tbuckley/cabot-search huggingface dataset:
CircR2Disease v2.0: An Updated Web Server for Experimentally Validated circRNA–Disease Associations and Its Application
Authors: Chunyan Fan, Xiujuan Lei, Jiaojiao Tie, Yuchen Zhang, Fang-Xiang Wu, Yi Pan
Journal: Genomics Proteomics & Bioinformatics (2021)

Abstract With accumulating dysregulated circular RNAs (circRNAs) in pathological processes, the regulatory functions of circRNAs, especially circRNAs as microRNA (miRNA) sponges and their interactions with RNA-binding proteins (RBPs), have been widely validated. However, the collected information on experimentally validated circRNA–disease associations is only preliminary. Therefore, an updated CircR2Disease database providing a comprehensive resource and web tool to clarify the relationships between circRNAs and diseases in diverse species is necessary. Here, we present an updated CircR2Disease v2.0 with the increased number of circRNA–disease associations and novel characteristics. CircR2Disease v2.0 provides more than 5-fold experimentally validated circRNA–disease associations compared to its previous version. This version includes 4201 entries between 3077 circRNAs and 312 disease subtypes. Secondly, the information of circRNA–miRNA, circRNA–miRNA–target, and circRNA–RBP interactions has been manually collected for various diseases. Thirdly, the gene symbols of circRNAs and disease name IDs can be linked with various nomenclature databases. Detailed descriptions such as samples and journals have also been integrated into the updated version. Thus, CircR2Disease v2.0 can serve as a platform for users to systematically investigate the roles of dysregulated circRNAs in various diseases and further explore the posttranscriptional regulatory function in diseases. Finally, we propose a computational method named circDis based on the graph convolutional network (GCN) and gradient boosting decision tree (GBDT) to illustrate the applications of the CircR2Disease v2.0 database. CircR2Disease v2.0 is available at http://bioinfo.snnu.edu.cn/CircR2Disease_v2.0 and https://github.com/bioinforlab/CircR2Disease-v2.0.
Abstract 10665: Pulse Wave Velocity Measured at End-Diastole Underestimates Aortic Stiffness
Authors: Anilkumar K Reddy, Mark L Entman, George E Taffet
Journal: Circulation (2021)

