tbuckley/cabot-search huggingface dataset:
Abstract 13841: Sex Disparities in ST-Elevation Myocardial Infarction Stratified by Age: Insights From Regional ST-Elevation Myocardial Infarction Systems of Care
Authors: Mehmet Yildiz, Georgia M Mattingly, Rebekah H Lantz, Brynn K Okeson, Ananya A Shah, Ross Garberich, Santiago A Garcia, Scott W Sharkey, Heather S Rohm, Timothy D Henry, Odayme Quesada
Journal: Circulation (2021)

Introduction: Sex disparities in STEMI care are well recognized, with worse outcomes reported for women; however, it remains unknown whether these disparities are seen across all age groups. Methods: Using prospective data from 2 large regional STEMI systems; Minneapolis Heart Institute, Minneapolis, MN, and The Christ Hospital, Cincinnati, OH, from 2010 to 2020, we analyzed 4,815 consecutive STEMI patients stratified by sex and age groups as follows; young (18 to 44 years), middle-aged (45 to 64 years), and older (≥65 years). Results: Among 4,815 patients with STEMI, 30.7% were women. Among young patients, women had more diabetes. There were no differences in reperfusion times, but young women received medical management more often and were more likely to receive aspirin or antiplatelet at discharge. There were no differences in outcomes at 1-year follow-up between young women or men. Among middle-aged patients, women had more diabetes, hypertension, and stroke. There were no differences in PCI rates, but middle-aged women presented directly to the PCI center had longer door-to-balloon time (DBT). Middle-aged women were less likely to receive antiplatelet or statin at discharge and had higher in-hospital death rates than men. Among older patients, women had more hypertension but less history of smoking or coronary artery disease. There were no differences in PCI rates, but older women transferred to the PCI center had longer DBT. Middle-aged women were less likely to receive antiplatelet or statin at discharge. There were no differences in outcomes at 1-year follow-up between older women or men (Table). Conclusions: In 2 large regional STEMI databases, sex disparities varied among different age groups, with less PCI use in young women and less guideline-directed medical therapy at discharge in middle-aged or older women, supporting the need for ongoing standardized protocols to eliminate sex disparities.
Covid-19 and pregnancy: vaccine hesitancy and how to overcome it
Authors: Gareth Iacobucci
Journal: BMJ (2021)

Some 80 000 pregnant women in England had received two doses of the covid-19 vaccine up to 31 October, up from 65 000 at the end of August, says the UK Health Security Agency.1 It’s not possible to say what proportion this is of all pregnant women, as England doesn’t collect data linking vaccinations, pregnancies, and births. But data from Public Health Scotland2 showed that only 15% (615/4069) of women who gave birth in August 2021 were fully vaccinated. Only 23% (165/704) of women aged 35-39 who delivered their baby in August 2021 had received two vaccine doses, compared with 71% of all adults aged 30-39 in the general population.

Pat O’Brien, consultant obstetrician and vice president of the Royal College of Obstetricians and Gynaecologists, believes that there are two main drivers. “The first is the natural and understandable reluctance of pregnant women to take anything unusual or new during pregnancy because of fear that it might harm their baby,” he told The BMJ .

The second is the initial advice from the Joint Committee on Vaccination and Immunisation (JCVI) that pregnant women were better to avoid the covid vaccine unless they were at high risk of serious disease, because of a lack of evidence on safety. This advice changed as new evidence emerged, and the JCVI advised in April 2021 that all pregnant women should be offered the vaccine.

