tbuckley/cabot-search huggingface dataset:
Integrative statistical analyses of multiple liquid biopsy analytes in metastatic breast cancer
Authors: Corinna Keup, Vinay Suryaprakash, Siegfried Hauch, Markus Storbeck, Peter Hahn, Markus Sprenger-Haussels, Hans-Christian Kolberg, Mitra Tewes, Oliver Hoffmann, Rainer Kimmig, Sabine Kasimir-Bauer
Journal: Genome Medicine (2021)

Abstract Background Single liquid biopsy analytes (LBAs) have been utilized for therapy selection in metastatic breast cancer (MBC). We performed integrative statistical analyses to examine the clinical relevance of using multiple LBAs: matched circulating tumor cell (CTC) mRNA, CTC genomic DNA (gDNA), extracellular vesicle (EV) mRNA, and cell-free DNA (cfDNA). Methods Blood was drawn from 26 hormone receptor-positive, HER2-negative MBC patients. CTC mRNA and EV mRNA were analyzed using a multi-marker qPCR. Plasma from CTC-depleted blood was utilized for cfDNA isolation. gDNA from CTCs was isolated from mRNA-depleted CTC lysates. CTC gDNA and cfDNA were analyzed by targeted sequencing. Hierarchical clustering was performed within each analyte, and its results were combined into a score termed Evaluation of multiple Liquid biopsy analytes In Metastatic breast cancer patients All from one blood sample (ELIMA.score), which calculates the contribution of each analyte to the overall survival prediction. Singular value decomposition (SVD), mutual information calculation, k-means clustering, and graph-theoretic analysis were conducted to elucidate the dependence between individual analytes. Results A combination of two/three/four LBAs increased the prevalence of patients with actionable signals. Aggregating the results of hierarchical clustering of individual LBAs into the ELIMA.score resulted in a highly significant correlation with overall survival, thereby bolstering evidence for the additive value of using multiple LBAs. Computation of mutual information indicated that none of the LBAs is independent of the others, but the ability of a single LBA to describe the others is rather limited—only CTC gDNA could partially describe the other three LBAs. SVD revealed that the strongest singular vectors originate from all four LBAs, but a majority originated from CTC gDNA. After k-means clustering of patients based on parameters of all four LBAs, the graph-theoretic analysis revealed CTC ERBB2 variants only in patients belonging to one particular cluster. Conclusions The additional benefits of using all four LBAs were objectively demonstrated in this pilot study, which also indicated a relative dominance of CTC gDNA over the other LBAs. Consequently, a multi-parametric liquid biopsy approach deconvolutes the genomic and transcriptomic complexity and should be considered in clinical practice.
Abstract 12572: Early Surgical Treatment versus Initial Conservative Management for Asymptomatic Severe and Very Severe Aortic Stenosis: A Meta-analysis
Authors: Yujiro Yokoyama, Hisato Takagi, Toshiki Kuno
Journal: Circulation (2020)

