tbuckley/cabot-search huggingface dataset:
Abstract 18550: Association Between a Healthy Cardiovascular Risk Factors Profile and Coronary Artery Calcium Score: Results From the Brazilian Longitudinal Study of Adults Health (ELSA-Brasil)
Authors: Isabela M Bensenor, Alessandra C Goulart, Itamar S Santos, Dora Chor, Alexandre C Pereira, Marcio S Bittencourt, Khurran Nasir, Ron Blankstein, Paulo A Lotufo
Journal: Circulation (2015)

Introduction: Few studies evaluated the relationship between a favorable lifestyle a healthy profile of cardiovascular risk factors and subclinical atherosclerosis measured by Coronary Artery Calcium Score (CAC). Hypothesis: to identify the association between lifestyle profile and CAC among mid-elderly men and women. Methods: We included 4058 participants of the Brazilian Longitudinal Study of Health aged 35-74 years who underwent CAC measurement. The 2010 Task Force of the American Heart Association cut-offs were used to define the ideal profile and included smoking, physical activity, diet, blood pressure, glucose/cholesterol levels, and body-mass index. Only 21 participants had at least 6 ideal metrics. Participants were categorized according the number of ideal risk factors (IRF): 0-1 (n=1152, 28.4%), 2 (n=1234, 30.4%), 3-4 (n=1489, 36.7%), or 5-7 (n=183, 4.5%). (Figure 1). Results: Compared to individuals with 0-1 IRF, the odds ratio (OR) of participants with 2 IRF presenting with CAC of 0 (compared to &gt;0), &lt;100 (compared to ≥100), and &lt;400 (compared to ≥400) was 0.65 (95% confidence interval [CI]: 0.54-0.79), 0.59 (95%CI: 0.45-0.77), and 0.61 (95%CI: 0.39-0.94), respectively. Similarly, the ORs of CACs of 0, &lt;100, and &lt;400 in individuals with 3-4 IRF were 0.54 (95%CI: 0.44-0.66), 0.42 (95%CI: 0.31-0.57), and 0.56 (95%CI: 0.34-0.92), respectively. The ORs of CACs of 0, &lt;100, and &lt;400 in individuals with 5-7 IRF were 0.33 (95%CI: 018-0.58), 0.17 (95%CI: 0.04-0.72), and zero, respectively. Conclusion: Subjects with more IRF had lower CAC compared to subjects with lower ICH metrics, but CAC &gt;0 was found even in these individuals.
Abstract 867: Blocking breast cancer metastasis by targeting HuR-FOXQ1 signaling axis
Authors: Xiaoqing Wu, Gulhumay Gardashova, Lan Lan, Yu Zhan, Jiajun Liu, Dan A. Dixon, Jeffrey Aubé, Danny R. Welch, Liang Xu
Journal: Cancer Research (2018)

