tbuckley/cabot-search huggingface dataset:
Abstract 12462: Improved Treatment Satisfaction Independent of Stroke and Bleeding Risk Among Patients Transitioned From a Vitamin K Antagonist to Rivaroxaban: A XANTUS-ACTS Analysis
Authors: Craig I Coleman, Sylvia Haas, Alexander G.G Turpie, Silvia Kuhls, Susanne Hess, Thomas Evers, Pierre Amarenco, Paulus Kirchhof, A. John Camm
Journal: Circulation (2016)

Introduction: The effectiveness, safety and ease of use of rivaroxaban may reduce anticoagulation treatment burden and improve nonvalvular atrial fibrillation (NVAF) patient satisfaction compared to vitamin K antagonists (VKAs). Objective: To assess consistency in changes in treatment satisfaction among patients transitioned from a VKA to rivaroxaban in routine practice across stroke and bleeding risk subgroups. Methods: Xarelto on Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation (XANTUS) was a prospective, non-interventional study in patients prescribed rivaroxaban for prevention of stroke in routine practice within 7 European countries and Canada. Patients receiving a VKA 4-weeks prior to the initial XANTUS study visit and switched to rivaroxaban were asked to complete the Anti-Clot Treatment Scale (ACTS). Changes in scores, as recorded during the initial and first follow-up visit at ~3-months (corresponding to a comparison of rivaroxaban vs. prior VKA) for the ACTS Burdens and Benefits scores, were calculated and reported as least squares (LS)-mean differences with standard errors. Results: After ~3-months’ rivaroxaban treatment, both Burdens and Benefits scores were significantly improved in NVAF patients with prior VKA treatment ( Table ). Improvements in Burden scores across subgroups were generally consistent (LS-mean difference range, 2.68 to 3.46) with the overall cohort findings. The Benefit score improved in the overall cohort, but was not found to significantly differ in any subgroup (LS-mean difference range, -0.26 to 0.58). Conclusions: In XANTUS, patients switching from a VKA to rivaroxaban for stroke prevention reported significant improvements in treatment satisfaction. Independent of stroke or bleeding risk, switching to rivaroxaban appears to improve patient treatment satisfaction; mainly due to a perceived lower treatment burden
Abstract 19336: High Prevalence of Mental and Substance Use Disorders Among Out-of-Hospital Sudden Unexpected Death Victims
Authors: Ankita Ashoka, Greta Bushnell, Golsa Joodi, Samantha Meltzer-Brody, Carter Devlin, Neil Patel, Irion W Pursell, Ross J Simpson
Journal: Circulation (2016)

Introduction: Adults with mental and substance use disorders are at an elevated risk for sudden cardiac death. Therefore, we estimated the prevalence of mental and substance use disorders and chron...
Abstract 17007: Interleukin 6-, 8- and 10-Dependent Elevation of In-Stent Stenosis in Apolipoprotein E Deficient Rats
Authors: Felix Vogt, Christian Flege, Nikolaus Marx, Mauricio Borinski
Journal: Circulation (2012)

Purpose: Recently, Apoliprotein E deficient (ApoE-/-) rats have been generated by genetic manipulation, while the bench-to-bedside relevance of this novel model for coronary stenosis research has not been elucidated. Here, we seek to characterize vascular inflammation and in-stent cross-sectional stenosis (ICS) development in the abdominal aorta of ApoE-/- rats. Methods: Trans-abdominal aorta bare-metal stent (Multi-LinkMini Vision, Abbott Vascular Inc., Santa Clara, CA; 2.5 x 8 mm; 12 atm) implantation was performed in ApoE-/- rats (Sigma Aldrich Genetic Engineering, Saint Louis, MO). At 7 and 28 days, quantification of ICS, neointimal (NI) area, injury score and inflammation score was conducted using image analysis software (DISKUS, Hilgers, Konigswinter). Blood serum analysis for Interleukin (IL)-6, -8 and -10 and for cholesterol levels was performed. Results: Serum cholesterol levels were elevated in ApoE-/- rats (8.63±1.73mmol/l vs. 1.98±0.55mmol/l; p<0.001) as compared to ApoE+/+ rats. IL-6 and (29...
The roles of metallothioneins in carcinogenesis
Authors: Manfei Si, Jinghe Lang
Journal: Journal of Hematology & Oncology (2018)