Background: Although current guidelines generally recommend watchful waiting strategy for patients with asymptomatic severe aortic stenosis (AS) until symptoms develop, the optimal timing of surgical intervention remains controversial. Objective: This study aimed to compare the outcomes of early surgery vs. conservative strategy for patients with asymptomatic severe AS. Methods: MEDLINE and EMBASE were searched through February, 2020 to identify clinical trials that investigatedearly surgery and conservative strategy for patients with asymptomatic severe AS. From each study, we extracted the hazard ratio (HR) of all-cause mortality and cardiovascular mortality. Subgroup analyses were conducted by dividing into severe AS (peak aortic jet velocity [Vmax] ≥4.0 m/s, mean aortic pressure gradient [PG] ≥40 mmHg, or aortic valve area [AVA] ≤1.0 cm 2 ) and very severe AS (Vmax ≥4.5 m/s, mean PG ≥50 mmHg, or AVA ≤0.75 cm 2 ) groups. Results: 1 randomized controlled, 7 observational trials were identified. Pooled analyses demonstrated that all-cause mortality and cardiovascular mortality for early surgery were significantly lower compared to conservative strategy (HR [95% Confidence Interval [CI]] =0.49 [0.36-0.68]; P &lt;0.0001, HR [95% CI] =0.42 [0.22-0.82]; P =0.01, respectively). Subgroup analyses showed significant reduction for early surgery in all-cause mortality (severe AS: HR [95% CI] =0.52 [0.35-0.78]; P =0.001, very severe AS: HR [95% CI] =0.38 [0.17-0.85]; P =0.02). Conclusions: We demonstrated that early surgery was associated with significant reduction in all-cause and cardiovascular mortality in patients with severe AS. Further randomized trials are warranted to confirm our findings.
Simultaneous detection of Akt and MAPK signaling pathway targets reveals reciprocal regulation of Phospho-Akt(S473) and Phospho-S6RP(S235/236 and S240/244) as a function of cell density
Authors: Nisar Pampori, Laura K. Schaefer, Sheldon Grove, Robert M. Umek, Paula D. Eason, Jacob N. Wohlstadter
Journal: Cancer Research (2006)

1680  Cell density is a potent regulator of the cell cycle during exponential growth and thus affects gene expression. Many recent studies have characterized cell-density as a controlling factor for cell-cell interactions and the binding of surface-associated adhesion molecules to the cytoskeleton. We examined the impact of cell density on two distinct signal transduction pathways, Protein kinase B (Akt) and Mitogen-activated protein kinases (MAPK). These pathways regulate cell proliferation, differentiation, and apoptosis, and exhibit cross-talk. Downstream, the MAPK and Akt pathways regulate p70S6kinase (p70S6K) and its substrate S6 ribosomal protein (S6RP). Whereas levels of phospho-S6RP are known to be regulated by phosphorylated-Akt, our findings suggest that in Jurkat cells this is dependent upon the cell density. We show that maximum phosphorylation of S6RP(S235/S236 and S240/244) is observed at lower cell densities (0.5x106 cells/mL). In contrast, levels of phosphorylated Akt increase with higher cell densities (1.3x106 cells/mL). In order to study the impact of cell density over a wide range of targets in the two pathways, we have developed highly sensitive multiplex assays that detect multiple phosphoproteins simultaneously in a single well with low microgram levels of cell lysate protein. Low and high density Jurkat cells were interrogated for the phosphorylation status in multiplex panels of S6RP/Akt/p70S6K/GSK3β and ERK/JNK/p38; the results from these studies will be presented.
Abstract 12568: Impact of Aortic Stenosis on Myofiber Stress: Translational Application of Left Ventricle-Aortic Coupling Simulations
Authors: Andrew D Wisneski, Yunjie Wang, Reza Salari, Steve Levine, Jiang Yao, Julius M Guccione
Journal: Circulation (2020)

