tbuckley/cabot-search huggingface dataset:
Abstract 12230: Increased Left Ventricular Myocardial Stiffness is Associated With Incident Heart Failure in African Americans: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Daisuke Kamimura, Takeki Suzuki, Michael E Hall, Wanmei Wang, Michael D Winniford, Kenneth R Butler, Thomas H Mosley
Journal: Circulation (2016)

Background: Increased left ventricular (LV) myocardial stiffness may be associated with future deterioration of LV hemodynamics and incident heart failure (HF). Diastolic wall strain (DWS) is a recently developed echocardiographic indicator of LV myocardial stiffness. We hypothesized that increased LV myocardial stiffness evaluated by DWS is associated with incident HF in a community-based African American cohort in the ARIC. Methods and Results: We investigated the association between LV myocardial stiffness and incident HF among 1553 African American participants (mean age 58.5 years, 66% women) without a history of cardiovascular diseases or LV wall motion abnormalities in the ARIC Study. Echocardiography was performed at Visit 3 in the African American cohort in Jackson, MS. DWS was calculated as (posterior wall thickness at end-systole - posterior wall thickness at end-diastole) / posterior wall thickness at end-systole. DWS quartiles were generated and used to make the Kaplan-Meier survival curves for incident HF with log-rank test. Cox proportional hazards models were used to evaluate the association between baseline DWS and incident HF. Over a median follow-up of 15.6 years, there were 251 HF events (incidence rate: 10.9 per 1,000 person-years). Participants with lower DWS (increased LV diastolic stiffness) had a higher incidence of HF than those with higher DWS (unadjusted hazard ratio 1.86, 95%CI 1.28-2.71 in 1 st quartile vs 4 th quartile, p=0.001). After adjustment for traditional risk factors and incident coronary heart disease during the course, DWS was independently associated with incident HF (hazard ratio 1.62, 95%CI 1.10-2.38 in 1 st quartile vs 4 th quartile, p=0.015). Conclusions: Increased LV myocardial stiffness evaluated by DWS was associated with an increased risk of HF in a community-based African American cohort in the ARIC. Increased LV myocardial stiffness may lead to future deterioration of LV hemodynamics and incident HF.
Abstract 13415: Monocyte/Macrophage-Specific Insulin-Like Growth Factor-1 Receptor Deficiency Promotes Lipid Accumulation and Inflammatory Responses in Macrophages, Leading to Increased Atherosclerosis
Authors: YusukeHigashi, Shaw-yungShai, SergiySukhanov, PatriceDelafontaine
Journal: Circulation (2014)

Macrophage (Mf) uptake of modified lipids, pro-inflammatory signaling and conversion to foam cells is a hallmark of atheroma formation. Insulin-like growth factor-1 (IGF-1) is a pleiotropic growth factor and its receptor (IGF1R) is expressed in various cell types including Mf, yet the role of Mf IGF1R signaling in atherogenesis is unknown. We created Mf-specific IGF1R-deficient mice on Apoe-/- background (Mf-IGF1R-KO) and found these mice had increased plaque burden (aortic root plaque size, 57.0 ± 14.9 % increase) and enhanced inflammatory phenotype (anti-Mac3 staining, Mf-IGF1R-KO, 31.3 ± 2.8 % vs. IGF1R flox, 22.5 ± 4.2 %). To determine mechanisms we exposed peritoneal Mf from Mf-IGF1R-KO mice (IGF1R-KO cells) and IGF1R-flox mice (IGF1R-WT cells) to acetylated LDL (acLDL) and oxidized LDL (oxLDL) and assessed proinflammatory cytokine and chemokine expression levels, lipid uptake, and cholesterol efflux. IGF1R-KO cells expressed higher levels of IL1α, IL6, and TNFα compared to IGF1R-WT cells (IL1α; 338±...
Abstract 18423: Associations Between Common ECG Findings and Out-of-Hospital Cardiac Arrest in a Primary Care Setting
Authors: Steen M Hansen, Jonas B Nielsen, Rikke Mortensen, Gunnar Gislason, Lars Køber, Freddy Lippert, Claus Graff, Stig Haunsø, Jesper H Svendsen, Kristian Kragholm, Adrian Pietersen, Bent Lind, Søren Hjortshøj, Anders G Holst, Johannes J Struijk, Christian Torp-Pedersen
Journal: Circulation (2016)

