tbuckley/cabot-search huggingface dataset:
Abstract 13881: Social Inequalities in All Cause and Cause Specific Mortality in a Country of the African Region
Authors: Silvia Stringhini, Valentin Rousson, Bharathi Viswanathan, Flavie Sinon, Jude Gedeon, Fred Paccaud, Pascal Bovet
Journal: Circulation (2013)

Background: Studies in high income countries consistently show low socioeconomic status (SES) to be associated with a higher mortality risk. Because of limited availability of mortality data this issue remains largely unexplored in low and middle income countries, particularly in the African region. Methods: Three independent population-based surveys of cardiovascular risk factors were conducted in representative samples of all adults aged 25-64 years in the Seychelles, a small island state located east to Kenya, in 1989 (N=1081), 1994 (N=1067) and 2004 (N=1255). All deaths are recorded in Seychelles and survey data were linked with vital statistics for the period 1989-2012. Analyses were based on 3246 participants with complete data on all risk factors considered for the study. Results: Over a mean follow-up for mortality of 15.0 years (range 0-24 years), 523 participants died (mortality rate 10.8 per 1000 person-years). Main causes of death were cardiovascular disease (CVD) (219 deaths) and cancer (142 ...
RILONACEPT IN RECURRENT PERICARDITIS: FIRST EFFICACY AND SAFETY DATA FROM AN ONGOING PHASE 2 PILOT CLINICAL TRIAL
Authors: Allan Klein, David Lin, Paul Cremer, Saifullah Nasir, Sharon Crugnale, Larisa Collins, Fang Fang, Anna Beutler, John F. Paolini
Journal: Journal of the American College of Cardiology (2019)
Abstract 394: The Role Of Camkii-dependent Late Sodium Current In Ischemia/reperfusion-associated Arrhythmogenesis
Authors: Amara Greer-Short, Taylor Howard, Tony Satroplus, Nehal Patel, Drew Nassal, Peter Mohler, Thomas Hund
Journal: Circulation Research (2018)

Ischemic heart disease is the leading cause of death in the world. Importantly, CaMKII activity is upregulated during ischemia/reperfusion (I/R). However, the mechanisms by which CaMKII induces arrhythmias remains incompletely understood. We tested the hypothesis that CaMKII-dependent upregulation of the late Na+ current (INa,L) via direct phosphorylation of Nav1.5 at Ser571 is responsible for increased arrhythmia susceptibility during I/R. The role of CaMKII-dependent regulation of INa,L was explored using mice harboring Nav channel variants Nav1.5-Ser571E (S571E, phosphomimetic) and Nav1.5-Ser571A (S571A, phosphorylation incompetent). Isolated, perfused WT, S571E and S571A hearts were subjected to global ischemia (15 min) followed by reperfusion (15 min). Immunoblots demonstrated a significant increase in phosphorylated Nav1.5 at Ser571 in WT hearts during I/R compared to baseline (2.2±0.3 vs 1.0±0.3, respectively; P&lt;0.05, n=5). Optical mapping using the voltage-sensitive dye di-4-ANEPPs (4 μM) revealed a significant increase in action potential duration in WT and S571E mice compared to S571A during I/R (WT: 55.2±0.6 ms*, S571E: 70.0±2.3 ms*, S571A: 46.0±2.9 ms; *P&lt;0.05 vs. S571A, n=5/genotype). Furthermore, spontaneous arrhythmia incidence was increased in WT and S571E hearts (WT: 0.60±0.06 events/min*, S571E: 0.81±0.14 events/min*, S571A : 0.23±0.03 events/min; *P&lt;0.05 vs. S571A, n=5/genotype). Interestingly, arrhythmia inducibility using an S1-S2 protocol was also increased in WT and S571E hearts (WT: 80%*, S571E: 100%*, S571A: 0%; *P&lt;0.05 vs. S571A, n=5/genotype). The Na+ channel blocker mexiletine (10 μM) normalized APD and decreased arrhythmia inducibility in WT hearts during I/R (0% arrhythmia incidence in WT hearts treated with mexiletine). These data indicate a central role for CaMKII-dependent phosphorylation of Nav1.5 and augmentation of INa,L in the development of arrhythmogenesis during I/R.