O’Brien rejects accusations of mixed messages. “We have more information about the safety of the vaccine in …
IMMU-47. THE ANTIGENIC PROFILE OF MURINE AND HUMAN MEDULLOBLASTOMA
Authors: Changlin Yang, Vrunda Trivedi, Kyle Dyson, Oleg Yegorov, Duane Mitchell
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Cancer immunogenomics represents a complementary approach to the application of genomics in developing novel immunotherapies. We performed a multi-faceted computer algorithm, the Open Reading Frame Antigen Network (O.R.A.N.), on medulloblastoma transcription profiles and predicted antigens across a broad array of antigen classes. METHODS Patient-specific HLA haplotypes were called via customized Optitype and Phlat algorithms. Preclinical models- sonic hedgehog driven (Ptch1) and Group 3 MYC-driven (NSC) medulloblastoma were derived from C57BL6 murine strain with known MHC haplotypes. Only expressed mutations such as single nucleotide variations, small indels, gene fusions, and personalized TAAs were used for antigenic epitope predictions. Patient-specific or murine tumor associated antigens (TAA) were selected only if expressed &amp;gt;1 transcript per million (TPM) in tumor and the standardized expression across a human tissue database (29 organs or sub-regions, n=9,141) or a mouse normal tissue database (ENCODE, n=99) was below 1 TPM, respectively. TAA sequences were passed through eight MHC class I and four MHC class II affinity algorithms. All epitopes were screened against a customized human or murine proteomic library to guarantee that epitopes were not shared by other expressed isoforms or genes. Immune deconvolution with single cell RNASeq integration was leveraged for teasing out medulloblastoma immunologic landscape. RESULTS MB patients harbor MHC-I restricted 1.9 SNV, 0.1 Indel, 0.5 gene fusions and MHC-II restricted 2.5 SNV, 0.1 Indel and 0.5 gene fusion. 79.4% patients have at least 1 neoantigen. 88.2% patients have at least one immunogenic TAA. Importantly, cancer testis antigens and previously unappreciated neurodevelopmental antigens were found expressed across all medulloblastoma subgroups. We predicted 6 neoantigens and 14 TAAs for murine NSC tumor and 19 neoantigens and 13 TAAs for Ptch1 tumor. CONCULSION: Using a custom antigen prediction pipeline, we identified potential human and murine tumor rejection antigens with important implications for development of medulloblastoma cellular therapies.
Single-cell proteo-genomic reference maps of the hematopoietic system enable the purification and massive profiling of precisely defined cell states
Authors: Sergio Triana, Dominik Vonficht, Lea Jopp-Saile, Simon Raffel, Raphael Lutz, Daniel Leonce, Magdalena Antes, Pablo Hernández-Malmierca, Diana Ordoñez-Rueda, Beáta Ramasz, Tobias Boch, Johann-Christoph Jann, Daniel Nowak, Wolf-Karsten Hofmann, Carsten Müller-Tidow, Daniel Hübschmann, Theodore Alexandrov, Vladimir Benes, Andreas Trumpp, Malte Paulsen, Lars Velten, Simon Haas
Journal: Nature Immunology (2021)

Abstract Single-cell genomics technology has transformed our understanding of complex cellular systems. However, excessive cost and a lack of strategies for the purification of newly identified cell types impede their functional characterization and large-scale profiling. Here, we have generated high-content single-cell proteo-genomic reference maps of human blood and bone marrow that quantitatively link the expression of up to 197 surface markers to cellular identities and biological processes across all main hematopoietic cell types in healthy aging and leukemia. These reference maps enable the automatic design of cost-effective high-throughput cytometry schemes that outperform state-of-the-art approaches, accurately reflect complex topologies of cellular systems and permit the purification of precisely defined cell states. The systematic integration of cytometry and proteo-genomic data enables the functional capacities of precisely mapped cell states to be measured at the single-cell level. Our study serves as an accessible resource and paves the way for a data-driven era in cytometry.
Abstract 13032: Endothelial Cell Response to Intravenous Immunoglobulin, Infliximab and Atorvastatin Treatment During the Acute Phase of Kawasaki Disease
Authors: Chisato Shimizu, Jihoon Kim, Ming He, Hal Hoffman, John Shyy, Jane Burns, Adriana H Tremoulet
Journal: Circulation (2021)

