tbuckley/cabot-search huggingface dataset:
Abstract 12775: Supervised Exercise Therapy Adherence and Six-Minute Walk Improvement in Peripheral Artery Disease. Findings From Two Randomized Clinical Trials
Authors: Michael M Hammond, Lu Tian, Lihui Zhao, Dongxue Zhang, Mary M McDermott
Journal: Circulation (2021)

Introduction: Supervised exercise therapy (SET) is first line therapy for improving walking ability in people with peripheral artery disease (PAD), but adherence to SET is poor. The association of SET adherence with change in six-minute walk distance in PAD is unclear. Methods: Data were combined from two randomized clinical trials of SET for PAD. In both trials, participants with PAD were randomized to exercise or a control group for six months. Those randomized to SET were asked to attend 72 exercise treadmill exercise sessions over six months in the presence of an exercise physiologist. Those randomized to attention control were asked to attend up to 24 educational sessions once weekly for six months. Adherence rates were defined as the number of attended intervention or control sessions divided by the number of expected sessions. Participants randomized to SET were categorized into tertiles of adherence, according to the proportion of exercise sessions attended. Six-minute walk was measured at baseline and at 6-month follow-up. Results: 281 randomized participants (mean age: 68±9 years; 43% female; 61% African American) were included. The mean adherence rate was 75±18 % in the SET group. The adherence rates for the three SET tertiles were: ≤ 69%, 69 – 85%, and ≥ 85% respectively. Baseline characteristics, within group 6-month changes in six-minute walk distance by intervention group, and pairwise comparisons results are shown in table. Conclusion: While greater adherence to SET was associated with greater six-minute walk distance improvement, even participants with PAD in the lowest tertile of adherence had significantly greater six-minute walk improvement, compared to control. These data suggest that even intermittent exercise activity significantly improves six-minute walk in people with PAD.
CBIO-12. KAT5 ACTIVITY CONTROLS GLIOBLASTOMA CELL CYCLE DYNAMICS AND TUMOR GROWTH
Authors: Anca Mihalas, Heather Feldman, Sonali Arora, John Bassett, Anoop Patel, Patrick Paddison
Journal: Neuro-Oncology (2021)

Abstract Current standard of care therapy for glioblastoma (GB) includes cytoreduction followed by ablative therapies that target rapidly dividing cell types. However, non-cycling, quiescent-like states (G0 phase cells) are present in both normal tissue and tumors and play important roles in maintaining heterogeneity and cellular hierarchies. The presence of quiescent-like/G0 states therefore represents a natural reservoir of tumor cells that are resistant to current treatments. Quiescence or G0 phase is a reversible state of “stasis” cells enter in response to developmental or environmental cues. However, it remains largely unclear to what degree or by what mechanisms tumor cells enter into or exit from quiescent-like states. To gain insight into how GB cells might regulate G0-like states, we performed a genome-wide CRISPR-Cas9 screen in patient-derived GB stem-like cells (GSCs) harboring a G0 reporter construct, which is stabilized when cells enter a G0-like state. Among the top screen hits were members of the Tip60/KAT5 histone acetyltransferase complex, including KAT5 itself. Remarkably, we show that knockout of KAT5 in vitro and in vivo dramatically increases G0 subpopulations in GSC cultures and GSC-induced tumors. Using genetically engineered GSC harboring KAT5 under the control of a Doxycyclin-titratable promoter, we establish that incrementally down regulating KAT5 activity is sufficient to slow cell cycle dynamics causing a build-up G0-like cells; and that partial inhibition of KAT5 leads to extended (mouse) patient survival. Further, in primary tumors, cell-based KAT5 activity assays revealed that high grade tumors harbor larger cell subpopulations with higher KAT5 activity than lower grade tumors. In summary, our results suggest that Tip60/KAT5 activity plays key roles in G0 ingress/egress for GBM tumors, may contribute to tumor progression, and may provide novel therapeutic opportunities.
