tbuckley/cabot-search huggingface dataset:
Abstract 131: Neutrophil extracellular trap mediate mitochondrial biogenesis in cancer cells to promote growth of metastases
Authors: Hamza Yazdani, Samer Tohme, Eva Roy, Patricia Loughran, Dirk Vander Windth, Hai Huang, Allan Tsung
Journal: Cancer Research (2018)

Abstract Neutrophils through the release of neutrophil extracellular traps (NETs) in response to surgical stress were shown to be able to capture circulating cancer cells, and in doing so, support the development of metastatic disease. In addition, NETs persist within the tumor microenvironment long after the surgical stress happens. The exact nature of the NETs-tumor interaction and the role that NETs play in dictating the tumor microenvironment is unclear. In vivo, subcutaneous and liver metastasis models of colorectal and hepatocellular cancer were performed in wild type and PAD4 KO mice that lack the ability to form NETs. In vitro, bioenergetics profiles of both HCC and CRC cancer cells were studied after co-culture with NETs, isolated from human and murine neutrophils. We found a 3-fold decrease in the tumor volume of PAD4 KO mice compared to control mice 3 weeks after tumor injection in both subcutaneous and liver metastatic models. PAD4 KO tumors showed significantly decreased neutrophil infiltration and no NET formation within the tumor compared to WT mice. PAD4 KO tumors had decreased proliferation rates and increased apoptosis. In vitro, stressed cancer cells release stress signals such as cytokines, chemokines, and DAMPs (HMGB1 and histones), that enhanced neutrophil migration towards them and subsequently triggered NET formation. In turn, NETs resulted in a 2-fold increase in the expression of mitochondrial biogenesis regulators in cancer cells. Increase mitochondrial mass was observed when treated cancer cells with NETs. A significant increase mitochondrial oxygen consumption rate (OCR) and ATP levels were observed when compared with DNase treatment. Taken together, we suggest that cancer cells help in recruiting NETs which in turn regulates mitochondrial bioenergetics for tumor growth and metastasis. Citation Format: Hamza Yazdani, Samer Tohme, Eva Roy, Patricia Loughran, Dirk Vander Windth, Hai Huang, Allan Tsung. Neutrophil extracellular trap mediate mitochondrial biogenesis in cancer cells to promote growth of metastases [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 131.
Abstract 1094: A role for olfactory-like chemosensory signaling in prostate cancer metastasis
Authors: Hong Lam, Wanqu Zhu, Hailun Wang, Jun Luo, Qizhi Zheng, Ken Valkenburg, Paula Hurley, Jennifer L. Pluznick, Phuoc T. Tran, Angelo M. De Marzo, William B. Isaacs, Kenneth J. Pienta, Steven S. An
Journal: Cancer Research (2018)

Abstract Odorant sensing G protein-coupled receptors (ORs) are the largest signaling family encoded by the mammalian genome. Historical understanding suggests these specialized receptors are only expressed on sensory neurons in the main olfactory epithelium and respond to external ligands involved in smell perception. More recently, olfactory-like chemosensory signaling has been found in a variety of non-sensory tissues and shown to be evoked by endogenous metabolic byproducts of anaerobic bacteria and hypoxia. Here we screened the full complement of ORs in the prostate and studied their expression and function in the context of metastatic-invasion of prostate cancer (PCa). In the germline of men with lethal PCa, we detected a large number of nonsynonymous coding changes in ~400 different OR genes including specific missense and loss-of-function mutations that are present in higher rates than would be predicted. RNA-Seq of clinical prostate samples showed higher OR51E2 expression in localized PCa than normal prostate. Most striking, we detected a low abundance of the OR51E2 transcript in PCa metastases to the bone relative to localized. Similarly, we found a marked reduction of OR51E2 expression in PCa cell lines that were derived from bone metastases, or those that had undergone an epithelial-mesenchymal transition (EMT) phenotype through co-culture with IL4-treated CD14+ monocytes. Using mouse models of PCa metastasis, we confirmed the overexpression of OR51E2 in localized tumors generated by subcutaneous injection while observing a marked reduction in PCa cells metastatic to the bone that also demonstrated a mesenchymal cellular phenotype. Together these findings establish, for the first time, a novel role for ‘sensory GPCRs' in PCa progression to metastasis. Grant supports: The Johns Hopkins Discovery Award; The Johns Hopkins Catalyst Award; Maryland Cigarette Restitution Fund Citation Format: Hong Lam, Wanqu Zhu, Hailun Wang, Jun Luo, Qizhi Zheng, Ken Valkenburg, Paula Hurley, Jennifer L. Pluznick, Phuoc T. Tran, Angelo M. De Marzo, William B. Isaacs, Kenneth J. Pienta, Steven S. An. A role for olfactory-like chemosensory signaling in prostate cancer metastasis [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 1094.
Exchange Protein Directly Activated by cAMP Mediates Slow Delayed-Rectifier Current Remodeling by Sustained β-Adrenergic Activation in Guinea Pig Hearts
Authors: MonaAflaki, Xiao-YanQi, LingXiao, BalazsOrdog, ArtavazdTadevosyan, XiaobinLuo, AngeMaguy, YanfenShi, Jean-ClaudeTardif, StanleyNattel
Journal: Circulation Research (2014)