Abstract As most of treatment options do not work very well for metastatic cancer. Patients with metastatic cancer have a greatly lower survival rate compared with patients with local cancer. Metastasis remains a life-threat to cancer patients and an unmet medical need. The RBP Hu antigen R (HuR) is overexpressed in virtually all malignancies tested, including breast cancer. Cytoplasmic HuR accumulation correlates with high-grade malignancy, poor distant disease-free survival and serves as a prognostic factor for poor clinical outcome in breast cancer. HuR promotes tumorigenesis by promoting mRNA stability and translation of proteins implicated in proliferation, survival, angiogenesis, invasion, and metastasis. We found that silencing of HuR inhibited cell invasion in vitro in breast cancer. Using RIP-seq (ribonucleoprotein immunoprecipitation-sequencing), a transcription factor FOXQ1, which is recently revealed to implicate in breast cancer invasion and metastasis processes, is found to be a direct HuR target. Furthermore, exogenous introduction of FOXQ1 can rescue cell invasive ability inhibited by HuR knockout. Taken together, HuR-FOXQ1 signaling axis is a potential target for blocking breast cancer metastasis. RNA-binding proteins had previously been considered “undruggable” due to lack of a well-defined binding pocket for target RNAs. Using high throughput screening followed by structure-based rational design and lead optimization, we have identified small molecules that inhibit HuR-mRNA interaction at nM to sub-µM potency. Our lead compound, KH-3, potently inhibits breast cancer cell growth and decreases cell invasion in vitro similar to HuR knockout, as well as increasing the expression of epithelial marker E-cadherin. FOXQ1 overexpression abolishes the effect of KH-3 on blocking metastasis in breast cancer cells, demonstrating that the HuR inhibitor KH-3 inhibits cell metastasis by blocking FOXQ1 function. Moreover, KH-3 treatment disrupts HuR-FOXQ1 interaction in RNP-IP and FOXQ1 3′-UTR luciferase reporter assays. In vivo efficacy studies show that KH-3 not only exhibits potent antitumor efficacy in orthotopic xenograft models of breast cancer, but also efficiently blocks lung metastasis in experimental metastatic cancer model. In conclusion, we identified a potent and specific small molecule disrupter of HuR-FOXQ1 interaction for potential novel anti-metastatic therapy of breast cancer with HuR overexpression. Citation Format: Xiaoqing Wu, Gulhumay Gardashova, Lan Lan, Yu Zhan, Jiajun Liu, Dan A. Dixon, Jeffrey Aubé, Danny R. Welch, Liang Xu. Blocking breast cancer metastasis by targeting HuR-FOXQ1 signaling axis [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 867.
High Levels of Dietary Advanced Glycation End Products Transform Low-Dersity Lipoprotein Into a Potent Redox-Sensitive Mitogen-Activated Protein Kinase Stimulant in Diabetic Patients
Authors: WeijingCai, John CijiangHe, LiZhu, MelpomeniPeppa, ChangyongLu, JaimeUribarri, HelenVlassara
Journal: Circulation (2004)

Background— LDL modification by endogenous advanced glycation end products (AGEs) is thought to contribute to cardiovascular disease of diabetes. It remains unclear, however, whether exogenous (diet-derived) AGEs influence glycoxidation and endothelial cell toxicity of diabetic LDL. Methods and Results— Twenty-four diabetic subjects were randomized to either a standard diet (here called high-AGE, HAGE) or a diet 5-fold lower in AGE (LAGE diet) for 6 weeks. LDL pooled from patients on HAGE diet (Db-HAGE-LDL) was more glycated than LDL from the LAGE diet group (Db-LAGE-LDL) (192 versus 92 AGE U/mg apolipoprotein B) and more oxidized (5.7 versus 1.5 nmol malondialdehyde/mg lipoprotein). When added to human endothelial cells (ECV 304 or human umbilical vein endothelial cells), Db-HAGE-LDL promoted marked ERK1/2 phosphorylation (pERK1/2) (5.5- to 10-fold of control) in a time- and dose-dependent manner compared with Db-LAGE-LDL or native LDL. In addition, Db-HAGE-LDL stimulated NF-κB activity significantly in ...
Abstract 5446: Serotonin modulates AKT-mTOR and Notch signaling pathways, promotes liver cancer cell steatosis and cell survival
Authors: Suresh Niture, Deepak Kumar
Journal: Cancer Research (2018)

