tbuckley/cabot-search huggingface dataset:
Comparison of International Guidelines for Assessment of Suspected Stable Angina
Authors: Philip D. Adamson, David E. Newby, C. Larry Hill, Adrian Coles, Pamela S. Douglas, Christopher B. Fordyce
Journal: JACC. Cardiovascular imaging (2018)

This study sought to compare the performance of major guidelines for the assessment of stable chest pain including risk-based (American College of Cardiology/American Heart Association and European Society of Cardiology) and symptom-focused (National Institute for Health and Care Excellence) strategies.Although noninvasive testing is not recommended in low-risk individuals with stable chest pain, guidelines recommend differing approaches to defining low-risk patients.Patient-level data were obtained from the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) and SCOT-HEART (Scottish Computed Tomography of the Heart) trials. Pre-test probability was determined and patients dichotomized into low-risk and intermediate-high-risk groups according to each guideline's definitions. The primary endpoint was obstructive coronary artery disease on coronary computed tomography angiography. Secondary endpoints were coronary revascularization at 90 days and cardiovascular death or nonfatal myocardial infarction up to 3 years.In total, 13,773 patients were included of whom 6,160 had coronary computed tomography angiography. The proportions of patients identified as low risk by the American College of Cardiology/American Heart Association, European Society of Cardiology, and National Institute for Health and Care Excellence guidelines, respectively, were 2.5%, 2.5%, and 10.0% within PROMISE, and 14.0%, 19.8%, and 38.4% within SCOT-HEART. All guidelines identified lower rates of obstructive coronary artery disease in low- versus intermediate-high-risk patients with a negative predictive value of ≥0.90. Compared with low-risk groups, all intermediate-high-risk groups had greater risks of coronary revascularization (odds ratio [OR]: 2.2 to 24.1) and clinical outcomes (OR: 1.84 to 5.8).Compared with risk-based guidelines, symptom-focused assessment identifies a larger group of low-risk chest pain patients potentially deriving limited benefit from noninvasive testing. (Scottish Computed Tomography of the Heart Trial [SCOT-HEART]; NCT01149590; Prospective Multicenter Imaging Study for Evaluation of Chest Pain [PROMISE]; NCT01174550).
Abstract 16509: Accessory Papillary Muscles are Associated With Sudden Cardiac Arrest of Unknown Cause
Authors: Jae-Sun Uhm, Hanchel Lee, Junbeom Park, Jin-Kyu Park, Boyoung Joung, Hui-Nam Pak, Moon-Hyoung Lee
Journal: Circulation (2013)

Background: The major causes of sudden cardiac arrest (SCA) in the general population are known as coronary artery disease, cardiomyopathies, channelopathies and so on. However, the cause of SCA in...
Scintigraphic Findings Beyond Ejection Fraction on Hepatobiliary Scintigraphy
Authors: Chad T. Christensen, Justin G. Peacock, Penny J. Vroman, Kevin P. Banks
Journal: Clinical Nuclear Medicine (2018)

To determine if classically reported findings associated with chronic cholecystitis on hepatobiliary scintigraphy (HBS), such as delayed small bowel (SB) transit, slow gallbladder (GB) filling, and reversal of the normal GB and SB transit, are associated with a depressed GB ejection fraction (GBEF). The secondary objectives were to determine whether GBEF is correlated with the time of GB filling, time of SB transit, or reversal of normal GB/SB filling sequence. We hypothesize that an association between a depressed GBEF and these classical HBS findings could validate them as surrogate markers for chronic GB disease.We reviewed all HBS exams over a retrospective 16-month period. Data from 221 patients (mean age, 45.3 ± 15.2 years; 152 female and 69 male subjects) who underwent HBS with GBEF determination for evaluation of chronic symptoms concerning for biliary etiology met inclusion criteria. Classically reported findings for cholecystitis were recorded for each patient. Comparisons were made using t test and Fisher test analysis.Comparing exams with normal and abnormal GBEF values, there were no significant differences based on age, sex, GB fill time, normal versus delayed SB transit, and reversal of normal GB/SB filling sequence. Additionally, we did not see a correlation between the measured GBEF and GB fill time, SB transit time, or reversal of normal GB/SB filling sequence.Delayed SB transit, slow GB filling time, and reversal of the normal GB and SB filling sequence on HBS imaging are not associated with the measured GBEF and not predictive of chronic GB disease.
Emerin Deregulation Links Nuclear Shape Instability to Metastatic Potential
Authors: Mariana Reis-Sobreiro, Jie-Fu Chen, Tatiana Novitskaya, Sungyong You, Samantha Morley, Kenneth Steadman, Navjot Kaur Gill, Adel Eskaros, Mirja Rotinen, Chia-Yi Chu, Leland W.K. Chung, Hisashi Tanaka, Wei Yang, Beatrice S. Knudsen, Hsian-Rong Tseng, Amy C. Rowat, Edwin M. Posadas, Andries Zijlstra, Dolores Di Vizio, Michael R. Freeman
Journal: Cancer Research (2018)