Rationale:β-Adrenoceptor activation contributes to sudden death risk in heart failure. Chronic β-adrenergic stimulation, as occurs in patients with heart failure, causes potentially arrhythmogenic reductions in slow delayed-rectifier K+ current (IKs). Objective:To assess the molecular mechanisms of IKs downregulation caused by chronic β-adrenergic activation, particularly the role of exchange protein directly activated by cAMP (Epac). Methods and Results:Isolated guinea pig left ventricular cardiomyocytes were incubated in primary culture and exposed to isoproterenol (1 μmol/L) or vehicle for 30 hours. Sustained isoproterenol exposure decreased IKs density (whole cell patch clamp) by 58% (P<0.0001), with corresponding decreases in potassium voltage-gated channel subfamily E member 1 (KCNE1) mRNA and membrane protein expression (by 45% and 51%, respectively). Potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) mRNA expression was unchanged. The β1-adrenoceptor antagonist 1-[2-((3-Carbamoy...
Abstract 2119: Bone Morphogenetic Protein Receptor 1a in myeloid cells regulates mouse prostate cancer growth
Authors: Desiree M. Straign, Sergey V. Novitskiy, Philip Owens
Journal: Cancer Research (2018)

Abstract The Bone Morphogenetic Protein (BMP) pathway is a member of the TGFβ signaling family and has mirrored the complex roles in diverse contexts during cancer development. BMP signaling is rarely mutated and can be frequently overexpressed in many human cancers. The dichotomous role of BMPs as both tumor promoters and suppressors appears to be largely context based in both the cancer cell and the surrounding microenvironment. Myeloid cells including macrophages and neutrophils have been shown to be tumor promoting when stimulated from BMP signaling. We discovered that conditional deletion of BMPR1a in myeloid cells (LysM-Cre) would affect tumor progression and found smaller tumors in a syngeneic FVBn prostate cancer model. Specific changes occurred in myeloid cells both in tumor-bearing mice and non-tumor naïve mice throughout multiple tissues. We profiled myeloid subsets both in the bone marrow, spleen and primary tumor. We found that BMPR1a loss in myeloid cells altered the differentiation and lineage capability of distinct populations by histologic, flow cytometry and high-dimensional mass cytometry analysis. These results indicate a distinct genetic requirement for BMP signaling in myeloid cells during tumor progression. Citation Format: Desiree M. Straign, Sergey V. Novitskiy, Philip Owens. Bone Morphogenetic Protein Receptor 1a in myeloid cells regulates mouse prostate cancer growth [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 2119.
Abstract 1474: Identifying novel chromatin binding sites of nucleolin protein in cancer cells
Authors: Guanhui Wu, Buket Onel, Danzhou Yang
Journal: Cancer Research (2018)