Metallothioneins (MTs) are small cysteine-rich proteins that play important roles in metal homeostasis and protection against heavy metal toxicity, DNA damage, and oxidative stress. In humans, MTs have four main isoforms (MT1, MT2, MT3, and MT4) that are encoded by genes located on chromosome 16q13. MT1 comprises eight known functional (sub)isoforms (MT1A, MT1B, MT1E, MT1F, MT1G, MT1H, MT1M, and MT1X). Emerging evidence shows that MTs play a pivotal role in tumor formation, progression, and drug resistance. However, the expression of MTs is not universal in all human tumors and may depend on the type and differentiation status of tumors, as well as other environmental stimuli or gene mutations. More importantly, the differential expression of particular MT isoforms can be utilized for tumor diagnosis and therapy. This review summarizes the recent knowledge on the functions and mechanisms of MTs in carcinogenesis and describes the differential expression and regulation of MT isoforms in various malignant tumors. The roles of MTs in tumor growth, differentiation, angiogenesis, metastasis, microenvironment remodeling, immune escape, and drug resistance are also discussed. Finally, this review highlights the potential of MTs as biomarkers for cancer diagnosis and prognosis and introduces some current applications of targeting MT isoforms in cancer therapy. The knowledge on the MTs may provide new insights for treating cancer and bring hope for the elimination of cancer.
Aromatase inhibitors and cardiac outcomes in women undergoing cardiac angiography after early breast cancer.
Authors: Bostjan Seruga, Vesna Zadnik, Cvetka Grasic Kuhar, Tanja Marinko, Darko Zorman, Tanja Cufer, Branko Zakotnik, Alberto Ocana, Eitan Amir
Journal: Journal of Clinical Oncology (2012)

558 Background: Data show that in post-menopausal women with early breast cancer, longer use of aromatase inhibitor (AI) is associated with increased odds of ischemic heart disease. Here we explore the association between adjuvant AI use and cardiac disease in women undergoing cardiac angiography after a diagnosis of early breast cancer. Methods: We linked a database of 7,681 women who underwent cardiac angiography at the University Clinical Center of Ljubljana between December 2004 and November 2010 with the Cancer Registry for Slovenia. Women with early breast cancer that subsequently underwent cardiac angiography were identified. Information on cardiovascular risk factors was retrieved from the patients’ charts and from discharge letters after cardiac angiography. The endpoint of interest was a diagnosis of ischemic heart disease or left ventricular dysfunction (IHD-LVD) without evidence of valvular heart disease at the time of angiography. Conditional, logistic regression was used to test for associations between variables. Results: Among 117 eligible women 75% (n=88) were postmenopausal and 62% (n=73) had hormonal receptor positive (HR+) disease. Of these 42% (n=31) were treated with AI. Overall, 48% (n=56) of women were found to have IHD-LVD. In patients with HR+ breast cancer, use of AIs was significantly associated with IHD-LVD as compared to tamoxifen alone (HR 2.50, 95% CI 1.01-6.29, p=0.046). For each year of AI therapy, there was a trend for higher odds of IHD-LVD (OR: 1.25, 95% CI 0.95-1.67, p=0.116). This effect appeared independent of age, body mass index, baseline hypertension, hypercholesterolemia, diabetes and heart disease or prior anthracyclines exposure. Among all patients, use of anthracyclines and left-sided irradiation was associated with non-significant increases in IHD-LVD (HR 2.37, 95% CI 0.89-6.09, p=0.45 and HR 1.28, 95% CI 0.69-2.40, p=0.44 respectively). Conclusions: Compared to tamoxifen, AIs are associated with a time dependent increase in IHD-LVD. This risk appears independent of other risk factors for heart disease. Anthracycline exposure and left breast or chest wall radiation showed non-significant associations with IHD-LVD in this small cohort.
Islet Hormone and Incretin Secretion in Cystic Fibrosis after Four Months of Ivacaftor Therapy
Authors: Andrea Kelly, Diva D. De Leon, Saba Sheikh, Devaney Camburn, Christina Kubrak, Amy J. Peleckis, Darko Stefanovski, Denis Hadjiliadis, Michael R. Rickels, Ronald C. Rubenstein
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Diabetes is associated with worse cystic fibrosis (CF) outcomes. The CFTR potentiator ivacaftor is suggested to improve glucose homeostasis in individuals with CF.To test the hypothesis that clinically indicated ivacaftor would be associated with improvements in glucose tolerance and insulin and incretin secretion.Oral glucose tolerance tests, mixed-meal tolerance tests, and glucose-potentiated arginine tests were compared preivacaftor initiation and 16 weeks postivacaftor initiation in CF participants with at least one CFTR gating or conductance mutation. Meal-related 30-minute (early phase) and 180-minute incremental area under the curves were calculated as responses for glucose, insulin, C-peptide, and incretin hormones; glucagon-like peptide-1; and glucose-dependent insulinotropic polypeptide. First-phase insulin secretion, glucose potentiation of arginine-induced insulin secretion, and disposition index were characterized by glucose-potentiated arginine stimulation tests.Twelve subjects completed the study: six male/six female; seven normal/five abnormal glucose tolerance (oral glucose tolerance test 1-h glucose ≥155 and 2-h glucose <200 mg/dl); of median (minimum-maximum) age (13.8 yr [6.0-42.0]), body mass index-Z of 0.66 (-2.4 to 1.9), and FEV1% predicted of 102 (39-122). Glucose tolerance normalized in one abnormal glucose tolerance subject. Ivacaftor treatment did not alter meal responses except for an increase in early phase C-peptide (P = 0.04). First-phase (P = 0.001) and glucose potentiation of arginine-induced (P = 0.027) insulin secretion assessed by acute C-peptide responses improved after ivacaftor treatment. Consistent with an effect on β-cell function, the disposition index relating the amount of insulin secreted for insulin sensitivity also improved (P = 0.04).Insulin secretion improved following 4 months of clinically indicated ivacaftor therapy in this relatively young group of patients with CF with normal to mildly impaired glucose tolerance, whereas incretin secretion remained unchanged.
Association of Hydrocodone Schedule Change With Opioid Prescriptions Following Surgery
Authors: Joe Habbouche, Jay Lee, Rena Steiger, James M. Dupree, Caitlin Khalsa, Michael Englesbe, Chad Brummett, Jennifer Waljee
Journal: JAMA Surgery (2018)

