tbuckley/cabot-search huggingface dataset:
Abstract 13791: Trends in the Use of Oral Anticoagulation for Nonvalvular Atrial Fibrillation in a Large Integrated Health Care System 2011-2020
Authors: Joseph Chronowski, Stacey Grassi, Patrick Roman, Stephen J Voyce
Journal: Circulation (2021)

Introduction: Direct Oral anticoagulants (DOACs) have demonstrated superiority or noninferiority to vitamin K antagonists (VKAs) for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). The uptake of DOACs into clinical medicine has been variable and may be influenced by many factors. Objective: To determine how the prescription (Rx) pattern for DOACs has evolved since their introduction and to evaluate the temporal effects of factors which may impact DOAC Rx. Methods: We performed a retrospective review of patients with NVAF within the Geisinger Health System from 2011-2020. We evaluated longitudinal yearly trends in anticoagulant use and new/initial Rx of DOAC vs VKA in NVAF. We examined subgroups based on clinical and demographic indices. Key points in the timeline regarding DOAC availability and medical society or institutional guidelines were incorporated to determine whether changes DOAC Rx were temporally associated with these events. Results: We identified 34, 936 patients with NVAF. The average age of the was 74.3 years, 48% were female and 98% white. The average CHA 2 DS 2 Vasc score was 2.5. There was a linear increase in overall and new Rx for DOACs with 77.7% of all new Rx for DOAC in 2020. The greatest increase in new DOAC Rx coincide with timepoints of DOAC incorporation into ACC/AHA Guidelines, approval of Xa reversal agent and institutional formulary change. Apixaban was the most common DOAC Rx since 2015 and now accounts for 70.9% of all new anticoagulation Rx and 91.3% of new DOAC Rx at our institution. Conclusions: There was a linear increase in DOACs use for NVAF over time and apixaban has become the most prescribed DOAC at our institution. Society guidelines, approval of reversal agents and institutional formulary changes appear to be temporally associated with increased Rx of DOACs for NVAF.
Abstract 18022: Mediator 1 Deficiency in Macrophage Increases Atherosclerosis via Modulation of Macrophage Polarization
Authors: Liang Bai, Zhao Li, Sihai Zhao, Jin Zhang, Jianglin Fan, John Y Shyy, Enqi Liu
Journal: Circulation (2017)

Introduction: Mediator 1 (MED1), a key subunit of the Mediator complex, interacts with several nuclear receptors and transcription factors [e.g., peroxisome proliferator-activated receptor γ (PPARγ...
High-Dose Melphalan in 1 Day Versus over 2 Days Followed By Autologous Stem Cell Transplantation As Consolidation Treatment in Patients with Multiple Myeloma
Authors: Mesire Aydin, Man Wai Tang, Marielle Wondergem, David C. de Leeuw, Jurgen J. Wegman, Bart J. Biemond, Niels W.C.J. van de Donk, Sonja Zweegman, Ellen Meijer, Erfan Nur
Journal: Blood (2021)
The Impact of EUTOS Long-Term Survival (ELTS) Score on Predicting Progression and Survival Among Turkish Patients with Chronic Myeloid Leukemia
Authors: Mert Bektaş, Tuğrul Elverdi, Ayşe Salihoğlu, Muhlis Cem Ar, Şeniz Öngören, Zafer Başlar, Teoman Soysal, Ahmet Emre Eşkazan
Journal: Blood (2021)
Abstract 12876: Identification of Pathogenic Immune Cell Subsets in Immunotherapy-Induced Myocarditis
Authors: Han Zhu, Francisco X Galdos, Sarah Waliany, Daniel Lee, Julia Ryan, Joel W Neal, Heather A Wakelee, Sunil A Reddy, Ronald M Witteles, Holden T Maecker, Mark Davis, Patricia K Nguyen, Sean M Wu
Journal: Circulation (2021)

