tbuckley/cabot-search huggingface dataset:
Abstract 2906: eEF1A2 interacts with and inhibits PKR to enhance cancer cell survival
Authors: Juan F. Martínez-Leal, Alejandro Losada, Maria Jose Muñoz, Marta Martinez-Diez, Juan Manuel Dominguez, Carlos M. Galmarini
Journal: Cancer Research (2018)

Abstract Human translation elongation factor 1α2, encoded by the eEF1A2 gene, is a pro-oncogenic protein absent from the majority of body tissues (with exception of brain, heart and skeletal muscle1), but expressed in many cancers1-3, where it provides tumor cells with improved fitness and survival. Though its canonical function is delivering aminoacyl-tRNAs to the ribosome, other “moonlighting” functions such as enhancing sphingosine kinase4,5 or antioxidant (most probably through peroxiredoxin-1 stimulation) activities6 have been described for the elongation factor. Recently, we have reported that eEF1A2 is the target for plitidepsin, a marine-derived cyclic depsipeptide currently under development for the treatment of relapsed or refractory multiple myeloma patients7. We have also confirmed that eEF1A2 interacted with previously described partners as PRDX1 and SPHK and enhanced their pro-survival activities8. Here we investigated the role of new “moonlighting functions” of eEF1A2 in the maintenance of the tumor phenotype and survival of cancer cells. Through co-immunoprecipitation and HPLC/MS we have uncovered the interaction between eEF1A2 and dsRNA-activated protein kinase (PKR, EIF2AK2). We have analyzed the kinase activity of PKR in the presence of eEF1A2, demonstrating that PKR activity is inhibited when complexed with eEF1A2. This complex is disrupted after plitidepsin binding to eEF1A2, rendering PKR active. Once activated, the kinase triggers a MAPK cascade and the NF-κB signaling pathway, leading to the activation of the extrinsic apoptotic pathway and the death of the tumor cell. Taken together, these results show that the fitness boost that the moonlighting functions of eEF1A2 provide to cancer cells, which are important for their growth and survival, constitutes an Achilles heel that can be purposely exploited in anticancer therapy. 1 Abbas, W., Kumar, A. &amp; Herbein, G. Front Oncol 5, 75 (2015). 2 Anand, N. et al. Nature genetics 31, 301-305 (2002). 3 Li, Z. et al. PloS one 5, e10755 (2010). 4 Leclercq, T. M., Moretti, P. A., Vadas, M. A. &amp; Pitson, S. M. J Biol Chem 283, 9606-9614 (2008). 5 Leclercq, T. M., Moretti, P. A. &amp; Pitson, S. M. Oncogene 30, 372-378 (2011). 6 Chang, R. &amp; Wang, E. J Cell Biochem 100, 267-278 (2007). 7 Losada, A. et al. Sci Rep 6, 35100 (2016) 8 Losada, A. et al. Abstract #1165, AACR Annual Meeting (2017) Citation Format: Juan F. Martínez-Leal, Alejandro Losada, Maria Jose Muñoz, Marta Martinez-Diez, Juan Manuel Dominguez, Carlos M. Galmarini. eEF1A2 interacts with and inhibits PKR to enhance cancer 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 2906.
A real world analysis of recurrence risk factors for early colorectal cancer T1 treated with standard endoscopic resection.
Authors: Clara Martinez Vila, Carles Pericay, Helena Oliveres, Paula Ribera Fernandez, Maria Marin Alcala, Juan Carlos Pardo Ruiz, Julia Giner Joaquin, Jose Manuel Cabrera Romero, Javier Serra, Eva Ballesteros, Antoni Malet Munte, Alejandro Casalots Casado, Ismael Macias, Eugeni Saigí
Journal: Journal of Clinical Oncology (2018)