Prone positioning and extracorporeal membrane oxygenation for severe acute respiratory distress syndrome: time for a randomized trial?
Authors: Christophe Guervilly, Eloi Prud’homme, Vanessa Pauly, Jérémie Bourenne, Sami Hraiech, Florence Daviet, Mélanie Adda, Benjamin Coiffard, Jean Marie Forel, Antoine Roch, Nicolas Persico, Laurent Papazian
Journal: Intensive Care Medicine (2019)
Efficacy and safety of intravenous ceftriaxone at home versus intravenous flucloxacillin in hospital for children with cellulitis (CHOICE): a single-centre, open-label, randomised, controlled, non-inferiority trial
Authors: Laila F Ibrahim, Sandy M Hopper, Francesca Orsini, Andrew J Daley, Franz E Babl, Penelope A Bryant
Journal: The Lancet Infectious Diseases (2019)
Association Between Sleep Apnea and Blood Pressure Control Among Blacks
Authors: Dayna A. Johnson, S. Justin Thomas, Marwah Abdalla, Na Guo, Yuichiro Yano, Michael Rueschman, Rikki M. Tanner, Murray A. Mittleman, David A. Calhoun, James G. Wilson, Paul Muntner, Susan Redline
Journal: Circulation (2019)

Background: Blacks have a high prevalence of hypertension and uncontrolled blood pressure (BP), each of which may be partially explained by untreated sleep apnea. We investigated the association of sleep apnea with uncontrolled BP and resistant hypertension in blacks. Methods: Between 2012 and 2016, Jackson Heart Sleep Study participants (N=913) underwent an in-home Type 3 sleep apnea study, clinic BP measurements, and anthropometry. Moderate or severe obstructive sleep apnea (OSA) was defined as a respiratory event index ≥15, and nocturnal hypoxemia was quantified as percent sleep time with &lt;90% oxyhemoglobin saturation. Prevalent hypertension was defined as either a systolic BP ≥130 mm Hg or diastolic BP &gt; 80mm Hg, use of antihypertensive medication, or self-report of a diagnosis of hypertension. Controlled BP was defined as systolic BP &lt;130 mm Hg and diastolic BP &lt;80 mm Hg; uncontrolled BP as systolic BP ≥130 mm Hg or diastolic BP ≥80 mm Hg with use of 1 to 2 classes of antihypertensive medication; and resistant BP as systolic BP ≥130 mm Hg or diastolic BP ≥80 mm Hg with the use of ≥3 classes of antihypertensive medication (including a diuretic) or use of ≥4 classes of antihypertensive medication regardless of BP level. Multinomial logistic regression models were fit to determine the association between OSA severity and uncontrolled BP or resistant hypertension (versus controlled BP) after multivariable adjustment. Results: The analytic sample with hypertension (N=664) had a mean age of 64.0 (SD,10.6) years, and were predominately female (69.1%), obese (58.6%), and college educated (51.3%). Among the sample, 25.7% had OSA, which was untreated in 94% of participants. Overall, 48% of participants had uncontrolled hypertension and 14% had resistant hypertension. After adjustment for confounders, participants with moderate or severe OSA had a 2.0 times higher odds of resistant hypertension (95% confidence interval [CI], 1.14–3.67). Each standard deviation higher than &lt;90% oxyhemoglobin saturation was associated with an adjusted odds ratio for resistant hypertension of 1.25 (95% CI 1.01–1.55). OSA and &lt;90% oxyhemoglobin saturation were not associated with uncontrolled BP. Conclusion: Untreated moderate or severe OSA is associated with increased odds of resistant hypertension. These results suggest that untreated OSA may contribute to inadequate BP control in blacks.