Introduction: Grading aortic stenosis (AS) has traditionally relied on measuring hemodynamic parameters of transvalvular pressure gradient, ejection jet velocity, or estimating valve orifice area. Recent research has highlighted limitations of these criteria at effectively grading AS in presence of left ventricle (LV) dysfunction. We hypothesize that simulations coupling the aorta and LV will provide meaningful insight into myocardial biomechanical derangements that accompany AS. Reference data from the normal ventricle should first be obtained. Methods: A multi-domain cardiac model with representative anatomy and material properties was used to create AS simulations. Finite element analysis was performed with ABAQUS FEA®. An anisotropic hyperelastic model was assigned to the aorta and LV passive properties, while time-varying elastance function governed LV active response. Mild and severe AS were created by restricting the aortic valve orifice area. Results: Global LV myofiber end systolic (ES) stress (mean±SD) was 9.31±10.33 kPa at baseline (no AS), 13.13±10.29 kPa for mild AS, and 16.18±10.59 kPa with severe AS. Mean LV myofiber ES strains were -22.4±8.7%, -22.2±8.9%, and -21.9±9.2%, respectively. Mild and severe AS had significant stress elevation compared to baseline (mild AS vs base; p&lt;0.01, severe AS vs base; p&lt;0.001) and when compared to each other (p&lt;0.01). See Figure 1 . Ventricular regions that experienced greatest magnitude ES stress were (severe AS vs baseline) basal inferior (39.87±14.73 vs 30.02±12.08 kPa; p&lt;0.01), mid-anteroseptal (32.29±11.56 vs 24.79±12.00 kPa; p&lt;0.001), and apex (27.99±8.44 vs 23.52±10.19 kPa; p&lt;0.001). Conclusions: Isolated AS in a normal heart was simulated, and significantly elevated LV myofiber stress was quantified. This data serves as a comparison to future studies that will incorporate patient-specific ventricular geometries and material parameters, aiming to correlate LV biomechanics to AS severity.
Neoadjuvant Сhemoradiotherapy of Locally Advanced Rectal Cancer with Local 5-Fluoracil Radiomodification
Authors: A. R. Akhtemzyanov, O. V. Korytov, L. I. Korytova, A. V. Meshechkin, N. D. Oltarzhevskaya, M. A. Korovina
Journal: Radiology - Practice (2021)

Chemoradiotherapy, along with following surgical treatment, including total mesorectal excision, is a current standard for treatment of locally advanced rectal cancer. Neoadjuvant chemoradiotherapy allows to downsize the tumor, up to complete clinical response in one third of all cases, which, in turn, allows increase in sphincter preserving operations, disease-free period and overall survivability. Derivatives of 5-fluoracil are used as basic chemotherapeutic agents. These drugs have a substantial amount of side effects, which lead to either plan corrections, or may even prevent its completion. Thus, search for new ways to increase chemotherapy agent in the tumor cells with reduction of systemic toxicity to improve neoadjuvant chemoradiotherapy results is an acute task for modern medicine. In this article authors suggest intrarectal application of sterile hydrogel material based on sodium alginate with incorporated 5-fluoracil as a method of neoadjuvant chemoradiotherapy.
Abstract 16644: Durable Septal Pacing Induced by Non-viral Tbx18 Gene Transfer and Tgfβ Inhibition in a Porcine Model of Complete Atrioventricular Block
Authors: Nam Kyun Kim, Ki Hong Lee, Jonathan Langberg, Jared Beyersdorf, Jinqi Fan, Angel Xiao, Natasha Fernandez, David Wolfson, Philip Santangelo, Hee Cho
Journal: Circulation (2020)

