tbuckley/cabot-search huggingface dataset:
Abstract 20513: A Common SCN10A Variant May Promote DNA Methylation of SCN5A Promoter and Decrease SCN5A Expression in Brugada Syndrome Patients Without SCN5A Exonic Mutation
Authors: Sho Okamura, Yukiko Nakano, Yousaku Ookubo, Naoya Hironobe, Mititaka Amioka, Shunsuke Tomomori, Tikaaki Motoda, Seiya Matumura, Akinori Sairaku, Yasuki Kihara
Journal: Circulation (2017)

The SCN5A is a major causative gene of Brugada syndrome (BrS), but it accounts for only 11-28% of cases and the majority of BrS patients have no genetic explanation. We resequenced SCN5A coding reg...
Abstract 18707: Neointima After Stent Implantation and Pathological Morphology of Underlying Plaque in Stent Edge Site
Authors: Rika Kawakami, Kenichi Fuji, Masahiko Shibuya, Takahiro Imanaka, Kenji Kawai, Ten Saita, Masaharu Ishihara, Tohru Masuyama, Seiichi Hirota
Journal: Circulation (2016)

Introductions: Previous study have shown penetration of stent struts into a lipid core was associated with increased neointimal thickness compared with stent struts in contact with fibrous plaque. ...
Abstract 19231: Transthyretin F64L Variant is Associated With Increased Risk of Heart Failure in a Large Clinical Cohort
Authors: Emily K Zern, Eric H Farber-Eger, Marcia A Blair, Quinn S Wells
Journal: Circulation (2016)

Introduction: Transthyretin-related cardiac amyloidosis (TTR-CA) is increasingly recognized as a cause of heart failure (HF). While TTR-CA is associated with >100 variants in the TTR gene, the clinical relevance of many of these variants remains unknown due to the lack of large cohorts of phenotyped individuals with corresponding genotype data. One rare TTR variant, a phenylalanine to leucine substitution at position 64 (F64L), has been described in single case reports of individuals with cardiac amyloid and cardiomyopathy, but whether this variant modifies risk for HF is unknown. In this study, we sought to examine the association of the F64L variant with HF in a large, electronic health record (EHR) based clinical cohort. Methods: The cohort was derived from black and white adult subjects genotyped using the Illumina Infinium Exomechip in BioVU, a Vanderbilt University resource linking DNA samples and genetic data to a de-identified EHR. The Exomechip contains ~250,000 coding variants, including TTR F64...
Abstract 5545: Heterodimeric interleukin 15 (hetIL-15) treatment decreases primary breast cancer 4T1 tumors and alleviates the metastatic burden
Authors: Dimitris Stellas, Konstantinos Dimas, Bethany A. Nagy, Antonio Valentin, Barbara K. Felber, George N. Pavlakis
Journal: Cancer Research (2018)

Abstract Introduction: In this preclinical study, we tried to model the therapeutic strategies often used in the clinic to treat breast cancer patients. We analyzed the role of hetIL 15 immunotherapy alone and in combination with chemotherapy and surgery using the 4T1, a triple-negative breast cancer cell line, murine breast cancer model. Experimental Procedures: We evaluated the therapeutic potential of combining surgery, chemotherapy (doxorubicin) and immunotherapy (hetIL-15) in the murine 4T1 breast cancer model. Cancer cells were orthotopically implanted into the mammary fat pad of Balb/c mice, and the efficacy of hetIL-15 in combination with doxorubicin on the growth of primary tumors and metastatic disease was assessed. In addition, we monitored the impact of surgery alone in the development of metastatic disease, and, finally, we evaluated the effects on the metastatic burden of the three different approaches combined. Results: hetIL-15 monotherapy and combination of doxorubicin chemotherapy with hetIL-15 immunotherapy inhibited the growth of primary tumors. Interrogating the role of these treatments on lung metastatic disease, the results were unexpected. Doxorubicin alone did not affect the numbers of the metastatic lesions in the lungs. In contrast, hetIL-15 monotherapy reduced the metastatic burden. The combination strategy did not show advantage as compared to hetIL-15 monotherapy. Surgical removal of the growing tumor also decreased metastatic burden, especially when performed at an early point. Chemotherapy with doxorubicin prior to and post-surgery had no impact on the metastatic disease. In contrast, hetIL-15 treatment strongly diminished or eliminated the metastatic burden. Conclusion: Our data strongly suggest that treatment with hetIL-15 as an adjuvant therapy after surgery, or as a neoadjuvant agent before surgery, significantly impacts metastatic disease. Citation Format: Dimitris Stellas, Konstantinos Dimas, Bethany A. Nagy, Antonio Valentin, Barbara K. Felber, George N. Pavlakis. Heterodimeric interleukin 15 (hetIL-15) treatment decreases primary breast cancer 4T1 tumors and alleviates the metastatic burden [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 5545.
Abstract 4451: Dynamic translational regulation of cancer-associated genes through mRNA structure
Authors: Lela Lynn Lackey, Aaztli Coria, Alain Laederach
Journal: Cancer Research (2018)