Introduction: Aortic stiffness (AS) is assessed using pulse wave velocity (= distance (D) between two aortic sites / foot-to-foot transit time of pressure or velocity pulse (ffPTT) between the sites ) which is considered as “gold standard”. But, PWV varies with cyclic pressure in the normal aorta and PWV measured at end-diastole underestimates AS. This underestimation is greatest when aorta is the stiffest. Hypothesis: We hypothesize that PWV measured at diastole is lower than that measured at systole and that PWV should be measured over the entire cardiac cycle for better representation of AS. Methods: We measured pressures invasively with a dual sensor catheter (0.46 mm dia) at two descending aortic sites (25 mm apart) in normal rats. We measured blood velocities noninvasively with two Doppler probes placed at aortic arch and abdominal aorta. The pressure and blood velocity signals were acquired simultaneously (at baseline &amp; post-esmolol admin). From the two pressure signals we measured PWVsp (at dicrotic notch; end-systolic fiducial marker) and PWVdp (at end-diastole; foot fiducial marker). PWVd (end-diastole; foot) was measured from the two blood velocity signals. Results &amp; Conclusions: We plotted the PWV versus blood pressure. We found that the slope of aPWVsp &gt; the slope of aPWVdp indicating that PWV varies with blood pressure within the cardiac cycle. We also found that slope of aPWVd &lt; aPWVdp because, D used to calculate PWVdp is fixed at 25mm, whereas D used to calculate aPWVd was estimated as the distance between Doppler probe tips on the surface of the skin (aortic arch curvature was not accounted for). In conclusion, a more representative AS can be assessed through 1. PWV measurement at systole &amp; diastole within the cardiac cycle of a noninvasively measured vessel wall motion (a pressure signal surrogate) where the systolic and diastolic fiducial points can be identified, and 2. use of two aortic sites on the straight part of the descending aorta for better estimating of D.
TAMI-49. JAK STAT INHIBITION REVERSES MYELOID CELL INDUCED ANTI TUMOR IMMUNITY IN T CELLS
Authors: Vidyha Ravi, Nicolas Neidert, Paulina Will, Kevin Joseph, Ulrich Hofmann, Jürgen Beck, Oliver Schnell, Dieter Henrik Heiland
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Many central questions about the immunosuppressive microenvironment in glioblastoma (GBM) remain unanswered, particularly the interaction with lymphoid and myeloid populations. Here, we combined single-cell (scRNA) and spatial transcriptomics (stRNA) to comprehensively characterize the immune interaction with GBM. MATERIAL AND METHODS We performed scRNA-Seq of 50k CD45+ cells (8 patients) and inferred transcriptional programs and fate decisions in T cells. A novel algorithm (Nearest functionally connected neighbor) was used to predict interacting cells, further validated using spatial transcriptomics and immunofluorescence. Our findings were validated in our human neocortical glioblastoma model with autografted T cells. RESULTS Integration of st/scRNA-seq revealed a transcriptional shift of T cells towards exhaustion/hypoxia induced dysfunction. Pseudo-time analysis revealed increased Interleukin 10 (IL10) response during the Tcell transformation from the effector to the exhausted state. Using NFCN we identified a subset of HMOX1+ myeloid cells (STAT/HMOX axis), responsible for this IL10 release. Computational findings were validated using our human neocortical glioblastoma model with autografted T cells, where IL10R-inhibition/myeloid cell depletion prevented T cell exhaustion/dysfunction (p &amp;lt; 0.01) . In order to target the STAT3/HMOX1 axis we used a JAK/STAT inhibitor in our model which showed a drastic reduction of IL10 release (p&amp;lt; 0.02) and concordant activation of T cells. Clinically, one patient treated with a JAK/STAT-inhibitor in a neoadjuvant setting, 4 weeks prior to the recurrent GBM surgery, led to a significant increase (p&amp;lt; 0.001) in effector T cell population. CONCLUSION Our findings suggest that targeting the myeloid compartment of GBM provides an opportunity to convert a “cold” into “hot” immune environment which might be helpful to improve all T cell based therapies in the future.
Abstract 11440: Subclinical Cardiovascular and Non-Cardiovascular Risk Factors for Heart Failure with Preserved and Reduced Ejection Fraction in Black Americans: The Jackson Heart Study
Authors: Li Zhao, Rani Zierath, Jenine John, Brian Claggett, Michael E Hall, Donald Clark, Kenneth R Butler, Adolfo Correa, Amil M Shah
Journal: Circulation (2021)

Introduction: Heart failure (HF) disproportionately burdens Black Americans. The contributions of impairments in cardiovascular (CV) and non-cardiovascular (non-CV) function to incident HF with reduced (HFrEF) and preserved (HFpEF) ejection fraction in this group remain unclear. Methods: Among 4,356 Black participants in the Jackson Heart Study (JHS) free of prevalent HF at visit 1 (2000-2004), multivariable Cox proportional hazard models were employed to assess the associations of measures of CV and non-CV organ function with incident HF, HFpEF, and HFrEF over a median follow-up of 13 years. Systems considered included: CV: left ventricular (LV) structure (mass index; LVMI), LV systolic function (LVEF), LV diastolic function (left atrial diameter; LAD), systemic arterial function (pulse pressure; PP); Non-CV: pulmonary function (percent predicted FEV1; ppFEV1), renal function (eGFR), body composition (waist circumference), and dysglycemia (hemoglobin A1c; HbA1c). Model covariates included age, sex, hypertension, diabetes, smoking status, and coronary disease history. Results: Average age was 54±13 years and 64% were women. Over median 13 (IQR 12-14) years follow-up, incident HF occurred in 315 participants (152 HFpEF, 134 HFrEF, 29 unknown LVEF). In multivariable models incorporating measures reflecting each organ system, significant predictors of incident HFpEF included greater LAD, higher PP, lower ppFEV1, lower eGFR, larger waist circumference, and higher HbA1c (Figure). Predictors of incident HFrEF included greater LVMI, lower LVEF, and lower eGFR. eGFR was the only independent predictor of both HFpEF and HFrEF. Conclusion: Subclinical impairments in CV and non-CV organ function differentially associate with risk of incident HFpEF and HFrEF among Black Americans. These findings support partially distinct mechanisms underlying HFrEF and HFpEF, and a greater contribution of multisystem non-cardiac impairments to HFpEF in particular.
EXTH-65. INSERTION OF MICRORNA TARGET SEQUENCES INTO RETROVIRAL REPLICATING VECTORS EFFECTIVELY RESTRICTS TRANSGENE EXPRESSION AND VIRAL REPLICATION IN HUMAN HEMATOPOIETIC STEM AND PROGENITOR CELLS
Authors: Sara Collins, Akihito Inagaki, Maria Barcova, Alicia Freedman, Megan Montoya, Alexander Haddad, Katrin Hacke, Suzanne Matsuura, Nina Timberlake, Amy Lin, Douglas Jolly, Noriyuki Kasahara
Journal: Neuro-Oncology (2021)