Implementation of Escort-HU Extension: European Sickle Cell Disease Cohort - Hydroxyurea - Extension Study : Interests and Methodology
Authors: Mariane de Montalembert, Ersi Voskaridou, Lena Oevermann, Giovanna Cannas, Anoosha Habibi, Gylna Loko, Laure Joseph, Raffaella Colombatti, Pablo Bartolucci, Valentine Brousse, Frédéric Galactéros
Journal: Blood (2021)
Abstract 13852: Key Value of Inspiratory Muscle Performance and Training in a Home-Based Program to Improve Functional Capacity in Older Heart Failure Patients
Authors: Rohan V Shah, Lawrence P Cahalin, Jacob M Haus, Kelly Allsup, Amanda Delligatti, James Kostra, Wolf Cody, Daniel J Gottlieb, Thomas Byard, Daniel E Forman
Journal: Circulation (2021)

Introduction: Patients with heart failure (HF) often have reduced exercise tolerance. Exercise training has putative value but is often limited by poor adherence or the effects of frailty. Baseline inspiratory muscle performance (IMP) may predict exercise limitation, and inspiratory muscle training (IMT) may have important clinical benefit, including offsetting the metaboreflex which may improve functional capacity by reducing sympathetic peripheral vasoconstriction induced by respiratory fatigue. We hypothesize that low IMP is an important predictor of exercise performance in older adults with HF and that IMT may be an effective home-based training program. Methods: Thirty-four male patients with HF (age and left ventricular ejection fraction of 69±7 years and 37±11%, respectively) were randomized into IMT (n=11) or aerobic and/or strength training (AST; n=23) for a 12-week home-based program. IMT was performed progressively from 50-85% of maximal inspiratory pressure (MIP) with the PrO 2 device (Smithfield, RI) which tracked data and adherence for comparison to AST regimens of cycle ergometry/walking and strength training individually advanced to achieve moderate to high intensities. Study endpoints included MIP, peak oxygen uptake (VO 2 ), 6-minute walk distance (6MWD), 30-second sit-to-stand (STS), grip strength, and leg strength (endurance, 1-rep max, and power). Results: IMT was well-tolerated with greater adherence (92±10% vs 79±34%) and a significantly greater MIP rise (25.3±25.0% vs 3.6±11.0%, p&lt;0.05). Baseline MIP greater than the median of 66 cmH 2 O across all exercise forms (n=18) was associated with significantly greater baseline and post-intervention peak VO 2 (16.4±5.0 vs 12.9±3.9 and 17.5±5.3 vs 13.4±3.1, p&lt;0.05) and was significantly correlated positively to change in 6MWD, STS, grip strength, and leg strength (r=0.352-0.504, p&lt;0.05). Conclusion: Home-based IMT significantly improved IMP and greater baseline IMP was associated with greater cardiorespiratory fitness, functional capacity, and trainability in older HF patients due likely to metaboreflex attenuation and greater adherence. Further study is needed to assess IMP and IMT performed alone or combined with AST regimens to address the growing HF population.