Abstract Abnormalities in nuclear shape are a well-known feature of cancer, but their contribution to malignant progression remains poorly understood. Here, we show that depletion of the cytoskeletal regulator, Diaphanous-related formin 3 (DIAPH3), or the nuclear membrane–associated proteins, lamin A/C, in prostate and breast cancer cells, induces nuclear shape instability, with a corresponding gain in malignant properties, including secretion of extracellular vesicles that contain genomic material. This transformation is characterized by a reduction and/or mislocalization of the inner nuclear membrane protein, emerin. Consistent with this, depletion of emerin evokes nuclear shape instability and promotes metastasis. By visualizing emerin localization, evidence for nuclear shape instability was observed in cultured tumor cells, in experimental models of prostate cancer, in human prostate cancer tissues, and in circulating tumor cells from patients with metastatic disease. Quantitation of emerin mislocalization discriminated cancer from benign tissue and correlated with disease progression in a prostate cancer cohort. Taken together, these results identify emerin as a mediator of nuclear shape stability in cancer and show that destabilization of emerin can promote metastasis. Significance: This study identifies a novel mechanism integrating the control of nuclear structure with the metastatic phenotype, and our inclusion of two types of human specimens (cancer tissues and circulating tumor cells) demonstrates direct relevance to human cancer. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/21/6086/F1.large.jpg. Cancer Res; 78(21); 6086–97. ©2018 AACR.
Abstract 18972: Safety and Efficacy of Vorapaxar in Secondary Prevention of Atherosclerotic Disease: A Meta-analysis of Randomized Control Trials
Authors: Aakash Garg, Abhishek Sharma, Saurav Chatterjee, Solomon Bagae, Giulio G Stefanini
Journal: Circulation (2015)

Background: A substantial risk of residual cardiovascular events remains despite the current standard antiplatelet therapy in patients with atherosclerotic disease. Protease activating receptor (PAR-1) antagonist Vorapaxar is a novel antiplatelet agent acting by inhibition of thrombin-induced platelet aggregation. Recently, FDA has approved vorapaxar for long term secondary prevention of vascular events in stable patients with a prior MI or PAD, and without history of stroke or transient ischemic attack. However, these recommendations are largely based on a single phase 3 randomized control trial (TRA 2P TIMI-50). Objective: To study the cumulative evidence for vorapaxar use in patients with atherosclerotic cardiovascular disease. Methods: A systematic review of randomized control trials in MEDLINE, EMBASE, EBSCO, CINAHL, Web of Science and Cochrane databases comparing vorapaxar with placebo was performed. Pre-specified efficacy endpoints were all-cause mortality, CV mortality, myocardial infarction, stroke and repeat revascularization. The pre-specified safety endpoint was the composite of TIMI major and minor bleeding. Risk ratios were used as the metric of choice by applying random effects models.. Results: A total of 5 RCTs with 40,630 patients were included. Compared with placebo, vorapaxar led to a significant risk reduction in terms of myocardial infarction [RR 0.93; 95% CI 0.80-0.92] and stroke [RR 0.84; 95% CI 0.72-0.97]. No differences were observed between vorapaxar and placebo with respect to all-cause mortality [RR 0.99; 95% CI 0.90-1.07], cardiovascular mortality [RR 0.93; 95% CI 0.84-1.02], and repeat revascularization [RR 0.96; 95% CI 0.85-1.08]. Vorapaxar was associated with a higher risk of TIMI major and minor bleeding [RR 1.30; 95% CI 1.02-1.65] compared with placebo. There was insignificant (I-squared) heterogeneity between studies. Conclusion: Vorapaxar reduces the risk of ischemic events in patients with atherosclerotic disease at the cost of an increased bleeding risk.
Heart failure leads to altered β2-adrenoceptor/cyclic adenosine monophosphate dynamics in the sarcolemmal phospholemman/Na,K ATPase microdomain
Authors: Zeynep Bastug-Özel, Peter T Wright, Axel E Kraft, Davor Pavlovic, Jacqueline Howie, Alexander Froese, William Fuller, Julia Gorelik, Michael J Shattock, Viacheslav O Nikolaev
Journal: Cardiovascular Research (2018)