575 Background: Currently, endoscopic resection of early colorectal cancer (ECC) defined as carcinoma with invasion limited to the mucosa (Tis), and submucosa (T1) is possible due to advances in instrumentation. However, when tumor invades submucosal layer, lymph node dissemination is present in 16.2% of cases, requiring additional surgery and limfadenectomy. Risk factors for lymph node dissemination and independent for relapse have been previously described in literature. Methods: We performed a retrospective analysis of all patients with colorectal T1 tumors, treated at our center with endoscopic resection and some with additional surgery between 2006 and 2017. Stadistical analysis was perfomed with IBM SPSS Statistics 24.0. Results: 159 patients (p) were treated with endoscopic resection, 56.6% (90p) underwent additional surgery. Mean age was 68.74 years and 69.9% (111p) were male. Endoscopic resection: negative margins 87.6%, vascular 3.1%, lymphatic 2.5% and perineural invasion 3.8%, high degree of histological differentiation 1.3%. Surgical resection: negative margins 100%, lymph node spread 8.8%. In a mean follow-up of 23.36 months since endoscopic treatment, 13 patients had relapsed. Risk of relapse did not differ between patients who received additional surgery and those who only underwent endoscopic resection (p = 0.791). On the other hand, lymph node dissemination (p = 0.007) and a positive margin (p = 0.01) were independent risk factors for risk of relapse. Vascular, lymphatic and perineural invasion, nor degree of histological differentation were stadistically significant. However, there was a positive association between lymph node dissemination and lymphatic (p = 0.07), vascular (p = 0.007) and perineural (p = 0.001) invasion and also degree of histological differentiation (p = 0.000). Conclusions: In our study, relapse rate was under 10% in eleven years. The only independent risk factors for relapse were a positive margin and lymph node dissemination. Perineural, vascular and lymphatic invasion obtained from polypectomy sample, could infer the probability of positive lymph nodes and indirectly be an indicator for risk of relapse.
Abstract PL02-01: Advancing cancer diagnostics with artificial intelligence
Authors: Jason D. Hipp, Martin Stumpe
Journal: Cancer Research (2018)

Abstract Rendering cancer diagnoses from tissues is a highly complex process that requires many years of expert training. It involves challenging tasks for pathologists, such as identifying rare events in very large images (e.g., micrometastases in lymph nodes) or classifying subtle differences between normal vs tumor or among similar-looking tumors that have very different treatment plans. These tasks are typically more challenging for human cognition, and, consequently, over- and underdiagnoses are not uncommon, resulting in nonoptimal treatment selection. Deep learning, a type of machine intelligence, has been successfully applied to solve similar identification and classification problems for Gmail, Google Maps, Google Photos, Google Translate, etc., and may have the potential to solve these similar challenges in the practice of pathology and help improve patient's diagnoses. This talk will begin by providing a brief background on deep learning and how it has been utilized at Google for health care and non-health care applications. The latter half of the talk will discuss the potential of deep learning to improve the accuracy and efficiency of the pathology workflow while highlighting recent advances towards that goal. Citation Format: Jason D. Hipp, Martin Stumpe. Advancing cancer diagnostics with artificial intelligence [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 PL02-01.
Abstract 4640: Sustained co-delivery of dendritic cells and oncolytic adenovirus co-expressing IL-12 and GM-CSF using biodegradable polymer matrix for cancer immunotherapy
Authors: Eonju Oh, Jung-Eun Oh, JinWoo Hong, YoonHo Chung, Yunki Lee, Ki Dong Park, Sung Wan Kim, Chae-Ok Yun
Journal: Cancer Research (2018)

