2011)

Protein O-GlcNAcylation, the addition of a single β-D-N-acetylglucosamine (GlcNAc) to serine/threonine residues, by OGT (O-GlcNAc transeferase) and removal by OGA (O-GlcNAcase), is a post-translational modification that regulates cardiovascular function. Regulation of O-GlcNAcylation serves as a metabolic/nutrient sensor, and is disrupted in diabetes. We hypothesize that altered O-GlcNAcylation of myofilament proteins is an important molecular mechanism that contributes to myofilament Ca 2+ desensitization in diabetes. To test the role of O-GlcNAc in this process we enzymatically removed endogenous O-GlcNAcylation in cardiac skinned fibers from normal and diabetic type 1 rats via a homologue of human OGA (CpNagJ). We found that removing endogenous O-GlcNAc restored myofilament response to Ca 2+ only in streptozotocin (STZ)-induced type 1 diabetic rat muscles (ECa 50 4.17±0.48 µM STZ Pre- CpNagJ vs. 2.73±0.22 µM STZ Post- CpNagJ, n =5 vs. n =4, p=0.029), whereas in control muscles it had no effect. Similarly, maximal Ca 2+ activated force (F max ) and myofilament cooperativity ( n Hill), remained unchanged after CpNagJ treatment in both groups. Immunoprecipitation experiments in normal and diabetic hearts uncovered OGT and OGA interactions with MyBP-C, α-actin, tropomyosin, and myosin light chain 1. Except for MyBP-C, these protein interactions were increased in the diabetic hearts. In normal myocytes, confocal and immuno-electron microscopy analyses, illustrated OGT and OGA compartmentalization at the Z-disk and A-band, respectively. Strikingly, analysis of their ultra-structural distribution reveal that in the diabetic myocardium OGT and OGA compartmentalization was lost, with both proteins exhibiting a more diffuse localization and increased immuno-staining. Moreover, OGT and OGA were readily detected within mitochondria, and OGT immuno-staining was elevated in diabetic mitochondria. Our data demonstrate that removal of endogenous myofilament O-GlcNAcylation, specifically from diabetic muscles, restores myofilament Ca 2+ sensitivity to normal. This suggests that altered GlcNAc “cycling” plays a key mechanistic role in the abnormal myofilament response to Ca 2+ in diabetic cardiac muscle.
Abstract 16747: Interaction Between Polymorphisms in Inflammation-Related Genes and Atrial fibrillation in Patients with Dilated Cardiomyopathy
Authors: Akiyoshi Ogimoto, Jun Suzuki, Katsuji Inoue, Kazuhisa Nishimura, Takayuki Nagai, Yuji Shigematsu, Hideki Okayama, Jitsuo Higaki
Journal: Circulation (2011)

Background: Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and a leading cause of cardiovascular morbidity. Recently, we reported the G allele at -2518 in the monocyte chemoattractant protein 1 ( MCP-1 ) gene may be a novel genetic marker of susceptibility to nonfamilial idiopathic dilated cardiomyopathy (DCM). In addition, it has been suggested that inflammation have a possible role in the development of AF. We hypothesized that polymorphisms in inflammation-related genes might be associated with AF in patients with DCM. Methods and Results: We genotyped polymorphisms (rs3759324 and rs1143629) in inflammation-related genes (lymphotoxin beta receptor, LTBR and interleukin-1beta, IL1B ) in 83 patients with DCM by using the TaqMan method. Patients were classified into AF group (n=21) if they had AF, and sinus rhythm (SR) group (n=62) if they had SR. Logistic-regression methods were used to determine the potential effect of each genotype and the interaction between them on the risk of AF. There was no significant increase in risk of AF with each polymorphism alone. However, there was a marked increase in the risk of AF among persons who were homozygous for both variants (The LTBR C/C and IL1B G/G genotypes, odds ratio 4.56, P=0.02). Conclusion: The LTBR C/C and IL1B G/G genotypes act synergistically to increase the risk of AF in patients with DCM. These data suggest that inflammation-related genes predispose to AF in patients with DCM.
Abstract 16766: A Human Induced Pluripotent Stem Cell-Derived Engineered Cardiac Tissue Model of Pompe Disease
Authors: Kunil K Raval, Willem J De Lange, John C Ralphe, Timothy J Kamp
Journal: Circulation (2011)