Frontline Consolidation with Blinatumomab for High-Risk Philadelphia-Negative Acute Lymphoblastic Adult Patients. Early Results from the Graall-2014-QUEST Phase 2
Authors: Nicolas Boissel, Francoise Huguet, Carlos Graux, Yosr Hicheri, Patrice Chevallier, Rathana KIM, Marie Balsat, Thibaut Leguay, Mathilde Hunault, Sébastien Maury, Anne Thiebaut-Bertrand, Martine Escoffre-Barbe, Thomas Cluzeau, Alban Villate, Florence Pasquier, Laure Farnault, Florence Van Obbergh, Philippe Rousselot, Yves Chalandon, Eric Delabesse, Cedric Pastoret, Emmanuelle Clappier, Veronique Lheritier, Herve Dombret
Journal: Blood (2021)
Abstract 10024: Single-Cell Transcriptomic Profiling of Immune Cell Phenotype Modulation in Murine Abdominal Aortic Aneurysm
Authors: Zhen Yuan, Shen Song, Tan Yuan, Xinjia Min, Zhejun Cai
Journal: Circulation (2021)

Background: Abdominal aortic aneurysm (AAA) is recently recognized as an autoimmune-induced vascular disease. Nonetheless, the inflammatory cellular heterogeneity and specialty within the aortic wall have not been fully identified. Methods: Infrarenal abdominal aortas of WT mice were perfused with PBS or elastase to simulate sham or AAA models. The aortas were harvested 14 days after surgery and digested for single-cell preparation. The cell pellet was mixed with CD45 microbeads, and proceeded with magnetic separation to isolate CD45 positive immune cell suspension. The cell suspension was loaded into Chromium microfluidic chips with 3’ chemistry and barcoded with 10х Chromium Controller (10X Genomics). All downstream single-cell analyses were performed using the CellRanger, Seurat, or clusterProliler R package. Results: Based on the filtered gene expression matrix, 18 clusters were identified in the final datasets. Enrichment analysis was performed to finger out the specific biological behaviors, such as inflammatory cytokine secretions and promotion of cell proliferation, in each clusters of immune cells. According to the highly expressed cell markers and biological behaviors, we divided each clusters of immune cells into macrophages, dendritic cells (DCs), T or B lymphocytes. It was shown in the t-SNE plot that the cellular quantity of CD45 positive immune cells, especially macrophages and DCs, were prominently altered in the AAA group. The refined subtypes of each kinds of inflammatory cells were distinguished and identified by limiting essential cell markers and increase dimensionality resolution. The specific marker-based analysis showed that the cell count difference of resident macrophages and monocyte-derived DCs (moDCs) are most noticeable between the AAA and the sham group, which might suggest these cells have eventful influence in aneurysm development. Conclusions: The integrated data exhibited the distinctive heterogeneity of CD45 positive immune cells within elastase-induced AAA samples. Some of these cells, such as resident macrophages and moDCs, may play an essential role through several pathways in the pathogenesis of AAA formation according to our scRNA-sequencing result.
Abstract 13316: Cardiomyopathy Induced by Metabolic and Hypertensive Stresses is Alleviated by SARM1 Deficiency
Authors: Christine Light, Chi Fung Lee
Journal: Circulation (2021)

Introduction: NAD depletion emerges as a hallmark of diseases. Strategies to replenish NAD levels have shown promise to treat heart disease, including heart failure with preserved ejection fraction (HFpEF). However, how NAD consumption mechanisms lead to NAD depletion are less understood. SARM1 is a novel intracellular NAD hydrolase that promotes axonal degeneration after axon injury, and its role in cardiomyopathy has not been tested. Hypothesis: We hypothesized that SARM1 deficiency will protect hearts against cardiomyopathy induced by metabolic and hypertensive stresses. Methods and Results: Aged-matched male C57BL/6 wild type (WT) and whole-body SARM1-KO mice were challenged with 16-week diabetic stress initiated by streptozotocin (STZ). SARM1 mRNA or protein levels were suppressed in KO hearts. STZ induced similar hyperglycemia (~600 mg/dL) in both WT and KO mice after 16 weeks. Chronic diabetic stress led to progressive decline in systolic function (FS: 50% vs 35%; P&lt;0.05; n=5) in WT mice, which was ameliorated in KO mice (48%; P&lt;0.05; n=5). Progressive decline in diastolic function by chronic diabetes (E’/A’: 1.53 vs 1.12; n=5) was also improved in diabetic KO mice (1.5; P&lt;0.05; n=5). Up-regulated Nppb in diabetic WT hearts was suppressed by SARM1 deficiency. No compensatory changes in expressions of other NAD hydrolases were observed in diabetic KO hearts. Cardiac fibrosis was induced in diabetic WT hearts and were suppressed in diabetic KO hearts after 16-week diabetic stress. WT and KO mice were challenged with high fat diet feeding (HFD) or HFD with L-NAME (a HFpEF regimen) for 16 weeks. Systolic function was unchanged in mice after HFD or HFpEF regimen, with or without SARM1 deficiency. However, SARM1 deficiency ameliorated diastolic dysfunction of male mice induced by HFD (WT vs KO E’/A’ = 1.07 vs 1.37, n=5) or HFpEF regimen (WT vs KO E’/A’ = 0.96 vs 1.31, n=6). Unlike diabetic cardiomyopathy induced by STZ, cardiac hypertrophy in WT mice was induced by HFD or HFpEF regimen, and KO mice showed decreases in hypertrophy induced by the two stressors. Conclusion: Our data support a protective role of SARM1 deficiency in cardiomyopathy. Pathogenic mechanisms of SARM1 in cardiomyopathy induced by metabolic or hypertensive stresses remain to be determined.