Introduction: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies used to activate the immune system against tumor cells. Despite therapeutic benefits, ICIs have the potential to cause immune related adverse events (irAE) such as myocarditis, a rare but serious side effect with up to 50% mortality in affected patients. Histologically, patients with ICI myocarditis have lymphocytic infiltrates in the heart, implicating T-cell-mediated mechanisms. However, the precise pathologic immune subsets and molecular changes in ICI myocarditis are unknown. Hypothesis: We hypothesize that ICI myocarditis is associated with significant quantitative and molecular changes in pathogenic immune cell subsets. Methods: To identify immune subset(s) associated with ICI myocarditis, we performed time-of-flight mass cytometry (CyTOF) on peripheral blood mononuclear cells from 40 patients and controls with autoimmune adverse events (irAE) on ICI including four patients with ICI myocarditis. We also profiled 15 patients/controls using single cell T-cell receptor (TCR) sequencing and RNA sequencing (scRNA-seq) with feature barcoding for surface marker expression confirmation. Results: With both methods, we found expansion of cytotoxic CD8+ T effector cells re-expressing CD45RA (Temra CD8+ cells) in ICI myocarditis patients compared to controls. Using TCR sequencing, these CD8+ Temra cells were clonally expanded in myocarditis patients. Transcriptomic analysis of these Temra CD8+ clones confirmed a highly activated and cytotoxic phenotype with expression of granzyme/perforin. Longitudinal study demonstrated progression of these Temra CD8+ cells into an exhausted phenotype two months after treatment with glucocorticoids. Differential expression of proinflammatory chemokines (CCL4/CCL4L2/CCL5) was uncovered in clonally expanded Temra CD8+ cells, and ligand-receptor analysis implicated their regulation of other inflammatory cells such as monocytes and NK cells. Conclusions: Clonal cytotoxic Temra CD8+ cells are significantly increased in patients with ICI myocarditis, and have unique transcriptional changes, including upregulation of chemokines CCL4/CCL4L2/CCL5, which may serve as attractive diagnostic/therapeutic targets.
HDAC Inhibition Effectively Induce Apoptosis in Diffuse Large B Cell Lymphoma with High Bfl-1
Authors: Eunchae Park, Chansub Lee, Jihyun Park, Jun Liu, Junshik Hong, Dong-Yeop Shin, Ja Min Byun, Youngil Koh, Sung-Soo Yoon
Journal: Blood (2021)
Evolution in Resource Utilization for Unique Toxicities Related to Chimeric Antigen Receptor T Cell Therapy from 2017 to 2020: A Database Review
Authors: Moazzam Shahzad, Muhammad Salman Faisal, Ernie Shippey, Qamar Iqbal, Laila Hashim, Clint Divine, Zahra Mahmoudjafari, Rajat Bansal, Muhammad Umair Mushtaq, Leyla Shune, Nausheen Ahmed
Journal: Blood (2021)
Abstract 10333: Recreational Multi Use Trails and Cardiovascular Disease: A Difference-in-Differences 18 Year Natural Experiment
Authors: Jonathan M McGavock, Erin Hobin, Heather Prior, Anders Swanson, Gillian Booth, Laura Rosella, Stephanie Whitehouse, Brendan Smith, Kelly Russell, Nicole Brunton, Charles Burchill
Journal: Circulation (2021)

Introduction: There is little experimental evidence of the impact of multi-use recreational trails that support physical activity on cardiovascular disease (CVD). Hypothesis: Neighbourhoods that added multi-use trails would experience a greater decline in CVD events and risk factors compared to neighbourhoods that did not. Methods: We used a difference in differences design to study the addition of four multi-use trails 4-7km in length on CVD-related outcomes using administrative health, census and built environment data available for all citizens 30 years of age and older from Winnipeg, Canada. A 400m buffer stratified intervention and comparison neighbourhoods. Bicycle counts were recorded via electromagnetic counters for 5 years on all trails. The primary and secondary outcomes were composite measures of incident CVD events (mortality, ischemic heart disease, cerebrovascular disease and congestive heart failure) and CVD risk factors (hypertension, diabetes and dyslipidemia) and assessed quarterly for 10 years prior to and 6 years following the intervention. Intervention and comparison areas were propensity score matched, using scores regressed from baseline measures of age, sex, socioeconomic indicators, and built environment attributes that support physical activity. Results: Between 2012 and 2018, 1,429,588 cyclists were recorded on the trails and cycling use varied ~2.0-fold across the trails. Between 2000 and 2018, there were 82,632 CVD events and 201,058 CVD risk events. During the 18-year natural experiment CVD event rates and risk factors declined ~33% in both comparison and intervention neighbourhoods. In propensity score matched regression models, the incident rate ratio was 1.06 (95% CI: 0.90 to 1.24) for CVD events and 0.92 (95% CI: 0.84 to 1.02) for CVD risk factors. Sensitivity analyses revealed greater effect sizes with increasing trail use (incident rate ratios for highest vs lowest cycling counts = 0.85; 95% CI: 0.75 to 0.96 vs 1.08; 95% CI: 0.92 to 1.27). Conclusions: The addition of recreational multi-use trails was not associated with changes in overall CVD events or risk factors in adjacent neighbourhoods, compared to distant neighbourhoods, however, the effects on CVD risk factors may be influenced by trail use.
The Eyes Have It
Authors: Miten Vasa, Thomas E. Baudendistel, Christine E. Ohikhuare, Elizabeth M. Grace, Wilson Yan, S. Andrew Josephson, Lawrence M. Tierney
Journal: New England Journal of Medicine (2012)