Cyclic adenosine monophosphate (cAMP) regulates cardiac excitation-contraction coupling by acting in microdomains associated with sarcolemmal ion channels. However, local real time cAMP dynamics in such microdomains has not been visualized before. We sought to directly monitor cAMP in a microdomain formed around sodium-potassium ATPase (NKA) in healthy and failing cardiomyocytes and to better understand alterations of cAMP compartmentation in heart failure.A novel Förster resonance energy transfer (FRET)-based biosensor termed phospholemman (PLM)-Epac1 was developed by fusing a highly sensitive cAMP sensor Epac1-camps to the C-terminus of PLM. Live cell imaging in PLM-Epac1 and Epac1-camps expressing adult rat ventricular myocytes revealed extensive regulation of NKA/PLM microdomain-associated cAMP levels by β2-adrenoceptors (β2-ARs). Local cAMP pools stimulated by these receptors were tightly controlled by phosphodiesterase (PDE) type 3. In chronic heart failure following myocardial infarction, dramatic reduction of the microdomain-specific β2-AR/cAMP signals and β2-AR dependent PLM phosphorylation was accompanied by a pronounced loss of local PDE3 and an increase in PDE2 effects.NKA/PLM complex forms a distinct cAMP microdomain which is directly regulated by β2-ARs and is under predominant control by PDE3. In heart failure, local changes in PDE repertoire result in blunted β2-AR signalling to cAMP in the vicinity of PLM.
XIAP-associated factor-1(XAF1) gene expression and promoter methylation status in lung cancer cell lines and tumor samples
Authors: Marcos Pinho, Luciene Schluckebier, Fernanda Costas, Laura Lamas, Emanuela Moraes, Carlos Ferreira
Journal: Cancer Research (2008)

3545   Lung cancer is the leading cause of cancer-related death worldwide. Most cases are detected in advanced and incurable stages. Conventional chemotherapy (platinum-based) is only palliative; it can improve survival and quality of life of advance stage patients, however most patients will suffer disease progression and die as a result of tumor chemoresistance. Genetic and epigenetic alterations of proto-oncogenes and tumor suppressor genes are frequently detected in lung cancer pathogenesis. Epigenetic inactivation of certain tumor suppressor genes by promoter hypermethylation is a frequently observed event in lung tumors and seems to play an important role in chemoresistance of this type of tumor. XIAP associated factor 1 (XAF1) has been identified as a tumor suppressor gene who antagonizes the anti-apoptotic effects of XIAP, the most potent caspase inhibitor of the IAP family. In several types of tumors, XAF1 expression is abrogated while is ubiquitously expressed in normal tissues. Splice variants have been identified including XAF1a, XAF1b and XAF1c. At the moment data suggests that isoforms are differentially expressed in cancer cells but its prognostic relevance is not yet recognized. Recent findings  in vitro  and  in vivo  demonstrate that transcriptional downregulation of XAF1 is correlated with promoter hypermethylation and reestablishment of transcription activity enhances apoptosis sensitivity to several apoptosis-inducing agents. To unravel the importance of tumor suppressor genes silenced by aberrant methylation in lung cancer, we determined XAF1 expression levels by real-time PCR and promoter methylation status by methylation specific PCR (MSPCR) in a panel of 6 lung cancer cell lines. In addition, we analyzed by real-time PCR the mRNA expression of XAF1a, b and c in resected paired samples obtained from 30 non-small cell lung cancer (NSCLC) patients. Aberrant promoter hypermethylation of CpG islands was detected in all lung cancer cell lines examined. XAF1 expression was also significantly lower in all lung cancer cell lines when compared to normal lung control (lung cDNA pool). Patient samples also showed a significantly lower mRNA expression of XAF1a, b ( p = 0.009 ) and XAF1c ( p =0.024 ) when compared to its adjacent non-tumoral counterpart. Our results suggest that low XAF1 expression is a common event in lung cancinogenesis and that promoter methylation is an essential mechanism for transcription downregulation of XAF1.
Abstract 17511: Microvesicles and MicroRNAs as Marker of Acute Kidney Injury After Cardiac Surgery in Children
Authors: Silvia Mariani, Nikol Sullo, Maria Teresa Jn Tala, William Dott, Marcin J Wozniak, Danny Chan, Tracy Kumar, Attilio A Lotto, Gavin J Murphy
Journal: Circulation (2015)