EFFICACY AND SAFETY OF ATRIAL FIBRILLATION ABLATION IN PATIENTS WITH HISTORY OF CEREBROVASCULAR ACCIDENTS
Authors: Amjad Abualsuod, Fuad Habash, Khaldia Khaled, Akshay Goel, Zaid Gheith, Bilal Alqam, Mohammed Eid Madmani, Srikanth Vallurupalli, Waddah Maskoun
Journal: Journal of the American College of Cardiology (2019)
SAFETY AND EFFICACY OF DIRECT ORAL ANTICOAGULANTS IN PATIENTS WITH ATRIAL FIBRILLATION AND VALVULAR HEART DISEASE
Authors: Matthew Lippmann, Nachiket Apte, Michael Pierpoline, Siva Sagar Taduru, Seyed Hamed Hosseini Dehkordi, Nicholas Isom, Tarun Dalia, Ethan Hacker, Alexander Robinson, Tyler Buechler, Mohammad-Ali Jazayeri, Reza Masoomi, Seth Sheldon, Madhu Reddy
Journal: Journal of the American College of Cardiology (2019)
MANAGEMENT OF TYPE 2 HEPARIN-INDUCED THROMBOCYTOPENIA PRIOR TO HEARTMATE 3 LEFT VENTRICULAR ASSIST DEVICE IMPLANTATION: A CASE SERIES
Authors: Syed Yaseen Naqvi, Jacqueline Morris, Jennifer Falvey, Igor Gosev, Bryan Barrus, Himabindu Vidula
Journal: Journal of the American College of Cardiology (2019)
CHANGES IN LEFT VENTRICULAR DIASTOLIC FUNCTION WITH CONTEMPORARY BREAST CANCER THERAPY
Authors: Jenica Upshaw, Brian Finkelman, Rebecca Hubbard, Amanda Smith, Hari Narayan, Linzi Arndt, Susan Domchek, Angela DeMichele, Kevin Fox, Payal Shah, Amy Clark, Angela Bradbury, Jennifer Matro, Srinath Adusumalli, Joseph Carver, Bonnie Ky
Journal: Journal of the American College of Cardiology (2019)
Epitope load identifies kidney transplant recipients at risk of allosensitization following minimization of immunosuppression
Authors: Renaud Snanoudj, Nassim Kamar, Elisabeth Cassuto, Sophie Caillard, Marie Metzger, Pierre Merville, Antoine Thierry, Isabelle Jollet, Philippe Grimbert, Dany Anglicheau, Marc Hazzan, Gabriel Choukroun, Bruno Hurault De Ligny, Bénedicte Janbon, Vincent Vuiblet, Anne Devys, Yann Le Meur, Michel Delahousse, Emmanuel Morelon, Elodie Bailly, Sophie Girerd, Kahina Amokrane, Christophe Legendre, Alexandre Hertig, Eric Rondeau, Jean-Luc Taupin
Journal: Kidney International (2019)
Avelumab (anti–PD-L1) as first-line switch-maintenance or second-line therapy in patients with advanced gastric or gastroesophageal junction cancer: phase 1b results from the JAVELIN Solid Tumor trial
Authors: Hyun Cheol Chung, Hendrik-Tobias Arkenau, Jeeyun Lee, Sun Young Rha, Do-Youn Oh, Lucjan Wyrwicz, Yoon-Koo Kang, Keun-Wook Lee, Jeffrey R. Infante, Sung Sook Lee, Margaret Kemeny, Ulrich Keilholz, Bohuslav Melichar, Alain Mita, Ruth Plummer, Denis Smith, Arnold B. Gelb, Huiling Xiong, Janet Hong, Vikram Chand, Howard Safran
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> We evaluated the antitumor activity and safety of avelumab, a human anti–PD-L1 IgG1 antibody, as first-line switch-maintenance (1 L-mn) or second-line (2 L) treatment in patients with advanced gastric/gastroesophageal cancer (GC/GEJC) previously treated with chemotherapy. <h3>Methods</h3> In a phase 1b expansion cohort, patients without (1 L-mn) or with (2 L) disease progression following first-line chemotherapy for advanced GC/GEJC received avelumab 10 mg/kg intravenously every 2 weeks. Endpoints