Direct Oral Anticoagulants in Sickle Cell Disease, Where We Stand and Where We Are Heading: A Systematic Review
Authors: Waail Rozi Kashgary, Elrazi Awadelkarim Awadelkarim Hamid Ali, Alaa Rahhal, Abdulrahman F Al-Mashdali, Yousef Hailan, Mohamed A Yassin
Journal: Blood (2021)
Abstract 14023: PRG4 in Calcified Atherosclerotic Plaque Induces Immune Tolerance in Macrophages, and is Implicated in Inflammation-Driven Vascular Calcification
Authors: Olivia J Waring, Nikolaos T Skenteris, Till Seime, Han Jin, Chang Lu, Pieter Goossens, Tannin Schmidt, Marjo Donners, Ljubica Matic, Erik L Biessen
Journal: Circulation (2021)

Atherosclerotic calcification is an independent predictor for a cardiovascular event, and its development is driven by macrophage-led inflammation. PRG4 was previously shown to be the most upregulated gene in microarray data of carotid endarterectomy-derived, high vs low-calcified atherosclerotic plaques. It was shown to be a pro-calcifying factor in the disease, modulating the pro-calcifying switch of vascular smooth muscle cells (VSMC). PRG4’s role in calcified plaque is largely unknown, however, we are able to show a profound effect on macrophage immune response. Transcriptomic data of a highly calcified plaque cohort (N=18 patients) shows PRG4 expression is correlated with inflammatory gene pathways, including toll-like receptor signalling; and immunohistochemistry of this cohort displays co-localization with CD68 + cells. Despite this, PRG4 is not expressed in macrophages in plaque single-cell datasets or transcriptomics datasets, and plaque origin is likely fibroblast and VSMC. Human peripheral blood mononuclear cell (PBMC)-derived macrophage incubation with 100μg/ml recombinant human (rh)PRG4 shows strong NF-κB activation, and secretion of TNF, IL-6, IL-12p70 and IL-10. rhPRG4 stimulation also significantly enhances inflammasome activation, increasing ASC activation (p&lt;0.003) and IL-1β secretion (p&lt;0.001). Moreover, it suppressed macrophage phagocytosis of both zymosan particles (p&gt;0.001), and hydroxyapatite particles (p=0.004). Subsequently, cells stimulated with rhPRG4 develop immune tolerance, a suppressed inflammatory response, to secondary stimulation with either rhPRG4 or lipopolysaccharide - with almost complete ablation of TNF secretion (p&lt;0.001). This phenomenon is accompanied by a 5-fold A20 upregulation (p&lt;0.001), a well-established key regulator of endotoxin tolerance. This immunosuppressive effect was coupled with increased resistance to mitochondrial stress (p&lt;0.001). In conclusion, we see a PRG4-specific phenotype in macrophages; suppressed phagocytosis capability, and acute pro-inflammatory activation of NF-κB and inflammasome pathways, that over longer exposure develops into immunosuppression. This may have profound implications for the overall disease mechanism.