In 2014, the US Drug Enforcement Administration moved hydrocodone-containing analgesics from schedule III to the more restrictive schedule II to limit prescribing and decrease nonmedical opioid use. The association of this policy change with postoperative prescribing is not well understood.To examine the hypothesis that the amount of opioids prescribed following surgery is associated with the rescheduling of hydrocodone.An interrupted time series analysis of outpatient opioid prescriptions was conducted to examine the trends in the amount of postoperative opioids filled before and after the schedule change. Opioid prescriptions filled between January 2012 and October 2015 were analyzed using insurance claims data from the Michigan Value Collaborative, which includes data from 75 hospitals across Michigan. A total of 21 955 adult inpatients 18 to 64 years of age who underwent 1 of 19 common elective surgical procedures and filled an opioid prescription within 14 days of discharge to home were eligible for inclusion.The primary outcome was the trends in the mean amount of opioids filled in oral morphine equivalents (OMEs) for the initial postoperative prescriptions before and after the schedule change date of October 6, 2014, compared using interrupted time series and multivariable regression analyses. Secondary outcomes included the total amount of opioids filled and the refill rate for the 30-day postoperative period. Subgroup analyses were performed by hydrocodone prescriptions, nonhydrocodone prescriptions, surgical procedure, and prior opioid use.Data from 21 955 patients undergoing surgical procedures across 75 hospitals and 5120 prescribers were analyzed. Cohorts before and after the schedule change were equivalent with respect to sex (10 197 of 15 791 [64.6%] vs 3966 of 6169 [64.3%] female; P = .69) and mean (SE) age (47.9 [11.2] vs 47.7 [11.3] years; P = .19). After the schedule change, the mean OMEs filled in the initial opioid prescription increased by approximately 35 OMEs (β = 35.1 [13.2]; P < .01), equivalent to 7 tablets of hydrocodone (5 mg). There were no significant differences in the total OMEs filled during the 30-day postoperative period before and after the schedule change (β = 18.3 [30.5]; P = .55), but there was a significant decrease in the refill rate (β = -5.2% [1.3%]; P < .001).Changing hydrocodone from schedule III to schedule II was associated with an increase in the amount of opioids filled in the initial prescription following surgery. Opioid-related policies require close follow-up to identify and address early unintended effects given the multitude of competing factors that influence health care professional prescribing behaviors.
Frequent Antiviral Treatment Failures in Patients Infected With Hepatitis C Virus Genotype 4, Subtype 4r
Authors: Slim Fourati, Christophe Rodriguez, Christophe Hézode, Alexandre Soulier, Isaac Ruiz, Lila Poiteau, Stéphane Chevaliez, Jean‐Michel Pawlotsky
Journal: Hepatology (2018)

