tbuckley/cabot-search huggingface dataset:
Abstract 19123: Elevated Growth and Differentiation Factor 15 (GDF15) Levels Predict Outcome in Patients With Severe Aortic Stenosis Undergoing Tavi
Authors: Nora Krau, Sandra Freitag-Wolf, Doreen Brehm, Rainer Petzina, Georg Lutter, Norbert Frey, Derk Frank
Journal: Circulation (2014)

Background: GDF15 belongs to the transforming growth factor superfamily and has a significant role in regulating inflammatory and apoptotic pathways. GDF15 is an emerging biomarker for risk stratification in cardiovascular disease. Here we analyze its prognostic value in patients with severe symptomatic aortic valve stenosis undergoing transcatheter aortic valve implantation (TAVI). Methods and Results: We prospectively enrolled 217 patients undergoing TAVI (using Edwards Sapien XT prostheses) at our institution over a continuous period of 35 month (2/2011-12/2013). All patients were available for complete follow up. Clinical parameters were determined before the procedure, biomarkers (GDF15 &amp; NTproBNP) were measured before, 3 and 7 days after TAVI. The primary endpoint was survival time, all available prognostic factors were studied by Cox regression analysis with backward selection based on the likelihood ratio criteria. At median follow-up of 349 d (Q1-Q3 106-660d), a total of n=66 deaths occurred. 30d mortality was 6.9%. Mean age was 81.8 years (± 6.0 y) and 55.8% were females. Mean log. Euroscore (ES) was 25.4% (± 17.2%). Median preprocedural GDF15 values were 2256 pg/ml (Q1-Q3 1585.5-3082.0). In univariate analyses, increased GDF15 levels (upper quartile compared to lower three quartiles) revealed a HR of 2.4 (CI 1.5-3.9, p&lt;0.001) for adverse outcome. In addition, also log. ES (p= 0.001), log. ES II (p=0.018), STS-Score (p=0.019), NTproBNP (p=0.037) and atrial fibrillation (p=0.02) demonstrated statistical significance for negative outcome. A multivariate Cox regression analysis including these factors and postprocedural aortic regurgitation, demonstrated that elevated GDF15 had a HR of 2.104 (CI 1.3-3.5; p=0.003) for negative outcome in patients undergoing TAVI, while elevated NTproBNP had HR of 1.412 (CI 0.8-2.4; p=0.212). Moreover, this analysis also revealed the log. ES as an independent risk factor (HR of 2.211, CI 1.3-3.7; p= 0.002). Conclusion: Increased GDF15 levels are associated with a poor prognosis in patients undergoing TAVI. Furthermore, GDF15 showed to be superior to the established biomarker NTproBNP in risk stratification of patients undergoing TAVI providing additional prognostic information.
Ultra-sensitive detection of biomarkers and applications in pharmaceutical discovery and development. Example application to rat cardiac troponin I assay via nanoparticle probes
Authors: P. Bao, T. Lubben, T. Holzman
Journal: Journal of Clinical Oncology (2009)

e14594 Although specific to heart, rat cardiac troponin I (cTnI) is an example of an important biomarker for assessing drug-induced cardiotoxicity in animal models used in various phases of drug discovery and development. Current commercially available assays can only detect 10 ∼ 100 pg/mL in serum at the lowest limits. To improve the sensitivity of rat cTnI assay, we have developed a generically applicable, microarray based nano-probe test. Our rat cTnI assay algorithm uses a multi-step robotic process, which relies on non- isotropically oriented antibodies on functionalized glass as multiplexed microarrays to capture cTnI from serum. Functionalized, 130 angstrom diameter gold nano-probes (measured by static light scattering, 5 nm S.D.) also bind to the troponin through a molecular-scale complex containing antibodies. The troponin-bound molecular complex is then quantified through silver enhancement of the functionalized gold. Assays in this format can be rapidly configured and implemented for a wide array of potential biomarkers. For cTnI we have demonstrated a robust and ultra-sensitive assay with an LOD of less than 500 femtograms of rat cTnI per mL serum, and an overall CV of less than 20%. The assay also shows very low background, a broad dynamic range and over 3 logs of linear dose response. As an example of the potential of high sensitivity, the nanoparticle-based rat cTnI assay could significantly increase the effectiveness of measuring drug-induced heart damage at very low drug dosages and early times. Such sensitive and early measurements can improve examination of the safety of drug candidates while correspondingly reducing drug development time and cost. [Table: see text]
Authors' redefinition is better but not perfect
Authors: O. R Dearlove, J. Rogers, A. Sharples
Journal: BMJ (1996)

