tbuckley/cabot-search huggingface dataset:
Abstract 17291: Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis: CREST-2 update
Authors: James Meschia, Brajesh K Lal, George Howard, Gary Roubin, Robert D Brown, Kevin M Barrett, Seemant Chaturvedi, Marc I Chimowitz, Bart M Demaerschalk, Virginia Howard, John Huston, Ronald M Lazar, Wesley S Moore, Claudia S Moy, Tanya N Turan, Jenifer Voeks, Thomas G Brott
Journal: Circulation (2015)

Purpose: The safety of revascularization for asymptomatic carotid stenosis, and the efficacy of medical therapy for stroke prevention have improved. Therefore, results of prior randomized trials may not apply to current treatment decisions. The NINDS-funded CREST-2 will compare carotid endarterectomy and intensive medical therapy (IMT) versus IMT alone (n=1240), and carotid stenting and IMT versus IMT alone (n=1240) in asymptomatic patients with≥70% stenosis. Materials &amp; Methods: CREST-2 consists of two parallel randomized clinical trials to be conducted at a target of ≈120 centers, including within NINDS StrokeNet. The composite primary outcome is stroke or death during the peri-procedural period or ipsilateral ischemic stroke thereafter up to 4 years. Blinded assessment of cognition will be done periodically. Centrally directed IMT includes tight control of blood pressure (systolic target &lt;140 mm Hg) and cholesterol (LDL target &lt;70 mg/dl) as well as lifestyle coaching. Results: As of June 12, 2015, 94 centers have been approved by the Site Selection Committee. Credentialing is ongoing, with 198 approved surgeons and 64 approved interventionists; 124 additional conditionally approved interventionists will be able to submit additional cases for review under the CREST-2 Registry. The Centers for Medicare and Medicaid will offer CAS reimbursement for Registry enrollees. As of June 12, 2015, there are 39 actively enrolling centers, and 37 patients have been randomized. Conclusion: CREST-2 is designed to identify the best approach for asymptomatic carotid stenosis. The first patient was randomized in December, 2014. An update will be provided regarding the numbers of patients randomized, centers certified, as well as surgeons and interventionists fully approved. Registration: ClinicalTrials.gov Identifier: NCT02089217
Abstract 2895: Verteporfin targets p62 in prostate cancer therapeutics
Authors: Lei Wang, Donghern Kim, James Wise, Xianglin Shi, Zhuo Zhang, Robert S. DiPaola
Journal: Cancer Research (2018)

Abstract To test the hypothesis that p62 is an optimal target for autophagy inhibition and Verteporfin, a clinically available drug approved by FDA to treat macular degeneration that inhibits autophagy by targeting p62 protein, can be developed clinically to improve therapy for advanced prostate cancer. Results showed that Verteporfin inhibited cell growth and colony formation in PC-3 cells. Verteporfin generated crosslinked p62 oligomers, resulting in inhibition of autophagy and constitutive activation of Nrf2 as well as its target proteins, Bcl-2 and TNF-α. In normal prostate epithelial cells, forced expression of p62 caused constitutive Nrf2 activation and development of apoptosis resistance and Verteporfin treatment exhibited inhibitory effects. Verteporfin treatments also inhibited starvation-induced autophagic influx of these cells. Verteporfin inhibited tumorigenesis of both normal prostate epithelial cells with p62 expression and prostate cancer cells and decreased p62, constitutive Nrf2, and Bcl-xL in xenograft tumor tissues, indicating that p62 can be developed as a drug target against prostate cancer. So p62 has a high potential to be developed as a therapeutic target. Verteporfin represents a prototypical agent with therapeutic potential against prostate cancer through inhibition of autophagy by a novel mechanism of p62 inhibition. Citation Format: Lei Wang, Donghern Kim, James Wise, Xianglin Shi, Zhuo Zhang, Robert S. DiPaola. Verteporfin targets p62 in prostate cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2895.
General Theory of Heart-Vector Projection
Authors: Ernestfrank
Journal: Circulation Research (1954)

