tbuckley/cabot-search huggingface dataset:
Abstract 1976: Identification of 4 novel markers in the chemotherapy resistance of esophageal adenocarcinoma
Authors: Jonathan P. Fleegel, Joeseph Abdo, Devendra Agrawal
Journal: Cancer Research (2018)

Abstract Esophageal adenocarcinoma (EAC) has seen a steady and steep rise in prevalence since the 1970's. This increase in incidence is correlated with the increase in gastro-esophageal reflux disease and Barrett's esophagus (BE). Unfortunately, where many other cancers have seen progress with advancements in treatments, EAC has not. This cancer is very resistant to almost all first line chemotherapy treatments including the most common platinum based treatments. Although few targeted therapies have been developed, they only show a modest survival advantage for eligible individuals and are not commonly integrated into patient treatment regimens. In our study, we have identified several markers associated with resistance to platinum based chemotherapies that have not previously been documented in EAC. Our study utilized a large-scale discovery mass spectrometric experiment such that the proteome of the 3 different tissue samples could be analyzed, (EAC, BE, and Normal). Part of the novelty of our experiment was that all the tissues collected were from esophagetomies of patients before they had received any chemotherapy. From the data generated we have identified 4 novel markers that are overexpressed in the BE and EAC tissue compared to the normal tissue. In BE tissue DAD1 was over expressed in 9/10 samples, ISG15 (10/10), S100P (10/10) and UBE2N (10/10). In the EAC samples, DAD1 was significantly overexpressed in 20 /20 samples, ISG15 (20/20), S100P (20/20) and UBE2N (19/20). DAD1 inhibits apoptosis and is upregulated by cisplatin and then contributes to cisplatin resistance. S100P has been shown to increase drug resistance in gastric cancer and decrease chemosensitivity 5-FU in vitro in colorectal cancer cells while facilitating proliferation and inhibiting apoptosis. UBE2N plays a role in glycolytic control and in various cellular damage responses. And ISG15 is important in development and metastatic progression of adenocarcinomas through the enhancement of cancer stem cells. We are confident that expression of these four markers can provide clinical utility in assessment of at risk patients with Barrett's esophagus while simultaneously informing treatment regimens. Our goal is to investigate the specific mechanisms by which these markers contribute to cancerous development and chemotherapy resistance in order to elucidate targets for future treatment of EAC. Citation Format: Jonathan P. Fleegel, Joeseph Abdo, Devendra Agrawal. Identification of 4 novel markers in the chemotherapy resistance of esophageal adenocarcinoma [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 1976.
Abstract 14649: Assessment of Acute Cryo and RF Ablation Lesions by Non-contrast and Contrast Enhanced MRI Techniques: Similarities and Differences
Authors: EugeneKholmovski, RaviRanjan, JoshuaSilvernagel, JoshuaBlauer, NassirMarrouche
Journal: Circulation (2014)

Introduction: MRI is used to assess acute RF lesions. Cryo-ablation is being increasingly used for EP procedures. No previous studies were performed to assess acute cardiac cryo ablations by MRI. In this study, we have compared visibility of acute cryo and RF lesions using non-contrast and contrast enhanced MRI techniques. Methods: Cryo and RF ablations of left and right ventricles were performed in 4 canines. Cryo lesions were created using cryo-catheter (Freezor MAX, Medtronic) with freeze times of 2 and 4 minutes. RF lesions were created by ThermoCool catheter (Biosense Webster) at 30 Watts for 30 seconds. Animals were then moved to a 3 Tesla MRI scanner (Verio, Siemens). Imaging included T1-weighted (T1w) and T2w scans, followed by injection of gadolinium-based contrast (0.15 mmol/kg, Multihance (Bracco)) and post-contrast T1w and late gadolinium enhancement (LGE) scans. Results: Representative T1w, T2w, and post-contrast T1w and LGE images of acute cryo and RF lesions are shown in Fig. 1. All RF lesi...
Abstract 15176: Serotonin Antagonist Inhibits Leukocyte-Endothelial Interactions in Vivo and in vitro: Potential Contribution of Pkc-Dependent Pathway
Authors: Hiroshi Kataoka, Mizuko Osaka, Michiyo Deushi, Kosaku Nitta, Masayuki Yoshida
Journal: Circulation (2012)

