tbuckley/cabot-search huggingface dataset:
Established and Emerging Roles of Biomarkers in Heart Failure
Authors: Nasrien E. Ibrahim, James L. Januzzi
Journal: Circulation Research (2018)

Heart failure (HF) is a complex syndrome with an enormous societal burden in terms of cost, morbidity, and mortality. Natriuretic peptide testing is now widely used to support diagnosis, prognostication, and management of patients with HF and are incorporated into HF clinical practice guidelines. Beyond the natriuretic peptides, novel biomarkers may supplement traditional clinical and laboratory testing to improve understanding of the complex disease process of HF and possibly to personalize care for those affected through better individual phenotyping. In this review, we will discuss natriuretic peptides and the more novel biomarkers by dividing them into categories based on the major pathophysiologic pathways they represent. Given the complex physiology in HF, it is reasonable to expect that the future of biomarker testing lies in the application of multimarker testing panels, precision medicine to improve HF care delivery, and the use of biomarkers in proteomics and metabolomics to further improve HF care.
Abstract 20010: Diet-induced Obesity Stimulates Inflammatory Monopoiesis From Hematopoietic Stem Progenitor Cells Through Activating Histone Methylation
Authors: Milie Fang, Rita Mirza, Timothy J Koh, Norifumi Urao
Journal: Circulation (2015)

Obesity-induced monopoiesis has been implicated in the development of obesity-related complications. Monopoiesis is largely dependent on hematopoietic stem progenitor cells (HSPCs) in the bone marrow (BM). However, little is known about hematopoietic control mechanisms in diet-induced obesity. In a mouse model of diet-induced obesity (DIO), we found leukocytosis (9.465 ± 0.7350 K/ul versus 7.277 ± 0.3450 K/ul in healthy controls, n=7 each? , p=0.023) and increased inflammatory Ly6Chi monocytes in circulation (377.2 ± 40.94/ul vs. 224.8 ± 39.18/ul in lean control; n=7; p=0.023), associated with increased myeloid progenitor cells (60% increase in granulocyte-monocyte progenitor cells, n=4) in the BM. By flow cytometry based profiling, we found that active marks for transcription, histone 3 lysine 4 trimethylation (H3K4me3), are upregulated (1.82-fold increase in mean fluorescent intensity (MFI) vs. lean mice, n=5, p&lt;0.05) in Ly6Chi inflammatory monocytes in DIO mice, along with increased inflammatory gene expression in response to TLR (toll-like receptor) 4 stimulation. In the BM, HSPCs but not myeloid progenitor cells have enriched H3K4me3 in DIO mice (2.84-fold in MFI in cKit+Sca1+Lin- cells, n=5, p&lt;0.05). This activated mark in HSPCs is associated with increased monopoiesis from HSPCs (1.55-fold increase in output CD11b+Ly6Chi monocytes from cultured HSPCs, n=3-5, p&lt;0.01) in response to TLR2 and TLR4 stimulations. Of note, HSPCs produce inflammatory cytokines to promote differentiation into inflammatory monocytes. Moreover, HIF-1a, a potential upstream of H3K4me3, is upregulated (2.29-fold in MFI, n=5, p&lt;0.05) in HSPCs in DIO mice. These results suggest that obesity increases HIF-1a-mediated H3K4me3 enrichment in HSPCs, which in turn contributes to inflammatory cytokine expression and to increased inflammatory monopoiesis. Thus, epigenetic marks in HSPCs could be a target for obesity-related complications.
Site-directed non-covalent polymer-drug complexes for inflammatory bowel disease (IBD): Formulation development, characterization and pharmacological evaluation
Authors: Siddharth S. Kesharwani, Rizwan Ahmad, Mohammed Ali Bakkari, Mrigendra K.S. Rajput, Rakesh Dachineni, Chaitanya K. Valiveti, Saurabh Kapur, G. Jayarama Bhat, Amar B. Singh, Hemachand Tummala
Journal: Journal of Controlled Release (2018)
Oxidative stress-modulating drugs have preferential anticancer effects - involving the regulation of apoptosis, DNA damage, endoplasmic reticulum stress, autophagy, metabolism, and migration
Authors: Jen-Yang Tang, Fu Ou-Yang, Ming-Feng Hou, Hurng-Wern Huang, Hui-Ru Wang, Kun-Tzu Li, Sundas Fayyaz, Chih-Wen Shu, Hsueh-Wei Chang
Journal: Seminars in Cancer Biology (2018)
Design considerations for early-phase clinical trials of immune-oncology agents
Authors: Nolan A. Wages, Cody Chiuzan, Katherine S. Panageas
Journal: Journal for ImmunoTherapy of Cancer (2018)

