tbuckley/cabot-search huggingface dataset:
Call for action in ANCA-associated vasculitis and lupus nephritis: promises and challenges of SGLT-2 inhibitors
Authors: Marcus Säemann, Andreas Kronbichler
Journal: Annals of the Rheumatic Diseases (2021)

Sodium-glucose cotransporter- 2 inhibitors (SGLT- 2i) have recently been demonstrated to exert profound cardio- and nephroprotection in large cardiovascular outcome trials. They reduce progression of chronic kidney disease (CKD) including albuminuria and improve outcomes in heart failure patients with and without type 2 diabetes on top of angiotensin-blocking agents. These benefits translate into improved mortality in cardiorenal risk patients. While the detailed molecular mechanisms underlying these surprising clinical outcomes are not fully understood, their antidiabetic properties are not causative. Rather reduction of glomerular hyperfiltration and tubuloprotection are involved as root cause mechanisms of their clinical effects. Finally, their side effect profile is advantageous especially in non-diabetic patients also reducing the risk of acute kidney injury. Among the independent risk factors for excess mortality, CKD is still one of the strongest predictors of a poor prognosis in patients with both ANCA- associated vasculitis (AAV) and lupus nephritis (LN). Since patients with autoimmune disease were excluded from all recent large renal outcome trials with SGLT-2i and given their strong nephroprotective potential, we herein advocate to study this unique class of disease-modifying therapies when it comes to kidney and cardiovascular health in patients with AAV and LN.
TAMI-30. THERAPY INDUCED REPROGRAMMING DRIVES GLIOMA VASCULAR TRANSDIFFERENTIATION AND TUMOR RECURRENCE
Authors: Sree Deepthi Muthukrishnan, Riki Kawaguchi, Pooja Nair, Rachna Prasad, Alvaro Alvarado, Yue Qin, Michael Condro, Harley Kornblum
Journal: Neuro-Oncology (2021)

Abstract Therapy-resistant glioma cells elicit phenotypic plasticity leading to aggressive tumor recurrence. Here, we employed single-cell and whole transcriptomic analyses to uncover that a standard glioma treatment, radiation induces a dynamic shift in functional states of glioma cells allowing for acquisition of mesenchymal-like and vascular-like phenotypes. The predominant phenotype switch induced by radiation in surviving tumor cells is transdifferentiation to endothelial-like and pericyte-like cells. The transdifferentiated cells in turn promote proliferation of radiated tumor cells, and their selective depletion results in reduced tumor growth and recurrence post-treatment. The acquisition of vascular-like phenotype is driven by increased chromatin accessibility in vascular genes, and blocking P300-mediated histone acetyltransferase activity prior to radiation treatment inhibits vascular transdifferentiation and tumor growth. Our findings indicate that radiation therapy reprograms tumor cells driving vascular transdifferentiation, and highlights HAT inhibitors as potential therapeutic target for preventing GBM relapse
Abstract 11069: Nutritional Risk Index is a Predictive Factor of Anthracycline-Induced Cancer Therapeutics-Related Cardiac Dysfunction
Authors: Daiki Yaegashi, Masayoshi Oikawa, Tetsuro Yokokawa, Tomofumi Misaka, ATSUSHI KOBAYASHI, Akiomi Yoshihisa, Kazuhiko Nakazato, Takafumi Ishida, Yasuchika Takeishi
Journal: Circulation (2021)