[Background] Serotonin (5-HT) is an important neurotransmitter and signaling molecule in wide variety of organs including vascular systems. Serotonin-induced platelet activation and smooth muscle cell contraction, via 5-HT2A receptors, plays an important role in atherosclerosis and vascular inflammation. Though 5-HT2A- serotonergic antagonist has been utilized in the treatment of vascular disease, its effect on vascular inflammation such as leukocyte-endothelial interactions has not been demonstrated. [Method and Results] We examined the effect of Sarpogrelate hydrochloride (SRPO), a 5-HT2A receptor antagonist, on leukocyte-endothelial cell interaction in vivo and in vitro. C57BL/6 mice were fed high-fat high-fructose diet (HFFD) containing 20% fat and 30% fructose, with or without SRPO 5mg/kg/day for 4 weeks. Intravital microscopy of the femoral artery revealed significant leukocyte recruitment after HFFD (p<0.001), which was reduced by SRPO (p<0.01). Serum level of MCP-1 was significantly elevated after...
Folliculotropic mycosis fungoides associated with<i>GATA2</i>deficiency: a new skin manifestation
Authors: L. Fertitta, F. Sicre de Fontbrune, M. Battistella, A. De Masson, A. Bergeron, D. Ranta, M-D. Vignon-Pennamen, M. Bagot, J.-D. Bouaziz
Journal: British Journal of Dermatology (2018)
Plaque Rupture After Short Periods of Fat Feeding in the Apolipoprotein E–Knockout Mouse
Authors: JasonJohnson, KevinCarson, HelenWilliams, SharadaKaranam, AndrewNewby, GianniAngelini, SarahGeorge, ChristopherJackson
Journal: Circulation (2005)

Background— These studies examined the early time course of plaque development and destabilization in the brachiocephalic artery of the apolipoprotein E–knockout mouse, the effects of pravastatin thereon, and the effects of pravastatin on established unstable plaques. Methods and Results— Male apolipoprotein E–knockout mice were fed a high-fat, cholesterol-enriched diet from the age of 8 weeks. Animals were euthanized at 1-week intervals between 4 and 9 weeks of fat feeding. Acutely ruptured plaques were observed in the brachiocephalic arteries of 3% of animals up to and including 7 weeks of fat feeding but in 62% of animals after 8 weeks, which suggests that there is a sharp increase in the number of plaque ruptures at 8 weeks. These acute plaque ruptures then appear to heal and form buried fibrous caps; after 9 weeks of fat feeding, mice had 1.05±0.15 buried fibrous caps at a single site in the brachiocephalic artery. Pravastatin (40 mg/kg of body weight per day for 9 weeks; resultant plasma concentrati...
Abstract 102: Cardiac-specific Overactivation of the Mechanistic Target of Rapamycin Complex 1 Induces Metabolic, Structural and Functional Remodeling
Authors: Giovanni Davogustto, Rebecca Salazar, Hernan Vasquez, Heinrich Taegtmeyer
Journal: Circulation Research (2015)

The heart remodels metabolically and structurally before it fails. Metabolically, the heart increases its reliance on carbohydrates for energy provision. Structurally, the heart hypertrophies to sustain increased hemodynamic stress. There is evidence suggesting that the activation of the mechanistic Target Of Rapamycin Complex 1 (mTORC1) pathway is closely tied to glucose uptake by the heart to drive the metabolic and structural remodeling. We have previously shown that with insulin stimulation or increases in workload, the glycolytic intermediate glucose 6-phosphate (G6P) is required to activate mTORC1. Sustained mTORC1 activation leads, in turn, to ER stress and contractile dysfunction. Studies by others in the kidney have shown that mTORC1 activation upregulates glucose transporter 1 (Glut1) expression and glucose uptake. We therefore test the hypothesis that chronic mTORC1 overactivation results in G6P accumulation, and precedes structural and functional remodeling in the heart. We developed mice with inducible, cardiac-specific deficiency of the protein tuberin (TSC2), a member of the tuberous sclerosis complex, the principal inhibitor of mTORC1. Intracellular G6P concentrations were measured enzymatically. Immunoblotting was performed on protein markers to confirm activation of mTORC1 downstream targets and of the unfolded protein response. Histologic analysis were performed to assess structural changes. Serial echocardiograms were performed to evaluate cardiac function. The results indicate that chronic mTORC1 activation through inducible, cardiac-specific deletion of TSC2 is accompanied by G6P accumulation and metabolic remodeling. Metabolic remodeling precedes structural and functional remodeling. We suggest that in the heart, sustained mTORC1 activation is a key driver of metabolic and structural remodeling.
High-sensitive troponin is associated with subclinical imaging biosignature of inflammatory cardiovascular involvement in systemic lupus erythematosus
Authors: Lea Winau, Rocio Hinojar Baydes, Axel Braner, Ulrich Drott, Harald Burkhardt, Shirish Sangle, David P D’Cruz, Gerry Carr-White, Mike Marber, Katrin Schnoes, Christophe Arendt, Karin Klingel, Thomas J Vogl, Andreas M Zeiher, Eike Nagel, Valentina O Puntmann
Journal: Annals of the Rheumatic Diseases (2018)