Abstract Our goal is to understand how disrupting translational regulation leads to cancer by analyzing the extent to which RNA structure contributes to the translational efficiency of mRNAs in different phases of the cell cycle. We hypothesize that RNA structure is a dynamic projection of the cellular environment and actively contributes to gene regulation by combining sequence-based and environment-induced structures to influence post-transcriptional regulation. We focus on cell cycle regulation as a common, dynamic cellular process that is highly relevant to cancer development and progression. Additionally, during the cell cycle the translational efficiency of many different mRNAs have been shown to change from one phase to the next. We have determined the secondary structures of eight translationally regulated 5'UTRs using SHAPE-MaP (Selective 2' Hydroxyl Acylation by Primer Extension and Mutational Profiling). This chemical structure probing technique is unique in that it reads through chemical modifications during reverse transcription and can be coupled to next generation sequencing and incorporated into RNA structural modeling. Furthermore, we are able to probe these structures in vivo during different stages of the cell cycle. Our data show important conformational rearrangements in 5'UTRs between G1-phase cells and S-phase cells. These results suggest that mRNA structure is a dynamic attribute that plays a role in translational regulation. Many genes involved in cell cycle regulation are implicated in cancer development and progression. Our results confirm that RNA structure of 5' UTRs is an important component of translation regulation and ultimately controls protein expression levels. Citation Format: Lela Lynn Lackey, Aaztli Coria, Alain Laederach. Dynamic translational regulation of cancer-associated genes through mRNA structure [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 4451.
Abstract 3981: Enhancement of the anticancer activity of methylenetetrahydrofolate dehydrogenase knockdown by folate depletion with carboxypeptidase G2
Authors: Gulam M. Rather, John E. Kerrigan, Kathleen W. Scotto, Joseph R. Bertino
Journal: Cancer Research (2018)

Abstract The mitochondrial folate enzyme, methylene tetrahydrofolate dehydrogenase (MTHFD2), is a promising anticancer target because 1) it is required for the generation of one-carbon units required for purine synthesis and generation of NADH/NADPH necessary for protection from ROS in the mitochondria; 2) it is markedly distinct from the cytoplasmic MTHFD1 enzyme with respect to location, catalytic activity and cofactors; 3) it is expressed at low levels in proliferating normal cells; 4) in contrast, it is highly expressed in a variety of rapidly proliferating malignant tumors; 5) knockdown (KD) of MTHFD2 has been shown to inhibit proliferation in a subset of tumor cells in vitro; and 6) MTHFD2 KD is predicted to have metabolic consequences (glycine auxotrophy, folate deficiency) that could be exploited for combination therapy. In this study we tested the hypotheses that downregulation of MTHFD2 will result in relative folate deficiency, which can be exploited by using a folate-depleting enzyme, carboxypeptidase G2 (CPG2), to enhance tumor cell kill. CPG2 is approved by the FDA for the treatment of methotrexate overdose in patients. It acts to inactivate MTX or naturally occurring folates by hydrolyzing the terminal glutamate from folates and MTX, generating a pteroate and glutamate. As pteroates cannot be used to resynthesize folates, or MTX, this treatment depletes cells from MTX or folates. The combination of CPG2 in cell lines, MCF7 and T47D with MTHFD2 KD, was done and the actual increase in growth inhibition showed enhanced antitumor effects, indicating that when effective inhibitors of MTHFD2 are available, this combination may have widespread clinical usefulness, especially in rapidly proliferating tumors that express high levels of MTHFD2. Citation Format: Gulam M. Rather, John E. Kerrigan, Kathleen W. Scotto, Joseph R. Bertino. Enhancement of the anticancer activity of methylenetetrahydrofolate dehydrogenase knockdown by folate depletion with carboxypeptidase G2 [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 3981.
Abstract 14952: Volumetric Echocardiographic Particle Image Velocimetry (V-Echo-PIV)
Authors: AhmadFalahatpisheh, ArashKheradvar
Journal: Circulation (2014)