Abstract The hormone serotonin is known as 5-hydroxytryptamine. It is a precursor of melatonin, derived from the amino acid tryptophan. Serotonin acts as a neurotransmitter and modulates several key functions in the human body, such as appetite, mood and sleep. Apart from its important roles in the central nervous system (CNS), serotonin regulates various extra-neuronal pathophysiological functions. Serotonin is synthesized by Enterochromaffin cells of the gut, mostly stored in platelets and about 2% of free serotonin released in the blood. The role of peripheral serotonin in adipocytes, pancreatic cells, macrophages and liver cells is not fully understood. In the current study, we investigated the role of serotonin in liver cancer cell signaling and liver cancer cell growth. Treatment of serotonin in liver cancer cells HepG2 and SK-Hep1 induced autophagy markers and effectors such as LC3 I/II, phospho-4EBP1, ATG3 and Beclin1, and, increased cell proliferation and cell survival. AKT/mTOR pathway controls cellular autophagy and our results demonstrated that exposure of serotonin to liver cancer cells inactivates AKT/mTOR signaling and induced autophagy. Also, we demonstrate that serotonin also activates Notch signaling pathway as evident by induction of Notch target gene Hes1. Notch inhibitors Avagacestat 2 and FLI-06 inhibited serotonin-mediated Notch signaling and cellular autophagy. Furthermore, by the activation of Notch signaling, serotonin-induced oleic acid-mediated cell steatosis in both HepG2 and SK-Hep1 liver cancer cells. In addition, treatment of serotonin also induced autophagy modulator proteins such as SIRT1 and Tumor Necrosis Factor Alpha Inducing Protein 8 (TNFAIP8) which participate in the modulation of cellular autophagy and cell survival. Taken together our data suggested that peripheral serotonin regulates liver cancer cell steatosis, cells survival and may promote liver carcinogenesis by the modulation of AKT/mTOR and Notch signaling pathways. Citation Format: Suresh Niture, Deepak Kumar. Serotonin modulates AKT-mTOR and Notch signaling pathways, promotes liver cancer cell steatosis and cell survival [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 5446.
Abstract 16958: Are We There Yet? Dissipating Sex Differences in Acute Coronary Syndromes. A Population Level Examination
Authors: Padma Kaul, Anamaria Savu, L. K Newby
Journal: Circulation (2016)

Objectives: Cardiovascular disease is a leading cause of death among both men and women in North America. Using a 12-year population-level cohort of patients hospitalized with acute coronary syndro...
Abolishing Myofibroblast Arrhythmogeneicity by Pharmacological Ablation of α-Smooth Muscle Actin Containing Stress Fibers
Authors: ChristianRosker, NicolòSalvarani, StephanSchmutz, TeddyGrand, StephanRohr
Journal: Circulation Research (2011)

Rationale:Myofibroblasts typically appear in the myocardium after insults to the heart like mechanical overload and infarction. Apart from contributing to fibrotic remodeling, myofibroblasts induce arrhythmogenic slow conduction and ectopic activity in cardiomyocytes after establishment of heterocellular electrotonic coupling in vitro. So far, it is not known whether α-smooth muscle actin (α-SMA) containing stress fibers, the cytoskeletal components that set myofibroblasts apart from resident fibroblasts, are essential for myofibroblasts to develop arrhythmogenic interactions with cardiomyocytes. Objective:We investigated whether pharmacological ablation of α-SMA containing stress fibers by actin-targeting drugs affects arrhythmogenic myofibroblast–cardiomyocyte cross-talk. Methods and Results:Experiments were performed with patterned growth cell cultures of neonatal rat ventricular cardiomyocytes coated with cardiac myofibroblasts. The preparations exhibited slow conduction and ectopic activity under con...
Corrigendum to “A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer” [J Hepatol 69 (2018) 385–395]
Authors: Takuma Tsuchida, Youngmin A. Lee, Naoto Fujiwara, Maria Ybanez, Brittany Allen, Sebastiao Martins, M. Isabel Fiel, Nicolas Goossens, Hsin-I. Chou, Yujin Hoshida, Scott L. Friedman
Journal: Journal of Hepatology (2018)
Effect of Vasa Vasorum Flow on Structure and Function of the Aorta in Experimental Animals
Authors: ChristodoulosStefanadis, CharalambosVlachopoulos, PanagiotisKarayannacos, HarisiosBoudoulas, CostasStratos, TheodorosFilippides, ManolisAgapitos, PavlosToutouzas
Journal: Circulation (1995)