With numerous and fast approvals of different agents including immune checkpoint inhibitors, monoclonal antibodies, or chimeric antigen receptor (CAR) T-cell therapy, immunotherapy is now an established form of cancer treatment. These agents have demonstrated impressive clinical activity across many tumor types, but also revealed different toxicity profiles and mechanisms of action. The classic assumptions imposed by cytotoxic agents may no longer be applicable, requiring new strategies for dose selection and trial design.This main goal of this article is to summarize and highlight main challenges of early-phase study design of immunotherapies from a statistical perspective. We compared the underlying toxicity and efficacy assumptions of cytotoxic versus immune-oncology agents, proposed novel endpoints to be included in the dose-selection process, and reviewed design considerations to be considered for early-phase trials. When available, references to software and/or web-based applications were also provided to ease the implementation. Throughout the paper, concrete examples from completed (pembrolizumab, nivolumab) or ongoing trials were used to motivate the main ideas including recommendation of alternative designs.Further advances in the effectiveness of cancer immunotherapies will require new approaches that include redefining the optimal dose to be carried forward in later phases, incorporating additional endpoints in the dose selection process (PK, PD, immune-based biomarkers), developing personalized biomarker profiles, or testing drug combination therapies to improve efficacy and reduce toxicity.
Abstract 20577: Heart Failure Patients Have Lower Diet Quality and Higher Added Sugar Consumption Compared to Age and Sex-Matched Community Dwelling Adults
Authors: JungHee Kang, Martha J Biddle, Debra K Moser, Terry A Lennie
Journal: Circulation (2016)

Introduction: Higher added sugar intake is associated with an increased risk of obesity, cardiovascular disease (CVD), poor well-being, and mortality. Differences in diet quality and added sugar in...
Transcranial Direct Current Stimulation vs Sham Stimulation to Treat Aphasia After Stroke
Authors: Julius Fridriksson, Chris Rorden, Jordan Elm, Souvik Sen, Mark S. George, Leonardo Bonilha
Journal: JAMA Neurology (2018)