Introduction: The two-dimensional (2D) echocardiographic particle image velocimetry technique that was introduced in 2010 received much attention in clinical cardiology. Cardiac flow visualization based on contrast echocardiography results in images with high temporal resolution that are obtainable at relatively low cost. This makes it an ideal diagnostic and follow-up tool for routine clinical use. However, cardiac flow in a cardiac cycle is multidirectional with a tendency to spin in three dimensions rather than two-dimensional curl. Here, for the first time, we introduce a volumetric echocardiographic particle image velocimetry technique that robustly acquires the flow in three spatial dimensions and in time: Volumetric Echocardiographic Particle Image Velocimetry (V-Echo-PIV). Methods: V-Echo-PIV technique utilizes matrix array 3D ultrasound probes to capture the flow seeded with an ultrasound contrast agent (Definity). For this feasibility study, we used a pulse duplicator with a silicone ventricular...
Abstract A21: Modeling of oncogenic chromosomal translocations of aggressive fusion-positive sarcomas by CRISPR-Cas9 genomic engineering
Authors: Lee Spraggon, Luciano Martelotto, Julija Hmeljak, Tyler Hitchman, Jiang Wang, Lu Wang, Emily Slotkin, Pang-Dian Fan, Jorge Reis-Filho, Marc Ladanyi
Journal: Clinical Cancer Research (2018)

Abstract A prominent challenge in fusion-positive sarcoma research is that the oncogenic driver is typically a chimeric transcription factor. Although considered the disease-specific molecular drivers, these chimeric transcription factors remain challenging to target pharmacologically. An alternative approach is the elucidation of molecular pathways controlled by the oncogenic transcription factor, with the aim of identifying druggable targets. However, many fusion-driven sarcomas have a paucity of suitable genetic models, with some lacking any patient-derived cell lines. In the situations where patient-derived cell lines are available, most have been passaged for decades, potentially adding further complexity and bias. Therefore, development of faithful model systems of oncogenic chromosomal translocations is of principal importance for these aggressive translocation-driven pediatric sarcomas. Here, we describe a novel approach that combines CRISPR-Cas9 genomic editing technology, with homology-directed repair (HDR) to engineer, capture, and modulate the expression of chromosomal translocation products in a human cell line. We have applied this approach to the genetic modeling of t(11;22)(q24;q12) and t(11;22)(p13;q12), translocation products of the EWSR1 gene and its 3 fusion partners FLI1 and WT1, present in Ewing's sarcoma and desmoplastic small round cell tumor, respectively. Our approach establishes an innovative platform for constructing isogenic and conditionally inducible biologically relevant models for a variety of sarcomas driven by chromosomal translocations. Citation Format: Lee Spraggon, Luciano Martelotto, Julija Hmeljak, Tyler Hitchman, Jiang Wang, Lu Wang, Emily Slotkin, Pang-Dian Fan, Jorge Reis-Filho, Marc Ladanyi. Modeling of oncogenic chromosomal translocations of aggressive fusion-positive sarcomas by CRISPR-Cas9 genomic engineering [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr A21.
Localization of Pacemaker Channels in Lipid Rafts Regulates Channel Kinetics
Authors: AndreaBarbuti, BiagioGravante, MonicaRiolfo, RaffaellaMilanesi, BenedettaTerragni, DarioDiFrancesco
Journal: Circulation Research (2004)