A mathematical and physical basis for heart-vector projection concepts is presented and its significance for current practices in frontal-plane and spatial electrocardiography is discussed. Assumptions underlying the theory are stated and utilized to derive a general relationship between the heart dipole and the potentials it produces in the body. Specific equations are given for unipolar and bipolar leads and the Wilson central-terminal voltage. Coefficients determined experimentally for human torso models differ markedly from those that stem from Einthoven's hypothesis. Einthoven's equilateral triangle represents a special case of the general theory. Geometric interpretations are applied to a quantitative frontal-plane example, to the Wilson central-terminal voltage and extended to the concept of an image surface corresponding to the human body surface.
Abstract 129: Smyd1 is an Essential Regulator of Adaptive Response to Glucose Starvation in Cardiomyocytes
Authors: Junco S Warren, Amira Sabry, Keiko Cawley, Aman Makaju, Marta W Szulik, James Cox, David Nix, Alexey V Zaitsev, Sarah Franklin
Journal: Circulation Research (2017)

Smyd1, a muscle-specific histone methyltransferase, has been implicated in global metabolic remodeling in cardiac hypertrophy and failure. We previously showed that cardiac-specific ablation of Smyd1 in mice led to metabolic perturbations prior to overt cardiac dysfunction, suggesting that Smyd1 positively regulates cardiac metabolism. However, the role of Smyd1 in adaptive response to nutritional stress (NS) in cardiomyocytes is largely unknown. Here, we found that glucose deprivation-induced NS led to upregulation of Smyd1 in cultured rat neonatal ventricular myocytes (NRVMs) (FC=1.87, p&lt;0.05), which was associated with the increased mRNA level of PGC-1α, a key regulator of mitochondrial energetics (FC=2.71, p&lt;0.05). Strikingly, siRNA-mediated knockdown of Smyd1 (Smyd1-KD) in NRVM prior to glucose starvation led to extensive cell death not observed in control NRVMs (scrambled siRNA), suggesting that Smyd1 is required for cell survival in NS. To elucidate the mechanism how Smyd1 is involved in adaptive response to NS, we performed unbiased proteomic and metabolomic screening of Smyd1-KD NRVMs. Bioinformatic analysis of proteins and metabolites that were differentially expressed in Smyd1-KD NRVM revealed that oxidative phosphorylation was the most perturbed metabolic pathway in Smyd1-KD NRVMs, concomitant with a reduction in mitochondrial substrates (BCAAs; pyruvate; lactate, all p&lt;0.05). Gene expression analyses using RT-PCR and RNA-seq in Smyd1-KD NRVMs further identified PGC-1α and Perm1 (the muscle-specific PGC-1α and ESRR induced regulator) as potential downstream targets of Smyd1 in regulation of cardiac energetics (FC=-1.92 and -1.66, respectively, both p&lt;0.05). Consistent with downregulation of Perm1, the known Perm1-target genes (Tfb1m; Ctp1b; Glut4; Myl2) were all downregulated at the mRNA levels in Smyd1-KD NRVMs (p&lt;0.05). Lastly, Smyd1-KD NRVMs exhibited accelerated loss of mitochondrial membrane potential during hypoxia, revealing an increased vulnerability to metabolic stress. Taken together, these results show that Smyd1 is an essential regulator of adaptive response and cell survival during metabolic insults, presumably through regulating PGC-1α/Perm1 gene expression.
Targeting Adhesion Molecules as a Potential Mechanism of Action for Intravenous Immunoglobulin
Authors: VarinderGill, ChristopherDoig, DerriceKnight, EmmaLove, PaulKubes
Journal: Circulation (2005)

Background— Intravenous immunoglobulin (IVIg) therapy has been shown to have therapeutic benefit in more than 50 inflammatory and immune-related diseases; however, the potential benefit of IVIg in cardiovascular disease is more limited, in part because our understanding of the mechanisms underlying the effects of IVIg in innate immunity is incomplete. Methods and Results— In this study, a systematic assessment of the role of IVIg in leukocyte recruitment was completed with an in vitro flow-chamber system and in vivo intravital microscopy in a feline ischemia-reperfusion model system. IVIg treatment of blood resulted in a profound decrease in recruitment of either immobilized P-selectin or E-selectin due to direct effects of IVIg on the leukocyte (not substratum). Similar results were observed on endothelium treated with histamine, which induces P-selectin–dependent rolling and β2-integrin–dependent adhesion. IVIg reduced P-selectin glycoprotein ligand-1 (PSGL-1) antibody binding to PSGL-1 on leukocytes. U...
Acute Antiinflammatory Properties of Statins Involve Peroxisome Proliferator–Activated Receptor-α via Inhibition of the Protein Kinase C Signaling Pathway
Authors: RéjanePaumelle, ChristopheBlanquart, OlivierBriand, OlivierBarbier, ChristianDuhem, GaëtaneWoerly, FrédéricPercevault, Jean-CharlesFruchart, DavidDombrowicz, CorineGlineur, BartStaels
Journal: Circulation Research (2006)