Abstract Administration of dendritic cells (DCs) combined with oncolytic adenovirus (Ad) expressing antitumor cytokines induces a potent antitumor effect and antitumor immunity by ameliorating the immunosuppressive tumor microenvironment. However, this combination therapy has significant limitations due to rapid dissemination and inactivation of the therapeutics at the tumor site, necessitating multiple injections of both therapeutics. In this study, we investigated injectable and biodegradable gelatin-based hydrogel as a carrier for oncolytic Ad co-expressing interleukin (IL)-12 and granulocyte-macrophage colony-stimulating factor (GM-CSF) (oAd) and DCs to elicit a potent antitumor effect with single administration. Gel matrix enabled sustained release of both oAd and DCs while preserving their biological activity over a considerable time period, leading to efficient retention of both therapeutics in tumor tissue. Further, tumors treated with oAd- and DC-loaded gel (oAd+DC/gel) showed a significantly greater expression level of IL-12, GM-CSF, and interferon-γ (IFN-γ) than either single treatment (oAd or DC) or oAd in combination with DC (oAd+DC), resulting in efficient activation of both endogenous and exogenous DCs, migration of DCs to draining lymph nodes, and tumor infiltration of CD4+ and CD8+ T cells. Moreover, oAd+DC/gel resulted in a significantly higher number of tumor-specific IFN-γ-secreting immune cells compared with oAd+DC. Lastly, oAd+DC/gel significantly attenuated tumor-mediated thymic atrophy, which is associated with immunosuppression in the tumor microenvironment, compared with oAd+DC. Taken together, these results demonstrate that gelatin gel-mediated co-delivery of oncolytic Ad and DCs might be a promising strategy to efficiently retain both therapeutics in tumor tissue and induce a potent antitumor immune response for an extended time period via a single administration. Citation Format: Eonju Oh, Jung-Eun Oh, JinWoo Hong, YoonHo Chung, Yunki Lee, Ki Dong Park, Sung Wan Kim, Chae-Ok Yun. Sustained co-delivery of dendritic cells and oncolytic adenovirus co-expressing IL-12 and GM-CSF using biodegradable polymer matrix for cancer immunotherapy [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 4640.
Abstract 359: Autosis is Triggered by Ischemia/Reperfusion in the Heart
Authors: Jihoon Nah, Peiyong Zhai, Beth Levine, Junichi Sadoshima
Journal: Circulation Research (2017)

Although autophagy generally acts as a protective function in cardiomyocytes (CMs), uncontrolled or excessive activation of autophagy can be detrimental to CMs under some conditions. However, whether autophagy mediates cell death for CMs remains largely unknown. Recently, it has been shown in HeLa cells that excessive activation of autophagy induces cell death with characteristic morphological and biochemical features, and this form of cell death is termed autosis. Here we investigated whether death of CMs is induced by autosis in the presence of TAT-Beclin1, an autophagy-inducing peptide, and ischemia/reperfusion. TAT-Beclin1 treatment dose-dependently increased the level of LC3-II and decreased that of p62. TAT-Beclin1-treated CMs showed increases in trypan-blue-positive cells suggesting that autophagy-related cell death is induced by TAT-Beclin1. TAT-Beclin1-treated CMs showed the typical morphological features of autosis, including increased autophagic vacuoles and empty vacuoles, perinuclear spaces with cytoplasmic materials, and ballooning under electron microscopic observation. TAT-Beclin1-induced autosis in CMs was not inhibited by inhibitors of apoptosis, necrosis, or lysosomal degradation. Although autosis is known to be inhibited by cardiac glycosides, since cardiomyocyte Na + -K + -ATPase in rodents is relatively resistant to cardiac glycosides, we generated adenovirus harboring shRNA-α1 subunit of Na + -K + -ATPase. We found that downregulation of the α1 subunit of Na + -K + -ATPase inhibits TAT-Beclin1-induced autosis in CMs. We also found that ischemia/reperfusion induces autosis in the mouse heart, as evidenced by the presence of characteristic morphological features of autosis, including the presence of autophagosomes, empty vacuoles, and perinuclear space. Lastly, in order to elucidate the molecular mechanism mediating autosis in the heart, we conducted unbiased screenings of 150 kinase inhibitors and identified several classes of kinase inhibitors suppressing TAT-Beclin1-induced autosis in CMs. These results indicate that autosis occurs in the heart during ischemia/reperfusion injury. Our findings may provide novel therapeutic targets for treatment of cardiac cell death during ischemia/reperfusion.
New Anti–Monocyte Chemoattractant Protein-1 Gene Therapy Attenuates Atherosclerosis in Apolipoprotein E–Knockout Mice
Authors: WeihuaNi, KensukeEgashira, ShiroKitamoto, ChuKataoka, MasamichiKoyanagi, ShujiroInoue, KatsumiImaizumi, ChiyukiAkiyama, Ken-ichiNishida, AkiraTakeshita
Journal: Circulation (2001)