Background Cardiovascular (CV) involvement in patients with systemic lupus erythematosus (SLE) is presumably subclinical for the major part of its evolution. We evaluated the associations between high-sensitive troponin T (hs-TropT), a sensitive marker of myocardial injury, and CV involvement using cardiac magnetic resonance (CMR). Methods and results This is a two-centre (London and Frankfurt) CMR imaging study at 3.0 Tesla of consecutive 92 patients with SLE free of cardiac symptoms, undergoing screening for cardiac involvement. Venous samples were drawn and analysed post-hoc for cardiac biomarkers, including hs-TropT, high-sensitive C reactive protein and N-terminal pro brain natriuretic peptide. Compared with age-matched/gender-matched non-SLE controls (n=78), patients had significantly raised cardiac biomarker levels, native T1 and T2, aortic and ventricular stiffness, and reduced global longitudinal strain (p&lt;0.01). In SLE, hs-TropT was significantly and independently associated with native T2, followed by the models including native T1 and aortic stiffness (Χ 2 0.462, p&lt;0.01). There were no relationships between hs-TropT and age, gender, CV risk factors, duration of systemic disease, cardiac structure or function, or late gadolinium enhancement. Conclusions Patients with SLE have a high prevalence of subclinical myocardial injury as demonstrated by raised high-sensitive troponin levels. CMR with T2 mapping reveals myocardial oedema as the strongest predictor of hs-TropT release, underscoring the inflammatory interstitial remodelling as the main mechanism of injury. Patients without active myocardial inflammation demonstrate diffuse interstitial remodelling and increased vascular stiffness. These findings substantiate the role of CMR in screening of subclinical cardiac involvement. Trial registration numer NCT02407197 ; Results.
Abstract LB-186: Evaluation of EGFR degradation as a mechanism of tumor evasion in EGFR-TKI resistant non-small cell lung cancer (NSCLC) cells compared to EGFR-TKI sensitive cells
Authors: Hernandez-Pedro Y. Norma, Soca-Chafre Giovanny, Orozco-Morales Mario, Barrios-Bernal Pedro, Arrieta Oscar
Journal: Cancer Research (2018)

Abstract The resistance mechanisms to EGFR-TKIs in Non-Small Cell Lung Cancer (NSCLC) are not well elucidated. Here we evaluate EGFR degradation as a mechanism of tumor evasion in EGFR-TKI resistant NSCLC cells (H1975) compared to EGFR-TKI sensitive cells (HCC827). After erlotinib treatment, EGFR protein half-life was quantified by cycloheximide chase. EGFR expression on cell membrane was measured by flow cytometry and transcription levels were measured by Real-Time PCR. EGFR half-life was shorter in H1975 compared to HCC827 cells after cycloheximide inhibition of protein synthesis. EGFR phosphorylation levels were not affected by erlotinib in H1975 while in HCC827 they were significantly reduced (p &amp;lt; 0.001). EGFR expression on cell membrane decreased similarly in both H1975 and HCC827 cell lines. Also the transcription levels of EGFR remained unaffected by erlotinib treatment in both cell lines. However, there was more apoptosis in HCC827 compared to H1975 with 64% vs. 22%. Our results suggest that H1975 cells present more EGFR degradation however, they show less cell death by apoptosis and this could represent a resistance mechanism to EGFR-TKIs. Citation Format: Hernandez-Pedro Y. Norma, Soca-Chafre Giovanny, Orozco-Morales Mario, Barrios-Bernal Pedro, Arrieta Oscar. Evaluation of EGFR degradation as a mechanism of tumor evasion in EGFR-TKI resistant non-small cell lung cancer (NSCLC) cells compared to EGFR-TKI sensitive 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 LB-186.
Abstract 344: A high-throughput functional screen reveals synthetic lethal interactions associated with replication stress in HORMAD1-expressing triple-negative breast cancers
Authors: Dalia Tarantino, Callum Walker, Daniel Weekes, Helen Pemberton, Jessica Frankum, Rachel Brough, Christopher J. Lord, Anita Grigoriadis, Andrew Tutt
Journal: Cancer Research (2018)