Introduction: Out-of-hospital cardiac arrest (OHCA) is often the first manifestation of previously unrecognized cardiac disease. Electrocardiogram (ECG) abnormalities encountered in primary care se...
Resveratrol, a Polyphenolic Phytoalexin Present in Red Wine, Enhances Expression and Activity of Endothelial Nitric Oxide Synthase
Authors: ThomasWallerath, GöranDeckert, ThomasTernes, HenrikAnderson, HuigeLi, KlausWitte, UlrichFörstermann
Journal: Circulation (2002)

Background— Estrogens can upregulate endothelial nitric oxide synthase (eNOS) in human endothelial cells by increasing eNOS promoter activity and enhancing the binding activity of the transcription factor Sp1. Resveratrol, a polyphenolic phytoalexin found in grapes and wine, has been reported to act as an agonist at the estrogen receptor. Therefore, we tested the effect of this putative phytoestrogen on eNOS expression in human endothelial cells. Methods and Results— Incubation of human umbilical vein endothelial cells (HUVEC) and HUVEC-derived EA.hy 926 cells with resveratrol for 24 to 72 hours upregulated eNOS mRNA expression in a time- and concentration-dependent manner (up to 2.8-fold). eNOS protein expression and eNOS-derived NO production were also increased after long-term incubation with resveratrol. Resveratrol increased the activity of the eNOS promoter (3.5-kb fragment) in a concentration-dependent fashion, with the essential trans-stimulated sequence being located in the proximal 263 bp of the...
Abstract 2524: A new mTOR-independent effect of rapamycin: Transcriptional regulation of TRIB3
Authors: Bojana Stefanovska, Cécile Vicier, Véronique Scott, Guillaume Meurice, Fabrice André, Olivia Fromigué
Journal: Cancer Research (2018)

Abstract Background: Mechanistic Target of Rapamycin (mTOR), a key component of the PI3K/Akt signaling pathway, coordinates various cellular processes such as metabolism, growth, cell proliferation and cell cycle progression. Dysregulations affecting mTOR frequently occur in cancer, and mTOR inhibitors/rapalogs are used as monotherapy or a part of combination therapy in breast or kidney metastatic cancer. Despite this, response rate is modest. Several mechanisms of resistance have been reported, but do not fully characterize insensitive tumor cells. Purpose: This study investigated new target genes of rapamycin/rapalogs. Methods: Expression levels of target genes were evaluated in a panel of cancer cell lines by transcriptomic analyses, real-time qPCR and western blot. Transcriptional regulation was investigated by in silico analyses of the promoter region, gene reporter assays using site-directed mutagenesis, and ChIP. Stably silenced cell lines were established by lentiviral transduction of shRNA sequences. Results: We identified one gene: TRIB3 (Tribbles Pseudokinase 3), whose expression is downregulated in the presence of rapamycin in a panel of cancer cell lines and in PBMCs isolated from cancer patients. This gene encodes for a pseudokinase involved in a glucose-induced insulin resistance in Type 2 Diabetes by inhibiting the activation of Akt1/2. We observed that silencing mTOR did not mimic rapamycin downregulation of TRIB3, suggesting an mTOR-independent effect of rapamycin. We identified a binding site for the transcriptional repressor GCF2/LRRFIP1 in the promoter region of TRIB3, and confirmed that the presence and the binding of GCF2 to TRIB3 promoter are required for TRIB3 downregulation by rapamycin. Finally, we identified FKBP3 (FK506-Binding Protein 3), a protein that can bind rapamycin with high affinity, as a GCF2 partner, confirming the direct effect of rapamycin on TRIB3 promoter. Conclusions: Taken together, our investigations identified a novel transcriptional target gene of rapamycin: TRIB3. We also characterized the molecular mechanism of regulation by rapamycin through a FKBP3/GCF2-dependent repression of TRIB3 promoter activity, and independently of mTOR signaling. Such variations in TRIB3 expression level in cancer cells could be linked to rapamycin sensitivity, and may represent a valuable therapeutic target. Citation Format: Bojana Stefanovska, Cécile Vicier, Véronique Scott, Guillaume Meurice, Fabrice André, Olivia Fromigué. A new mTOR-independent effect of rapamycin: Transcriptional regulation of TRIB3 [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 2524.
Abstract 267: Nonsteroidal anti-inflammatory drugs induce ER stress- and BID-dependent immunogenic cell death to suppress colorectal tumorigenesis
Authors: Rochelle Elayne Fletcher, Brian Leibowitz, Yijun Wang, Fernando Concha-Benavente, Robert Ferris, Robert Schoen, Jian Yu, Lin Zhang
Journal: Cancer Research (2018)