Introduction: Damage to coronary arteries (CA) during the acute phase of Kawasaki disease (KD) is linked to inflammatory cell infiltration, myofibroblast generation (EndMT: endothelial-mesenchymal transition), and endothelial cell (EC) dysfunction. To promote EC health, we performed a Phase I/IIa clinical trial (6-week course) of atorvastatin in patients with acute KD and coronary artery Z score &gt; 2.5. We demonstrated that atorvastatin was safe and well-tolerated. However, its effect on EC in KD has not been systematically studied. Hypothesis: Treatment with atorvastatin added to intravenous immunoglobulin (IVIG) and infliximab (IFX) promotes EC health in acute KD patients. Methods: We performed RNAseq on human umbilical vein ECs (HUVECs) incubated with pooled sera from KD patients (pre-treatment or subacute illness day 17-25) treated with IVIG and IFX with or without atorvastatin added to their initial treatment. Results: Differentially expressed genes (DEGs) from HUVECs incubated with sera pooled from 5 KD patients collected pre- and post-treatment (IVIG + IFX) that were suppressed by treatment included IL-8 , CCL2 and ICAM1 , molecules in the TNFα and IL1β pathways that have key roles in recruitment of inflammatory cells to EC. Subacute sera pooled from 5 patients treated with IVIG + IFX + atorvastatin induced expression of NOS3 , KLF2 and KLF4 , molecules that promote EC homeostasis and angiogenesis, and suppressed expression of TGFB2 and Dickkopf WNT signaling pathway inhibitor 1 ( DKK1 ), molecules in the TGFβ and WNT signaling pathways. These results were validated by RT-PCR on HUVECs incubated with independent individual sera from patients treated with/without atorvastatin. Conclusions: HUVECs incubated with pre- or post-treatment sera from KD patients showed upregulation of IL1 and TNFα pathway genes that were dramatically suppressed after treatment with IVIG and IFX. Incubation of HUVECs with post-treatment sera from patients who also received atorvastatin showed reduced expression of DKK1 and TGFB2 , suggesting reduced EndMT, and increased NOS3 and KLF4 , key mediators of EC homeostasis. These results suggest that atorvastatin improves EC health and may block KD-induced myofibroblast proliferation in the CA wall.
Abstract 12617: Acute Myocardial Infarction in Cocaine Users: Prognosis, Outcomes and Clinical Characteristics
Authors: Douglas Salguero Lopez, Marissa A Donatelle, Everett Rogers, Christian Torres, Karthik Vedantam, Nirat Beohar
Journal: Circulation (2021)

Introduction: Cocaine use is rising in the USA. It is linked to high cardiovascular morbidity, mortality and increases ischemic events. Little epidemiological data exists exploring the relationship between NSTEMI &amp; STEMI in cocaine users. We sought to examine the National Inpatient Sample (NIS) database to describe demographics &amp; in-hospital outcomes of this cohort. Methods: The NIS database was queried from 2016-2018 to identify adults admitted with an MI &amp; stratified by cocaine exposure using ICD-10 codes. Weights were applied to produce national estimates. Chi-square &amp; logistic regression were used to calculate odds ratios. Multivariate analysis was applied to control for confounders. Results: A total of 25,000 cocaine positive patients were identified. These patients were younger (NSTEMI 53 vs 68-yo; STEMI 51-yo vs. 63-yo; p&lt;.05), more likely to be male (NSTEMI 78% vs. 59%, p&lt;.05; STEMI 81% vs. 69%, p&lt;.05) &amp; African American (NSTEMI 54% vs. 12%, p&lt;.05; STEMI 45% vs. 8%, p&lt;.05). Common comorbidities included hypertension, smoking, &amp; coronary artery disease. Cocaine users presenting with NSTEMI were less likely to have CAD (70% vs. 81%, p&lt;.05), but more likely to abuse alcohol (NSTEMI 23% vs. 3%, p&lt;.05; STEMI 22% vs. 3%, p&lt;.05). Age, sex, &amp; race did not affect mortality despite the higher prevalence of young, male, &amp; African American subjects. In the cocaine users’ group, pre-existing heart failure raised mortality rates 2.4-fold (p&lt;.05) in those with STEMI &amp; ESRD increased the odds of mortality 4.9-fold (p&lt;.05) in those with NSTEMI. Rates of revascularization within 24-hours of admission were lower in cocaine users (NSTEMI 11% vs. 18%, p&lt;.05; STEMI 45% vs. 53%, p&lt;.05). Conclusions: Patients with an MI who were cocaine positive represent a diverse group distinct from the larger cocaine negative group. The use of cocaine should be investigated in patients with certain pre-existing medical conditions, as they had the highest risk of mortality in our study.
Abstract P403: Three-dimensional Bioprinting Of Adhesive Cardiac Patch Systems
Authors: Shuai Chen, Martin Tomov, Liqun Ning, Carmen Gil, Boeun Hwang, Holly Bauser-Heaton, Vahid Serpooshan
Journal: Circulation Research (2021)