Background It is known that vasa vasorum flow contributes substantially to the nutrition of the outer layers of the thoracic aorta. This investigation was undertaken to test the hypothesis that impairment of vasa vasorum flow would alter the structure of the aortic wall and change the elastic properties of the aorta. Methods and Results The periaortic fat that contains the vasa vasorum for the ascending aorta was removed in seven anesthetized dogs, and the results were compared with those obtained from six weight-matched sham-operated control dogs. Aortic pressures, aortic diameters, and aortic distensibility were obtained before and 30 minutes and 15 days after removal of the periaortic vasa vasorum network. Aortic pressures were measured directly with a fluid-filled catheter. Aortic diameters were measured simultaneously with aortic pressures with an elastic, air-filled ring connected to a transducer. Aortic distensibility was calculated by the formula 2×pulsatile change in aortic diameter/(diastolic ao...
Functional Consequences of Integrin Gene Mutations in Mice
Authors: DanielBouvard, CordBrakebusch, ErikaGustafsson, AttilaAszódi, ThereseBengtsson, AlejandroBerna, ReinhardFässler
Journal: Circulation Research (2001)

Integrins are cell-surface receptors responsible for cell attachment to extracellular matrices and to other cells. The application of mouse genetics has significantly increased our understanding of integrin function in vivo. In this review, we summarize the phenotypes of mice carrying mutant integrin genes and compare them with phenotypes of mice lacking the integrin ligands.
Abstract LB-106: Allorepertoire-derived HLA class I/peptide-specific T cell receptor transgenic CD4+T cells mediate antitumor responses in Ewing sarcoma mimicking allo-rejection
Authors: Sebastian J. Schober, Melanie Thiede, David Schirmer, Dirk Wohlleber, Guenther Richter, Dirk H. Busch, Uwe Thiel, Stefan E. Burdach
Journal: Cancer Research (2018)

Abstract Introduction: Innovative therapies are urgently warranted to cure patients with advanced Ewing sarcoma (ES). Specific cellular-based approaches for immunotherapy of solid cancers show promising results in first clinical trials. Mostly, CD8+ effector T cells are genetically modified to recognize and kill tumor cells. In organ transplantation, alloreactive CD4+ T helper 1 cells have shown to be an underestimated key player in allo-rejection. In previous works we observed massive CD4+ cell tissue-infiltration in tumor-free Rag2-/-c-/- mice after adoptive transfer of ES-specific CD8+ T cells combined with peripheral mononuclear cells in tumor bearing mice, suggesting an important role of CD4+ cells in disease control. In this study we transduce CD4+ T cells from healthy donors with an HLA class I allorepertoire-derived TCR specific for the ES-associated antigen STEAP1130 for which in vivo ES control by adoptively transferring CD8+ cells with the same transgene was demonstrated in previous works. Methods: STEAP1/HLA-A*02:01 specific TCR transgenic CD4+ T cells were generated and characterized by flow cytometry, interferon-, granzyme-B release and xCelligence assays to study direct cytotoxicity and tumor growth inhibition, in comparison to STEAP1/HLA-A*02:01 specific TCR transgenic CD8+ T cells. In vivo functionality was validated in Rag2-/-c-/- mice. Results: STEAP1/HLA-A*02:01 specific TCR CD4+ transduced T cells exhibit high peptide specificity. In vitro, CD4+ TCR transgenic T cells show similar tumor growth inhibition compared to CD8+ cells with the same transgene. Furthermore, in vivo data suggest a synergistic anti-ES effect of CD4+ and CD8+ cells transduced with the same STEAP1/HLA-A*02:01 specific TCR. Conclusion: STEAP1/HLA-A*02:01 TCR transgenic CD4+ T cells exhibit direct cytotoxicity and execute synergistic helper functions. Combination of adoptively transferred TCR transgenic CD4+ and CD8+ T cells may result in better tumor control compared to transfer of respective TCR transgenic CD4+ or CD8+ T cells alone. * U.T. and S.E.G.B. share senior authorship Citation Format: Sebastian J. Schober, Melanie Thiede, David Schirmer, Dirk Wohlleber, Guenther Richter, Dirk H. Busch, Uwe Thiel, Stefan E. Burdach. Allorepertoire-derived HLA class I/peptide-specific T cell receptor transgenic CD4+ T cells mediate antitumor responses in Ewing sarcoma mimicking allo-rejection [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 LB-106.
Ionic Mechanisms of Regional Action Potential Heterogeneity in the Canine Right Atrium
Authors: JianlinFeng, LixiaYue, ZhiguoWang, StanleyNattel
Journal: Circulation Research (1998)