Abstract Nucleolin is an important regulator of cell proliferation and has been reported to play a role in c-Myc transcriptional regulation. Elevated expression levels of nucleolin have been shown in a number of malignant cells, but how nucleolin contributes to cancer development and progression remains unknown. Recently, G-quadruplexes (G4s) have been shown in vivo to form in G-rich sequences with biological importance. Nucleolin has been reported to bind to G-quadruplexes for its biological functions. In particular, G4s have been shown to form in the MYC promoter and inhibit MYC transcription; nucleolin was found to display a remarkable binding affinity to the c-Myc promoter G4 over its best-known RNA target. CX-3543, the first-in-class G-quadruplex-targeting small molecule, was shown to induce nucleolin redistribution from the cell nucleolus to the cell nucleoplasm and apoptosis in cancer cells, which was suggested to act through the c-Myc promoter G-quadruplex. Therefore, unbiased analysis of the genomic binding sites of nucleolin in human chromatin is pivotal in understanding nucleolin's biological functions. Using chromatin immunoprecipitation (ChIP) assay, we demonstrated that nucleolin binds to the c-Myc NHE III1 region in vivo. Using an anti-nucleolin antibody, the isolated DNA from the immunoprecipitated DNA-protein complexes from HeLa cells yielded numerous c-Myc promoter sequences that were determined by real-time PCR, suggesting the direct interaction between nucleolin and the c-Myc promoter G4-forming region in vivo. G4-interactive ligands have been shown to facilitate the formation of G4 structures in cells. To elucidate the association of nucleolin with G-quadruplexes in vivo, we monitored cellular localization of nucleolin before and after G4 ligand treatments and observed a rapid cellular translocation of nucleolin from the cell nucleolus to the cell nucleoplasm. Using ChIP coupled with next-generation sequencing analysis (ChIP-seq), we identified several binding sites of nucleolin in human chromatin. The determined chromatin binding sites of nucleolin will provide insights into the biological functions of nucleolin and its relationship with G-quadruplexes in cancer cells. Citation Format: Guanhui Wu, Buket Onel, Danzhou Yang. Identifying novel chromatin binding sites of nucleolin protein in cancer cells [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 1474.
Abstract 14900: Clinical Outcomes of Elective Percutaneous Coronary Intervention (PCI) for Stable Angina at Hospital With or Without Onsite Cardiac Surgery Backup
Authors: TomonoriAkasaka, SeijiHokimoto, NoriakiTabata, KenjiSakamoto, KenichiTsujita, SunaoKojima, KoichiKaikita, HisaoOgawa
Journal: Circulation (2014)

Background: Based on 2011 ACCF/AHA/SCAI PCI guidelines, it is recommended that PCI should be performed at hospital with onsite cardiac surgery. But, recent foreign data suggests that there is no significant difference in clinical outcomes following primary and elective PCI between hospitals with and without onsite cardiac surgery. The proportion of PCI centers without onsite cardiac surgery comprises approximately more than half of all PCI centers in Japan. We examined the impact of with or without onsite cardiac surgery on clinical outcomes following elective PCI for stable angina. Methods: From Aug 2008 to March 2011, subjects (n=3931) were enrolled from the Kumamoto Intervention Conference Study (KICS), which is a multicenter registry, and enrolling consecutive patients undergoing PCI in 15 centers in Japan. Patients were assigned to two groups treated in hospitals with (n=3455) or without (n=476) onsite cardiac surgery. Clinical events were followed up for 12 months. Primary endpoint was in-hospital d...
Abstract 11661: Readmissions Following Congenital Heart Surgery in Infants and Children
Authors: Oscar Benavidez, Wei He
Journal: Circulation (2015)

Introduction: Thirty-day readmission among infants and children after congenital heart surgery (CHS) has been under studied despite the complexity and vulnerability of these patients. Hypothesis: Readmissions after pediatric CHS are common. There exist risk factors for unplanned readmission. Methods: We obtained State Inpatient Databases for Washington, New York, Florida, and California 2009-2011 and selected admissions &lt; 19 years with ICD-9 CM codes indicating CHS. We defined readmission as non-elective hospitalization for a given patient &lt; 31 days of discharge from the index CHS admission. We examined patient demographic and clinical variables and defined complications using the Society of Thoracic Surgeons Congenital Heart complication short list. Case mix was adjusted by using Risk Adjustment for Congenital Heart Surgery-1 (RACHS-1) categories. We defined High Resource Use (HRU) admissions as those &gt; 90 th percentile for total hospital charges. Multivariate analyses using generalized estimating equations estimated to adjusted odds for readmission. Results: Among 8,585 index admissions we identified 967 readmissions (11.3%). Median length of stay for readmissions was 5 days, median total charge of $31,973 and mortality rate 1.8%. Among readmissions 16 (1.6%) were for another CHS of which 44% were HRU, complication rate 88% and mortality 6.25%. Common indications for readmission were Pulmonary (pleural effusion, respiratory distress, pneumonia/bronchiolitis), Cardiac (heart failure, pericardial effusion), Infectious (fever, UTI), and GI (dehydration, feeding difficulty, GERD). On multivariable analysis age 1 month - 1 year (adjusted odds ratio [AOR] 1.3 p=0.01); Hispanic AOR 1.2 p=0.03; government-insurance AOR 1.3 p=0.01; RACHS-1 3 complexity AOR 2.4 p&lt;0.001; RACHS-1 4+ complexity 2.0 p=0.001; HRU AOR 1.4 p=0.02; complications AOR 1.1 p=0.04; and emergent index admission AOR 2.0 p&lt;0.001 were risk factors for readmission. Conclusions: Over 11% of pediatric CHS admissions result in unplanned readmission. CHS during readmission had higher resource use, complications and death rates. Hispanic race, government insurance, HRU, higher case complexity, complications and emergent index admission are risk factors for readmission.
Abstract MP17: Relationship of Accelerometer-assessed Physical Activity and Sedentary Behavior with Predicted CVD Risk in Older Women: Results From the Objective Physical Activity and Cardiovascular Health (OPACH) Study
Authors: Michael J LaMonte, Eileen Rillamus-Sun, Kelly R. Evenson, I-Min Lee, Dori E. Rosenberg, Chongzhi Di, David Buchner, Andrea Z. LaCroix
Journal: Circulation (2016)