Statins are inhibitors of 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase used in the prevention of cardiovascular disease (CVD). In addition to their cholesterol-lowering activities, statins exert pleiotropic antiinflammatory effects, which might contribute to their beneficial effects not only on CVD but also on lipid-unrelated immune and inflammatory diseases, such as rheumatoid arthritis, asthma, stroke, and transplant rejection. However, the molecular mechanisms involved in these antiinflammatory properties of statins are unresolved. Here we show that the peroxisome proliferator–activated receptor (PPAR) α mediates antiinflammatory effects of simvastatin in vivo in models of acute inflammation. The inhibitory effects of statins on lipopolysaccharide-induced inflammatory response genes were abolished in PPARα-deficient macrophages and neutrophils. Moreover, simvastatin inhibited PPARα phosphorylation by lipopolysaccharide-activated protein kinase C (PKC) α. A constitutive active form of PKCα ...
Chronic Variant of Myocarditis Associated With Hepatitis C Virus Infection
Authors: MasanoriOkabe, KeisukeFukuda, KikuoArakawa, MasahiroKikuchi
Journal: Circulation (1997)

Background Although molecular biological studies suggest a pathogenic link between enterovirus infection and dilated cardiomyopathy (DCM), the frequency of detection of enteroviral RNA is not consistently high in myocardial tissue from patients with DCM. A recent study has suggested that hepatitis C virus (HCV) may also be involved in the development of DCM. Methods and Results We performed genomic analysis for HCV in three patients with chronic active myocarditis. In all three patients, serum aminotransferase activities remained within normal ranges until the terminal stage of heart failure. At necropsy, all three livers showed evidence of tissue damage caused by chronic congestion, and one liver had evidence of chronic hepatitis. Routinely processed, paraffin-embedded tissue blocks of myocardium and liver were analyzed. Renal specimens were also analyzed to exclude the possibility of myocardial contamination with HCV material from the circulating blood. RNA extracted from the heart, liver, and kidney wa...
Abstract 17059: Single and Multiple Dose Pharmacokinetics, Pharmacodynamics and Safety of a Novel PCSK9 Synthesis Inhibitor, ALN-PCSsc, in Subjects With Elevated LDL Cholesterol
Authors: Prasoon Chaturvedi, S. Eralp Bellibas, David G Kallend, Kevin Fitzgerald, Gabriel J Robbie, Peter L Wijngaard
Journal: Circulation (2016)

Background: ALN-PCSsc (PCSK9si) is an RNAi therapeutic consisting of double-stranded oligonucleotide covalently linked to N-acetylgalactosamine targeting PCSK9 mRNA in hepatocytes. The potency for ...
Abstract 1708: Nanofluidic drug-eluting seed for sustained intratumoral immunotherapy in triple negative breast cancer
Authors: Corrine Ying Xuan Chua, Priya Jain, Marco Folci, Andrea Ballerini, Jessica Rhudy, April Gilbert, Shail Shaibala, Giacomo Bruno, Carly S. Filgueira, Cassian Yee, E. Brian Butler, Alessandro Grattoni
Journal: Cancer Research (2018)