Introduction: AKI is very common in paediatric cardiac surgery patients. The diagnosis relies on changes in serum creatinine and urine output, which lack specificity and sensitivity especially in newborns and premature infants. Diagnostic changes also occur late in the injury phase when interventions have limited effectiveness. Microvesicles (MV) are small particles (&lt;1μm) in plasma that often contain miRNA. Their levels have been shown to be altered in animal models of AKI where they regulate injury responses. Hypothesis: MV and associated miRNA provide specific and early-detection markers for AKI and a tool to investigate AKI pathogenesis. Methods: Study subjects were 24 children (&lt;17 yrs), undergoing cardiac surgery with cardiopulmonary bypass (CPB) without pre-existing inflammatory state, AKI or extracorporeal life support. AKI was diagnosed following the KDIGO definition. Blood and urine samples were collected pre-operatively and at 6 and 24 hours. Cytokines were measured on a MAGPIX platform. Leukocyte and platelets activation, and MV derivation was assessed by flow cytometry and NanoSight device. miRNAs were isolated from MV preps and analyzed by RT-PCR using Applied Biosystems kits. Results: AKI was diagnosed in 14 patients and was confirmed by urinary NGAL increase at 6 hours after the operation (25±3.45 ng/ml vs 10.44±2.9 ng/ml; p 0.006). Patients with AKI were younger, underwent longer CPB, received higher volumes of red blood cells, and required higher inotrope support (Table). AKI subjects had increased levels of monocyte and B1-integrin MV. That correlated well with IL-8 and MCP-3 levels and monocyte activation. These changes were also reflected in miRNA profile in both groups. Conclusions: MV and miRNA could potentially serve as early AKI markers in children and their analysis reveals mechanistic parallels with adults.
Cardiac diastolic dysfunction predicts poor prognosis in patients with decompensated liver cirrhosis
Authors: Soon Kyu Lee, Myeong Jun Song, Seok Hwan Kim, Hyo Jun Ahn
Journal: Clinical and Molecular Hepatology (2018)

Left ventricular diastolic dysfunction (LVDD) is an early manifestation of cardiac dysfunction in patients with liver cirrhosis (LC). However, the effect of LVDD on survival has not been clarified, especially in decompensated LC.We prospectively enrolled 70 patients with decompensated LC, including ascites or variceal bleeding, at Daejeon St. Mary's Hospital from April 2013 to April 2015. The cardiac function of these patients was evaluated using 2D echocardiography with tissue Doppler imaging. The diagnosis of LVDD was based on the American Society of Echocardiography guidelines. The primary endpoint was overall survival.Forty-four patients (62.9%) had LVDD. During follow-up (22.3 months), 18 patients died (16 with LVDD and 2 without LVDD). The survival rate was significantly lower in patients with LVDD than in those without LVDD (31.1 months vs. 42.6 months, P=0.01). In a multivariate analysis, the Child-Pugh score and LVDD were independent predictors of survival. Moreover, patients with a ratio of early filling velocity to early diastolic mitral annular velocity (E/e') ≥ 10 (LVDD grade 2) had lower survival than patients with E/e' ratio < 10.The presence of LVDD is associated with poor survival in patients with decompensated LC. Therefore, it may be important to monitor and closely follow LVDD patients.
Immune and metabolic shifts during neonatal development reprogram liver identity and function
Authors: Brenda Naemi Nakagaki, Kassiana Mafra, Érika de Carvalho, Mateus Eustáquio Lopes, Raquel Carvalho-Gontijo, Hortência Maciel de Castro-Oliveira, Gabriel Henrique Campolina-Silva, Camila Dutra Moreira de Miranda, Maísa Mota Antunes, Ana Carolina Carvalho Silva, Ariane Barros Diniz, Débora Moreira Alvarenga, Maria Alice Freitas Lopes, Viviane Aparecida de Souza Lacerda, Matheus Silvério Mattos, Alan Moreira Araújo, Paula Vieira Teixeira Vidigal, Cristiano Xavier Lima, Germán A.B. Mahecha, Mila Fernandes Moreira Madeira, Gabriel Rocha Fernandes, Raquel Ferraz Nogueira, Thais Garcias Moreira, Bruna Araújo David, Rafael Machado Rezende, Gustavo Batista Menezes
Journal: Journal of Hepatology (2018)
Abstract 16528: The Recruitment of Neural Crest-Like Stem Cells Contributes to Vascular Regeneration
Authors: Aijun Wang, Zhenyu Tang, Jian Yu, Zhiqiang Yan, Benjamin L Lee, Song Li
Journal: Circulation (2011)