Background: Use of accelerometers to objectively measure physical activity (PA) and sedentary behavior (SB) in epidemiologic studies may improve understanding of associations with CVD, particularly in older adults. This cross-sectional study examined associations between accelerometer measures of PA and SB with cardiovascular health in 4870 race-ethnically diverse postmenopausal women, ages 63 to 99 years (mean 78.9) enrolled in OPACH, an ancillary study of the Women’s Health Initiative program. Methods: Vector magnitude counts per 15-sec epoch from hip worn triaxial accelerometers (minimum of 4 days with ≥10 hours/day wear time) were used to define time spent in SB (0-18 counts/15 sec), low light intensity (19-225), high light intensity (226-518), and moderate-to-vigorous intensity PA (MVPA; ≥519) based on count cutpoints determined from a laboratory calibration study among women of similar age. Predicted 10-year risk of CVD was computed using the Reynolds risk score (RRS), for which higher values reflect higher predicted CVD risk. Relationships between SB, PA and RRS were examined using generalized linear model analyses, adjusting for accelerometer wear time. Results: The mean RRS was 13.7±11.9 (range 0.8 to 94.3). Based on regression analysis, every hour/day spent in SB was associated with an average 2.3% increase in the RRS. In contrast, every hour/day spent in low-light, high-light, or MVPA resulted in an average 1.1%, 1.5%, and 5.2% reduction, respectively, in the RRS. A significant positive association was observed between SB and decile of RRS (trend, p&lt;.0001); whereas, significant inverse gradients for time spent in each PA level were observed across decile of RRS (trend, p&lt;.001 for all). Mean hours/day associated with the lowest and highest decile of RRS, respectively, were 12.0 and 13.1 for SB; 3.6 and 3.1 for low light; 1.9 and 1.4 for high light; and 1.3 and 0.6 for MVPA. These patterns of association for SB and PA with RRS were also observed when stratified by race-ethnicity and age. Conclusion: Based on objectively assessed SB and PA, this study confirms that prolonged SB is adversely related with cardiovascular health in older women. Results further suggest that even light intensity PA could have cardiovascular benefit in older women. Because a large proportion of daily activity time is spent at lower intensity among older adults, this finding has important public health implications. Prospective studies are needed to confirm these cross-sectional results.
Abstract 11833: Cost-Effectiveness Analysis of the Polypill Approach vs Periodic Risk Assessment for Prevention of Cardiovascular Disease
Authors: Bart S Ferket, Myriam Hunink, Mohammed Khanji, Isha Agarwal, Kirsten E Fleischmann, Steffen E Petersen
Journal: Circulation (2016)

Introduction: There is an international trend towards recommending medication to prevent cardiovascular disease (CVD) in individuals at increasingly lower cardiovascular risk. We sought to assess the cost-effectiveness of a population approach with a Polypill including statin and antihypertensives and periodic risk assessment with different risk thresholds. Methods: We developed a microsimulation model for lifetime predictions of CVD events, diabetes, and death in 259,146 asymptomatic UK Biobank participants aged 40 to 69, who attended 2006-2010 baseline visits. We assessed incremental costs and quality-adjusted life-years (QALYs) for Polypill scenarios differing for starting age, and periodic risk assessment with 10-year CVD risk thresholds of 10% and 20%. Analyses were undertaken from a UK health service perspective. Results: Restrictive risk assessment, in which statins and antihypertensives were prescribed when risk exceeded 20% ( Old guidelines ), was the optimal strategy gaining 123 QALYs (95% CI -173 to 387) per 10,000 individuals at an extra cost of £1.45 million (95% CI 0.89 to 1.94) as compared with current practice with an incremental cost effectiveness ratio of £11,797/QALY (see Figure ). Although less restrictive risk assessment and Polypill scenarios prevented more CVD events and attained larger survival gains, these benefits were offset by the additional costs and disutility of daily medication use. Lowering the risk threshold for prescription of statins to 10% ( Current guidelines ) was economically unattractive, costing £40K per QALY gained. Starting the Polypill from age 60 onwards became the most cost-effective scenario when annual drug prices were to be reduced below £240. All Polypill scenarios would save costs at prices below £50. Conclusions: Periodic risk assessment using lower risk thresholds is unlikely to be cost-effective. A population approach with the Polypill would become cost-effective if drug prices were to be reduced.
Abstract 10420: Utilization of Cardiac Resynchronization Therapy in Patients Hospitalized With Heart Failure: Has it Changed and is it Associated With Patient Outcomes?
Authors: Tiffany C Randolph, Anne S Hellkamp, Emily P Zeitler, Phillip J Shulte, Gregg C Fonarow, Adrian F Hernandez, Clyde W Yancy, Eric J Peterson, Sana M Al-Khatib
Journal: Circulation (2015)