Rapid advancements in 3D bioprinting have enabled the design of functionalized bioinks to create scaffolds with robust adhesive properties. These constructs are of great interest in cardiac tissue engineering, where the integration of grafted patch with the host myocardium, through sutures, staples, or adhesives, faces risks such as bleeding, cytotoxicity, and infection. We introduce the first generation of functional adhesive bioinks that can be bioprinted through various modalities to fabricate patch structures with intrinsic adhesive properties. A dopamine-modified hyaluronic acid methacrylate (HAMA-Dopa) and gelatin methacrylate (gelMA) composite bioink is used to create the patch via air and embedded bioprinting. Constructs are crosslinked onto a collagen sheet substrate simulating the host cardiac tissue ( Figure 1A-C ). We developed novel in vitro methods to assess adhesion properties of printed patch under shear, tension, or dynamic loading ( Figure 1C ). Our approach allowed for steady and precise application of stress to the adhesion interface. Embedded-printed HAMA-Dopa/gelMA scaffold showed significantly enhanced adhesion strength (1025 Pa) compared to gelMA (495 Pa) and HAMA (477 Pa) control groups under tension, and under shear (548 Pa vs. 234 and 239 Pa). The adhesion strength of air-printed HAMA-Dopa/gelMA constructs was markedly higher (10,128 Pa) than the embedded ones, possibly due to the more effective, in-situ crosslinking. We also investigated the dynamic adhesive properties in aqueous environment using an ex vivo beating heart model. Air-printed HAMA-Dopa/gelMA showed the greatest adhesion under wet conditions, tolerating 345,600 cycles. We further characterized printing fidelity, mechanical properties, swelling, and biocompatibility of HAMA-Dopa/gelMA constructs, demonstrating adequate functionality of this bioprinted adhesive scaffold for cardiac tissue engineering applications. Figure 1 . Summary of workflow to develop bioprinted adhesive scaffolds. A: Embedded (top) or air (bottom) bioprinting was used to create 3D patch geometries. B: Printing fidelity assessment and optimization. C: Different adhesion mechanisms were assessed using novel customized tools and approaches to apply tensile ( C-i ), shear ( C-ii ), and dynamic ( C-iii ) loading.
Abstract 14073: Deterioration of Functional Status and Timing of Intervention in Patients With Aortic Stenosis: Results From the PROGRESSA Study
Authors: Lionel Tastet, Mylene Shen, Romain Capoulade, Marie Arsenault, Elisabeth Bédard, Nancy Cote, Marie-annick A Clavel, Philippe Pibarot
Journal: Circulation (2021)