within the new journal can be divined.There is no reference to the second hand methodology, just the quoting of subjectively attractive and unqualified conclusions, fourth hand.Those who are concerned with validity will examine raw data and access much more exten- sive databases by standard methods on the Inter- net on a more comprehensive scale at only second hand level.Those who are not concerned with validity will find a ready substitute for
Abstract 1097: Very-low Dose Endotoxemia Induces High Density Lipoprotein Remodeling and Reduces Cholesterol Efflux in the Absence of a Clinical Inflammatory Response
Authors: Sean P Heffron, Nehal N Mehta, Margarita de la Llera-Moya, Karen Terembula, Christine Hinkle, Megan Wolfe, Muredach P Reilly
Journal: Circulation (2007)

Introduction: Chronic low-grade inflammation is thought to induce atherogenic changes in HDL function. Indeed, we have demonstrated HDL particle remodeling during experimental human endotoxemia (3ng/kg). However, this model is associated with marked clinical symptoms, and may not reflect the chronic low-grade inflammation characteristic of insulin resistant atherogenic states. Hypothesis: We hypothesized that very low-dose human endotoxemia (LPS; 0.6ng/kg) induces sub-clinical inflammation causing changes in HDL composition and function, without generating measurable clinical responses. Methods: Ten healthy, human volunteers (50% male, 90% Caucasian, mean age 22.7 ± 3.8) were randomized to separate 36-hour inpatient visits (placebo versus intravenous LPS 0.6ng/kg) in a double-masked, placebo-controlled, crossover study. Serial plasma and serum samples were collected for measurement of cytokines, acute phase reactants, lipids and lipoproteins. Ex-vivo 3 H-cholesterol efflux from FU5AH cells (SR-BI model) to the HDL fraction from serum, serially isolated during placebo/endotoxemia, was examined (N=5). Repeated measures ANOVA was applied to the data. Results: There was no significant difference between placebo and LPS in the clinical measures of inflammatory response, including body temperature and heart rate. Relative to placebo, LPS produced a peak 20-fold increase in TNFα (p = 0.01) and a 15-fold increase in CRP (p &lt;0.001). LPS had no effect on levels of HDL cholesterol, apoA-I, apoA-II or apoB lipoproteins. However, endotoxemia was associated with a significant decrease in plasma phospholipids (p = 0.03) and a 7-fold increase in HDL-associated SAA (p &lt;0.001). Further, LPS induced a 40% reduction in cholesterol efflux to HDL by 12 hours post-LPS administration (p = 0.026) which recovered only slightly by 24 hours post-LPS. Conclusions: A very low-dose of endotoxin produces relatively low-grade innate immune responses, without clinical symptoms, but with significant changes in HDL composition and function. This study provides evidence that a modest inflammatory response, consistent with chronic inflammation in atherogenic states in vivo , induces atherogenic changes in HDL.
Abstract 12023: Relationship of Beta-Blocker (BB) Dose with Outcomes in Ambulatory Heart Failure (HF) Patients with Systolic Dysfunction: Results from the HF-ACTION Trial
Authors: Mona Fiuzat, Daniel Wojdyla, David Whellan, Karen Chiswell, Dalane Kitzman, William Kraus, Steven Keteyian, Herb Patterson, Kirkwood Adams, Jerome Fleg, Ileana Pina, Christopher M O'Connor
Journal: Circulation (2011)
Pathophysiology Underlying the Bimodal Edema Phenomenon After Myocardial Ischemia/Reperfusion
Authors: Rodrigo Fernández-Jiménez, Jaime García-Prieto, Javier Sánchez-González, Jaume Agüero, Gonzalo J. López-Martín, Carlos Galán-Arriola, Antonio Molina-Iracheta, Roisin Doohan, Valentin Fuster, Borja Ibáñez
Journal: Journal of the American College of Cardiology (2015)