Background—Monocyte recruitment into the arterial wall and its activation may be the central event in atherogenesis. Monocyte chemoattractant protein-1 (MCP-1) is an important chemokine for monocyte recruitment, and its receptor (CCR2) may mediate such in vivo response. Although the importance of the MCP-1/CCR2 pathway in atherogenesis has been clarified, it remains unanswered whether postnatal blockade of the MCP-1 signals could be a unique site-specific gene therapy. Methods and Results—We devised a new strategy for anti–MCP-1 gene therapy to treat atherosclerosis by transfecting an N-terminal deletion mutant of the human MCP-1 gene into a remote organ (skeletal muscle) in apolipoprotein E–knockout mice. This strategy effectively blocked MCP-1 activity and inhibited the formation of atherosclerotic lesions but had no effect on serum lipid concentrations. Furthermore, this strategy increased the lesional extracellular matrix content. Conclusions—We conclude that this anti–MCP-1 gene therapy may serve not...
Both Donor and Recipient Origins of Smooth Muscle Cells in Vein Graft Atherosclerotic Lesions
Authors: YanhuaHu, ManuelMayr, BernhardMetzler, MartinErdel, FergusDavison, QingboXu
Journal: Circulation Research (2002)

Smooth muscle cell (SMC) accumulation in the inner layer of the vessel wall is a key event in the pathogenesis of atherosclerosis in vein grafts, but the origin of the cells in these lesions has yet to be shown. Herein, we use animal models of vein grafts in transgenic mice to clearly identify the sources of SMCs in atherosclerosis. Vena cava segments were isografted to carotid arteries between four types of transgenic mice, including SM-LacZ expressing β-galactosidase (β-gal) in vascular SMCs, SM-LacZ/apoE−/−, ROSA26 expressing β-gal in all tissues, and wild-type mice. β-gal–positive cells were observed in neointimal and atherosclerotic lesions of all vein segments grafted between LacZ transgenic and wild-type mice. Double staining for β-gal and cell nuclei revealed that about 40% of SMCs originated from hosts and 60% from the donor vessel. This was confirmed by double labeling of the Y-chromosome and α-actin in the lesions of sex-mismatched vein grafts. The possibility that bone marrow cells were the so...
Abstract 17403: Prognositic Significance of T peak - T end Interval in Transthyretin Cardiac Amyloidosis
Authors: Alan Sugrue, Ammar M Killu, JoJo Hai, Stehpanie Joppa, Grace Lin, Martha Grogan, Angela Dispenzieri, Peter Brady
Journal: Circulation (2015)