<h3>Importance</h3> Aphasia is a debilitating language disorder for which behavioral speech therapy is the most efficient treatment, but therapy outcomes are variable and full recovery is not always achieved. It remains unclear if adjunctive brain stimulation (anodal transcranial direct current stimulation [A-tDCS]) applied during aphasia therapy can improve outcomes. <h3>Objective</h3> To examine the futility of studying A-tDCS as an adjunctive intervention during speech therapy to improve speech production (naming) for individuals with long-term poststroke aphasia. <h3>Design, Setting, and Participants</h3> Double-blinded, prospective randomized clinical trial using a futility design to test adjunctive A-tDCS during speech therapy. The setting was an outpatient clinic. Enrollment of individuals began in August 2012 and was completed in March 2017, and the duration of follow-up was 6 months. Analyses began in April 2017. The study recruited from a volunteer sample, and 89 patients were screened. Patients with long-term (&gt;6 months) aphasia due to 1 previous left hemisphere stroke were enrolled. In comparing A-tDCS and sham tDCS, patients were matched based on site (University of South Carolina or Medical University of South Carolina), baseline age, type of aphasia, and aphasia severity. <h3>Interventions</h3> Outpatient speech therapy for 3 weeks (15 sessions, 45 minutes each) combined with either A-tDCS vs sham tDCS applied to preserved left temporal lobe regions. <h3>Main Outcomes and Measures</h3> The primary outcome was the ability to name common objects, assessed twice before and after therapy. <h3>Results</h3> A total of 74 patients were enrolled. Participants had a mean (SD) age of 60 (10) years, had 15 (2) years of education, and were 44 (40) months from stroke onset. There were 52 men (70%) and 62 non-Hispanic white individuals (84%). Most were retired or not employed (59 [80%]). Broca aphasia was the most common aphasia type (39 [52.7%]). The adjusted mean (SE) change from pretreatment baseline in correct naming was 13.9 (2.4) words (95% CI, 9.0-18.7) for A-tDCS and 8.2 (2.2) words (95% CI, 3.8-12.6) for sham tDCS, with mean (SE) A-tDCS difference of 5.7 (3.3) words (95% CI, −0.9 to 12.3), indicating a relative 70% increase in correct naming for A-tDCS relative to sham. The futility hypothesis<i>P</i>value was .90, indicating failure to reject the null hypothesis and, therefore, providing no evidence that further study of A-tDCS is futile. No serious adverse events were associated with A-tDCS. <h3>Conclusions and Relevance</h3> Our findings provide motivation to proceed with another trial to study the effect of A-tDCS on the outcome of aphasia treatment in individuals poststroke. Anodal tDCS during speech therapy is feasible and potentially transformative for aphasia treatment and should be further studied. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT01686373
Refusing to TAP out: 16 new human TEIPPs identified
Authors: Mathieu Gigoux, Jedd Wolchok
Journal: The Journal of Experimental Medicine (2018)

In this issue of JEM, Marijt et al. (https://doi.org/10.1084/jem.20180577) report their discovery of 16 novel human TAP-independent TEIPP peptides, whereas only one had been previously identified. This opens the door to new therapeutic options for patients with TAP-deficient tumors.
Abstract 17874: The Association of Sleep Disturbance and Depression with Prodromal Symptoms of Coronary Heart Disease in Women: Secondary Data Analysis from a Multi-Site, Longitudinal Study
Authors: Christina Pettey, Christopher J Swearingen, Jean C McSweeney
Journal: Circulation (2014)

Purpose: Estimate the association between sleep disturbance and depression with prodromal symptoms of coronary heart disease (CHD) in women. Background: Over 240,000 women die from CHD yearly. CHD kills more women than all other causes of death combined. Sleep disturbance and depression have been implicated in the development of CHD in women. The Nurses study, (n = 71,617) found an age-adjusted relative risk of 1.82 (95% CI: 1.34-2.41) for women sleeping <5 hours per night. Depression is also associated with an increased risk of CHD and is commonly comorbid with it. Few studies have collected longitudinal data to examine the correlation of sleep disturbance and depression with prodromal symptoms of CHD in women. This is important because the identification of risk factors and prodromal symptoms may assist clinicians in diagnosing CHD earlier in women. Methods: Data for this multi-site, longitudinal study were collected from women without CHD from cardiology practices in two southern states. They were quer...
Methallotionein expression and outcome in patients with metastatic breast cancer (MBC).
Authors: Jorge Arturo Rios-Perez, Sameem Abedin, Margaret Quinn Rosenzweig, Su Yon Jung, Rohit Bhargava, Adam Brufsky
Journal: Journal of Clinical Oncology (2012)