included best overall response, progression-free survival (PFS), overall survival (OS), and safety. <h3>Results</h3> Overall, 150 patients were enrolled (1 L-mn, <i>n</i> = 90; 2 L, <i>n</i> = 60) and median follow-up in the 1 L-mn and 2 L subgroups was 36.0 and 33.7 months, respectively. The confirmed objective response rate was 6.7% in both subgroups (95% CI, 2.5–13.9% and 1.8–16.2%, respectively), including complete responses in 2.2% of the 1 L-mn subgroup (<i>n</i> = 2). In the 1 L-mn and 2 L subgroups, median duration of response was 21.4 months (95% CI, 4.0–not estimable) and 3.5 months (95% CI, 2.8–8.3) and disease control rates were 56.7 and 28.3%, respectively. Median PFS in the 1 L-mn and 2 L subgroups was 2.8 months (95% CI, 2.3–4.1) and 1.4 months (95% CI, 1.3–1.5), with 6-month PFS rates of 23.0% (95% CI, 14.7–32.4%) and 7.9% (95% CI, 2.6–17.2%), and median OS was 11.1 months (95% CI, 8.9–13.7) and 6.6 months (95% CI, 5.4–9.4), respectively. In the 1 L-mn subgroup, median OS measured from start of 1 L chemotherapy was 18.7 months (95% CI, 15.4–20.6). Across both subgroups, 20.7% had an infusion-related reaction of any grade. Other common treatment-related adverse events (TRAEs) of any grade included fatigue (10.0%) and nausea (6.7%). Treatment-related serious adverse events occurred in 4.0% of patients. Overall, 8.7% had a grade ≥3 TRAE, including 1 treatment-related death. <h3>Conclusion</h3> Avelumab showed clinical activity and an acceptable safety profile in patients with GC/GEJC. <h3>Trial registration</h3> ClinicalTrials.govNCT01772004; registered 21 January 2013.
RELEVANCE AND SIGNIFICANCE OF LEFT VENTRICULAR EJECTION FRACTION IN CHRONIC HEART FAILURE PHENOTYPES IN A LARGE COHORT OF HEART FAILURE PATIENTS: RESULTS FROM THE PINNACLE REGISTRY AND PLANNED VALIDATION WITH LINKED MEDICARE DATA AND SWEDISH HEART FAILURE REGISTRY
Authors: Hanna Kim Gaggin, Asa K. Hedman, Yang Song, Sanjiv Shah, Lars Lund, Qi Gao, Nasrien Ibrahim, Gianluigi Savarese, Gheorghe Doros, Ulf Dahlstrom, James Januzzi
Journal: Journal of the American College of Cardiology (2019)
Study of Metabolic Acidosis in Sickle Cell Disease Patients
Authors: Maud Cazenave, Vincent Audard, Jean-Philippe Bertocchio, Anoosha Habibi, Caroline Bertoye, Thomas Stehle, Jugurtha Berkenou, Frédéric Galactéros, Pascal Houillier, Pablo Bartolucci, Marie Courbebaisse
Journal: Blood (2018)
Novel Epigenetic Vulnerabilities for Diffuse Large B-Cell Lymphoma
Authors: Deepak Jha, George Q. Daley, Benoit Laurent, Cheng Zhang, Caroline Kubaczka, Bjoern Chapuy, Patricia Sousa, Pavlos Missios, R. Grant Rowe, Yu-Chung Huang, Yang Tan, Jessica Barragan, Trista North, Thorsten Schlaeger, Hu Li, Yang Shi, Margaret A. Shipp
Journal: Blood (2018)
HOSPITAL TRANSFUSION CULTURE INDEPENDENTLY PREDICTS LIKELIHOOD OF TRANSFUSION FOLLOWING INPATIENT CARDIOVASCULAR PROCEDURES
Authors: Eirini Apostolidou, Dhaval Kolte, Kevin F. Kennedy, Charles E. Beale, Dawn J. Abbott, Afshin Ehsan, Hitinder Gurm, Jeffrey Carson, Shafiq Mamdani, Herbert D. Aronow
Journal: Journal of the American College of Cardiology (2019)
Titration of Medical Therapy for Heart Failure With Reduced Ejection Fraction