Abstract—Atrial action potential heterogeneity is a major determinant of atrial reentrant arrhythmias, but the underlying ionic mechanisms are poorly understood. To evaluate the basis of spatial heterogeneity in canine right atrial repolarization, we isolated cells from 4 regions: the crista terminalis (CT), appendage (APG), atrioventricular ring (AVR) area, and pectinate muscles. Systematic action potential (AP) differences were noted: CT cells had a “spike-and-dome” morphology and the longest AP duration (APD; value to 95% repolarization at 1 Hz, 270±10 ms [mean±SEM]); APG and pectinate muscle cells had intermediate APDs (180±3 and 190±3 ms, respectively; P<0.001 versus CT for each), with APG cells having a small phase 1; and AVR cells had the shortest APD (160±4 ms, P<0.001 versus other regions). The inward rectifier and the slow and ultrarapid delayed rectifier currents were similar in all regions. The transient outward K+ current was significantly smaller in APG cells, explaining their small phase 1 ...
A Novel Strategy to Identify Placebo Responders: Prediction Index of Clinical and Biological Markers in the EMBARC Trial
Authors: Madhukar H. Trivedi, Charles South, Manish K. Jha, A. John Rush, Jing Cao, Benji Kurian, Mary Phillips, Diego A. Pizzagalli, Joseph M. Trombello, Maria A. Oquendo, Crystal Cooper, Daniel G. Dillon, Christian Webb, Bruce D. Grannemann, Gerard Bruder, Patrick J. McGrath, Ramin Parsey, Myrna Weissman, Maurizio Fava
Journal: Psychotherapy and Psychosomatics (2018)

Background: One in three clinical trial patients with major depressive disorder report symptomatic improvement with placebo. Strategies to mitigate the effect of placebo responses have focused on modifying study design with variable success. Identifying and excluding or controlling for individuals with a high likelihood of responding to placebo may improve clinical trial efficiency and avoid unnecessary medication trials. Methods: Participants included those assigned to the placebo arm (n = 141) of the Establishing Moderators and Biosignatures for Antidepressant Response in Clinical Care (EMBARC) trial. The elastic net was used to evaluate 283 baseline clinical, behavioral, imaging, and electrophysiological variables to identify the most robust yet parsimonious features that predicted depression severity at the end of the double-blind 8-week trial. Variables retained in at least 50% of the 100 imputed data sets were used in a Bayesian multiple linear regression model to simultaneously predict the probabilities of response and remission. Results: Lower baseline depression severity, younger age, absence of melancholic features or history of physical abuse, less anxious arousal, less anhedonia, less neuroticism, and higher average theta current density in the rostral anterior cingulate predicted a higher likelihood of improvement with placebo. The Bayesian model predicted remission and response with an actionable degree of accuracy (both AUC > 0.73). An interactive calculator was developed predicting the likelihood of placebo response at the individual level. Conclusion: Easy-to-measure clinical, behavioral, and electrophysiological assessments can be used to identify placebo responders with a high degree of accuracy. Development of this calculator based on these findings can be used to identify potential placebo responders.
Abstract 2795: Screening and characterization of drugs that inhibit the ubiquitin-proteasome system
Authors: Karthik Selvaraju, Arjan Mofers, Paola Pellegrini, Ellin-Kristina Hillert, Padraig D'Arcy, Stig Linder
Journal: Cancer Research (2018)