A 69-year-old man presented to the emergency department 2 hours after awakening with slurred speech. He also reported difficulty chewing, blurry vision in both eyes, generalized weakness, and unsteady gait.
Abstract 11734: 'Whispering Stroke' May Be Very Common in Southeastern African Americans With Uncontrolled High Blood Pressure
Authors: Justin G Lee, joanna Ringel, Elizabeth Baquero, Doyle M Cummings, Jacquie Halladay, Stephanie Hart, Monika Safford
Journal: Circulation (2021)

Introduction: High blood pressure (BP) increases risk for stroke, but individuals experiencing stroke symptoms don’t always seek medical attention. Such ‘whispering stroke’ symptoms are reportedly common but have not been examined in African Americans with persistently uncontrolled hypertension. Hypothesis: Stroke symptoms without a stroke diagnosis are more common in African Americans with uncontrolled hypertension and are associated with stroke risk factors. Methods: We used data from the Southeastern Collaboration to Improve Blood Pressure Control, a randomized controlled trial that enrolled 1596 African Americans from rural AL and NC with persistently uncontrolled hypertension (mean clinic systolic BP &gt;140 mm Hg in the year prior to enrollment, and research-grade BP &gt; 140/90 mm Hg at enrollment). Stroke symptoms were detected using the Questionnaire to Verify Stroke-Free Status (QVSS) that detects 6 symptoms that could represent stroke. Stroke risk factors included age, blood pressure, diabetes, and cigarette smoking. Multivariable Poisson regression models estimated prevalence ratios (PR) and 95% confidence intervals (CI) for the association between stroke risk factors and report of any stroke symptom without stroke diagnosis. Results: The 1239 individuals who reported never having had a stroke or transient ischemic attack (TIA) diagnosis had mean age 57.0 + 12.0 years, 37.4% were men, and 36.1% reported having experienced a stroke symptom. In adjusted models, report of stroke symptoms without a stroke diagnosis were associated with age (PR 0.99, 95% CI 0.99-1.00), systolic blood pressure (PR 1.03, 95% CI 1.00-1.05), diabetes (PR 1.33, 95% CI 1.15-1.55), and current smoking (PR 1.29, 95% CI 1.08-1.55). Conclusions: Over one third of this relatively young sample reported stroke symptoms without a stroke diagnosis. Stroke risk factors were associated with stroke symptoms without a stroke diagnosis. Screening for stroke symptoms in individuals with persistently uncontrolled hypertension may be warranted.
Abstract 13056: The Novel Cardiokine GDF3 Predicts Fibrotic Remodeling Post-Myocardial Infarction
Authors: nihar masurkar, Marion Bouvet, Damien Logeart, Clement DELACROIX, Jean Jacq Mercadier, marc sirol, Barnabas Gellen, David-Alexandre Trégouët, Giovanna Marazzi, David Sassoon, Mariana Valente, Jean S Hulot
Journal: Circulation (2021)

Introduction: Myocardial infarction (MI) induces a repair response that ultimately generates a stable fibrotic scar. Although the scar prevents cardiac rupture, an excessive profibrotic response impairs optimal recovery. Hypothesis: To explore the regulation of fibroblasts proliferation through a paracrine action of cardiac stromal cells post-MI Methods: We carried out a bioinformatic secretome analysis of cardiac stromal PW1 + cells isolated from normal and post-MI mouse hearts to identify novel secreted proteins. Functional assays were used to screen secreted proteins that promote fibroblast proliferation. The expressions of secreted proteins candidates were subsequently analyzed in mouse and human hearts and plasmas. The relation between levels of circulating protein candidates and adverse post-MI cardiac remodeling was examined in a cohort of 80 patients with a first ST-elevation MI and serial cardiac magnetic resonance imaging (MRI) evaluations. Results: Cardiac stromal PW1 + cells undergo a change in paracrine behavior post-MI and secrete factors that promote fibroblast proliferation. Among these factors, growth differentiation factor 3 (GDF3), a member of the transforming growth factor-β family, was markedly upregulated in the ischemic hearts and induced fibroblast proliferation at high level. In humans, GDF3 was detected in the plasma at day 4 post-MI and GDF3 circulating levels were significantly associated with an increased risk of adverse remodeling 6-month post-MI (adjusted Odds Ratio (OR) = 1.76 [1.03 - 3.00], p = 0.037). Conclusions: Our findings define a mechanism for the pro-fibrotic action of cardiac stromal cells through secreted cardiokines, such as GDF3, a candidate marker of adverse fibrotic remodeling following MI.
Abstract 10306: Right Heart Dysfunction in Adults with Coarctation of Aorta - Prevalence and Prognostic Implications
Authors: Ahmed Goda, Likhita Shaik, Renuka Reddy Katta, Janaki Devara, Momina Iftikhar, Alexander C Egbe, Heidi M Connolly
Journal: Circulation (2021)