Abstract Prodrug activator gene therapy with a retroviral replicating vector (RRV) has shown a highly favorable safety profile and long-term survival in early-phase trials for recurrent high-grade glioma. Overall endpoints were not met in a recent Phase 3 trial, but highly statistically significant survival was observed in prespecified patient subgroups as compared to randomized matched control patients receiving standard-of-care treatments, and further clinical evaluation is being focused on these subgroups. Additional strategies to enhance therapeutic potency may require two or more RRVs to deliver multiple transgenes simultaneously, but RRVs encoated with the same envelope protein will compete for the same cellular receptors, interfering with efficient co-infection. The current clinical vector (formerly Toca511, now DB107) is encoated by amphotropic murine leukemia virus (MLV) envelope, which binds to inorganic phosphate transporter PiT-2/SLC20A2. To switch RRV tropism, we developed RRVs pseudotyped with a heterologous envelope from Gibbon ape leukemia virus (GALV), which utilizes an alternative phosphate transporter, PiT-1/SLC20A1, for cell entry. Efficient co-infection of established and primary human glioblastoma cells with MLV- and GALV-pseudotyped RRV was achieved, without receptor competition. However, human hematopoietic stem/progenitor cells (HSPC) also express high levels of PiT-1, which may increase potential genotoxicity of GALV-pseudotyped RRV. Accordingly, as a novel strategy to restrict gene expression and replication in HSPC, we have developed and tested new RRV designs incorporating microRNA target sequences (miRT). Insertion of miRT recognized by hematopoietic lineage-specific microRNA-142-3p resulted in complete suppression of RRV replication in primary human CD34+ HSPC, with the percentage of infected cells below 1% after vector inoculation at multiplicities of infection (MOI) 0.05 and 0.1, and remaining below 3% even after inoculation at MOI 0.5 and 1.0. In vivo models have been developed for on-going studies to evaluate miRT-mediated restriction strategies for avoidance of potential genotoxicity by RRV in normal hematopoietic cells.
NCOG-35. THE LATE INTRACRANIAL ADVERSE EVENTS OCCUR MORE FREQUENTLY IN INTRACRANIAL GERMINOMAS TREATED WITH HIGH DOSE RADIOTHERAPY
Authors: Yoshiki Arakawa, Etsuko Yamamoto, Katsutsugu Umeda, Yohei Mineharu, Megumi Uto, Junko Takita, Takashi Mizowaki, Susumu Miyamoto
Journal: Neuro-Oncology (2021)