Introduction: Cardiac pacing can be created by myocardial delivery of TBX18. However, evidence for overt fibrosis at the injection site and the use of viral vectors impede clinical translation of this concept. We hypothesized that non-viral gene transfer of TBX18 combined with prevention of fibrosis with a Tgfβ inhibitor enables durable ventricular pacing in the porcine model of CAVB. Methods: All pigs underwent transvenous RF ablation of the AV node to achieve complete heart block on day-1. The pigs were implanted with a backup pacemaker (VVI=50 bpm) and with osmotic pumps designed to release A83-01, an inhibitor of Tgfβ receptors. Synthetic mRNA encoding either TBX18 (n=7) or GFP (n=2) in saline was injected in the high interventricular septum with a NOGA-MYOSTAR™ catheter. Continuous and ambulatory ECG, blood pressure (BP) and activity were recorded for the 4-week study period with telemetry. Results: The control pigs were dependent on backup pacing throughout 4 weeks with retrograde conduction from the RV apex. In contrast, TBX18 injected pigs showed higher heart rate (HR) compared to control (4-week mean HR of 58±7 vs 52±7, p &lt;0.05), exhibiting antegrade conduction from the high septum with narrow QRS complexes. Max. HR was higher in TBX18 pigs compared to control with a 4-week average of 70±9 vs 55±11 bpm ( p &lt;0.05). TBX18 pigs exhibited diurnal HR oscillations that directly correlated with their physical activity, indicating chronotropic competence. Likewise, mean BP correlated tightly with mean HR in TBX18 injected pigs ( p &lt;0.01) but not in control ( p =0.164), indicating superior hemodynamic measures. Radiopaque agent-enabled, real-time fluoroscopic visualization revealed that the injected biologic spread beyond the intended delivery site in 2 of 7 TBX18 pigs. The mean and max. HR of the 2 pigs were slower than the other five TBX18 pigs, suggesting that conventional imaging can be leveraged to identify redosing criteria, and minimize non-responders. No increase in spontaneous or induced arrhythmias was observed in TBX18 pigs compared to control. Conclusions: mRNA delivery of TBX18 combined with Tgfβ inhibition achieved durable septal pacing for 4 weeks in a porcine model chronic heart block, demonstrating therapeutic efficacy with greater safety profiles.
Abstract P202: Early To Midlife Smoking Trajectories And Cognitive Function In Middle Aged Us Adults: The Coronary Artery Risk Development In Young Adults Study
Authors: Amber Bahorik, Stephen Sidney, Jonathan Kramer-Feldman, David R Jacobs, Amanda Mathew, Jared Reis, Kristine Yaffe
Journal: Circulation (2021)

Introduction: Smoking starts in early adulthood and persists throughout the lifecourse, but the association between these trajectories and midlife cognition remains unclear. We assessed the hypothesis that individuals with a heavy smoking trajectory from early adulthood to midlife would be more likely to demonstrate poor cognition at midlife. Methods: We studied 3364 participants (mean age: 50.1±3.6, 56% female, 46% black) from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Smoking trajectories were derived in latent class analysis among 1638 ever smokers based on smoking measures every 2-5 years from baseline (age 18-30, 1985-86) through Year 25 (2010-11). We estimated poor cognition using cognitive domain scores ≥1SD below the mean from tests of processing speed (Digit Symbol Substitution Test), executive function (Stroop) and memory (Rey Auditory Verbal Learning Test) at Year 25. Using adjusted logistic regression models, we examined the odds associated with poor midlife cognition and smoking trajectories (reference never smokers, n=1726) from early adulthood to midlife. Results: Five smoking trajectories emerged over 25-years: quitters (20%, 20/100), and minimal stable (40%, 40/100), moderate stable (20%, 20/100), heavy stable (15%, 15/100) and heavy declining smokers (5%, 5/100). As shown in the Figure, heavy stable smokers demonstrated poor cognition on all 3 domains compared to never smokers. Compared to never smokers, both heavy declining and moderate stable smokers exhibited slower processing speed, and heavy declining smokers additionally demonstrated poor executive function. For minimal stable smokers and quitters, no association was observed. Conclusions: In conclusion, we observed a dose-dependent association between early to midlife smoking and cognitive health risk at midlife. Our results underscore the cognitive health risk of moderate and heavy smoking trajectories in early and midlife periods and highlight the potential benefits of quitting, even in midlife.
Abstract 12567: Circulating Factors Induce Cardiomyopathy After Burn Injury
Authors: Jake J Wen
Journal: Circulation (2020)