Abstract 11938: Mechanisms of Significant Functional Tricuspid Regurgitation in Pulmonary Arterial Hypertension
Authors: Nicholas Kassis, Habib Layoun, Amit Goyal, Tiffany Dong, Anas M Saad, Rishi Puri, Gustavo A Heresi, Adriano Tonelli, Samir R Kapadia, Serge C Harb
Journal: Circulation (2021)

Introduction: The relationship between pulmonary arterial hypertension (PAH) and secondary (or functional) tricuspid regurgitation (STR) is well-established, and the simultaneous presence of both conditions portends particularly poor outcomes. Yet not all patients with PAH develop significant STR, and the mechanisms underlying this phenomenon remain unclear. Methods: From the Cleveland Clinic Pulmonary Hypertension Registry, patients diagnosed with PAH between 2007-2013 were included. STR, defined by absent primary tricuspid valve disease on transthoracic echocardiogram (TTE), was considered significant if ≥moderate in severity (≥2+ grade) on TTE. Right-sided chambers, annular, and valvular anatomic and functional characteristics by cardiac computed tomography and TTE were compared between patients with significant vs. nonsignificant STR. Results: Among 88 included patients, 52 had significant STR. The median age was 57 years, and 78% were female. No differences were observed in all baseline clinical characteristics between groups. Relative to those with nonsignificant STR, patients with significant STR had worse right ventricular (RV) dysfunction as evidenced by lower tricuspid annular planar systolic excursion [1.5 (1.3,1.7) vs 2.1 (1.7,2.4); p=0.02] and fractional area change, and worse RV global longitudinal strain and RV free wall strain. Significant STR was further associated with increased RV sphericity as denoted by a smaller sphericity index [1.8 (1.6,2.1) vs. 2 (1.7,2.5); p=0.004], with similar annular dimensions and shape, mural and septal leaflets’ length and angle, and tenting height. Conclusion: Anatomic and functional alterations in the RV rather than in the tricuspid valve are implicated in the development of STR in patients with PAH. The underlying mechanism may be linked to RV dyfunction and remodeling, via increasing RV size and sphericity.
Abstract 12991: Staged Hybrid Convergent Procedure for Persistent Atrial Fibrillation: Single Center Outcomes From a Community Hospital
Authors: Kriti Lnu, Uba C Udeh, David B Loran, Chinmay P Patel, Michael G Link, nikhil P theckumparampil
Journal: Circulation (2021)

Introduction: Hybrid-Convergent procedure(HCP) has been recently approved for treatment of persistent atrial fibrillation(AF). This was studied as a same day procedure which posed significant scheduling challenges with regards to procedure space and personnel. Staging the procedure was more convenient in smaller and busy Community Hospitals like ours. We report our experience with Staged HCP. Methods: We retrospectively analyzed all patients who underwent HCP at our Hospital from January 1,2017 to December 31,2020. Same day HCP were excluded. Outcomes at 6 month and 1 year follow up after the procedure were analyzed. Results: A total of 29 patients with persistent AF underwent Staged HCP. The mean age was 62.3 years with 75.86% being men. Periprocedural and 30 day mortality was 0%. The mean time between epicardial ablation and endocardial ablation was 46.15 days (SD :17.5 days, interquartile range 6-78). Freedom from AF (normal sinus rhythm on electrocardiograms and/or &lt;1% AF burden on &gt;24 hour monitoring) was seen in 77.78% and 88% patients at 6 months and 1 year respectively. Success of procedure (freedom from AF with maintenance as before procedure, decrease in dose of or complete cessation of Class I/III anti-arrhythmic drug) was seen in 70.4% and 76% at 6 months and 1 year respectively. The de-escalation in treatment (complete cessation or dose reduction of Class I/III anti-arrhythmic drug) at 6 month and 1 year follow up was seen in 57.14% and in 54.55% patients respectively. Conclusions: Staged HCP can be done safely with excellent outcomes on par with results seen in the CONVERGE Clinical Trial