1085 Background: Platinum-based agents are important components of therapy of metastatic breast cancer (MBC) and triple negative breast cancer. Their use can be limited by development of resistance. Metallothioneins (MT) are low molecular weight proteins believed to bind bivalent metal ions such as platinum and zinc. MT expression has been associated with decreased survival in breast cancer patients. A proposed mechanism confers resistance to platinum-based agents by their inactivation or limitation of their activity by MT binding. Methods: MT expression in 99 women with MBC (selected at random from our database of 800 women with MBC) was determined from primary breast cancer tissue (n=80) or metastatic tissue n=19). MT expression was determined by immunohistochemistry, and graded as negative, weak, moderate or strong. Clinical data was obtained through our database and supplemented by chart review. Overall survival from breast cancer diagnosis (OS), progression free survival for first metastastic regimen (PFS), and time from first metastasis to death or last update (metastatic survival, MS), were calculated through December 2011 using the log rank test. Results: Consistent with prior studies, moderate to strong MT expression was associated with decreased 5-year OS (p=.03). There was no correlation between MT expression and PFS or MS in this cohort. Surprisingly, MT expression at any degree was strongly associated with better MS in patients with MBC that received carboplatin-based regimens in the first line (n=25, p=.0005) or at any line (n=41, p=.0437). Conclusions: Consistent with prior studies, MT expression was associated with decreased survival in patients with MBC. Surprisingly, MT expression was associated with longer MS in patients with MBC that received carboplatin. These findings are inconsistent with the hypothesis that MT expression causes chemoresistance to platinum based agents in patients with metastatic breast cancer. Further studies are needed to elucidate the mechanisms behind these findings.
Effects of simulated visual acuity and ocular motility impairments on SSVEP brain-computer interface performance: an experiment with Shuffle Speller
Authors: Betts Peters, Matt Higger, Fernando Quivira, Steven Bedrick, Shiran Dudy, Brandon Eddy, Michelle Kinsella, Tab Memmott, Jack Wiedrick, Melanie Fried-Oken, Deniz Erdogmus, Barry Oken
Journal: Brain-Computer Interfaces (2018)

Individuals with severe speech and physical impairments may have concomitant visual acuity impairments (VAI) or ocular motility impairments (OMI) impacting visual BCI use. We report on the use of the Shuffle Speller typing interface for an SSVEP BCI copy-spelling task under three conditions: simulated VAI, simulated OMI, and unimpaired vision. To mitigate the effect of visual impairments, we introduce a method that adaptively selects a user-specific trial length to maximize expected information transfer rate (ITR); expected ITR is shown to closely approximate the rate of correct letter selections. All participants could type under the unimpaired and simulated VAI conditions, with no significant differences in typing accuracy or speed. Most participants (31 of 37) could not type under the simulated OMI condition; some achieved high accuracy but with slower typing speeds. Reported workload and discomfort were low, and satisfaction high, under the unimpaired and simulated VAI conditions. Implications and future directions to examine effect of visual impairment on BCI use is discussed.
The Harm Principle Cannot Replace the Best Interest Standard: Problems With Using the Harm Principle for Medical Decision Making for Children
Authors: Johan Christiaan Bester
Journal: The American Journal of Bioethics (2018)