Post-ischemia/reperfusion (I/R) myocardial edema was recently shown to follow a consistent bimodal pattern: an initial wave of edema appears on reperfusion and dissipates at 24 h, followed by a deferred wave that initiates days after infarction, peaking at 1 week.This study examined the pathophysiology underlying this post-I/R bimodal edematous reaction.Forty instrumented pigs were assigned to different myocardial infarction protocols. Edematous reaction was evaluated by water content quantification, serial cardiac magnetic resonance T2-mapping, and histology/immunohistochemistry. The association of reperfusion with the initial wave of edema was evaluated in pigs undergoing 40-min/80-min I/R and compared with pigs undergoing 120-min ischemia with no reperfusion. The role of tissue healing in the deferred wave of edema was evaluated by comparing pigs undergoing standard 40-min/7-day I/R with animals subjected to infarction without reperfusion (chronic 7-day coronary occlusion) or receiving post-I/R high-dose steroid therapy.Characterization of post-I/R tissue changes revealed maximal interstitial edema early on reperfusion in the ischemic myocardium, with maximal content of neutrophils, macrophages, and collagen at 24 h, day 4, and day 7 post-I/R, respectively. Reperfused pigs had significantly higher myocardial water content at 120 min and T2 relaxation times on 120 min cardiac magnetic resonance than nonreperfused animals. Permanent coronary occlusion or high-dose steroid therapy significantly reduced myocardial water content on day 7 post-infarction. The dynamics of T2 relaxation times during the first post-infarction week were altered significantly in nonreperfused pigs compared with pigs undergoing regular I/R.The 2 waves of the post-I/R edematous reaction are related to different pathophysiological phenomena. Although the first wave is secondary to reperfusion, the second wave occurs mainly because of tissue healing processes.
bFGF as a therapeutic target for chemosensitization in colorectal cancer.
Authors: Bei Yu, Yong Wei, Saeheum Song, M. Guillaume Wientjes, Jessie Ls Au
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

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Our laboratory has shown that two fibroblast growth factors (aFGF and bFGF) expressed in solid tumors induce broad-spectrum resistance to anticancer drugs with diverse chemical structures and action mechanisms. We further showed that nontoxic doses of suramin, a nonspecific inhibitor of these growth factors, enhanced the anti-tumor activity of chemotherapeutic agents in breast, prostate, bladder and lung tumors. As advanced colorectal tumors express high levels of FGFs, the present study evaluated whether FGF antagonists enhance the activity of chemotherapy. The hypothesis was tested using the human HT-29 colon xenograft model and FGF antagonists (monoclonal antibodies to aFGF and bFGF, and nontoxic suramin). FGF antibodies were injected intratumorally, whereas CPT-11 and suramin were administered systemically. The results showed that the FGF antagonists, when administered alone, had no antitumor activity. However, when used in combination with CPT-11, anti-bFGF antibody or nontoxic suramin significantly enhanced the therapeutic efficacy (increased apoptotic index and median survival time, p<0.05). These benefits were attained without increasing the body weight loss. We further found that anti-bFGF antibody or suramin suppressed the expression of phosphorylated FGF receptors and survivin. These data support bFGF as a potential therapeutic target for chemosensitization in colon cancer. Supported in part by R01CA97067 and R01CA100922, NCI, DHHS.
Abstract 13128: Use of Dabigatran for Peri-Procedural Anticoagulation in Patients Undergoing Catheter Ablation for Atrial fibrillation: A New Paradigm in Peri-Procedural Anticoagulation
Authors: Mohamed Bassiouny, Walid Saliba, John Rickard, Maurice Khoury, Dunia El Hareth, Samir Alam, Peter Borek, Bryan Baranowski, Jay Sengupta, Mark Niebauer, Bernard Abi-Saleh, Thomas Callahan, Niraj Varma, Mina Chung, Patrick Tchou, Mohamed Kanj, Thomas Dresing, Bruce Lindsay, Oussama Wazni
Journal: Circulation (2011)
Abstract 3990: Identification of microRNAs from exosomes of bulk and stem cells from prostate cancer by next generation sequencing
Authors: Catherine A. Sanchez, Eliana Andahur, Rodrigo Valenzuela, Enrique Castellon, Christian Ramos, Juan Carlos Triviño
Journal: Cancer Research (2015)