Introduction: Vascular grafts are widely used to replace diseased vessels. To facilitate the integration of vascular grafts into the host vasculature, it is critical to understand the mechanisms of...
Topical resiquimod dosing regimens in patients with multiple actinic keratoses: a multicentre, partly placebo‐controlled, double‐blind clinical trial
Authors: E. Stockfleth, G.F.L. Hofbauer, U. Reinhold, G. Popp, U.R. Hengge, R.M. Szeimies, H. Brüning, M. Anliker, T. Hunger, R. Dummer, C. Ulrich, R. Kenzelmann, C. Surber, L.E. French
Journal: British Journal of Dermatology (2018)

Topical immune response modifiers are established for actinic keratosis (AK) treatment and efforts are underway to make further improvements to their efficacy and safety. To investigate the optimal dosing regimens of the Toll‐like receptor 7/8 agonist resiquimod in terms of efficacy, safety and tolerability. In a multicentre, partly placebo‐controlled, double‐blind clinical trial, we randomized 217 patients with AK lesions to 0·03% resiquimod gel once‐daily application three times per week for 4 weeks or seven times within 2 weeks or five times for 1 week (arms 1/2/3) followed by a treatment‐free interval of 8 weeks and one repetition of the cycle. In two additional arms (arms 4/5), patients applied either resiquimod gel 0·01% or 0·03% three times per week up to a biological end point defined by skin erosion or for a maximum duration of 8 weeks. Clearance was assessed clinically and histologically. Complete clinical clearance ranged from 56% to 85% with the highest rate observed in arm 2. Resiquimod 0·03% gel was more effective than 0·01% gel. Clearance rates in arms 1/2/3 were comparable and higher than with placebo and were reached with 24, 14 and 10 gel applications, respectively. Overall, 128 patients (59%) experienced treatment‐related adverse reactions. Resiquimod 0·03% gel is more effective than 0·01% gel. From the perspectives of safety and tolerability, the lower concentration and shorter duration are preferable. The clinical response in arms 2/3 was reached with fewer gel applications. The dosing regimens that used the biological end point (arms 4/5) proved equally efficacious as predefined treatment durations and may therefore be suitable for personalized AK treatment.
Tyrosine Phosphorylation of Mitochondrial Creatine Kinase 1 Enhances a Druggable Tumor Energy Shuttle Pathway
Authors: Kiran Kurmi, Sadae Hitosugi, Jia Yu, Felix Boakye-Agyeman, Elizabeth K. Wiese, Thomas R. Larson, Qing Dai, Yuichi J. Machida, Zhenkun Lou, Liewei Wang, Judy C. Boughey, Scott H. Kaufmann, Matthew P. Goetz, Larry M. Karnitz, Taro Hitosugi
Journal: Cell Metabolism (2018)
A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates
Authors: Huiping Ding, Norikazu Kiguchi, Dennis Yasuda, Pankaj R. Daga, Willma E. Polgar, James J. Lu, Paul W. Czoty, Shiroh Kishioka, Nurulain T. Zaveri, Mei-Chuan Ko
Journal: Science Translational Medicine (2018)

The small-molecule AT-121 is an agonist of nociceptin and mu opioid peptide receptors and mediates analgesia without opioid-associated side effects in nonhuman primates.
Abstract 17222: Surgical as Opposed to Transcatheter Aortic Valve Replacement for Aortic Stenosis Improves Associated Basal Septal Hypertrophy/Dysfunction
Authors: Hidetoshi Yoshitani, Jae-Kwan Song, Jeong Yoon Jang, Yasufumi Nagata, Misako Toki, Byung-Joo Sun, Shota Fukuda, Dae-Hee Kim, Nobuyuki Kagiyama, Atsushi Hayashi, Tetsu Miyamoto, Akihiro Hayashida, Jong-Min Song, Yasushi Oginosawa, Shinjo Sonoda, Masaaki Takeuchi, Kiyoshi Yoshida, Robert A Levine, Yutaka Otsuji
Journal: Circulation (2016)

Background: Basal interventricular septal (IVS) hypertrophy (BSH) is frequently associated with aortic stenosis (AS) and its mechanism is not established. The shape of BSH suggests the possibility ...