Introduction: The T peak - T end interval (Tpe) is a measure of transmural dispersion of repolarisation with prolongation of this interval linked to an increased risk of ventricular arrhythmias and sudden death. Patients with cardiac amyloid experience a high rate of sudden cardiac death. Objective: To determine the prognostic utility of the Tpeak-Tend interval in patients with transthyretin (TTR) cardiac amyloidosis. Methods: Of the 240 patients who underwent evaluation for TTR amyloidosis at our tertiary referral center from 1966 to 2010, 39 met inclusion criteria (65 excluded for AF, 66 BBB/Paced Rhythm, 25 CAD, 21 other). Inclusion criteria were presence of histological diagnosis of TTR amyloid and confirmed cardiac involvement by echocardiogram or biopsy and absence of atrial fibrillation (AF) or bundle branch block/paced rhythm on the index surface ECG, or history of coronary heart disease (CAD). Tpe was measured in leads V3 and V5. Cox proportional hazards model were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Kaplan-Meier curves were used to estimate overall survival and differences between curves were estimated using log rank. Primary endpoints were death or heart transplantation. Results: Of the 39 patients, 85% were male, and 69% were mTTR. Mean age 66.4 ± 13.9 years. Mean follow up period of 4.2 ± 3.2 years, 25 died and 5 received heart transplants. Median survival was 3.8 years, with 5 year survival 34%. On univariate analysis, Tpe in lead V3 was predictive of adverse outcome, HR per 10msec, 1.195 (1.051-1.370). Further multivariate analysis, in a model accounting for age, gender, Lead V3 Tpe was independently associated with survival, HR per 10msec, 1.207, (1.094-1.411, p=0.009). Conclusions: The Tpe interval in Lead V3 at diagnosis is a novel, noninvasive independent predictor of survival in transthyretin cardiac amyloidosis patients in sinus rhythm.
Abstract 12869: Uncontrolled Blood Pressure is a Predictor of Left Atrial Remodeling and Adverse Clinical Outcome After Pulmonary Vein Isolation in Patients With Paroxysmal Atrial Fibrillation
Authors: MasashiKamioka, HitoshiSuzuki, YoshiyukiMatsumoto, MinoruNodera, TakashiKaneshiro, YoshiyukiKamiyama, YasuchikaTakeishi
Journal: Circulation (2016)

Aims: Little is known about the relation of blood pressure (BP) control with left atrial (LA) remodeling and clinical outcome after atrial fibrillation (AF) ablation. Methods: A 101 symptomatic paroxysmal AF patients (85 males, 62.2±8.4 years) undergoing successful pulmonary vein isolation (PVI) were enrolled. Uncontrolled hypertension (HT) was defined as BP more than 140/90 mmHg calculated as mean value being recorded at least 5 different days before PVI. LA wall thickness along ablation line was measured using computed tomography before PVI. LA dimension was measured by echocardiography before and 6 months after PVI. The recurrence was determined by the documentation of AF or atrial tachycardia lasting more than 30 sec. In case of the recurrence, the second procedure was performed based on the patient’s consent. At the second procedure, if AF sustained or was induced after the pulmonary vein (PV) re-isolation or when PV was still isolated, substrate modification such as linear ablation or complex fracti...
Only Hibernating Myocardium Invariably Shows Early Recovery After Coronary Revascularization
Authors: BharatiShivalkar, AlexMaes, MarcelBorgers, JannieAusma, IlseScheys, JohanNuyts, LucMortelmans, WillemFlameng
Journal: Circulation (1996)

Background The aims of this study were to identify hibernating myocardium (hypocontractile, hypoperfused viable myocardium that regains contractility after revascularization) in the clinical setting and to predict functional outcome in patients with coronary artery disease after coronary revascularization. Methods and Results Preoperative data related to the anterior free wall of the left ventricle were collected in 50 coronary bypass surgery candidates (positron emission tomography [PET], [13N]NH3 for flow, and [18F]FDG for metabolism [MET]; equilibrium-gated nuclear angiography [EGNA] for regional ejection fraction [REF]; and histological data from myocardial biopsies for percentage fibrosis and viable myocytes). Three months after surgery, the patients had follow-up PET and EGNA investigations. A principal-components analysis identified four patient clusters. Cluster 1 (n=9) had normal viable myocardium. Cluster 2 (n=18) had viable hypocontractile myocardium (REF, 39±12%) showing a PET mismatch pattern...
Prospective Study of Potentially Virulent Strains of Helicobacter pylori and Coronary Heart Disease in Middle-Aged Men
Authors: PeterWhincup, JohnDanesh, MaryWalker, LucyLennon, AndrewThomson, PaulAppleby, ChrisHawkey, JohnAtherton
Journal: Circulation (2000)