Abstract OBJECTIVE The standard treatment for intracranial germinoma has been radiotherapy covering the whole ventricle together with chemotherapy. Radiotherapy is important, but it is a cause of the late brain damages. Therefore, the recent clinical trials have been planned to evaluate the reduced radiation dose. The aim of this study was to evaluate the intracranial adverse events in the patients with intracranial germinomas treated in our hospital. PATIENTS AND METHODS 65 patients were diagnosed as intracranial germinoma. Patients with hCG &amp;gt; 100 IU/l and/or AFP &amp;gt; 10 ng/ml were excluded. Patients, who were diagnosed as germinoma by imaging without histology, were included. RESULTS Follow-up time was from 2 to 467 months (median 136 months). Until 2005, 37 patients were treated with radiotherapy &amp;gt;30 Gy alone or with chemotherapy. After then, 23 patients received whole-ventricle radiotherapy 24-30 Gy with chemotherapy. 2 patients were treated with chemotherapy alone, 3 were unknown. 10-year PFS was 82.05% in radiotherapy &amp;gt;30 Gy alone, 86.36% in radiotherapy &amp;gt;30 Gy with chemotherapy and 100% in radiotherapy 24-30 Gy with chemotherapy. The intracranial adverse events after the initial treatment were identified, such as pituitary dysfunction: 6 (9.2%), hearing disturbance: 2 (3.1%), neurocognitive dysfunction 6 (9.2%), microbleeds 10 (15.4%), cavernous angioma 6 (9.2%), brain tumor 1 (1.5%), cerebral artery stenosis 1 (1.5%). The frequency of late adverse brain events is higher in radiotherapy &amp;gt;30 Gy with/without chemotherapy than 24-30 Gy (total events, 25 vs. 9, P&amp;lt; 0.03). CONCLUSION Patients with intracranial germinoma obtain long-term survival but suffer from the late intracranial adverse events. The late intracranial adverse events occur more frequently in intracranial germinomas treated with radiotherapy &amp;gt;30 Gy than 24-30 Gy. Long-term follow-up is important to promptly identify and deal with the late brain damages.
Fitusiran, an Investigational siRNA Therapeutic Targeting Antithrombin for the Treatment of Hemophilia: First Results from a Phase 3 Study to Evaluate Efficacy and Safety in People with Hemophilia a or B <i>without</i> Inhibitors (ATLAS-A/B)
Authors: Alok Srivastava, Savita Rangarajan, Kaan Kavakli, Robert Klamroth, Gili Kenet, Liane Khoo, Chur-Woo You, Weiqun Xu, Niel Malan, Laurent Frenzel, Catherine N. Bagot, Oleksandra Stasyshyn, Chia-Yau Chang, Stacey Poloskey, Shauna Andersson, Zhiying Qiu, Baisong Mei, Steven W. Pipe
Journal: Blood (2021)
Abstract 13922: Association Between Quadrileaflet Tricuspid Valve and Location of Regurgitation Jet Origin in Patients With Functional Severe Tricuspid Regurgitation
Authors: Omori Taku, Shunsuke Kagawa, Goki Uno, Florian Rader, Robert J Siegel, Takahiro Shiota
Journal: Circulation (2021)

Introduction: It has been known that the posterior leaflet of the tricuspid valve (PTL) has several indentations or clefts in its free edge, giving the tricuspid valve (TV) equal to or more than four leaflets appearance. However, little is known about whether the indentations or clefts can be a location of tricuspid regurgitation (TR) jet origin in severe TR. Hypothesis: This study aimed to investigate the association between quadrileaflet TV and location of TR jet origin in patients with functional severe TR. Methods: We retrospectively studied 85 functional severe TR patients who underwent 3D transesophageal echocardiography which was performed using the EPIQ7 ultrasound system with a X8-2t probe (Philips Medical Systems). The morphology of the TV leaflets was ascertained using 3D volume-rendered images. Clefts extending over 50% of the depth of the leaflets were determined as a landmark between 2 adjacent leaflets. The location of TR jet origin and vena contracta area (VCA) were ascertained using real-time 3D color Doppler images. All images were analyzed by using QLAB 3D quantification software (Philips Medical Systems). Results: In 85 functional severe TR patients, a total of 3 (4%) patients with bileaflet, 60 (71%) patients with trileaflet and 22 (26%) patients with quadrileaflet were identified. All quadrileaflet TV had dichotomous PTLs (PTL 1 and PTL 2) and there was no patient who had equal to or more than five leaflets. In 22 patients with quadrileaflet, 10 (45%) patients showed TR jet origin located between PTL 1 and PTL 2 (Figure A). Also, quadrileaflet TV patients with TR jet origin located between PTL 1 and PTL 2 had significantly larger VCA than those without (185 vs. 62 mm2, P&lt;0.001, Figure B). Conclusions: In patients with functional severe TR, one fourth patients showed quadrileaflet TV morphology. Furthermore, TR jet origin located between PTL 1 and PTL 2 can be seen only in a condition of TR beyond severe.
Abstract 14494: 5 Year Outcomes After Transcatheter & Surgical Aortic Valve Replacements in Chronic Liver Disease Patients
Authors: Rahul Raiker, Haig Pakhchanian, Charles DeYoung, Arka Chatterjee
Journal: Circulation (2021)