Abstract Prevention or early detection represents a key approach for reducing the mortality and morbidity of CRC. Use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with decreased risk of CRC in numerous epidemiological studies, clinical trials, and animal model studies. However, the mechanism by which NSAIDs suppress colorectal tumorigenesis has remained unclear. We previously demonstrated that the chemopreventive effect of NSAIDs is mediated by a synthetic lethal interaction between death receptor signaling and loss of the gatekeeper APC tumor suppressor, which is dependent on the BH3-only Bcl-2 family member BID. In this study, we found a critical role of endoplasmic reticulum (ER) stress upstream of death receptor signaling and BID activation. Elevated levels of ER stress and cell death markers were detected in advanced adenomas from patients taking NSAIDs including aspirin. Inhibiting ER stress using a pharmacological approach abolished the apoptotic effect of NSAIDs in CRC cells and normal colonic epithelial cells with APC loss and also suppressed the chemopreventive activity of the NSAID sulindac in APCMin/+ mice. Importantly, our results unveiled a critical role of ER stress and BID-dependent cell death in triggering immune-mediated elimination of nascent cells that lose APC. Markers of immunogenic cell death (ICD), including plasma membrane translocation of calreticulin and phagocytosis by dendritic cells, were suppressed in cells with BID knockout or ER stress inhibition. BID knockout or ER stress inhibition also reduced tumor infiltrating lymphocytes (TILs) in sulindac-treated APCMin/+ mice. Collectively, our results suggest that NSAIDs suppress colorectal tumorigenesis by enhancing immunosurveillance through ER stress and BID-dependent ICD. These results provide novel insight into the chemopreventive mechanism of NSAIDs, which may help design more effective chemopreventive strategies and agents. Citation Format: Rochelle Elayne Fletcher, Brian Leibowitz, Yijun Wang, Fernando Concha-Benavente, Robert Ferris, Robert Schoen, Jian Yu, Lin Zhang. Nonsteroidal anti-inflammatory drugs induce ER stress- and BID-dependent immunogenic cell death to suppress colorectal tumorigenesis [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 267.
Phosphorylation of Smooth Muscle 22α Facilitates Angiotensin II–Induced ROS Production Via Activation of the PKCδ-P47phox Axis Through Release of PKCδ and Actin Dynamics and Is Associated With Hypertrophy and Hyperplasia of Vascular Smooth Muscle Cells In Vitro and In Vivo
Authors: PinLv, Sui-BingMiao, Ya-NanShu, Li-HuaDong, GeorgeLiu, Xiao-LiXie, MinGao, Yu-CanWang, Ya-JuanYin, Xiao-JuanWang, MeiHan
Journal: Circulation Research (2012)

Rationale:We have demonstrated that smooth muscle (SM) 22α inhibits cell proliferation via blocking Ras-ERK1/2 signaling in vascular smooth muscle cells (VSMCs) and in injured arteries. The recent study indicates that SM22α disruption can independently promote arterial inflammation through activation of reactive oxygen species (ROS)-mediated NF-κB pathways. However, the mechanisms by which SM22α controls ROS production have not been characterized. Objective:To investigate how SM22α disruption promotes ROS production and to characterize the underlying mechanisms. Methods and Results:ROS level was measured by dihydroethidium staining for superoxide and TBA assay for malondialdehyde, respectively. We showed that downregulation and phosphorylation of SM22α were associated with angiotensin (Ang) II–induced increase in ROS production in VSMCs of rats and human. Ang II induced the phosphorylation of SM22α at Serine 181 in an Ang II type 1 receptor–PKCδ pathway–dependent manner. Phosphorylated SM22α activated the...
Ischemic Preconditioning Attenuates Cardiac Sympathetic Nerve Injury via ATP-Sensitive Potassium Channels During Myocardial Ischemia
Authors: ToshiroMiura, ShujiKawamura, HironariTatsuno, YasuhiroIkeda, ShunsukeMikami, HiroshiIwamoto, TakayukiOkamura, MitsuoIwatate, MasayasuKimura, YukaDairaku, TsuyoshiMaekawa, MasunoriMatsuzaki
Journal: Circulation (2001)