Lipid rafts are discrete membrane subdomains rich in sphingolipids and cholesterol. In ventricular myocytes a function of caveolae, a type of lipid rafts, is to concentrate in close proximity several proteins of the β-adrenergic transduction pathway. We have investigated the subcellular localization of HCN4 channels expressed in HEK cells and studied the effects of such localization on the properties of pacemaker channels in HEK and rabbit sinoatrial (SAN) cells. We used a discontinuous sucrose gradient and Western blot analysis to detect HCN4 proteins in HEK and in SAN cells, and found that HCN4 proteins localize to low-density membrane fractions together with flotillin (HEK) or caveolin-3 (SAN), structural proteins of caveolae. Lipid raft disruption by cell incubation with methyl-β-cyclodextrin (MβCD) impaired specific HCN4 localization. It also shifted the midpoint of activation of the HCN4 current in HEK cells and of If in SAN cells to the positive direction by 11.9 and 10.4 mV, respectively. These la...
Abstract 16294: Omega-3 Fatty Acid Added to Statin Prevents Progression of Fibrous Coronary Artery Plaque Compared to Statin Alone in Patients With Coronary Artery Disease
Authors: Abdulhamied Alfaddagh, Tarec Elajami, Francine Welty
Journal: Circulation (2016)

Introduction: In the Japan Eicosapentaenoic acid (EPA) Lipid Intervention Study, 1.8 g of the omega-3 fatty acid (FA), EPA, added to a statin reduced major coronary events by 19% (p=0.011) compared...
Abstract 16134: Impact of Perioperative Management on Prevention of Prosthetic Valve Detachment After Aortic Valve Replacement for Patient With Takayasu’s Arteritis
Authors: ShunsukeSato, KenjiMinatoya, TomoyukiFujita, TatsuyaOda, YoshimasaSeike, TatsuyaItonaga, YusukeShimahara, HirokiHata, HiroakiSasaki, HatsueIshibashi-Ueda, JunjiroKobayashi
Journal: Circulation (2014)

Background: Patients with Takayasu’s arteritis sometimes complain of aortic regurgitation. We investigate the impact of perioperative management on prevention of prosthetic valve detachment after aortic valve replacement for patient with Takayasu’s arteritis. Methods: Eighty-six Takayasu’s arteritis patients who underwent aortic valve replacement were enrolled in this study. Thirty-eight patients (44.2%) were administered steroid preoperatively. Preoperative steroid dose was 1-9mg of prednisolone per day in 9 patients (10.5%), 10-19mg/day in 21 (24.4%), and 20-30mg/day in 8 (9.3%). Follow-up period was 12.1+-8.1 years. Results: Forty-four patients (51.8%) had active inflammation of the aortic valve. Survival rate was 77.1% at 10 years and 56.6% at 20 years. Prosthetic valve detachment free rate was 80.8% at 10 years and 71.1% at 20 years. In multivariate study, active inflammation, young age and high CRP at 30 days after operation were risk factors for valve detachment (Table). Conclusion: Inflammation is...
Abstract 3644: Blood tumor mutational burden (bTMB) from circulating tumor DNA (ctDNA) as a biomarker for both mutational status and tumor burden in non-small cell lung cancer (NSCLC)
Authors: Andrew A. Davis, Carlos Galvez, Alan Pan, Nisha Mohindra, Victoria Villaflor, Young Kwang Chae
Journal: Cancer Research (2018)