Abstract HORMAD1, expression of which is usually restricted to germline cells, is expressed in ~60% of triple-negative breast cancers (TNBCs) where it is associated with higher levels of allelic imbalance. In experimental systems, HORMAD1 also drives Homologous Recombination (HR) deficiency, PARP inhibitor and cisplatin sensitivity. To provide further insights into the role of HORMAD1 in TNBC, we generated a doxycycline-inducible HORMAD1 expression system in the copy number stable, HORMAD1-negative, TNBC cell line SUM159. Clonal, HORMAD1-positive, populations were established which displayed increased levels of genomic instability and reduced levels of homologous recombination. To identify synthetic lethal therapeutic targets associated with HORMAD1 expression in TNBC, we performed an RNAi library screen, in which the viability of HORMAD1-expressing SUM159 clonal cell populations was assessed following the targeted depletion of 1743 genes. Candidate synthetic lethal (SL) genes were validated in a secondary screen using 3 additional HORMAD1-expressing SUM159 clones. The primary siRNA screen identified 63 genes which were SL with elevated HORMAD1 expression, including XRCC1, TDP1, Pol η, BRIP1 and ATR - genes with a known function in mitigating replication stress. DNA polymerase η (POLH) is a Y-family DNA polymerase involved in translesion synthesis (TLS), a DNA damage tolerance pathway employed by proliferating cells to bypass replication fork stalling DNA lesions and to prevent replication fork collapse. We hypothesised that HORMAD1 expression leads to Pol η localisation to replication factories, to mediate lesion bypass. Consistent with this, we found an enrichment in Pol η and monoubiquitylated-PCNA in the chromatin fraction of HORMAD1-expressing SUM159 cells, suggesting that Pol η and TLS might buffer the effect of elevated HORMAD1 expression in TNBC. Our data suggest that HORMAD1 expression in mitotic cells leads to a dependency on pathways implicated in preventing or resolving replication stress, such as TLS, and suggests that vulnerabilities associated with specific DNA repair processes could be used to target HORMAD1-positive TNBCs. Citation Format: Dalia Tarantino, Callum Walker, Daniel Weekes, Helen Pemberton, Jessica Frankum, Rachel Brough, Christopher J. Lord, Anita Grigoriadis, Andrew Tutt. A high-throughput functional screen reveals synthetic lethal interactions associated with replication stress in HORMAD1-expressing triple-negative breast cancers [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 344.
Phase 1 study of MEDI3902, an investigational anti–Pseudomonas aeruginosa PcrV and Psl bispecific human monoclonal antibody, in healthy adults
Authors: S.O. Ali, X.Q. Yu, G.J. Robbie, Y. Wu, K. Shoemaker, L. Yu, A. DiGiandomenico, A.E. Keller, C. Anude, M. Hernandez-Illas, T. Bellamy, J. Falloon, F. Dubovsky, H.S. Jafri
Journal: Clinical Microbiology and Infection (2018)

MEDI3902 is a bivalent, bispecific human immunoglobulin G1κ monoclonal antibody that binds to both the Pseudomonas aeruginosa PcrV protein involved in host cell cytotoxicity and the Psl exopolysaccharide involved in P. aeruginosa colonization and tissue adherence. MEDI3902 is being developed for the prevention of nosocomial P. aeruginosa pneumonia in high-risk patients.This phase 1 dose-escalation study (NCT02255760) evaluated the safety, pharmacokinetics, antidrug antibody (ADA) responses and ex vivo anticytotoxicity and opsonophagocytic killing activities of MEDI3902 after a single intravenous infusion in healthy adults aged 18 to 60 years. Fifty-six subjects were randomized in a 3:1 ratio to receive 250, 750, 1500 or 3000 mg of MEDI3902 or placebo and followed for 60 days afterwards.Treatment-emergent adverse events (TEAEs) were mild or moderate in severity; no serious TEAEs were observed. The most common TEAEs were infusion-related reactions. MEDI3902 exhibited approximately linear pharmacokinetics across the 250, 750 and 1500 mg doses and nonlinear pharmacokinetics between the 1500 and 3000 mg doses. One subject in the 3000 mg group tested positive for ADA on day 61 and had a lower MEDI3902 serum concentration from days 43 to 61 than ADA-negative subjects. Serum anticytotoxicity antibody concentrations and opsonophagocytic killing activity were correlated with MEDI3902 serum concentrations across all doses.Phase 1 study results of MEDI3902 in healthy subjects support further evaluation of its safety and efficacy in subjects at risk for P. aeruginosa pneumonia.
Comparison of Thrombolysis Followed by Broad Use of Percutaneous Coronary Intervention With Primary Percutaneous Coronary Intervention for ST-Segment–Elevation Acute Myocardial Infarction
Authors: NicolasDanchin, PierreCoste, JeanFerrières, Philippe-GabrielSteg, YvesCottin, DidierBlanchard, LoïcBelle, BernardRitz, GilbertKirkorian, MichaelAngioi, PhilippeSans, BernardCharbonnier, HélèneEltchaninoff, PascalGuéret, KhalifeKhalife, PhilippeAsseman, JacquesPuel, PatrickGoldstein, Jean-PierreCambou, TabassomeSimon
Journal: Circulation (2008)