Background: Infantile-onset Pompe disease is a lethal autosomal recessive lysosomal storage disorder caused by the complete loss of acid α-glucosidase activity resulting in glycogen accumulation within lysosomes. Skeletal and cardiac muscle pathology develop due to aberrant glycogen metabolism and lysosomal dysfunction. This work presents the first in vitro human cardiac tissue model of Pompe disease documenting the classic Pompe cellular phenotype within a multicellular engineered cardiac tissue preparation. Methods: Pompe disease-specific human induced pluripotent stem (iPS) cell derived cardiomyocyte (iPS-CMs) were seeded into a polymerizing fibrin mixture to form mechanically integrated multicellular engineered cardiac tissue (ECT) constructs that were evaluated over a one-month period in parallel with healthy human iPS cell derived ECTs. Weekly measurements of isometric force and intracellular calcium transients were recorded under varying work load imposed by electrical pacing and β1 adrenergic stimulation. Structural assessment was performed using electron microscopy and immunohistochemistry. Results: Healthy and Pompe iPS-CMs can form cylindrically shaped ECTs of 1-2 mm diameter and 1.5-2 cm in length composed of coupled CMs that generate force in the milli-newton range along the cylindrical axis. We report structural changes in the ECT model consistent with the hallmarks of Pompe disease including progressive intracellular glycogen accumulation, lysosomal disruption, and myofibrillar disarray. Both healthy and Pompe ECTs generate higher twitch forces in response to mechanical stretch, have a negative force-frequency relationship characteristic of immature myocardium, and have an inotropic response to dobutamine stimulation. Conclusion: Human iPS-CM ECTs obey the Frank-Starling law and produce calcium cycling and force kinetics that respond to β1 adrenergic stimulation. The Pompe ECT provides a novel cardiac tool in which to further study the pathophysiology of this disease and test novel therapeutic approaches.
Abstract 16723: Dopamine D <sub>3</sub> Receptor Decreases NHE3 Expression and Function by Inhibiting the Activity of the De-Ubiquitinylating Enzyme, USP48, in Renal Proximal Tubule Cells
Authors: Ines Armando, Van Anthony M Villar, Xiaoyan Wang, Laureano Asico, Hewang Li, Crisanto S Escano, Robin Felder, Pedro A Jose, John E Jones
Journal: Circulation (2011)