Abstract Cancer stem cells (CSCs) are related with cancer initiation, metastasis, resistance and recurrence, by regulating their environment in different ways, including the release of exosomes that modify surrounding and distant cells. Exosomes contain, among other molecules, miRNAs. By identifying the entire spectrum of miRNAs included in exosomes from prostate cancer (PCa) cells by next generation sequencing (NGS), is possible to identify miRNAs specifically released by CSCs, and those related with microenvironment regulation. We stablished adherent primary cell cultures (bulk cells) from PCa tissue from 5 patients. Later, from these cells we obtained CSCs enriched prostatospheres. From bulk and CSCs cultures we purified exosomes by precipitation (ExoQuick-TC, SBI) for miRNAs extraction (mirVana, Ambion). Quality of miRNAs was assessed by Bioanalizer (Agilent Technologies). NGS was performed in the Illumina platform (MiSeq, Illumina) according to manufacturer instructions. Bioinformatic analyses were carried out by Sistemas Genómicos. Overexpressed miRNAs were detected in plasma exosomes by TaqMan miRNA Assays (Lifetechnologies). We identified 1839 miRNAs in exosomes, and 223 species were differentially expressed between bulk and CSCs, but only 26 significantly. Nineteen of them were known species including 6 that were overexpressed in CSCs respect to bulk cells. These miRNAs target genes related with cell differentiation, matrix remodeling and genic expression. From all miRNA detected, 3 were highly overexpressed among all, and were detected in exosomes isolated from plasma of men with prostatic disease. Our study extensively characterizes the miRNA from exosomes of PCa cells. Exosomes contain high diversity of miRNAs, different in CSCs and bulk cells, suggesting differential regulation of their microenvironment. From these, CSCs exosome-related miRNAs could be released to bloodstream and play a role in PCa progression and metastasis (FONDECYT 11121525/1140417). Citation Format: Catherine A. Sanchez, Eliana Andahur, Rodrigo Valenzuela, Enrique Castellon, Christian Ramos, Juan Carlos Triviño. Identification of microRNAs from exosomes of bulk and stem cells from prostate cancer by next generation sequencing. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3990. doi:10.1158/1538-7445.AM2015-3990
Abstract 4005: Morning Preference In The Onset of Tako-Tsubo Cardiomyopathy
Authors: Rodolfo Citro, Ospedale San Luca, Mario Previtali, Daniella Bovelli, Costantino Astarita, Quirino Ciampi, Olga Vriz, Ospedale Civile, Gennaro Provenza, Ospedale San Luca, Rita Camporotondo, Massimo Gallerani, Eduardo Bossone, Roberto Manfredini
Journal: Circulation (2008)

Background : Aim of this study is to assess the circadian variation in the occurrence of Tako-tsubo cardiomyopathy(TTC). Methods: We evaluated 78 consecutive pts (76 F, median age 61 yy) with TTC occurring between 2002 and 2008 at the Tako-Tsubo Cardiomyopathy Italian Network (TIN) Centers. All pts fulfilled the following diagnostic criteria for TTC: transient akinesia/diskinesia beyond a single major coronary artery vascular distribution; no angiographic evidence of significant coronary artery disease; new electrocardiographic changes; absence of intracranial bleeding, pheochromocitoma, myocarditis or hypertrophic cardiomyopathy. The time of symptom onset during day was categorized into four 6-hour intervals (night: 00:00 – 06:00; morning: 06:00 –12:00; afternoon: 12:00 –18:00; evening: 18:00 –24:00) for circadian analysis. Information on timing of the event that allowed categorization in to 1 of the 4 groups was available in 70 of 78 cases (90%). The distribution was tested for uniformity by the χ 2 test goodness of fit. Results: A circadian pattern, characterized by a significant peak in the morning (χ 2 =13,38, p=0.004), was found in patents with TTC (figure ). This pattern persisted even after adjustment according to a worst-case scenario in which untimed cases were arbitrarily assigned equally to each period according to the null amplitude hypothesis. Conclusions : Our data indicate a morning prevalence in the onset of TTC similar to other cardiovascular conditions and might be related to the circadian catecholamine activity.
Fewer dopamine transporter receptors in the prefrontal cortex of cocaine users
Authors: Ana Hitri, Manuel F. Casanova, Joel E. Kleinman, Richard Jed Wyatt
Journal: American Journal of Psychiatry (1994)