For many years the prevailing paradigm for medical decision making for children has been the best interest standard. Recently, some authors have proposed that Mill's "harm principle" should be used to mediate or to replace the best interest standard. This article critically examines the harm principle movement and identifies serious defects within the project of using Mill's harm principle for medical decision making for children. While the harm principle proponents successfully highlight some difficulties in present-day use of the best interest standard, the use of the harm principle suffers substantial normative and conceptual problems. A medical decision-making framework for children is suggested, grounded in the four principles. It draws on the best interest standard, incorporates concepts of harm, and provides two questions that can act as guide and limit in medical decision making for children.
APRIL signaling via TACI mediates immunosuppression by T regulatory cells in multiple myeloma: therapeutic implications
Authors: Yu-Tzu Tai, Liang Lin, Lijie Xing, Shih-Feng Cho, Tengteng Yu, Chirag Acharya, Kenneth Wen, Phillip A. Hsieh, John Dulos, Andrea van Elsas, Nikhil Munshi, Paul Richardson, Kenneth C. Anderson
Journal: Leukemia (2018)
Prognostic Value of a Long Non-coding RNA Signature in Localized Clear Cell Renal Cell Carcinoma
Authors: Le Qu, Ze-lin Wang, Qi Chen, Yao-ming Li, Hao-wei He, James J. Hsieh, Song Xue, Zhen-jie Wu, Bing Liu, Hao Tang, Xiao-feng Xu, Feng Xu, Jie Wang, Yi Bao, An-bang Wang, Dong Wang, Xiao-ming Yi, Zhong-kui Zhou, Chang-jie Shi, Ke Zhong, Zheng-cheng Sheng, Yu-lin Zhou, Jun Jiang, Xiao-yuan Chu, Jia He, Jing-ping Ge, Zheng-yu Zhang, Wen-quan Zhou, Cheng Chen, Jian-hua Yang, Ying-hao Sun, Lin-hui Wang
Journal: European Urology (2018)
Abstract 14841: Definitions of Stage D Heart Failure and Survival: Comparing INTERMACS Profiles, ESC Criteria, and Physician Assessment
Authors: Jeffrey S Hedley, Ayman S Tahhan, Andrew A McCue, Jonathan B Bjork, Mariyah Yazdani, Raghda Al-Anbari, Javed Butler, Vasiliki V Georgiopoulou, Andreas Kalogeropoulos
Journal: Circulation (2015)

Introduction: Care for patients with stage D heart failure (HF) is becoming increasingly complex in the era of mechanical circulatory support (MCS). However, an operational consensus definition of stage D HF is currently lacking. Hypothesis: Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles better identify outpatients with stage D HF compared to European Society of Cardiology Heart Failure Association (ESC-HFA) criteria and physician assessment. Methods: We evaluated 474 outpatients with systolic HF (ejection fraction [EF] &lt;40%) who received care in Q1 2012 and have not previously received advanced therapies (age, 61±15 years; 35.4% women; 44.7% white, 46.8% black; EF 24±10%; 67.2% with ischemic heart disease; 6.3% on home inotropes). We applied INTERMACS profiles (defining stage D as profiles 2-5) and ESC-HFA criteria to identify stage D HF, and compared with physician-derived stage D identification based on evaluations for advanced therapies (MCS, heart transplant, or palliative care). We then compared 3-year mortality across definitions. Results: INTERMACS profiles, ESC-HFA criteria, and physicians identified 50 (10.5%), 59 (12.4%), and 64 (13.5%) of 474 patients, respectively, as having stage D HF. Concordance between definitions was low, with κ =0.35 (optimal: 1.0). After a median of 3.1 years (1.6, 3.3), 95 patients died (3-year mortality: 21.4%). In addition, 24 patients received MCS and 11 received heart transplant. Mortality was 51.2%, 43.7%, and 34.5% for INTERMACS-, ESC-HFA-, and physician-identified stage D HF patients, respectively ( Figure 1 ). The INTERMACS definition provided the best prognostic separation between stage D and C HF patients, as measured by the Royston’s R 2 statistic ( Figure 1 ). Conclusions: INTERMACS profiles provide a reasonable alternative for the identification of stage D patients in ambulatory systolic HF populations and offer better prognostic information than the ESC-HFA criteria.
Inactivation of caspase 8 in liver parenchymal cells confers protection against murine obstructive cholestasis
Authors: Francisco Javier Cubero, Jin Peng, Lijun Liao, Huan Su, Gang Zhao, Miguel Eugenio Zoubek, Ricardo Macías-Rodríguez, Astrid Ruiz-Margain, Johanna Reißing, Henning W. Zimmermann, Nikolaus Gassler, Tom Luedde, Christian Liedtke, Maximilian Hatting, Christian Trautwein
Journal: Journal of Hepatology (2018)
Abstract 16872: Continuous Perfusion With a Preservation Solution Supplemented by a Mesenchymal Stem Cell Conditioned Medium Protects the Older Hearts From Prolonged Cold Storage Followed by Warm Reperfusion
Authors: Shiliang Li, Sevil Korkmaz-Icöz, Mihály Ruppert, Tamás Radovits, Kunsheng Li, Xiaoxin Sun, Paige Brlecic, Matthias Karck, Gábor Szabó
Journal: Circulation (2016)