Introduction: Chronic Liver Disease (CLD) patients are known to have increased morbidity and mortality when undergoing surgical procedures. While short term outcomes among patients undergoing trans...
Abstract 15712: Activation of JNK Signaling in Polymicrobial Sepsis Increases the Expression of B-Type Natriuretic Peptide, Which Promotes Septic Hypotension
Authors: Matthew Hoffman, Ioannis D Kyriazis, Alexandra Dimitriou, Santosh K Mishra, Walter J Koch, Konstantinos Drosatos
Journal: Circulation (2019)

Introduction: Elevated plasma BNP is associated with low blood pressure, and suggests poor prognosis in septic patients. However, the relationship between elevated BNP and septic hypotension has no...
Abstract 14088: Ventricular Longitudinal Function by CMR Predicts Heart Failure Associated Morbidity in Patients With Heart Failure and Reduced Ejection Fraction
Authors: Jonathan Berg, Julius Åkesson, Robert Jablonowski, Kristian Solem, Einar Heiberg, Rasmus Borgquist, Håkan Arheden, Marcus Carlsson
Journal: Circulation (2021)

Ventricular longitudinal function measured as basal-apical atrioventricular plane displacement (AVPD) or global longitudinal strain (GLS) are potent predictors of mortality and could potentially be predictors of morbidity in heart failure (HF). We hypothesize that decreased AVPD and GLS are associated with increased morbidity measured. Patients with HFrEF (EF≤40%) referred to a CMR exam were considered for inclusion. Ventricular longitudinal function, ventricular volumes and myocardial fibrosis or infarctions were analyzed. National registries provided data on cause of cardiovascular hospitalizations and cardiovascular mortality and this was used as a composite endpoint. A time-to-event analysis capable of including reoccurring events were employed with 5-year follow-up. HFrEF patients (n=287, age 62±12, 78% male) had EF 26.5% (SEM 0.5), AVPD 7.8 mm (SEM 0.1) and GLS -7.5% (SEM 0.2). There were 578 events in total and the vast majority was HF hospitalizations (n=418). Other major events were revascularizations (n=64), cardiovascular deaths (n=40) and myocardial infarctions (n=21), and 155 (54%) patients experienced at least one event (Mean 2.0, range 0-64). Patients in the bottom AVPD or GLS tertile (&lt;6.8mm or &gt;-6.1%) experienced over 3 times as many events compared to the top tertile (&gt;8.8 mm or &lt;-8.4%, p&lt;0.001) (Figure 1). In multivariate analysis adjusted for significant variables, AVPD and GLS remained as independent predictors of events (HR 1.12 per-mm-decrease and HR 1.13 per-%-increase) (Table 1). In conclusion, ventricular longitudinal function, measured either as AVPD or GLS, have independently prognostic implications for morbidity in HFrEF patients.
Abstract 12074: Rhythm Control Strategy in Recent Atrial Fibrillation: An Online Educational Intervention Improved Physician Knowledge, Competence, and Confidence
Authors: Margaret Harris, Walid Amara, Lih-Fan Chang, Michael Lacouture, Philippe Guedj
Journal: Circulation (2021)