Background: Prior work has demonstrated that cardiac resynchronization therapy (CRT) reduces heart failure hospitalization (HFH) and mortality particularly in patients who are female, have non-ischemic disease, low ejection fraction and wide QRS. However, patterns of use in clinical practice remain largely unknown. We investigated temporal trends in the utilization of CRT among patients hospitalized for HF and assessed whether CRT use was associated with differences in all-cause mortality. Methods: We included 72,008 patients with EF ≤35% admitted for HFH at 388 sites in the Get With the Guidelines-Heart Failure (GWTG-HF) registry from 2005 - 2014. Using logistic regression we evaluated the association of race, gender, and time with CRT use. Among 15,619 patients linked to Medicare inpatient data 2005 - 2012, Cox proportional hazards models assessed association between CRT and mortality. Results: The majority of patients were men (60.0%), white (61.9%), and had ischemic heart disease (59.3%). CRT had already been in place, was implanted during admission, or prescribed at discharge in 26.3% of patients. Women were less likely to have CRT than men over time, and black patients were consistently less likely than white patients to receive CRT. (Figure) CRT was associated with reduced mortality during the study period (hazard ratio [95% confidence interval]) (HR [CI]) (0.90 [0.84, 0.96]), p=0.002, and there was a trend towards increased benefit in more recent years (p-interaction=0.06, (2011-2012) (HR [CI]) (0.82 [0.73 - 0.92]). Conclusions: CRT use has increased, but it continues to be underutilized in many HF patients. A new gender disparity has developed despite evidence that women are more likely than men to benefit from CRT. There is an association between CRT and reduced mortality that has strengthened over time. Future initiatives should address the disparity in CRT utilization among women and black patients to help them derive mortality benefit from this therapy.
TRAIL/Apo2L Mediates the Release of Procoagulant Endothelial Microparticles Induced by Thrombin In Vitro
Authors: StéphanieSimoncini, Makon-SébastienNjock, StéphaneRobert, LaurenceCamoin-Jau, JoséSampol, Jean-RobertHarlé, CatherineNguyen, FrançoiseDignat-George, FrancineAnfosso
Journal: Circulation Research (2009)

Microparticles are small vesicles playing a crucial role in cell communication by promoting prothrombotic and proinflammatory responses. However, the molecular mechanisms underlying their release are still elusive. We previously established that thrombin promoted the generation of endothelial microparticles (EMPs). In the present study, gene profiling identified TRAIL/Apo2L, a cytokine belonging to the tumor necrosis factor-α superfamily, as a target of thrombin. Thrombin increased the expression of cell-associated and soluble forms of TRAIL (sTRAIL) in HMEC-1 cells and human umbilical vein endothelial cells (HUVECs). Blocking TRAIL by specific antibodies or by small interfering RNA reduced both the number and the procoagulant activity of EMPs released by thrombin. Consistent with an involvement of sTRAIL in thrombin-induced EMP release, we showed that (1) exogenously added sTRAIL generated procoagulant EMPs; (2) supernatants from thrombin-stimulated endothelial cells induced EMP release by HMEC-1 cells a...
Abstract 15924: Ectopy on a Single 12-lead Electrocardiogram and Incident Cardiac Myopathy in the Community
Authors: Kaylin T Nguyen, Thomas A Dewland, Jonathan W Dukes, Eric Vittinghoff, Elsayed Z Soliman, Phyllis K Stein, John S Gottdiener, Alvaro Alonso, Lin Y Chen, Bruce M Psaty, Susan R Heckbert, Gregory M Marcus
Journal: Circulation (2016)

Introduction: Premature atrial contractions (PACs) and premature ventricular contractions (PVCs) quantified by 24-hour ambulatory electrocardiogram (ECG) monitoring predict incident atrial fibrilla...