The authors investigated dopamine transporter receptor binding in the post-mortem prefrontal cortex of 13 subjects with histories of cocaine use who had positive blood screens for cocaine at autopsy and 13 comparison subjects with no history of cocaine use and negative blood screens for cocaine at autopsy. Synaptosomes from pulverized prefrontal cortex were assayed with [3H]GBR 12935 for dopamine transporter receptor. There was a 38% decrease in number of binding sites but no change in affinity constants in the cocaine users.
Abstract 11727: Effects of Single Time Dietary Counselling by Dieticians on Salt Reduction in Cardiology Outpatients Who Consumed Large Amount of Salt
Authors: Tsuneaki Sadanaga, Tamami Yamasaki, Shinichi Hirota
Journal: Circulation (2014)

Introduction:  Salt reduction is very difficult to achieve for individual patients as well as for the population.   Purpose:  To assess the effects of single time dietary counselling by expert dieticians on salt reduction in Japanese cardiology outpatients.   Methods:  A total of 72 patients (73 ±11 y/o, 30 female) who visited a cardiology outpatient clinic and took more than 8 g/day of salt were included in this study. They received dietary counselling for salt restriction by expert dieticians at the time of enrollment. The daily dietary salt intake (salt excretion) was estimated by spot urine before dietary counselling, during 3-9 weeks (next office visit), and during 24-56 weeks of follow-up.   Results:  Hypertension was observed in 57 (79%), congestive heart failure in 16 (22%), and atrial fibrillation in 15 (21%) patients.The baseline estimated salt excretion was 11.3± 1.5 (range: 8.6-16.4) g/day, which was reduced to 9.6 ± 2.3 (range: 4.6-14.4) g/day (p   Conclusion:  The efficacy of salt reduction using single time dietary counselling by expert dieticians in patients who consumed large amount of salt was modest and temporary. Repeated dietary counselling may be a possible next step for further salt reduction.
The PAX-FKHR fusion proteins transcriptionally activate MyoD while inhibiting its function, thereby inducing a limited myogenic phenotype resembling that of alveolar rhabdomyosarcoma
Authors: Friedrich Graf Finckenstein, Elai Davicioni, Violette Shahbazian, Michael J. Anderson
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

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The pediatric tumor alveolar rhabdomyosarcoma (RMS) exhibits a limited muscle phenotype, but escapes terminal differentiation. Aberrant regulation of myogenesis by the tumor specific PAX3-FKHR and PAX7-FKHR (PAX-FKHR) fusion transcription factors may contribute to this RMS phenotype. To identify the molecular mechanism behind this possible role for PAX-FKHR we characterized their regulation of MyoD, the key regulator of myogenesis, and their influences on myogenic differentiation. We show by reporter assays that MyoD is a transcriptional target of PAX-FKHR, and that PAX-FKHR proteins transactivate MyoD expression through its 258 bp core enhancer. MyoD is a direct target of PAX-FKHR, since in gel shift assays PAX-FKHR physically bind a core enhancer sequence that shows similarity to previously described PAX3 and PAX-FKHR consensus binding sequences. NIH3T3 fibroblasts transduced with PAX3-FKHR stably express MyoD and myogenin proteins. Compared to NIH3T3 cells ectopically expressing MyoD, however, PAX3-FKHR expressing cells are inhibited from terminally differentiating in low-serum growth conditions as shown by the lack of myogenin induction, low myosin heavy chain expression, and absence of myotube formation. Using reporter assays we show that MyoD transcriptional function is attenuated in PAX3-FKHR expressing NIH3T3 cells in differentiation conditions. Posttranslational modification of MyoD, detectable as increased phosphorylation, appears to be the underlying mechanism for the observed inhibition of MyoD function. Studies in progress suggest that these changes in phosphorylation are mediated by FGF signaling. In conclusion, our data demonstrate that in a single experimental system PAX-FKHR can simultaneously induce limited myogenesis by directly activating MyoD expression while preventing complete differentiation. We propose a mechanism whereby the PAX-FKHR proteins commit a yet undefined precursor cell to the myogenic lineage while at the same time inhibit its differentiation into a mature muscle cell, thereby leading to the formation of alveolar RMS. We are currently studying candidate genes from a PAX-FKHR transcriptional signature generated by expression profiling in order to identify pathways that mediate the PAX-FKHR inhibitory effects on myogenesis in alveolar RMS. We believe this work will identify molecular targets for intervention and provide novel options for the treatment of RMS.