Hepatitis C virus (HCV) genotype 4 is highly heterogeneous. HCV subtype 4r has been suggested to be less responsive to direct‐acting antiviral (DAA) drug treatment than other genotype 4 subtypes. Among 537 DAA‐treated patients who experienced a virological failure (VF) in France between 2015 and 2018, 121 (22.5%) were infected with genotype 4 and 27 of them (22.3%) with subtype 4r; subtype 4r was thus over‐represented as compared to its prevalence in the French general population. Population sequencing of the nonstructural protein (NS) 3, NS5A, and NS5B genes was performed in all subtype 4r patients at treatment failure and in 6 at baseline, whereas full‐length HCV genome sequencing was performed in two baseline and three treatment failure samples by means of an original shotgun metagenomics method based on deep sequencing. At treatment failure, all subtype 4r patients harbored two to three dominant NS5A resistance‐associated substitutions (RASs), including at least L28A/C/I/M/V and L30R. Among 13 patients exposed to sofosbuvir and an NS5A inhibitor (daclatasvir, ledipasvir, or velpatasvir), 5 (38.5%) also harbored NS5B S282C/T RASs at treatment failure. An additional patient harbored S282C/T RASs at treatment failure by deep sequencing. Prevalence of S282C/T RASs at treatment failure was significantly higher in patients infected with genotype 4r than with other genotypes, including other subtypes of genotype 4. Conclusion : The lower rates of sustained virological response in patients infected with subtype 4r are related to the frequent preexistence at treatment baseline and subsequent selection by DAA treatment of both NS5A and NS5B S282 RASs. Our study suggests that these patients should be identified and receive a triple DAA combination regimen as first‐line treatment.
Abstract 15234: A Novel Purification Method of Cardiomyocytes Derived From iPS Cells, Based on Their Affinity to Laminin-221 in Terms of Clinical Applications
Authors: Fumiya Ohashi, Shigeru Miyagawa, Satsuki Fukushima, Yukiko Imanishi, Shyouhei Yoshida, Atsuhiro Saito, Shigeo Masuda, Hiroko Iseoka, Emiko Ito, Tsuyoshi Ishikawa, Tadashi Sameshima, Kiyotoshi Sekiguchi, Yoshiki Sawa
Journal: Circulation (2016)

Introduction: Although cardiomyocytes (CMs) derived from human-induced pluripotent stem cells (hiPSCs) have the potential to treat heart diseases, quality control of differentiated CMs, especially in terms of purification, is crucial for clinical application. We hypothesized that the ability of CMs to adhere to laminin (LM) - that is, the major extracellular matrix components in myocardium - may lead to new purification methods of hiPSCs-derived CMs. Methods: (1) The expression pattern of integrins on the cell surface of differentiated CMs and undifferentiated hiPSCs were analyzed by quantitative PCR to check which type of LM was suitable for effective purification in CMs. (2) We compared various extracellular matrix-coated dishes to determine whether they had high affinity to CMs and could be purified by 30 min plating of CMs. (3) We implanted a post-purified CMs sheet (post group: n=5) and a pre-purified CMs sheet (pre group: n=5) to nude rat chronic infarction models and evaluated functional recovery c...
mTOR Signaling in X/A‐Like Cells Contributes to Lipid Homeostasis in Mice
Authors: Ziru Li, Ruili Yu, Wenzhen Yin, Yan Qin, Liangxiao Ma, Michael Mulholland, Weizhen Zhang
Journal: Hepatology (2018)