Introduction: Chronic elevation of left heart filling pressure causes pulmonary vascular remodeling, pulmonary hypertension, and right heart dysfunction. Although diastolic dysfunction is relatively common in patients with coarctation of aorta (COA), there are limited data about the prevalence and prognostic implications of pulmonary hypertension and right heart dysfunction in this population. The purpose of the study was to assess right heart function and hemodynamics in patients with COA, and to determine the relationship between right heart indices and clinical outcomes. Methods: Right heart structure, function and hemodynamics were assessed with these indices: right atrial (RA) volume, RA pressure, RA reservoir strain, right ventricular (RV) global longitudinal strain, RV end-diastolic area, RV systolic pressure, and tricuspid regurgitation severity. These indices were used to generate a composite right heart hemodynamic score (RHHS), range 0-5. We then assessed the relationship between RHHS and primary outcome (death/transplant) and secondary outcomes (heart failure hospitalization and hepatorenal function). Results: Of 821 COA patients, RA dysfunction, RV dysfunction, and pulmonary hypertension were present in 16%, 14%, and 20% of patients respectively. RHHS was independently associated with primary and secondary outcomes (p&lt;0.001). For every unit increase in RHHS, we observed 83% increase in death/transplant and 71% increase in heart failure hospitalization. Conclusions: The current study underscores an important point, which is that COA is not just a disease of the left heart but can result in right heart dysfunction, and that the onset of right heart dysfunction is associated with adverse outcomes.
Elucidating the Mechanisms of Leukemogenesis Driven By <i>FBXO11</i> Depletion
Authors: Angela Mo, Linda Ya-Ting Chang, Gerben Duns, Xuan Wang, Gregg Morin, Tammy Lau, Rod Docking, Shane Colborne, Se-Wing Grace Cheng, Shujun Huang, Hayle Kincross, Nadia Gharaee, Elijah Willie, Jihong Jiang, Jeremy Parker, Aly Karsan
Journal: Blood (2021)
Abstract 13046: ALDH2-Mediated 4-HNE Contributes the Pathogenesis of Pulmonary Arterial Hypertension in Atherosclerotic Mice
Authors: Yen-Hung Chou, Yi-Nan Lee, Lee Hsin-I, Chin-Ling Hsieh, Cheng-Huang Su, Hung-I Yeh, Yih-jer Wu
Journal: Circulation (2021)