Abstract Conventional systemic immunotherapy administration often results in insufficient anti-tumor immune response and adverse side effects. Delivering immunotherapeutics intratumorally could maximize tumor exposure, elicit robust anti-tumor immune response, and minimize toxicity. To fulfill the unmet clinical need for sustained local drug delivery and to avoid repeated intratumoral injections, we developed a nanofluidic-based device for intratumoral drug delivery called the nanofluidic drug-eluting seed (NDES). The NDES is inserted intratumorally using a minimally invasive trocar method similar to brachytherapy seed insertion and offers a clinical advantage of intratumoral drug elution. Drug diffusion from the NDES is regulated by physical and electrostatic nanoconfinement, thereby resulting in constant and sustained immunotherapeutic delivery without the need for repeated injections or clinician intervention. In this study, the NDES was utilized to deliver immunotherapeutics intratumorally in the 4T1 orthotopic murine mammary carcinoma model, which recapitulates triple negative breast cancer. We demonstrated that NDES-mediated intratumoral release of agonist immunotherapeutic monoclonal antibodies, OX40 and CD40, resulted in potentiation of local and systemic anti-tumor immune response and significant inhibition of tumor growth compared to control mice. Further, mice treated with NDES-CD40 demonstrated minimal liver damage compared to systemically treated mice. Collectively, our study highlights the NDES as an effective platform for sustained intratumoral immunotherapeutic delivery. The potential clinical impact is tremendous given that the NDES is applicable to a broad spectrum of drugs and solid tumors. Citation Format: Corrine Ying Xuan Chua, Priya Jain, Marco Folci, Andrea Ballerini, Jessica Rhudy, April Gilbert, Shail Shaibala, Giacomo Bruno, Carly S. Filgueira, Cassian Yee, E. Brian Butler, Alessandro Grattoni. Nanofluidic drug-eluting seed for sustained intratumoral immunotherapy in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1708.
Misregulation of SDF1-CXCR4 Signaling Impairs Early Cardiac Neural Crest Cell Migration Leading to Conotruncal Defects
Authors: SophieEscot, CédrineBlavet, SonjaHärtle, Jean-LoupDuband, ClaireFournier-Thibault
Journal: Circulation Research (2013)

Rationale:Cardiac neural crest cells (NCs) contribute to heart morphogenesis by giving rise to a variety of cell types from mesenchyme of the outflow tract, ventricular septum, and semilunar valves to neurons of the cardiac ganglia and smooth muscles of the great arteries. Failure in cardiac NC development results in outflow and ventricular septation defects commonly observed in congenital heart diseases. Cardiac NCs derive from the vagal neural tube, which also gives rise to enteric NCs that colonize the gut; however, so far, molecular mechanisms segregating these 2 populations and driving cardiac NC migration toward the heart have remained elusive. Objective:Stromal-derived factor-1 (SDF1) is a chemokine that mediates oriented migration of multiple embryonic cells and mice deficient for Sdf1 or its receptors, Cxcr4 and Cxcr7, exhibit ventricular septum defects, raising the possibility that SDF1 might selectively drive cardiac NC migration toward the heart via a chemotactic mechanism. Methods and Results...
Abstract 1310: Systematic evaluation of gene networks for discovery of disease genes
Authors: Justin K. Huang, Daniel E. Carlin, Michael K. Yu, Wei Zhang, Jason F. Kreisberg, Pablo Tamayo, Trey Ideker
Journal: Cancer Research (2018)

Abstract Gene networks are rapidly growing in size and number, raising the question of which networks are most appropriate for a particular application. Here, we evaluate 21 human genome-wide interaction networks for their ability to recover gene sets associated with 446 different diseases and 9 cancer hallmarks. While all networks have some ability in these recovery tasks, we observe a wide range of performance with STRING, GeneMANIA and GIANT networks having the best performance overall. A general tendency is that performance scales with network size, suggesting that new interaction discovery currently outweighs the detrimental effects of false positives. Correcting for size, we find that the DIP network provides the highest efficiency (value per interaction). Based on these results we create a parsimonious composite network with both high efficiency and absolute performance, which outperforms any single resource. This work provides a benchmark for selection of molecular networks in human disease research. Citation Format: Justin K. Huang, Daniel E. Carlin, Michael K. Yu, Wei Zhang, Jason F. Kreisberg, Pablo Tamayo, Trey Ideker. Systematic evaluation of gene networks for discovery of disease genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1310.
Abstract 18184: Prognostic Value of Subjective and Objective Findings of Ischemia in Patients With Heart Failure
Authors: Yin Ge, Jack V Tu, Peter C Austin, Xuesong Wang, Douglas S Lee
Journal: Circulation (2015)