Background—Studies are needed to test claims that potentially virulent strains of Helicobacter pylori are more strongly related to coronary heart disease (CHD) than are other strains. Methods and Results—We measured serum IgG antibodies to mixed H pylori antigens and separately to the virulence-associated H pylori antigen CagA (cytotoxin-associated gene product A) in 505 CHD cases and in 1025 age-matched controls “nested” in a prospective study of 7735 British men (mean duration of follow-up in controls, 16 years). Of the 505 cases, 401 (79%) were seropositive for H pylori antibodies compared with 740 (72%) of the 1025 controls, yielding an odds ratio for CHD of 1.55 (95% CI 1.19 to 2.03), which fell to 1.30 (95% CI 0.88 to 1.90) after adjustments were made for standard vascular risk factors and indicators of socioeconomic status. Of the CHD cases, 240 (48%) were seropositive for IgG antibodies to CagA compared with 450 (44%) of the controls. When CagA-seropositive individuals were compared with H pylori–...
Abstract 13701: Impact of Stent Platform on Longitudinal Stent Deformation: an in vivo 3-dimensional Optical Coherence Tomography Study
Authors: RyotaroYamada, TeruyoshiKume, KenzoFukuhara, TerumasaKoyama, TomitakaHiga, YojiNeishi, HiroyukiOkura
Journal: Circulation (2014)

Introduction: Recently, longitudinal coronary stent deformation has been highlighted as a possible cause of drug-eluting stent failure. Although bench tests and in-vivo studies have demonstrated difference in longitudinal stent strength among the stents with different platforms, its clinical impact is still unknown. The aim of this study was to investigate the longitudinal deformation of the everolimus-eluting stents (EES) with different stent platforms by using 3-dimensional frequency domain optical coherence tomography (3D FD-OCT). Methods: Fifty-nine lesions treated with EES (Xience Prime (CoCr-EES): n=28, Promus element (PtCr-EES): n=31) were studied. Stent length was measured by 3D FD-OCT. Percent longitudinal stent shortening (%SS) was defined as the longitudinally shortened stent length standardized by nominal stent length. Longitudinal stent deformation was defined as %SS >10%. Results: Patients’ and procedural characteristics were similar between CoCr- and PtCr-EES. There was no difference in mea...
Amino acid-based Poly(ester urea) copolymer films for hernia-repair applications
Authors: Nathan Z. Dreger, Zhaobo Fan, Zachary K. Zander, Chinnapatch Tantisuwanno, Molly C. Haines, Morgan Waggoner, Trenton Parsell, Claus S. Søndergaard, Michael Hiles, Christopher Premanandan, Matthew L. Becker
Journal: Biomaterials (2018)
Histone Acetylation and Recruitment of Serum Responsive Factor and CREB-Binding Protein Onto SM22 Promoter During SM22 Gene Expression
Authors: PingQiu, LiLi
Journal: Circulation Research (2002)

Chromatin acetylation and deacetylation catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs) are closely related to eukaryotic gene transcription. Although the binding of serum response factor (SRF) to the CArG boxes in the promoter region is necessary for SM22 expression, it has never been examined whether the local chromatin modification is involved in SM22 gene regulation. In this study, we used the SM22 gene as a model to address whether transcriptional activation of the gene can be manipulated through adjusting histone acetylation of the chromatin template and whether SRF- and HAT-containing coactivators can be recruited onto the SM22 promoter region during gene activation. Here, we showed that the stimulation of the SM22 promoter by the coactivator CREB-binding protein (CBP) was dependent on HAT activity. Overexpression of HDACs decreased SM22 promoter activity, whereas trichostatin A, an HDAC inhibitor, stimulated SM22 promoter activity in a CArG box-dependent manner and ...