Abstract Pharmacological inhibition of proteasomal cysteine deubiquitinase (DUB) activity (i.e., USP14 and UCHL5 DUBs) has been shown to be particularly cytotoxic to cancer cells and to result in inhibition of tumor growth in several in vivo models. Most proteasome DUB inhibitors contain α, β-unsaturated ketones with the potential to covalently bind DUB active site cysteines. We here performed a screen of 5000 compounds containing α, β-unsaturated ketones in order to identify novel proteasome DUB inhibitors and to examine the question of the specificity of such compounds. Surprisingly, only ~3% of 5000 compounds containing α, β-unsaturated ketones showed anti proliferative activity at 5 uM. Almost one third of these cytotoxic compounds were found to block proteasome processing. Treatment of cells with the hit compounds induced the accumulation of proteasome bound high molecular weight polyubiquitin conjugates, induction of the chaperone HSP70B' and the oxidative stress marker heme oxygenase-1 (HO-1) and to induce an apoptotic response. A subset of 10 compounds were studied in detail and found to inhibit proteasome DUB activity in vitro. Importantly, hit compounds did not show inhibitory activity on a panel of recombinant non-proteasome DUBs. Inhibition of proteasome processing by hit compounds was not due to inhibition of 20S proteasome enzymatic activity. Exposure of multiple myeloma cells to the hit compounds resulted in thermostabilization of USP14 at the relevant concentrations using CETSA. These results suggest that α, β-carbonyls-containing compounds are promising candidates for development of drugs targeting proteasome DUBs and that drugs showing unexpected selectivity can be identified. Citation Format: Karthik Selvaraju, Arjan Mofers, Paola Pellegrini, Ellin-Kristina Hillert, Padraig D'Arcy, Stig Linder. Screening and characterization of drugs that inhibit the ubiquitin-proteasome system [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 2795.
Chronic Constriction of the External and Internal Carotid Arteries in Dogs: Its Effect on the Blood Pressure
Authors: Paulkezdi
Journal: Circulation Research (1960)

Narrowing of the internal and external carotid arteries by a clamp does not lead to hypertension if the carotid sinus nerves remain intact. Subsequent disruption of the carotid sinus nerves results in hypertension. It is concluded that the cause of the chronic hypertension in dogs with constriction of the carotid sinus is not due to altered cerebral hemodynamics, but rather to disruption of the carotid sinus nerves.
Abstract 19642: Immuno-Peptidome Profiling Identifies Human Cathelicidin hCAP18 as a Potential CD8+ T Cell Auto-Immune Protein Involved in Atherosclerosis
Authors: Peter M Mihailovic, Wai Man Lio, Juliana Yano, Xiaoning Zhao, Jianchang Zhou, Bo Zhou, Wei Yang, Michael Freeman, Kuang-Yuh Chyu, Prediman K Shah, Bojan Cercek, Paul Dimayuga
Journal: Circulation (2016)

Background: Auto-immunity is believed to contribute to inflammation in atherosclerosis. Mass spectrometry (MS) enables analysis of patient immuno-peptidomes (IPs). We profiled the IP of a patient with known coronary artery disease (CAD) and tested the relevance of disease-related IPs in a mouse model of atherosclerosis. Methods and Results: HLA-I/peptide complexes were immuno-precipitated from the plasma of a male CAD patient and an age-matched healthy control. HLA-I/peptide complexes were confirmed by Western blotting. Peptides were extracted by denaturation and size-exclusion, and subjected to MS analyses using rapid Collisional-Induced Dissociation (rCID) and High-energy Collisional Dissociation (HCD). Results of the MS showed congruence of signal intensities of peptides common to both control and patient samples using the rCID output (R2=0.498; P<0.0001). Among peptides unique to the CAD patient, the highest intensity on both rCID and HCD methods was a fragment of hCAP18. The biological relevance of t...