Introduction: Previous studies have shown that cardiac ischemia is a marker of poor prognosis in congestive heart failure. We determined the outcomes associated with subjective symptoms and objective findings of ischemia in patients presenting with acute heart failure. Methods: We studied 10,030 participants (mean age 76±12 years, 48% male) who presented to a hospital in Ontario, Canada with a primary diagnosis of acute heart failure. Using linked administrative databases, we analyzed the long-term impact of chest pain, ST segment depression, and positive troponin on vital status, hospital readmission, diagnostic testing, and coronary revascularization. Results: 1,724 participants presented with symptoms of chest pain, of which 348 had objective evidence of cardiac ischemia (ST segment depression or positive troponin). Of the 8,306 participants without chest pain 1,602 had objective evidence of ischemia. At baseline, the chest pain cohort had higher proportion of participants with a history of heart failure, coronary disease, revascularization, and impaired LV function. In multivariate analysis, ST segment depression and positive troponin were associated with higher cardiovascular death (HR 1.11 and 1.41, both P&lt;0.05), revascularization events (HR 1.41 and 1.48, both P&lt;0.01), hospitalization for myocardial infarction (HR 1.35 and 1.69, both P&lt;0.01) and heart failure (HR 1.08 and 1.15, both P&lt;0.05). Rates of admission for non-cardiovascular hospitalization did not differ. The presence of chest pain was associated with increased use of diagnostic testing for ischemia (HR 1.14, P&lt;0.01) and admission for ischemic symptoms (HR 1.10, P&lt;0.05), but lower risk of cardiovascular death (HR 0.86, P&lt;0.01 Figure 1). Conclusions: In this large, community-based cohort of patients presenting with acute heart failure, the presence of objective findings, but not subjective symptoms of ischemia, was associated with higher risk of major adverse cardiac outcomes.
Abstract 3351: Myc inhibition by Omomyc impairs melanoma growth and progression through genome-wide gene expression reprogramming
Authors: Mariano F. Zacarias-Fluck, Génesis Martín, Daniel Massó-Vallés, Laia Foradada, Jonathan R. Whitfield, Marie-Eve Beaulieu, Laura Soucek
Journal: Cancer Research (2018)

Abstract Myc encodes for a transcription factor deregulated in the vast majority of human cancers, mainly by amplification or constant upstream oncogenic signaling. Previous work from our laboratory showed that targeting Myc by transgenic expression of the Myc inhibitor Omomyc is an effective strategy to inhibit tumor progression and cause tumor regression in a wide array of mouse cancer models, without any evidence of toxicity in normal tissues. Our goal now is to assess whether Myc inhibition can be an effective approach to treat melanoma, the most dangerous form of skin cancer. For this purpose, we transfected human melanoma cell lines with a doxycycline-dependent vector expressing Omomyc-RFP and characterized the effect of Myc inhibition on proliferation and colony formation, as well as the expression of different cell cycle related proteins. We observed that Omomyc significantly reduced proliferation of a wide variety of cell lines, regardless of their driving mutations. In p53 wild type cells, Omomyc expression was accompanied by p53 stabilization and concomitant p21 upregulation, and in BRaf or NF1 mutated melanoma cells, by downregulation of cyclin D1. In order to elucidate the mechanism of action underlying this anti-tumorigenic effect, we performed a microarray analysis of A375 melanoma cells in the presence or absence of Omomyc-RFP expression. This analysis showed that Omomyc affected genome-wide gene expression. More in detail, Gene Set Enrichment Analysis showed that Omomyc significantly blunts the expression of both Myc and E2F targets, as well as RNA biogenesis, DNA replication and different cell cycle checkpoints, among many others relevant gene sets. Importantly, Omomyc significantly reduced the expression of genes related to melanoma metastases. Finally, in order to validate Omomyc therapeutic impact in vivo, A375 and SkMel147 cells were s.c. implanted into nude mice and the effect of Omomyc expression on tumor progression was evaluated. Our results show that Omomyc expression significantly impairs the growth of both cell lines, increasing the survival of tumor-bearing mice. These results combined clearly show that Omomyc-mediated Myc inhibition is an effective means to impair melanoma progression, by directly targeting Myc, inhibiting cell cycle and decreasing melanoma aggressiveness. Citation Format: Mariano F. Zacarias-Fluck, Génesis Martín, Daniel Massó-Vallés, Laia Foradada, Jonathan R. Whitfield, Marie-Eve Beaulieu, Laura Soucek. Myc inhibition by Omomyc impairs melanoma growth and progression through genome-wide gene expression reprogramming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3351.