Introduction: Our previous results in vivo indicated PDE5-cGMP-PKG was involved in burn-induced heart dysfunction and PDE5A inhibitor restored the dysfunction. It’s unknown if circulating factors after burn would injure cardiomyocytes. Hypothesis: Circulating factors released after burn induce cardiomyopathy. Methods: Human cardiomyocytes (AC16) were treated with sham-serum, burn-serum (24 hpb-serum) and burn/sildenafil-serum (24 hpb/SIL). We performed cut-edged biochemistry technologies and Illumina RNA sequencing (RNA-seq) in this study. GraphPad Prism 8.4.2 was used for statistics. Results: We found a significant decrease of cGMP level and an increase of cTN1 in 24 hpb-serum group. Treatment with the PDE5A inhibitor Sildenafil completely reversed this change similar to our in vivo work. To understand what bioactive molecules would be involved in the alterations by burn injury, human cardiomyocytes (Ac16) were employed to test the cardiomyocyte response to burn-induced circulating factors. We observed that 24 hpb-serum significantly 1) decreased cell viability and cell proliferation; as well as 2) increased cell cytotoxicity, cell apoptosis and cell ROS production. We also found 24 hpb-serum resulted in cell mitochondrial dysfunction by decreasing ATP production and mitochondrial membrane integrity/potential and increasing mitochondrial ROS. Seahorse and O2K approaches confirmed 24 hpb-serum-induced cardiomyocyte mitochondrial dysfunction as evidenced by decreases of mitochondrial basal respiration, proton leak, ATP production, and maximal respiration. 24 hpb/SIL serum rescued 24 hpb serum-induced Ac 16 cell response, at least partially. Advanced bioinformatic analyses identified 1415 upregulated genes and 1091 downregulated genes in 24 hpb-serum group and 776 upregulated genes and 113 downregulated genes restored in 24 hpb/SIL-serum group. We also analyzed and validated the differentially expressed genes. Conclusions: Our study not only confirmed burn induced heart dysfunction, but also provided evidence for understanding the pathogenic mechanism of circulating factors released after burn injury and preliminary genomic evidence for the mechanism for cardiomyopathy after burn injury.
Insights from immuno-oncology: the Society for Immunotherapy of Cancer Statement on access to IL-6-targeting therapies for COVID-19
Authors: Paolo Antonio Ascierto, Bernard A Fox, Walter J Urba, Ana Carrizosa Anderson, Michael B Atkins, Ernest C Borden, Julie R Brahmer, Lisa H Butterfield, Alessandra Cesano, Daniel S Chen, Tanja D de Gruijl, Robert O Dillman, Charles G Drake, Leisha A Emens, Thomas F Gajewski, James L Gulley, F Stephen Hodi, Patrick Hwu, David Kaufman, Howard L Kaufman, Michael T Lotze, Douglas G McNeel, Kim A Margolin, Francesco M Marincola, Michael J Mastrangelo, Marcela V Maus, David R Parkinson, Pedro J Romero, Paul M Sondel, Stefani Spranger, Mario Sznol, George J Weiner, Jon M Wigginton, Jeffrey S Weber
Journal: BMJ (2020)
Gendered effects of COVID-19 on young girls in regions of conflict
Authors: Sophia N Nesamoney, Gary L Darmstadt, Paul H Wise
Journal: The Lancet (2021)

The Series on Women's and Children's Health in Conflict Settings provides important guidance for addressing the health of women and children in areas of poor security and instability. However, we write to call special attention to the gender inequalities in areas of armed conflict and, in particular, the effects of the COVID-19 pandemic on young, school-age girls (aged 5–18 years). In settings of violent conflict, young girls are about 25 times more likely to be out of school than their male counterparts, and the COVID-19 pandemic appears to have exacerbated this disparity.1Georgetown Institute of Women, Peace, and SecurityAdolescent girls' access to education in conflict-affected settings.https://giwps.georgetown.edu/resource/closing-the-gap/Date: 2016Date accessed: January 24, 2021Google Scholar The pandemic has also had substantial indirect effects on levels of poverty and child malnutrition which appear to have fallen hardest on young girls. In some areas of civil conflict, the pandemic has increased the power of armed non-state groups that threaten girls' access to education and other public goods. Several of these groups, such as the Taliban in Afghanistan and Boko Haram in Nigeria, routinely threaten girls' education, at times even conducting acid attacks, kidnappings, and killings of young girls and their families.2Human Rights WatchAfghanistan: girls struggle for an education.https://www.hrw.org/news/2017/10/17/afghanistan-girls-struggle-education/Date: 2020Date accessed: January 24, 2021Google Scholar The pandemic has also destabilised the security situation in ways that have expanded the exploitation of young girls in the sex trade and as child soldiers, as was seen in Boko Haram's use of girls as young as 7 years as suicide bombers.3Bloom M Matfess H Women as symbols and swords in Boko Haram's terror.Prism. 2016; 1: 105-121Google Scholar The effects of the COVID-19 pandemic have been far-reaching, but its impact on the health and wellbeing of young girls in areas of conflict and political instability deserves focused, urgent attention. PHW was a contributor to the Lancet Series on Women's and Children's Health in Conflict Settings. We declare no other competing interests.
Reductions in Management Distress Following a Randomized Distress Intervention Are Associated With Improved Diabetes Behavioral and Glycemic Outcomes Over Time
Authors: Danielle Hessler, Lisa Strycker, Lawrence Fisher
Journal: Diabetes Care (2021)