Authors: Stephen J Greene, Gregg C Fonarow, Adam D DeVore, Puza P Sharma, Muthiah Vaduganathan, Nancy M Albert, Carol I Duffy, C Larry Hill, Kevin McCague, J Herbert Patterson, John A Spertus, Laine Thomas, Fredonia B Williams, Adrian F Hernandez, Javed Butler
Journal: Journal of the American College of Cardiology (2019)
Association of Urinary Oxalate Excretion With the Risk of Chronic Kidney Disease Progression
Authors: Sushrut S. Waikar, Anand Srivastava, Ragnar Palsson, Tariq Shafi, Chi-yuan Hsu, Kumar Sharma, James P. Lash, Jing Chen, Jiang He, John Lieske, Dawei Xie, Xiaoming Zhang, Harold I. Feldman, Gary C. Curhan
Journal: JAMA Internal Medicine (2019)

Oxalate is a potentially toxic terminal metabolite that is eliminated primarily by the kidneys. Oxalate nephropathy is a well-known complication of rare genetic disorders and enteric hyperoxaluria, but oxalate has not been investigated as a potential contributor to more common forms of chronic kidney disease (CKD).To assess whether urinary oxalate excretion is a risk factor for more rapid progression of CKD toward kidney failure.This prospective cohort study assessed 3123 participants with stages 2 to 4 CKD who enrolled in the Chronic Renal Insufficiency Cohort study from June 1, 2003, to September 30, 2008. Data analysis was performed from October 24, 2017, to June 17, 2018.Twenty-four-hour urinary oxalate excretion.A 50% decline in estimated glomerular filtration rate (eGFR) and end-stage renal disease (ESRD).This study included 3123 participants (mean [SD] age, 59.1 [10.6] years; 1414 [45.3%] female; 1423 [45.6%] white). Mean (SD) eGFR at the time of 24-hour urine collection was 42.9 (16.8) mL/min/1.73 m2. Median urinary excretion of oxalate was 18.6 mg/24 hours (interquartile range [IQR], 12.9-25.7 mg/24 hours) and was correlated inversely with eGFR (r = -0.13, P < .001) and positively with 24-hour proteinuria (r = 0.22, P < .001). During 22 318 person-years of follow-up, 752 individuals reached ESRD, and 940 individuals reached the composite end point of ESRD or 50% decline in eGFR (CKD progression). Higher oxalate excretion was independently associated with greater risks of both CKD progression and ESRD: compared with quintile 1 (oxalate excretion, <11.5 mg/24 hours) those in quintile 5 (oxalate excretion, ≥27.8 mg/24 hours) had a 33% higher risk of CKD progression (hazard ratio [HR], 1.33; 95% CI, 1.04-1.70) and a 45% higher risk of ESRD (HR, 1.45; 95% CI, 1.09-1.93). The association between oxalate excretion and CKD progression and ESRD was nonlinear and exhibited a threshold effect at quintiles 3 to 5 vs quintiles 1 and 2. Higher vs lower oxalate excretion (at the 40th percentile) was associated with a 32% higher risk of CKD progression (HR, 1.32; 95% CI, 1.13-1.53) and 37% higher risk of ESRD (HR, 1.37; 95% CI, 1.15-1.63). Results were similar when treating death as a competing event.Higher 24-hour urinary oxalate excretion may be a risk factor for CKD progression and ESRD in individuals with CKD stages 2 to 4.
Hepatocellular carcinoma surveillance in the 21st century: Saving lives or causing harm?