Background: It has been reported that nutritional risk index (NRI) is one of prognostic factors in cardiovascular diseases, but little is known about its relation to the onset of cancer therapeutics-related cardiac dysfunction (CTRCD). Methods and Results: Consecutive 202 cancer patients planed for anthracycline treatment were enrolled and followed up for 12 months in our hospital from February 2017 to June 2019. The patients were divided into 2 groups based on NRI value at 100 before chemotherapy (high NRI group, n=141, 110.5 [104.7-115.6]; low NRI group, n=61, 93.7 [89.6-97.6]). Baseline left ventricular end systolic volume index and left ventricular ejection fraction (LVEF) before chemotherapy were similar between two groups. After chemotherapy, the occurrence of CTRCD was higher in low NRI group than in high NRI group (14.8% vs. 3.5%, P=0.012). Furthermore, there was a correlation between the severity of NRI categories and the development of CTRCD. When we set the cut-off value of baseline NRI from ROC analysis at 100.8, sensitivity, specificity, and area under the curve to predict the occurrence of CTRCD were 71.4%, 70.7%, and 0.698, respectively. Multivariable logistic regression analysis revealed that baseline NRI value was an independent predictor of the development of CTRCD (odds ratio 0.935, 95% CI [0.881-0.992], P=0.026). The value of net reclassification index and integrated discrimination improvement for detecting CTRCD reached statistical significance when baseline NRI value was added to the regression model including known risk factors such as age, female gender, the presence of hypertension, chronic kidney disease, cumulative anthracycline dose, the usage of HER2 inhibitor, and radiation therapy; 0.872 (95% CI [0.421-1.323], P&lt;0.001) for net reclassification index and 0.035 (95% CI [0.002-0.067], P=0.033) for integrated discrimination improvement. Conclusion: Baseline NRI is a novel parameter to predict anthracycline-induced CTRCD.
Abstract 120: Pericytes Contribute To Myofibroblast Expansion And Vascular Maturation In The Infarcted Heart
Authors: Linda Alex, Kai Su, Izabela Tuleta, Nikolaos G Frangogiannis
Journal: Circulation Research (2021)

Infarct healing is dependent on recruitment of inflammatory leukocytes and subsequent activation of myofibroblasts (MF) and neovessel formation, ultimately resulting in formation of a highly vascularized collagen-enriched scar. Though the heart has an abundant population of periendothelial pericytes, its role in wound healing upon myocardial infarction (MI) has not been studied. We hypothesized that in the infarcted myocardium, pericytes may become activated, contributing to inflammatory, fibrotic and angiogenic responses. We used pericyte/fibroblast reporter mice (NG2 DsRed ;PDGFRα GFP ), lineage tracing studies and in vitro approaches to study the fate and role of pericytes in the infarcted myocardium. In normal hearts, NG2+/PDGFRα- pericytes and PDGFRα+/NG2- fibroblasts had distinct transcriptomic profiles. Pericytes expressed mural genes like Acta2 , Pdgfrb and low amounts of extracellular matrix (ECM) genes, whereas fibroblasts synthesized collagens, Timp2/3 and matricellular genes. 7 days post-MI, expansion of the NG2+ population in the infarct zone was associated with emergence of non-mural NG2+/αSMA+ cells with MF characteristics. FACS-sorted NG2+/PDGFRα- cells from 7-day infarcts expressed higher levels of collagens when compared to NG2+/PDGFRα- cells from normal hearts. Infarct pericytes had high integrin and MMP14 expression, reflecting an activated migratory phenotype. Lineage tracing using NG2CreER TM ;Rosa tdTomato ;PDGFRα GFP mice showed that 5.7%±1.04 of PDGFRα+ fibroblasts and 10.49%±2.73 of infarct MFs were derived from NG2+ lineage. Pericyte-derived fibroblasts exhibited higher ECM gene synthesis, in comparison to fibroblasts from non-pericyte origin, while pericyte-derived mural cells showed accentuated inflammatory cytokine gene expression. Immunostaining showed pericytes actively contribute to vascular maturation, forming a mural cell coat enwrapping infarct neovessels. In vitro, TGFβ induced integrins, collagens and MMPs in human pericytes, similar to the changes observed in infarct pericytes. Taken together, our evidences show that after MI, pericytes become activated and contribute to repair by undergoing conversion to a subset of myofibroblasts and by coating infarct neovessels.
Response to BNT162b2 Sars-Cov-2 Vaccine in Recipients of Allogeneic Hematopoietic Stem Cell Transplant
Authors: Francesco Saraceni, Alessandro Fiorentini, Sonia Morè, Selene Guerzoni, Bruna Puglisi, Benedetta Corvaro, Sara Caucci, Stefano Menzo, Andrea Costantini, Luca Butini, Nadia Viola, Ilaria Scortechini, Giorgia Mancini, Maria Vittoria Dubbini, Irene Federici, Shahram Kordasti, Massimo Offidani, Francesca Patriarca, Marta Lisa Battista, Martina Chiarucci, Giuseppe Visani, Sadia Falcioni, Piero Galieni, Annalisa Natale, Doriana Vaddinelli, Stella Santarone, Fabrizia Colasante, Angelo Michele Carella, Giorgia Battipaglia, Fabrizio Pane, Attilio Olivieri
Journal: Blood (2021)
Abstract P447: Layer-by-layer Fabrication Of Thick Cardiac Muscle Patches With High Viability And Maturity
Authors: Lu Wang, Jianyi Zhang
Journal: Circulation Research (2021)