Background— Intravenous thrombolysis remains a widely used treatment for ST-elevation myocardial infarction; however, it carries a higher risk of reinfarction than primary PCI (PPCI). There are few data comparing PPCI with thrombolysis followed by routine angiography and PCI. The purpose of the present study was to assess contemporary outcomes in ST-elevation myocardial infarction patients, with specific emphasis on comparing a pharmacoinvasive strategy (thrombolysis followed by routine angiography) with PPCI. Methods and Results— This nationwide registry in France included 223 centers and 1714 patients over a 1-month period at the end of 2005, with 1-year follow-up. Sixty percent of the patients underwent reperfusion therapy, 33% with PPCI and 29% with intravenous thrombolysis (18% prehospital). At baseline, the Global Registry of Acute Coronary Events score was similar in thrombolysis and PPCI patients. Time to initiation of reperfusion therapy was significantly shorter in thrombolysis than in PPCI (med...
Abstract 12999: Senescence Marker Protein 30 Protect the Cardiac Injury From After Ischemia Reperfusion
Authors: ShinpeiKadowaki, TetsuroShishido, TaroNarumi, YukiHonda, SatoshiNishiyama, HirokiTakahashi, TakanoriArimoto, TakuyaMiyamoto, TetsuWatanabe, YasuchikaTakeishi, IsaoKubota
Journal: Circulation (2014)

Background: Successful myocardial reperfusion is effective therapy for improving the clinical outcome after acute myocardial infarction, nevertheless reperfusion injury can paradoxically induces cardiomyocyte dysfunction. Moreover, recovery of cardiac function is impaired with aging. Glycogen synthase kinase-3β (GSK-3β) and p70 ribosomal S6 kinase (p70S6K) are cardioprotective against I/R via mitochondrial dysfunction. Senescence marker protein-30 (SMP30), which regulates mitochondrial quality and decreases with aging, is an organ-protective protein; however the protective role of SMP30 against ischemia/reperfusion (I/R) has not been clearly determined yet. Methods and Result: Firstly, we confirmed that SMP30 expressions in the heart were progressively decreased with aging. In vitro study, we also found that reactive oxygen species decreased expression levels of SMP30 in neonatal cardiomyocyte. Depletion of SMP30 increased apoptotic cardiomyocyte death after hydrogen peroxide stimulation. To evaluate the ...
Coronary Insufficiency: Relations Between Hemodynamic, Electrical, and Biochemical Parameters
Authors: JamesScheuer, NormanBrachfeld
Journal: Circulation Research (1966)

Perfusion of the left coronary artery of open chest dogs at fixed control and ischemic flow rates demonstrated that ST alterations in the electrocardiogram were always associated with significant hemodynamic and metabolic changes. Decreased pressure time per minute, atrial hypertension, increased myocardial oxygen extraction, and the presence of  lactate accompanied ischemia. In three dogs, hemodynamic changes, the presence of excess lactate, or both, preceded significant electrocardiographic changes. Whenever coronary flow was insufficient to meet myocardial oxygen demands, a series of metabolic shifts occurred. The most significant of these was inadequate aerobic energy production and stimulation of anaerobic glycolysis. This acceleration of anaerobic myocardial metabolism may be present without notably altering the surface electrocardiogram. The absence of ST shifts does not rule out the presence of concomitant and potentially severe myocardial ischemia.