Background: In clinical practice, rhythm control strategies, including antiarrhythmic drugs (AAD), are currently used for the management of patients with arrhythmias. Despite latest guideline updates and randomized trials on early rhythm control strategies, physicians remain uncertain on the selection of a good strategy for these patients. Purpose: To determine if an online continuing medical education intervention could improve knowledge, competence, and confidence of cardiologists and surgeons related to latest data on rhythm control strategies and the use of AAD in patients with recent AF. Methods: Cardiologists and surgeons electively participated in a video-based, 3-faculty educational panel discussion on earlier rhythm control strategies in recent AF. A repeated pairs pre-/post-assessment study design was used and a paired samples t-test for overall and McNemar’s test at the question level ( P &lt;.05 is considered significant) assessed statistical significance. Data were collected March 3, 2021 through June 1, 2021. Results: Overall significant improvements were seen after education for both cardiologists (N = 525) and surgeons (N = 2180). Pre-assessment, the average correct response rate was 55% for cardiologists and 51% for surgeons, while post-assessment average correct response rates increased to 66% and 64%, respectively. Significant improvements were observed in cardiologists’ and surgeons’ knowledge and competence related to the use of rhythm control strategies in recent AF (Table). As a result of the education, 39% of cardiologists and 48% of surgeons had a measurable improvement in their confidence on rhythm control strategies choice in recent AF. Conclusion: The statistically significant improvements observed in this intervention demonstrate that participation in a video-based panel discussion to increase knowledge, competence, and confidence of cardiologists regarding the selection of rhythm control strategies in recent AF.
RADT-14. TOWARDS IMAGE-GUIDED MODELING OF PATIENT-SPECIFIC RHENIUM-186 NANOLIPOSOME DISTRIBUTION VIA CONVECTION-ENHANCED DELIVERY FOR GLIOBLASTOMA MULTIFORME
Authors: Chengyue Wu, David Hormuth, Chase Christenson, Michael Abdelmalik, William Phillips, Thomas Hughes, Andrew Brenner, Thomas Yankeelov
Journal: Neuro-Oncology (2021)

Abstract Convection-enhanced delivery (CED) of Rhenium-186 nanoliposomes (RNL) is a promising approach to provide precise delivery of large, localized doses of radiation with the goal of extending overall survival for patients with recurrent GBM. A central component of successful CED, is achieving optimal catheter placement for delivery of the therapy. While surgical planning software exists for this purpose, current approaches are designed for small molecules and therefore are not appropriate for larger particles like RNL. To address this concern, we have developed a mathematical model to predict the distribution of RNL via CED on a patient-specific basis. The model is defined on the 3D brain domain which consists of 1) pressure and flow fields generated by accounting for catheter infusion, flow through brain, and fluid loss into capillaries, and 2) the transport of RNL governed by an advection-diffusion equation. We utilize pre-operative MRI to assign patient-specific tissue geometry and properties (e.g., diffusivity, conductivity), and calibrate the model with SPECT measurements within 24 h post the RNL delivery. This model is implemented on one patient enrolled in NCT01906385. The accuracy of model calibration and prediction is evaluated by the Dice score and concordance correlation coefficient (CCC) between modeled and measured distributions of RNL. Our model calibration achieves Dice scores of 0.80, 0.81, 0.69 and CCC of 0.92, 0.93, 0.73 for RNL distributions at the mid-delivery, end of delivery, and 24 h after the delivery, respectively. Long-term model prediction achieves Dice scores of 0.69 and 0.52 at 144 h and 196 h after the delivery, respectively, and CCC of 0.57 and 0.31. Preliminary results demonstrate a proof-of-concept for a patient-specific model to predict the spatiotemporally-resolved distribution of nanoparticles. Ongoing efforts focus on improving our model by accounting backflow and angle of catheter placement, and applying to more patients. Funding: NIH R01CA235800, CPRIT RR160005.