Introduction: The assessment of changes in functional status during follow-up is critical to determine the timing of intervention in patients with aortic stenosis (AS). Fast progression of AS (annualized progression of peak jet velocity [V peak ] ≥30 cm/s) is among the risk markers recommended in the guidelines to trigger early intervention in asymptomatic severe AS. We investigated the association between the progression of AS hemodynamic severity and the change in functional status during follow-up of patients with asymptomatic mild to moderate AS. Methods: 285 patients with AS prospectively recruited in the PROGRESSA study (NCT01679431) were included in this analysis. Functional status was evaluated using the New York Heart Association (NYHA) classification. Results: Baseline NYHA class was similar (class I, II, III: 57%, 41%, 2% versus 58%, 41%, 1%; p=0.75) between patients with moderate (V peak progression ≥12 cm/s/year; median of cohort) versus those with slow AS progression rate. During a mean follow-up of 3.9±2.4 years, patients with moderate AS progression rate had larger increase in NYHA class compared to those with slow progression (+0.13±0.48 versus +0.01±0.21 class/year; p=0.008). From baseline to 2 years, a significant worsening of NYHA class occurred but only in the moderate AS progression group ( Figure ). In multivariable analysis, AS progression rate remained significantly associated with the change in NYHA class (p=0.04).A total of 156 clinical events (110 AVR and 46 deaths) occurred during a mean follow-up of 1.1±1.5 years after the last echocardiographic visit. Patients with ≥1 class increase in NYHA (n=70) had significantly higher risk of events (adjusted hazard ratio: 1.75 [95% CI: 1.12-2.75]; p=0.01). Conclusions: In this prospective cohort of patients with mild to moderate AS at baseline, the decline in functional status occurs early in the course of the disease and is in large part determined by the progression rate of AS hemodynamic severity.
An NR2F1-specific agonist suppresses metastasis by inducing cancer cell dormancy
Authors: Bassem D. Khalil, Roberto Sanchez, Tasrina Rahman, Carolina Rodriguez-Tirado, Stefan Moritsch, Alba Rodriguez Martinez, Brett Miles, Eduardo Farias, Mihaly Mezei, Ana Rita Nobre, Deepak Singh, Nupura Kale, Karl Christoph Sproll, Maria Soledad Sosa, Julio A. Aguirre-Ghiso
Journal: The Journal of Experimental Medicine (2021)

We describe the discovery of an agonist of the nuclear receptor NR2F1 that specifically activates dormancy programs in malignant cells. The agonist led to a self-regulated increase in NR2F1 mRNA and protein and downstream transcription of a novel dormancy program. This program led to growth arrest of an HNSCC PDX line, human cell lines, and patient-derived organoids in 3D cultures and in vivo. This effect was lost when NR2F1 was knocked out by CRISPR-Cas9. RNA sequencing revealed that agonist treatment induces transcriptional changes associated with inhibition of cell cycle progression and mTOR signaling, metastasis suppression, and induction of a neural crest lineage program. In mice, agonist treatment resulted in inhibition of lung HNSCC metastasis, even after cessation of the treatment, where disseminated tumor cells displayed an NR2F1hi/p27hi/Ki-67lo/p-S6lo phenotype and remained in a dormant single-cell state. Our work provides proof of principle supporting the use of NR2F1 agonists to induce dormancy as a therapeutic strategy to prevent metastasis.
Dietary Insulinemic Potential and Risk of Total and Cause-Specific Mortality in the Nurses’ Health Study and the Health Professionals Follow-up Study
Authors: Yi Wan, Fred K. Tabung, Dong Hoon Lee, Teresa T. Fung, Walter C. Willett, Edward L. Giovannucci
Journal: Diabetes Care (2021)