Introduction: A high residual mortality for patients with pulmonary arterial hypertension (PAH) in this PAH-targeted therapy era implies the existence of untargeted pathways. High fat diet-fed ApoE knockout mice were found to develop PAH phenotype. Monocrotaline (MCT)-induced PAH rats also express high levels of 4-hydroxynenonal (4-HNE), a lipid peroxidation related aldehyde, in pulmonary vessels. Aldehyde dehydrogenase-2 (ALDH2), an important enzyme responsible for the removal of 4-HNE, is functionally defective near 50% of East Asians. Whether 4-HNE and its cognate detox enzyme ALDH2 participate in lipid dysregulation-induced PAH remains poorly understood. Methods and Results: Compared with ApoE knockout mice fed with normal chow, those with Piagen diet developed hypercholesterolemia, higher right ventricular systolic pressure (RVSP), and higher Fulton index (RV hypertrophy). Atherosclerotic plaques were widely distributed in the entire major arteries as well as pulmonary arteries. The lung tissue of Paigen diet-fed mice had higher levels of ALDH2 protein but lower levels of ALDH2 enzymatic activity, which was negatively associated with serum 4-HNE levels. Importantly, lung ALDH2 activities were negatively (R= -0.829, P=0.041), and serum 4-HNE levels positively (R=0.936, P=0.006) associated with RVSP. This data suggests that, in our model, ALDH2 expression may be upregulated to counteract but still exhausted by the high levels of lipid peroxidation products, such as 4-HNE. Conclusions: This data suggests that lipid dysregulation related 4-HNE/ALDH2 imbalance, at least in part, participates in PAH development and may potentially serve as a novel PAH target, particularly for East Asian people.
IMMU-39. EVALUATION OF CD317-TARGETING CAR T CELLS AS A NOVEL IMMUNOTHERAPEUTIC STRATEGY AGAINST GLIOBLASTOMA
Authors: Lena Hänsch, Matthias Peipp, Renier Myburgh, Manuela Silginer, Tobias Weiss, Dorothee Gramatzki, Flavio Vasella, Markus Manz, Michael Weller, Patrick Roth
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma remains one of the deadliest cancers despite aggressive treatment, which is why novel therapeutic approaches are urgently needed. Chimeric antigen receptor (CAR) T cell therapy has demonstrated significant success in the field of hematological malignancies. However, treating glioblastoma with this type of therapy is more difficult for several reasons such as the lack of suitable target antigens. Here, we generated a second-generation CAR construct targeting the transmembrane protein CD317 (BST-2, HM1.24), which is expressed by human glioma cell lines in vitro as well as in vivo. We demonstrate strong anti-glioma activity of CD317-CAR T cells against different glioma target cells with varying CD317 expression levels. Glioma cells harboring a CRISPR/Cas9-mediated CD317 knockout were not susceptible for these CAR T cells, demonstrating their target antigen-specificity. CD317 is also expressed on T cells and transduction with a CD317-directed CAR impaired expansion of T cells due to residual CD317 expression and subsequent fratricide. Therefore, we silenced CD317 in the transduced T cells by co-expressing the CAR construct with a specific shRNA, which significantly increased the viability, proliferation and cytotoxicity of the CAR T cells. Finally, we observed strong anti-glioma activity of CD317-CAR T cells in clinically relevant orthotopic xenograft glioma mouse models resulting in prolonged survival of CAR T cell-treated animals. Taken together, these data reveal a promising role of CD317 as a novel target for CAR T cell therapy in glioblastoma and warrant further evaluation of this strategy in clinical neuro-oncology.
TMOD-18. DIRECT IN VIVO CRISPR SCREEN IDENTIFIES COOPERATING TUMOR SUPPRESSORS THAT DRIVE PROGRESSION OF IDH1-MUTANT LOW-GRADE GLIOMA TO AGGRESSIVE GLIOBLASTOMA
Authors: Connor Yanchus, Kristen Drucker, Thomas Kollmeyer, Ricky Tsai, Lingyan Jiang, Asma Ali, Brittany Carson, Judy Pawling, Ahmad Malik, Khalid Al-Zahrani, Sampath Kumar Loganathan, Jerome Fortin, Lily Zhou, Andrew Elia, James W Dennis, Tak Mak, Michael Taylor, Gelareh Zadeh, Peter Dirks, Robert Jenkins, Daniel Schramek
Journal: Neuro-Oncology (2021)

Abstract Low-grade glioma (LGG) are generally slowly growing brain cancers, that frequently undergo malignant progression to aggressive, secondary glioblastoma with a dismal prognosis. By combining genetically engineered Idh1-mutant mice with in vivo CRISPR gene editing we generated a mouse model faithfully recapitulating the founder mutations of LGG. Clonal activation of the neomorphic Idh1 R132H mutation cooperates with Trp53 and Atrx mutations to trigger development of brain tumors but only with ~30% penetrance and very long latency. To elucidate the molecular mechanisms underlying the malignant progression of IDH1-mutant LGG, we devised and deployed a direct in vivo CRISPR screen targeting genes commonly mutated in human IDH-mutant secondary glioblastoma. Stereotaxic delivery of a lentiviral sgRNA library targeting the mouse orthologs of these genes into the brain of Idh1 R132H ;Trp53;Atrx;Cas9 and control Idh1 wt ;Trp53;Atrx;Cas9 compound mutant mice resulted in rapid formation of tumors that recapitulate human Idh1-mutant glioblastoma. Deconvoluting the screen showed that PI3K pathway members Pten and Pik3ca as well as Notch1, Smarca4 and Fat1 are preferentially enriched in Idh1 R132H-tumors, while Rb1 and NF2 were enriched in Idh1 wt tumors. Co-mutation analysis further identified additional co-occurring driver combinations such as Bcor-Met, Olig2-Met, Olig2-Med12 or Bcor-Olig2. We validated the tumor suppressive function of Notch1 and Pten using conventional floxed knock-out alleles and found that Notch1 functions in a haploinsufficient manner. Interestingly, Idh1 R132H did not alter tumor latency or pathology in a high grade p53;Pten;Rb1 mutant background, indicating that the neomorphic IDH-mutations can drive low but not high grade glioma development. Our study provides a functional landscape of gliomagenesis suppressors in vivo.