Introduction: Heart transplantation is the first choice of therapy for end-stage heart failure patients. Because of the shortage of donor hearts with increasing numbers of patients waiting for transplantation, transplant programs are using older donors and accepting longer ischemic times. Although preservation solutions ensure a safe cold ischemic time of 4h, they do not completely prevent the adverse effects of myocardial ischemia/reperfusion (IR) injury. Previous studies have suggested beneficial effects of mesenchymal stem cell (MSC) administration or the administration of their conditioned medium (MSC CM) in animal models of IR injury. Hypothesis: Older donor hearts’ preservation by a continuous conditioned medium from MSC (MSC CM) was investigated in the experimental set up of prolonged cold IR injury during heart transplantation. Methods: The hearts were explanted from 15-month-old Lewis donor rats and continuously perfused for 5h with oxygenated cold (4 °C) cardioplegia, including either Custodiol ...
Abstract 13524: A Global Comparison of Length of Hospital Stay Among Patients Presenting With Atrial Fibrillation in the Acute Care Setting: The RHYTHM-AF Study
Authors: Harry J Crijns, Anselm K Gitt, Lori D Bash
Journal: Circulation (2011)

Purpose: Length of stay (LoS) in hospital for atrial fibrillation (AF) can vary, though regional variations have not been well described. LoS of AF hospitalization across cardioversion therapies am...
Abstract 10384: Validation of a Simple Score to Determine Risk of Hospital Mortality After the Norwood Procedure
Authors: Shahryar M Chowdhury, Eric M Graham, Andrew M Atz, Scott M Bradley, Minoo M Kavarana, Ryan J Butts
Journal: Circulation (2015)

Background: The NIH/NHLBI Pediatric Heart Network Single Ventricle Reconstruction (SVR) trial identified risk factors for hospital mortality after the Norwood procedure. However, the ability to quantify pre-operative risk remains elusive. This study aimed to develop an accurate and clinically feasible score to assess the risk of hospital mortality in neonates undergoing the Norwood procedure. Methods: All patients (n = 549) in the publically available SVR database were included in the analysis. Patients were randomly divided into a derivation (75%) and validation (25%) cohort. Pre-operative patient, center, and surgeon-related covariates found to be associated with mortality upon univariate analysis (p &lt; 0.2) were included in the initial multivariable logistic regression model. The final model was derived by including only variables independently associated with mortality (p &lt; 0.05). A risk score was then developed using relative magnitudes of the covariates’ odds ratio. The score was then tested in the validation cohort. Results: A 20-point risk score using 6 variables (see Table) was developed. The derivation and validation cohorts did not differ in age, sex, mortality, and the score covariates. Mean score in derivation and validation cohort were 5.2 ± 3.2 and 5.6 ± 3.5, p = 0.35, respectively. In weighted regression analysis, model predicted risk of mortality correlated closely with actual rates of mortality in the derivation (R 2 = 0.87, p &lt; 0.01) and validation cohorts (R 2 = 0.82, p 10). Patients were classified as low (score 0-5), medium (6-10), or high risk (&gt;10). Mortality differed significantly between risk groups in the derivation (6% vs. 22% vs. 77%, p &lt; 0.01) and validation (4% vs. 30% vs. 53%, p &lt; 0.01) cohorts. Conclusion: This mortality score is accurate in determining risk of hospital mortality in neonates undergoing the Norwood operation. The score has the potential to be used in clinical practice to aid in risk assessment prior to surgery.