Abstract Background: Tissue tumor mutational burden (tTMB) has emerged as a viable biomarker for response to immune checkpoint blockade (ICB) in multiple histologies including NSCLC. Blood TMB (bTMB) is a novel summative measure of ctDNA genomic alterations in the peripheral blood. Few studies have examined the clinical utility and correlation of bTMB with tumor burden and survival. Methods: We identified 53 patients, retrospectively, who had paired blood (Guardant Health) and tissue (Foundation Medicine) next-generation sequencing testing. bTMB was determined by taking the number of reported mutations over the sequencing length of ctDNA. bTMB was calculated for research purposes and has not been approved for clinical use. From the cohort, 36 patients had baseline CT scans with measurable scores by RECIST version 1.1. Survival analyses by quartile were performed for the subset of patients (N=18 PFS, N=19 OS) treated with ICB. Results: bTMB was significantly correlated with baseline RECIST tumor burden estimations (p=0.010, Pearson Correlation, r=0.42, Table 1). There was a trend toward mutant allele frequency (MAF) of the highest clone in blood correlating with RECIST score (p=0.061). No significant correlation was found when comparing blood and tissue TMB scores in paired patients (p=0.70). In the subset of patients treated with ICB, higher bTMB was significantly associated with shorter PFS (HR 1.81 [1.03-3.18], p=0.038) and OS (HR 2.23 [1.09-4.58], p=0.029). Conclusions: This study demonstrated the feasibility and clinical utility of bTMB. Our findings may indicate that bTMB reflects tumor shedding into the blood as a surrogate for tumor burden and heterogeneity given the correlation with RECIST scores. In survival analyses, higher bTMB predicted shorter survival, which also reflects bTMB as a biomarker for tumor burden. Prospective studies are necessary to study bTMB in larger cohorts of patients treated with ICB. Correlation CoefficientPRECIST-Blood TMB r = 0.424P = 0.010RECIST-Tissue TMB r = 0.238P = 0.198RECIST-MAFr = 0.316P = 0.061MAF-Blood TMB r = 0.182P = 0.289MAF-Tissue TMB r = 0.336P = 0.065Tissue TMB-Blood TMB r = 0.073P = 0.695 Citation Format: Andrew A. Davis, Carlos Galvez, Alan Pan, Nisha Mohindra, Victoria Villaflor, Young Kwang Chae. Blood tumor mutational burden (bTMB) from circulating tumor DNA (ctDNA) as a biomarker for both mutational status and tumor burden in non-small cell lung cancer (NSCLC) [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 3644.
P2Y12 H2 Haplotype Is Associated With Peripheral Arterial Disease
Authors: PierreFontana, PascaleGaussem, MartineAiach, Jean-NoëlFiessinger, JosephEmmerich, Jean-LucReny
Journal: Circulation (2003)

Background— We recently described a gain-of-function haplotype, called H2, of the adenosine diphosphate (ADP) receptor P2Y12 gene associated with increased ADP-induced platelet aggregation ex vivo in healthy volunteers. Because platelets play a key role in atherosclerosis and arterial thrombosis, we tested the possible link between the H2 haplotype and the risk of peripheral arterial disease (PAD) in a case-control study. Methods and Results— We studied 184 consecutive male patients under 70 years of age with PAD and 330 age-matched control subjects free of symptomatic PAD and with no cardiovascular history. Mean age was 57.1±7.2 years (cases) and 56.7±7.6 years (control subjects). The H2 haplotype was more frequent in patients with PAD than in control subjects (30% and 21%, respectively; OR, 1.6; CI, 1.1 to 2.5; P=0.02 in univariate analysis). This association with PAD remained significant in multivariate regression analysis (OR, 2.3; CI, 1.4 to 3.9; P=0.002) after adjustment for diabetes, smoking, hyper...
Abstract 14776: GM1 Ganglioside-containing Nanoliposomes Protect Against AL Amyloid Light Chain-induced Human Microvascular Endothelial Dysfunction
Authors: Seth Truran, Volkmar Weissig, Daniel A Franco, Camelia Burciu, Subhadip Senapati, Diana Guzman-Villanueva, Stuart Lindsay, Marina Ramirez-Alvarado, Parameswaran Hari, Raymond Q Migrino
Journal: Circulation (2014)

AL amyloidosis involves multiorgan tissue damage from amyloid-forming light chain proteins (LC). We previously showed the potential of phosphatidic acid-containing nanoliposomes in mitigating LC-in...
Effect of a Behavioral Intervention for Underserved Preschool-Age Children on Change in Body Mass Index
Authors: Shari L. Barkin, William J. Heerman, Evan C. Sommer, Nina C. Martin, Maciej S. Buchowski, David Schlundt, Eli K. Po’e, Laura E. Burgess, Juan Escarfuller, Charlotte Pratt, Kimberly P. Truesdale, June Stevens
Journal: JAMA (2018)

Prevention of obesity during childhood is critical for children in underserved populations, for whom obesity prevalence and risk of chronic disease are highest.