OBJECTIVE Insulin response is related to overall health. Diet modulates insulin response. We investigated whether insulinemic potential of diet is associated with risk of all-cause and cause-specific mortality. RESEARCH DESIGN AND METHODS We prospectively followed 63,464 women from the Nurses’ Health Study (1986–2016) and 42,880 men from the Health Professionals Follow-up Study (1986–2016). Diet was assessed by food frequency questionnaires every 4 years. The insulinemic potential of diet was evaluated using a food-based empirical dietary index for hyperinsulinemia (EDIH), which was predefined based on predicting circulating C-peptide concentrations. RESULTS During 2,792,550 person-years of follow-up, 38,329 deaths occurred. In the pooled multivariable-adjusted analyses, a higher dietary insulinemic potential was associated with an increased risk of mortality from all-cause (hazard ratio [HR] comparing extreme quintiles: 1.33; 95% CI 1.29, 1.38; P-trend &amp;lt;0.001), cardiovascular disease (CVD) (HR 1.37; 95% CI 1.27, 1.46; P-trend &amp;lt;0.001), and cancers (HR 1.20; 95% CI 1.13, 1.28; P-trend &amp;lt;0.001). These associations were independent of BMI and remained significant after further adjustment for other well-known dietary indices. Furthermore, compared with participants whose EDIH scores were stable over an 8-year period, those with the greatest increases had a higher subsequent risk of all-cause (HR 1.13; 95% CI 1.09, 1.18; P-trend &amp;lt;0.001) and CVD (HR 1.10; 95% CI 1.01, 1.21; P-trend = 0.006) mortality. CONCLUSIONS Higher insulinemic potential of diet was associated with increased risk of all-cause, CVD, and cancer mortality. Adopting a diet with low insulinemic potential might be an effective approach to improve overall health and prevent premature death.
A Real World Experience of Combined Treatment with Romidepsin and Azacitidine in Patients with Peripheral T-Cell Lymphoma
Authors: Matko Kalac, Constantine S. Tam, Mendel Goldfinger, Zhengrui Xiao, Francesca Montanari, Jennifer A. Kanakry, Owen A. O'Connor, Enrica Marchi
Journal: Blood (2021)
Mapping the Glucocorticoid Gene Regulatory Network and Alterations That Contribute to Steroid Resistance in Childhood Acute Lymphoblastic Leukemia
Authors: Brennan P. Bergeron, Jonathan Diedrich, Yang Zhang, Qian Dong, Daniel Ferguson, Robert J Autry, Wenjian Yang, Baranda S Hansen, Kristine R. Crews, Ching-Hon Pui, Yiping Fan, Shondra M. Pruett-Miller, Mary V. Relling, Jun J. Yang, Chunliang Li, William E. Evans, Daniel Savic
Journal: Blood (2021)
Abstract 12219: Pre-Treatment With P2Y12 Inhibitor in Patients With Non-ST Elevation Acute Coronary Syndrome; a Meta-Analysis
Authors: Abdullah Al-abcha, Yehia Saleh, Layan El-khatib, Ahmed Elshafie, Harith Ghnaima, Sandeep Banga, george Abela
Journal: Circulation (2021)

Introduction: The guidelines for the management of acute coronary syndrome in patients presenting without persistent ST-segment elevation (NSTE-ACS) recommend against the routine use of pre-treatment with P2Y12 inhibitors when early invasive management is planned. Recently, multiple randomized clinical trials (RCTs) were published to compare the efficacy and safety of pre-treatment with P2Y12 inhibitors Hypothesis: Pre-treatment with P2Y12 inhibitors improves clinical outcomes in NSTE-ACS. Methods: We conducted a meta-analysis of all studies that evaluated clinical outcomes of pre-treatment with P2Y12 inhibitors versus no-pretreatment in the treatment of NSTE-ACS. The primary outcome was 30-days major adverse cardiovascular events (MACE). Secondary outcomes included risk of major bleeding, all-cause mortality, myocardial infarction (MI), and target vessel revascularization (TVR). Results: A total of 7 studies, and 103,678 patients were included. In regards to the primary outcome, the rate of MACE was similar between the two groups (OR 0.89; 95% CI 0.67-1.19; p=0.44). On the other hand, the rate of major bleeding was significantly higher in the pre-treatment group when compared to no- pre-treatment (Pre-treatment 2.6% vs control 1.7%, p=0.008). All-cause mortality, risk of MI, and risk of TVR were similar between the two treatment groups (Figure 1). Conclusions: Our findings correlate with the ESC guidelines, and we recommend against the routine use of pre-treatment with P2Y12 inhibitors in patients with NSTE-ACS.