Disruption of the dopamine D 3 receptor gene in mice (D 3 R -/- ) results in high blood pressure, salt sensitivity, decreased ability to excrete a sodium load and increased renal expression of sodium/hydrogen exchanger isoform 3 (NHE3) protein (180%, P&lt;0.05) but not mRNA, and D 3 R blockade in wild-type mice increased (2 fold, P&lt;0.04) NHE3 protein expression. We hypothesized that renal D 3 R regulates NHE3 expression/function. In human renal proximal tubular cells (hRPTCs), the colocalization and co-immunoprecipitation of D 3 R and NHE3 are increased by D 3 R stimulation (PD 128907, 1μM), associated to internalization of D 3 R and NHE3 (confocal microscopy) and inhibition (80%, P&lt;0.05) of NHE3 dependent Na + transport. D 3 R stimulation also increases NHE3 ubiquitinylation and internalization of the ubiquitinylated NHE3 in the cytoplasm (150%, P&lt;0.05) suggesting that D 3 R activation promotes NHE3 ubiquitinylation and internalization. To determine the mechanism of the D 3 R-mediated NHE3 ubiquitinylation we performed a yeast-two hybrid screening which showed that the 3 rd intracytoplasmic loop of human D 3 R interacts with human ubiquitin-specific peptidase 48 (USP48), a de-ubiquitinylating enzyme. D 3 R and USP48, and USP48 and NHE3 co-localized and co-immunoprecipitated in hRPTCs. USP48 accounted for ~30% of hRPTCs' total de-ubiquitinylating activity. D 3 R stimulation increased the interaction between D 3 R and USP48 and resulted in a 35% reduction in USP48 de-ubiquitinylating activity, indicating that D 3 R inhibits USP48 activity in hRPTCs. USP48 silencing increased the degradation of NHE3 (vehicle t 1/2 = 6.1 hr; USP48 siRNA t 1/2 = 12.9 hr; P&lt;0.05) while over-expressing USP48 increased NHE3 half -life (t 1/2 = 21.8 hr; P&lt;0.05 vs. vehicle) indicating that USP48 protects NHE3 from degradation via de-ubiquitinylation. Moreover, selective renal USP48 silencing in mice by subcapsular infusion of USP48 siRNA decreases NHE3 expression (25%, P&lt;0.04) and systolic blood pressure measured under anesthesia (vehicle: 102±2 vs. siRNA 78±2 mmHg; P&lt;0.03). Our data demonstrate that agonist activation of D 3 R promotes the degradation of NHE3 via the inhibition of USP48 and thus provide a novel mechanism by which the D 3 R engenders natriuresis and regulates blood pressure.
Abstract 16739: Regional Variation in the Relationship of Infarct Size to Left Ventricular Ejection Fraction: Implications for Risk Stratification for Sudden Cardiac Death
Authors: Alejandro Aquino, Jeffrey J Goldberger, Edwin Wu, Maria L Carr, Lara Bakhos, Maria M Izquierdo Gomez, Brandon Benefield, Alan H Kadish, Daniel C Lee
Journal: Circulation (2011)

Introduction: In patients with coronary artery disease (CAD), guidelines for primary prevention of sudden cardiac death (SCD) use left ventricular ejection fraction (LVEF) ≤35%. The substrate for SCD is myocardial infarction (MI); indeed, MI size expressed as percent of LV mass (IM%) measured by cardiac magnetic resonance imaging (CMR) has been shown to be a better predictor of inducible ventricular tachycardia (VT) on electrophysiologic study than LVEF, with a cutoff of &gt; 10% providing the highest sensitivity. Purpose: To examine the influence of MI location on the relationship between IM% and LVEF. Methods: We analyzed cine and late gadolinium enhanced (LGE) CMR images for 412 patients with CAD (81% male, age 62.3 ± 11.4) and a history of MI from the DEfibrillators To REduce Risk by MagnetIc ResoNance Imaging Evaluation Trial (DETERMINE trial, www.clinicaltrials.gov ). LVEF and IM% were quantified (Medis QMass MR 7.2). We performed segmental visual scoring of cine (from 0 = normal to 4 = dyskinesis) and LGE images (from 0 = none to 4 = 76-100%). Each of the 17 segments was assigned to a coronary artery territory based on American Heart Association segmentation recommendations. MI location was calculated as the territory with the highest LGE score: left anterior descending (LAD), left circumflex (LCX), and right coronary artery (RCA). Results: Overall, 206/412 (50%) of patients had IM% &gt; 10% while maintaining LVEF &gt; 35%. The distribution of MI location was LAD (205), LCX (84), and RCA (123). The impact of increasing IM% on LVEF differed based on MI location (figure). The expected IM% required to reduce LVEF to 35% for a LCX MI was 19%, for LAD was 26%, and for RCA was 34%. Conclusions: As a marker of MI burden, LVEF is insensitive and is strongly influenced by MI location. As it best represents the substrate for SCD and is related to both mortality and inducible VT, further efforts are required to investigate IM% as a predictor of SCD, independent of LVEF.
Abstract 16636: The Procardiomyogenic Effect of miR499 is Synergistically Enhanced by miR133
Authors: Elisabetta Cervio, Lucio Barile, Federica Pisano, Claudia Altomare, Giuseppe Malpasso, Maria Chiara Ciuffreda, Antonio Zaza, Massimiliano Gnecchi
Journal: Circulation (2011)