Background During myocardial ischemia, massive norepinephrine (NE) is released from the cardiac sympathetic nerve terminals, reflecting the sympathetic nerve injury. A brief preceding ischemia can reduce infarct size; this is known as ischemic preconditioning (PC). The effect of PC on sympathetic nerves, however, including its underlying mechanisms in dog hearts, has remained unclear. Thus, this study was designed to elucidate whether the activation of ATP-sensitive potassium (KATP) channels is involved in the mechanism of cardiac sympathetic nerve protection conferred by PC. Methods and Results Interstitial NE concentration was measured by the in situ cardiac microdialysis method in 45 anesthetized dogs. Five minutes of ischemia followed by 5 minutes of reperfusion was performed as PC. In the controls, the dialysate NE concentration (dNE) increased 15-fold after the 40-minute ischemia. PC decreased dNE at 40-minute ischemia by 59% (P<0.01), which was reversed by glibenclamide. A KATP channel opener, nico...
His Bundle Pacing
Authors: Pugazhendhi Vijayaraman, Mina K. Chung, Gopi Dandamudi, Gaurav A. Upadhyay, Kousik Krishnan, George Crossley, Kristen Bova Campbell, Byron K. Lee, Marwan M. Refaat, Sanjeev Saksena, John D. Fisher, Dhananjaya Lakkireddy
Journal: Journal of the American College of Cardiology (2018)
Abstract 3967: Potent treatment combinations with CIB1 depletion in triple-negative breast cancer
Authors: Alexander H. Chung, Tina M. Leisner, Gabrielle Dardis, Marissa Bivins, Leslie V. Parise
Journal: Cancer Research (2018)

Abstract The current standard of care for triple-negative breast cancer (TNBC) patients is limited to chemotherapy, radiation, and/or surgery. Therefore, there is a pressing need for new targeted therapies to improve clinical efficacy, reduce toxicity, and overcome resistance. We previously found that CIB1 depletion induces cell death selectively in TNBC cells, while sparing normal cells. The purpose of this study was to ask whether depleting CIB1 further enhances tumor-specific killing when combined with either the commonly used chemotherapeutic, docetaxel, or the cell death-inducing ligand, TRAIL. To address this, we targeted CIB1 by RNA interference in MDA-MB-436, MDA-MB-231, MDA-MB-468 TNBC cells and ME16C normal breast epithelial cells alone or combination with docetaxel or TRAIL. Cell death was quantified via trypan blue exclusion using FACS and cell death mechanisms were analyzed by Western blotting. We found that the combination of CIB1 depletion with docetaxel significantly enhanced tumor-specific cell death relative to each treatment alone. The enhanced cell death strongly correlated with caspase-8 activation, a hallmark of death receptor-mediated apoptosis. Because CIB1 depletion also upregulated the death receptor, TRAIL-R2, we tested for sensitization to TRAIL. While TRAIL alone had no effect on cell viability, CIB1 depletion profoundly sensitized tumor cells to TRAIL, resulting in a synergistic increase in cell death. In addition to death receptor-mediated apoptosis, both combination treatments activated a non-apoptotic mechanism, called paraptosis. Interestingly, these combination treatments also induced nearly complete death of docetaxel-resistant MDA-MB-436 cells, again via apoptosis and paraptosis. In contrast, neither combination treatment induced cell death in normal ME16C cells. In conclusion, our results demonstrate that the novel combinations of CIB1 depletion with docetaxel or TRAIL significantly enhance naive and docetaxel-resistant TNBC cell death via increased death receptor-mediated apoptosis and paraptosis, suggesting that targeting CIB1 may also overcome resistance to chemotherapeutics. Taken together, combination therapies that target CIB1 could prove to be a safe and durable strategy for treatment of TNBC and potentially other cancers. Citation Format: Alexander H. Chung, Tina M. Leisner, Gabrielle Dardis, Marissa Bivins, Leslie V. Parise. Potent treatment combinations with CIB1 depletion 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 3967.
Abstract SY05-02: Polycomb dysregulation by oncohistones
Authors: Peter W. Lewis
Journal: Cancer Research (2018)