Authors: Ibrahim A. Hanouneh, Naim Alkhouri, Amit G. Singal
Journal: Clinical and Molecular Hepatology (2019)

Hepatocellular carcinoma (HCC) is the third most common cause of cancer related death worldwide. Prognosis and treatment options largely depend on tumor stage at diagnosis, with curative treatments only available if detected at an early stage. However, two thirds of patients with HCC are diagnosed at a late stage and not eligible for cure. Therefore several liver professional societies recommend HCC surveillance using abdominal ultrasound with or without alpha fetoprotein in at-risk populations, including patients with cirrhosis and subsets of those with chronic hepatitis B. Available data suggest HCC surveillance can significantly improve early tumor detection, curative treatment eligibility, and overall survival. However, the potential benefits of HCC surveillance must be considered in light a shifting HCC demographic from a viral-mediated cancer to an increasing proportion of patients having non-alcoholic steatohepatitis, which has been shown to limit ultrasound sensitivity and may mitigate observed benefits. Further, benefits of HCC surveillance must be weighed against potential physical, financial and psychological harms. Continued data for both benefits and harms of HCC surveillance in contemporary populations are necessary. In the interim, providers should continue to strive for high quality HCC surveillance in at-risk patients.
Abstract 255: Mechanical Stretch is Not a Major Cause of Ectopic Activation During Early Stage Regional Ischemia in an Isolated Left-Ventricular Working Heart Model
Authors: Hanyu Zhang, Han Yu, Gregory P Walcott, Jack M Rogers
Journal: Circulation Research (2018)

Background: Acute regional ischemia is a leading cause of death. Ectopic beats may initiate ventricular arrhythmias in the first hour after coronary occlusion; however, the origin of these beats remains poorly understood. Some studies suggest that abnormal mechanical stretch at the ischemic border zone may contribute to the initiation of ectopy. If mechanical stretch plays a major role in triggering ectopic beats, we therefore expect: I , left ventricular working (LVW) hearts will have higher frequency of post-occlusion ectopic activity than non-beating (NB) hearts; II , in LVW hearts, ectopic beats will arise from ventricular sites undergoing mechanical stretch. Methods and Results: Isolated pig hearts were assigned to NB or LVW groups (8 per group) and prepared for Langendorff or LVW perfusion, respectively. Contraction of NB hearts was suppressed with 10 μM blebbistatin. Acute regional ischemia was induced by LAD occlusion. Using a newly developed optical mapping system, electrical activity and mechanical deformation were simultaneously recorded from 0 to 60 minutes after LAD occlusion. Mechanical stretch (positive strain in 2 principal directions) was observed in the ischemic and border zones of LVW but not NB hearts (Figure, Panel A). There was no significant difference in the number of ectopic events in LVW hearts compared to NB hearts (58±35 vs. 32±36, p=0.17). Of the 45 ectopic events that originated from the LV mapping region in LVW hearts, &lt;20% (6) were from sites that underwent mechanical stretch in the prior cardiac cycle (Figure, Panel B). Conclusion: Mechanical stretch does not play a major role in triggering ectopic beats in early acute regional ischemia in this model.
Activin type II receptor signaling in cardiac aging and heart failure
Authors: Jason D. Roh, Ryan Hobson, Vinita Chaudhari, Pablo Quintero, Ashish Yeri, Mark Benson, Chunyang Xiao, Daniel Zlotoff, Vassilios Bezzerides, Nicholas Houstis, Colin Platt, Federico Damilano, Brian R. Lindman, Sammy Elmariah, Michael Biersmith, Se-Jin Lee, Christine E. Seidman, Jonathan G. Seidman, Robert E. Gerszten, Estelle Lach-Trifilieff, David J. Glass, Anthony Rosenzweig
Journal: Science Translational Medicine (2019)

Activin type II receptor signaling regulates cardiac function in aging and heart failure by modulating proteasome-dependent SERCA2a degradation.