Background: it has been described that miR499, 1 and 133 are involved in cardiac development and stem cell differentiation. In particular, miR499 enhances the differentiation of embryonic and adult stem cells into cardiomyocytes (CMC). However, it is currently unknown if different miR may act synergistically to improve differentiation efficiency. Methods: we used mouse P19 cells as cardiogenic differentiation model. P19 cells were transduced with a viral vector expressing EGFP under the control of a cTnI promoter. miR499 was transiently overexpressed in P19 cells individually or together with miR1 or miR133. Cardiac differentiation was quantified by: 1) count of spontaneous beating areas; 2) qPCR of the cardiac markers Nkx2.5, GATA4, MEF2c, MLC2v, Cx43 and cTnT; 3) Western Blot and ICC of cTnT and Cx43; 4) measure of inducibility of RyR-mediated Ca++ transients in P19 exposed to caffeine; 5) recording of mechanical activity after Ca++ depletion and in the presence of nifedipine or ryanodine. Results: the overexpression of miR499 alone increased the number of beating CMC by 1.7 fold compared with P19 CTRL (p&lt;0.05). The association of miR499+133, but not miR499+1, further increased the number of beating CMC (2.02 fold vs. P19 CTRL, p&lt;0.01). qPCR showed that the combination of miR499+133 increase the expression of GATA4, Nkx2.5, Cx43 and cTnT compared with P19 CTRL (p&lt;0.01) and MEF2c and MLC2v compared with miR499 alone (p&lt;0.05). Western Blot and ICC for Cx43 and cTnT confirmed these findings. Caffeine responsiveness was increased by 2.6 fold by miR499+133 compared with P19 CTRL (32.5 vs. 12.5%, p&lt;0.05) and was directly correlated with the activation of the cTnI promoter. Cyclic contractions were reversibly abolished by extracellular Ca++ depletion and by both nifedipine and ryanodine. Finally, the overexpression of miR499+133 is associated with an earlier activation of cTnI promoter. Conclusions: our results show that concomitant overexpression of miR499 and miR133 significantly enhance cardiac differentiation. Most importantly the functional studies have demonstrated that the areas spontaneously contracting possess electrophysiological and pharmacological characteristics compatible with true cardiac excitation-contraction coupling.
Identification of the characteristics and prognostic impact of <i>FUS::ERG</i> and <i>RUNX1::CBFA2T3</i> fusion genes in adult <scp>acute myeloid leukemia</scp> patients
Authors: Ziyue Zhou, Nanfang Zhuo, Yile Zhou, Caihong Sun, Yiyi Yao, Liping Mao, Yi Zhang, Qing Hong, Peifeng Pan, Hongyan Tong, Jie Jin, Huafeng Wang
Journal: American Journal of Hematology (2024)
Corrigendum to “Design and fabrication of high-performance self-setting trimagnesium phosphate” [Bioact. Mater. 28 (2023) 348-357]
Authors: Jiawei Liu, Wen Hou, Wenying Wei, Jian Peng, Xiaopei Wu, Chenxi Lian, Yanan Zhao, Rong Tu, Takashi Goto, Honglian Dai
Journal: Bioactive Materials (2024)

[This corrects the article DOI: 10.1016/j.bioactmat.2023.05.019.].
Brain delivery of fibronectin through bioactive phosphorous dendrimers for Parkinson's disease treatment via cooperative modulation of microglia
Authors: Waicong Dai, Mengsi Zhan, Yue Gao, Huxiao Sun, Yu Zou, Régis Laurent, Serge Mignani, Jean-Pierre Majoral, Mingwu Shen, Xiangyang Shi
Journal: Bioactive Materials (2024)