Abstract 11670: Psychological Distress and Health Status Perception in Patients With a Previous Myocardial Infarction or Stroke
Authors: Aparna Narendrula, Kiran Ajani, Jacob Lang, Ellen Brinza, Chris Longenecker
Journal: Circulation (2021)

Introduction: While understanding the impact of mental health on health status perception improves patient-centered care, this relationship is not well-established in cardiac patients. We examined the association between psychological distress and health status perception in patients with a previous myocardial infarction (MI) and/or stroke. Methods: We extracted data for patients with a previous MI and/or stroke from the 2019 National Health Interview Survey (NHIS). Health perception was self-reported and grouped as poor/fair (0) or good/very good/excellent (1). Anxiety and depression were estimated using the Generalized Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-8 (PHQ-8) and grouped based on severity. Multivariable logistic regressions controlling for sex, age, education level, smoking status, race, and BMI were performed to assess our hypothesis that higher GAD-7 and PHQ-8 scores are associated with worse health perception in patients with a previous MI/stroke. Results: Of 31,948 individuals for whom data on MI/stroke was available, 6.8% (n=2,181) reported a previous MI and/or stroke. Of these patients, 36.6% (n=799) had scores consistent with anxiety and/or depression on the GAD-7 or PHQ-8. The odds of reporting good/very good/excellent health status were lower for individuals with anxiety (OR 0.245, 95% CI = 0.192-0.314, P &lt;0.001) or depression (OR 0.243, 95% CI = 0.197-0.298, P &lt;0.001) compared to those without anxiety/depression. Increasing severity of anxiety/depression was also associated with worse perception of health status ( Table 1 ). Respondents identifying as “Black” or “Other” race and those with lower education levels also demonstrated significantly worse perceived health status. Conclusion: Patients with previous MI/stroke and concomitant psychological distress have worse perception of health status. Understanding the range of patient health perceptions can help physicians provide more patient-centered care.
iPSC-derived cranial neural crest-like cells can replicate dental pulp tissue with the aid of angiogenic hydrogel
Authors: Yoshifumi Kobayashi, Julie Nouet, Erdenechimeg Baljinnyam, Zain Siddiqui, Daniel H. Fine, Diego Fraidenraich, Vivek A. Kumar, Emi Shimizu
Journal: Bioactive Materials (2021)

The dental pulp has irreplaceable roles in maintaining healthy teeth and its regeneration is a primary aim of regenerative endodontics. This study aimed to replicate the characteristics of dental pulp tissue by using cranial neural crest (CNC)-like cells (CNCLCs); these cells were generated by modifying several steps of a previously established method for deriving NC-like cells from induced pluripotent stem cells (iPSCs). CNC is the anterior region of the neural crest in vertebrate embryos, which contains the primordium of dental pulp cells or odontoblasts. The produced CNCLCs showed approximately 2.5-12,000-fold upregulations of major CNC marker genes. Furthermore, the CNCLCs exhibited remarkable odontoblastic differentiation ability, especially when treated with a combination of the fibroblast growth factors (FGFs) FGF4 and FGF9. The FGFs induced odontoblast marker genes by 1.7-5.0-fold, as compared to bone morphogenetic protein 4 (BMP4) treatment. In a mouse subcutaneous implant model, the CNCLCs briefly fated with FGF4 + FGF9 replicated dental pulp tissue characteristics, such as harboring odontoblast-like cells, a dentin-like layer, and vast neovascularization, induced by the angiogenic self-assembling peptide hydrogel (SAPH), SLan. SLan acts as a versatile biocompatible scaffold in the canal space. This study demonstrated a successful collaboration between regenerative medicine and SAPH technology.