OBJECTIVE To explore associations between reductions in diabetes distress (DD) and improvements in glycemic outcomes among adults with type 1 diabetes (T1D) in the context of a DD randomized clinical trial. RESEARCH DESIGN AND METHODS Adults with T1D (N = 301) participated in a two-arm trial aimed at reducing DD (DD-focused OnTrack group vs. education-oriented KnowIt group). Mean age was 45.1 years; mean baseline HbA1c was 8.8% (73 mmol/mol). Individuals were assessed at baseline and 9 months later on DD, self-care, HbA1c, and frequency of hypoglycemia. Structural equation models evaluated hypothesized pathways among changes in DD, self-care, and glycemic outcomes in the total sample and by intervention group. RESULTS Reductions in DD were significantly and independently associated with better self-care, including fewer missed insulin boluses, more frequent insulin adjustment, improved problem-solving skills, more blood glucose monitoring, and greater adoption of continuous glucose monitoring (all P &amp;lt; 0.05). In turn, better self-care was linked with better glycemic outcomes, including fewer episodes of hypoglycemia and improved HbA1c over time. Fit indices indicated good fit of the model to the data (confirmatory fit index = 0.94, root mean square error of approximation = 0.05), with stronger and more meaningful associations for OnTrack than for KnowIt. CONCLUSIONS In the context of an intervention to reduce DD for adults with T1D, results indicate that reductions in DD do not affect glycemic outcomes directly but through improvements in self-care behavior. Findings support the importance of integrating disease management with DD interventions to maximize improvements in glycemic outcomes.
treeclimbR pinpoints the data-dependent resolution of hierarchical hypotheses
Authors: Ruizhu Huang, Charlotte Soneson, Pierre-Luc Germain, Thomas S.B. Schmidt, Christian Von Mering, Mark D. Robinson
Journal: Genome biology (2021)

Abstract treeclimbR is for analyzing hierarchical trees of entities, such as phylogenies or cell types, at different resolutions. It proposes multiple candidates that capture the latent signal and pinpoints branches or leaves that contain features of interest, in a data-driven way. It outperforms currently available methods on synthetic data, and we highlight the approach on various applications, including microbiome and microRNA surveys as well as single-cell cytometry and RNA-seq datasets. With the emergence of various multi-resolution genomic datasets, treeclimbR provides a thorough inspection on entities across resolutions and gives additional flexibility to uncover biological associations.
Barriers and Opportunities in Accrual of HIV-Positive Minority Underserved Patients with Non-Hodgkin Lymphoma, into AIDS Malignancy Consortium (AMC) Clinical Trials: A Retrospective 12- Year Single Institution Experience
Authors: Sakshi Jasra, Ali Mustafa, Amara Gayathri Nandikolla, Urvi A Shah, Yifei Zhang, Ioannis Mantzaris, Aditi Shastri, Adam F. Binder, Ira Braunschweig, Noah Kornblum, Amit Verma, David M. Aboulafia, Murali Janakiram
Journal: Blood (2017)