Effective treatment of Parkinson's disease (PD), a prevalent central neurodegenerative disorder particularly affecting the elderly population, still remains a huge challenge. We present here a novel nanomedicine formulation based on bioactive hydroxyl-terminated phosphorous dendrimers (termed as AK123) complexed with fibronectin (FN) with anti-inflammatory and antioxidative activities. The created optimized AK123/FN nanocomplexes (NCs) with a size of 223 nm display good colloidal stability in aqueous solution and can be specifically taken up by microglia through FN-mediated targeting. We show that the AK123/FN NCs are able to consume excessive reactive oxygen species, promote microglia M2 polarization and inhibit the nuclear factor-kappa B signaling pathway to downregulate inflammatory factors. With the abundant dendrimer surface hydroxyl terminal groups, the developed NCs are able to cross blood-brain barrier (BBB) to exert targeted therapy of a PD mouse model through the AK123-mediated anti-inflammation for M2 polarization of microglia and FN-mediated antioxidant and anti-inflammatory effects, thus reducing the aggregation of α-synuclein and restoring the contents of dopamine and tyrosine hydroxylase to normal levels in vivo. The developed dendrimer/FN NCs combine the advantages of BBB-crossing hydroxyl-terminated bioactive per se phosphorus dendrimers and FN, which is expected to be extended for the treatment of different neurodegenerative diseases.
Macrophage based drug delivery: Key challenges and strategies
Authors: Qian Guo, Zhong-Ming Qian
Journal: Bioactive Materials (2024)

As a natural immune cell and antigen presenting cell, macrophages have been studied and engineered to treat human diseases. Macrophages are well-suited for use as drug carriers because of their biological characteristics, such as excellent biocompatibility, long circulation, intrinsic inflammatory homing and phagocytosis. Meanwhile, macrophages' uniquely high plasticity and easy re-education polarization facilitates their use as part of efficacious therapeutics for the treatment of inflammatory diseases or tumors. Although recent studies have demonstrated promising advances in macrophage-based drug delivery, several challenges currently hinder further improvement of therapeutic effect and clinical application. This article focuses on the main challenges of utilizing macrophage-based drug delivery, from the selection of macrophage sources, drug loading, and maintenance of macrophage phenotypes, to drug migration and release at target sites. In addition, corresponding strategies and insights related to these challenges are described. Finally, we also provide perspective on shortcomings on the road to clinical translation and production.
Genetically engineered nanomodulators elicit potent immunity against cancer stem cells by checkpoint blockade and hypoxia relief
Authors: Yuanwei Pan, Ling Yu, Lujie Liu, Jing Zhang, Shuang Liang, Badri Parshad, Jialin Lai, Li-Min Ma, Zhaohui Wang, Lang Rao
Journal: Bioactive Materials (2024)

Rapid development of checkpoint inhibitors has provided significant breakthroughs for cancer stem cell (CSC) therapy, while the therapeutic efficacy is restricted by hypoxia-mediated tumor immune evasion, especially hypoxia-induced CD47 overexpression in CSCs. Herein, we developed a genetically engineered CSC membrane-coated hollow manganese dioxide (hMnO2@gCMs) to elicit robust antitumor immunity by blocking CD47 and alleviating hypoxia to ultimately achieve the eradication of CSCs. The hMnO2 core effectively alleviated tumor hypoxia by inducing decomposition of tumor endogenous H2O2, thus suppressing the CSCs and reducing the expression of CD47. Cooperating with hypoxia relief-induced downregulation of CD47, the overexpressed SIRPα on gCM shell efficiently blocked the CD47-SIRPα "don't eat me" pathway, synergistically eliciting robust antitumor-mediated immune responses. In a B16F10-CSC bearing melanoma mouse model, the hMnO2@gCMs showed an enhanced therapeutic effect in eradicating CSCs and inhibiting tumor growth. Our work presents a simple, safe, and robust platform for CSC eradication and cancer immunotherapy.