TIME TO TELEMEDICINE DIAGNOSIS (TTD): AN IMPORTANT NEW METRIC FOR AMI STRATEGIES
Authors: Sameer Mehta, Roberto Botelho, Francisco Fernandez, Jamil Cade, Mauricio Prudente, Ricardo Cavalcanti, Cesar Dusilek, Nabil Hamdan, Luis Calderon, Edgar Hurtado, Marco Alcocer Gamba, Odin De Los Rios, Alejandro Ricalde, Lorena Villagran, Daniel Rodriguez, Lucas Lauar Cortizo Vidal
Journal: Journal of the American College of Cardiology (2019)
PERSISTENCE OF VALVULOPATHY IN THE CAMELLIA-TIMI 61 TRIAL OF LORCASERIN IN OBESE OR OVERWEIGHT PATIENTS AT INCREASED CARDIOVASCULAR RISK
Authors: Christina Fanola, Erin Bohula, Neil Weissman, Stephen Wiviott, Arman Qamar, Julia Kuder, KyungAh Im, Silvio Inzucchi, Darren McGuire, Anthony Keech, Steven Smith, Carlos Perdomo, Wenfeng Miao, Tushar Patel, Marc Sabatine, Benjamin M. Scirica
Journal: Journal of the American College of Cardiology (2019)
LONG-TERM RESIDUAL RISK AND PREDICTORS OF CARDIOVASCULAR DISEASE IN INDIVIDUALS TAKING STATINS FOR PRIMARY PREVENTION: INSIGHTS FROM THE CARTAGENE STUDY
Authors: Maxime Robert-Halabi, Jiayi Ni, Anh Nguyen, Marie-Pierre Dube, Ahmed AlTurki, Mark Sherman, George Thanassoulis, Jean Gregoire, Jean Claude Tardif, Thao Huynh
Journal: Journal of the American College of Cardiology (2019)
Neddylation Inactivation Facilitates FOXO3a Nuclear Export to Suppress Estrogen Receptor Transcription and Improve Fulvestrant Sensitivity
Authors: Xiaoqing Jia, Chunjie Li, Lihui Li, Xiaoli Liu, Lisha Zhou, Wenjuan Zhang, Shuaishuai Ni, Yun Lu, Li Chen, Lak Shin Jeong, Jinha Yu, Yingjian Zhang, Jianping Zhang, Simin He, Xin Hu, Hefen Sun, Keda Yu, Guangyu Liu, Hu Zhao, Yanmei Zhang, Lijun Jia, Zhi-Ming Shao
Journal: Clinical Cancer Research (2019)

Abstract Purpose: How the neddylation pathway functions in breast tumor and regulation of estrogen receptor (ER) expression is rarely reported. The purpose of this study was to identify the role of neddylation in breast cancer and ER expression, and further explore the underlying mechanisms. Experimental Design: Expression patterns of nedd8-activating enzyme (NAE) and nedd8, two key proteins in the neddylation pathway, were examined in human breast specimens. ER-α expression was investigated using animal 18F-FES-PET/CT and immunoblotting upon NAE inhibitor MLN4924 treatment. Chromatin immunoprecipitation assay, luciferase reporter promoter assay, and the CRISPR-Cas9 system were used to elucidate the mechanism of ER-α regulation by MLN4924. The ER-positive breast cancer mouse model was used to determine the synergetic effect of MLN4924 and fulvestrant on tumor growth. All statistical tests were two-sided. Results: Both NAE1 and nedd8 expressions were higher in the ER-positive subgroup. Higher expressions of NAE1 and nedd8 indicated poorer prognosis. Importantly, ER-α expression was significantly downregulated upon MLN4924 treatment in vitro and in vivo. Mechanistically, MLN4924 treatment delayed serum and glucocorticoid-induced protein kinase (SGK) degradation and induced Forkhead box O3a (FOXO3a) nuclear export as well as decreased binding to the ESR1 promoter. Importantly, MLN4924 single or synergized with fulvestrant significantly suppressed the growth of ER-positive breast cancer in vitro and in vivo. Conclusions: Our proof-of-principle study determines the activation of neddylation in breast tumor tissues for the first time and reveals a new ER-α regulatory mechanism, as well as further explores an effective approach to improve fulvestrant sensitivity through a neddylation inactivation combination.