Abstract Covalent modifications to both the DNA and the histone proteins allow chromatin to act as a dynamic information hub that integrates diverse biochemical stimuli to regulate genomic DNA access to the transcription machinery and ultimately establish and maintain cellular phenotypes. Moreover, there is increasing appreciation that chromatin alterations per se, including DNA and histone modifications, are involved in the pathogenesis of cancer. Nowhere is this better supported than with the groundbreaking discoveries of high-frequency, somatic mutations in histones that are drivers of oncogenesis. These mutations (collectively called "oncohistones") cause amino acid substitutions that localize to conserved residues in the N-terminal tail of histone H3 and all seem to be linked, either directly or indirectly, to disruption of normal levels and distribution of histone H3 methylation and thus genomic regulation. Specifically, oncohistones directly or indirectly promote aberrant genome-wide distribution of lysine 27 methylation on histone H3. H3K27 methylation, catalyzed by the Polycomb Repressive Complex 2 (PRC2), is mechanistically linked to establishment and maintenance of gene repression. We are currently using a combination of biochemical and genomic approaches to investigate how oncohistone-driven changes in histone H3 K27 methylation lead to altered chromatin states that profoundly influence gene expression patterns. I will discuss some of our recent mechanistic and functional work on various oncohistone mutations. Citation Format: Peter W. Lewis. Polycomb dysregulation by oncohistones [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 SY05-02.
Abstract 5150: Loss of CYLD promotes cell invasion via ALK5 stabilization in oral squamous cell carcinoma
Authors: Satoru Shinriki, Hirofumi Jono, Manabu Maeshiro, Takuya Nakamura, Jianying Guo, Jian-Dong Li, Ryoji Yoshida, Masanori Shinohara, Hideki Nakayama, Hirotaka Matsui, Yukio Ando
Journal: Cancer Research (2018)

Abstract Oral squamous cell carcinoma (OSCC) has a very poor prognosis because of its highly invasive nature, and the 5-year survival rate has not changed appreciably for the past 30 years. Although cylindromatosis (CYLD), a deubiquitinating enzyme, is thought to be a potent tumor suppressor, its biological and clinical significance in OSCC is largely unknown. This study aimed to clarify the roles of CYLD in OSCC progression. Our immunohistochemical analyses revealed significantly reduced CYLD expression in invasive areas in OSCC tissues, whereas CYLD expression was conserved in normal epithelium and carcinoma in situ. Furthermore, downregulation of CYLD by siRNA led to acquisition of mesenchymal features and increased migratory and invasive properties in OSCC cells and HaCaT keratinocytes. It is interesting that CYLD knockdown promoted TGF-β signaling by inducing stabilization of TGF-β receptor I (ALK5) in a cell autonomous fashion. In addition, the response to exogenous TGF-β stimulation was enhanced by CYLD downregulation. The invasive phenotypes induced by CYLD knockdown were completely blocked by an ALK5 inhibitor. Also, lower CYLD expression was significantly associated with the clinical features of deep invasion, poor overall survival, and increased Smad3 phosphorylation, which is an indicator of activation of TGF-β signaling in invasive OSCC. These findings suggest that downregulation of CYLD promotes invasion with mesenchymal transition via ALK5 stabilization in OSCC cells. Citation Format: Satoru Shinriki, Hirofumi Jono, Manabu Maeshiro, Takuya Nakamura, Jianying Guo, Jian-Dong Li, Ryoji Yoshida, Masanori Shinohara, Hideki Nakayama, Hirotaka Matsui, Yukio Ando. Loss of CYLD promotes cell invasion via ALK5 stabilization in oral squamous cell carcinoma [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 5150.
Abstract B09: Novel sarcoma treatments identified via drug sensitivity/resistance screening of sarcoma cell lines
Authors: Iwona Grad, Pilar Ayuda, Robert Hanes, Jorrit Enserink, Ola Myklebost
Journal: Clinical Cancer Research (2018)

Abstract Sarcomas comprise a plethora of subtypes and each should be regarded as ultra-orphan malignancy. Over the last century incremental improvements of sarcoma therapies have provided better survival; however, treatment options appear to have been exhausted and new alternatives beyond traditional chemotherapeutic regimens are much needed. To broaden the repertoire of antisarcoma drugs, we applied a direct drug testing approach. Using a library of 349 anticancer compounds (FDA-approved/under clinical trial) and panels of liposarcoma and osteosarcoma cell lines, we selected a group of potential novel antisarcoma therapeutics and retested them against cells from primary tumors. We are also investigating genomic and molecular features to find potential drug response biomarkers. Since all those compounds have been approved or are under clinical trials, they present a unique shortcut repurposing opportunity for personalized sarcoma treatment. Citation Format: Iwona Grad, Pilar Ayuda, Robert Hanes, Jorrit Enserink, Ola Myklebost. Novel sarcoma treatments identified via drug sensitivity/resistance screening of sarcoma cell lines [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 B09.