Gastric mechanistic target of rapamycin (mTOR) signaling is inversely associated with the expression and secretion of ghrelin, a 28‐aa peptide hormone produced by gastric X/A‐like cells. Ghrelin contributes to obesity and hepatic steatosis. We sought to control global lipid metabolism via the manipulation of gastric mTOR signaling in X/A‐like cells. We established a ghrl‐cre transgene in which the Cre enzyme is expressed in X/A‐like cells under the control of the ghrelin‐promoter. mTORflox/flox and tuberous sclerosis 1 ( TSC1)flox/flox mice were separately bred with ghrl‐cre mice to generate mTOR‐ghrl‐cre or TSC1‐ghrl‐cre mice, within which mTOR signaling was suppressed or activated, respectively. Lipid metabolism in liver and adipose depots was analyzed. Under the control of the ghrelin‐promoter, the Cre enzyme was exclusively expressed in stomach X/A‐like cells in adult animals. Knockout of mTOR in X/A‐like cells increased circulating acyl‐ghrelin and promoted hepatic lipogenesis with effects on adipose depots. Activation of mTOR signaling by deletion of its upstream inhibitor, TSC1, decreased ghrelin expression and secretion, altering lipid metabolism as evidenced by resistance to high‐fat diet–induced obesity and hepatic steatosis. Both ghrelin administration and injection of rapamycin, an inhibitor of mTOR, altered the phenotypes of TSC1‐ghrl‐cre mice. Conclusion: Gastric mTOR signaling in X/A‐like cells contributes to organism lipid homeostasis by regulating hepatic and adipose lipid metabolism. Gastric mTOR signaling may provide an alternative strategy for intervention in lipid disorders.
Effect of Intracoronary Metformin on Myocardial Infarct Size in Swine
Authors: George Techiryan, Brian R. Weil, Beth A. Palka, John M. Canty
Journal: Circulation Research (2018)

Rationale: Metformin has been demonstrated to decrease infarct size (IS) and prevent postinfarction left ventricular (LV) remodeling in rodents when given intravenously at the time of reperfusion. It remains unclear whether similar cardioprotection can be achieved in a large animal model. Objective: The objective of this study was to determine whether intravascular infusion of metformin at the time of reperfusion reduces myocardial IS in a porcine model of acute myocardial infarction. Methods and Results: In a blinded and randomized preclinical study, closed-chest swine (n=20) were subjected to a 60-minute left anterior descending coronary artery occlusion to produce myocardial infarction. Contrast-enhanced computed tomography was performed during left anterior descending coronary artery occlusion to assess the ischemic area-at-risk. Animals were randomized to receive either metformin or vehicle as an initial intravenous bolus (5 mg/kg) 8 minutes before reperfusion, followed by a 15-minute left coronary artery infusion (1 mg/kg per minute) commencing with the onset of reperfusion. Echocardiography and computed tomographic imaging of LV function were performed 1 week later, at which time the heart was removed for postmortem pathological analysis of area-at-risk and IS (triphenyltetrazolium chloride). Baseline variables including hemodynamics and LV function were similar between groups. Peak circulating metformin concentrations of 374±35 µmol/L were achieved 15 minutes after reperfusion. There was no difference between the area-at-risk as a percent of LV mass by computed tomography (vehicle: 20.7%±1.1% versus metformin: 19.7%±1.3%; P =0.59) or postmortem pathology (22.4%±1.2% versus 20.2%±1.2%; P =0.21). IS relative to area-at-risk averaged 44.5%±5.0% in vehicle-treated versus 38.2%±6.8% in metformin-treated animals ( P =0.46). There was no difference in global function 7 days after myocardial infarction as assessed by echocardiography or computed tomographic ejection fraction (56.2%±2.6% versus 56.3%±2.4%; P =0.98). Conclusions: In contrast to rodent hearts, postconditioning with high-dose metformin administered immediately before reperfusion does not reduce IS or improve LV function 7 days after myocardial infarction in swine. These results reinforce the importance of rigorously testing therapies in large animal models to facilitate clinical translation of novel cardioprotective therapies.
Abstract 19986: MicroRNA-29b is a Regulator and Therapeutic Target of Aortic Stiffness in Type 2 Diabetes
Authors: Isabel N Schellinger, Lena Mattes, Karin Mattern, Joshua M Spin, Lars Maegdefessel, Gerd Hasenfuß, Philip S Tsao, Uwe Raaz
Journal: Circulation (2016)

Introduction: Accelerated arterial stiffening is a common complication of type 2 diabetes that is patho-mechanistically linked to a severely increased cardiovascular risk. Unfortunately, up to date...