Conventionally manufactured human cardiac muscle patches (hCMPs) typically rely on diffusion for oxygen and nutrient delivery to the cells and, consequently, the thickness of the hCMP is limited to 100-200 μm. Here, we tested our hypothesis that our layer-by-layer (lbl) manufacturing protocol could increase hCMP thickness without compromising the viability of individual cell populations. Human induced-pluripotent stem cells were differentiated into cardiomyocytes (CMs) or endothelial cells (ECs); then, layers composed of CMs or ECs were fabricated by mixing a cell-containing fibrinogen solution with thrombin and pouring the mixture into a mold, and the layers were stacked into a CM-EC-CM “sandwich”. hCMP viability was assessed via TUNEL staining, vascularization via expression of the EC marker CD144, and maturation via immunofluorescence and qPCR assessments of the expression of contractile (cTnT, cTnI), connective (Cx43, N-cad), and calcium-handling (RyR2, SERCA2, BIN1, Kir2.1) proteins. Sarcomere length was evaluated by staining for α-sarcomeric actinin, and hCMP ultrastructure was examined via transmission electron microscopy. The lbl-manufactured hCMP was 10 mm x 10 mm and 1.8 mm thick after fabrication. Minimal cells in the lbl-hCMP were apoptotic or necrotic. Compared to assessments in a single-layered patch containing the same number and proportion of cells, the lbl-hCMP was vascularized with higher levels of contractile, connective, and calcium-handling protein expression. Contractile proteins were also better aligned in the lbl-hCMP (deviation from global alignment 12.3 ± 3° vs. 24.3° ± 1.9°, p&lt;0.05). The lbl-hCMP contained longer sarcomeres (2.05 ± 0.015 vs. 1.74 ± 0.026 um, p&lt;0.05) with well-ordered I-bands, A-bands, M-lines, Z-lines, desmosomes, and intercalated discs. Thus, our lbl-manufacturing technique produced thicker and more mature patches that can be potentially clinically applicable for hearts with postinfarction LV remodeling.
Abstract 13529: Efficacy and Safety of Direct Oral Anticoagulants and the Watchman™ Atrial Appendage Closure Device in Non-Valvular Atrial Fibrillation: A Network Meta-Analysis of Randomized Controlled Trials
Authors: Muhammad Haisum Maqsood, David L Brown, Marye Gleva
Journal: Circulation (2021)

Introduction: The efficacy and safety of the Watchman TM (WM) left atrial appendage closure device in atrial fibrillation (AF) was determined in randomized controlled trials (RCTs) with warfarin treatment of the control group. Direct oral anticoagulants (DOAC) have largely superseded warfarin in contemporary clinical practice for stroke and thromboembolism prevention in AF. Network meta-analysis (NMA) allows integration of direct and indirect evidence in evaluating relative effects of three or more interventions. Because there are no direct comparisons of WM with DOACs, we performed a NMA to compare the efficacy and safety of WM to DOACs in patients with AF. Methods: We searched PubMed, EMBASE, and Google Scholar from January 1990 until March 2021 for prospective RCTs that evaluated the efficacy and safety of warfarin, WM, and DOACs in pairwise comparisons of patients with AF. The co-primary outcomes of interest were i) thromboembolic events including stroke, and ii) major bleeding events. Comparative outcomes were assessed by odds ratios (OR) with 95% confidence intervals (CI). Stata version 17.0 software was used for the analysis. Results: A total of 60,652 patients with AF enrolled in 10 RCTs were included. There was no difference in stroke or thromboembolism prevention between WM and DOAC [OR =1.04 (95% CI: 0.61-1.75; 9 trials) (Figure panel A). Similarly, there was no significant difference in major bleeding risk between WM vs DOAC [OR = 1.87 (95% CI: 1.0 – 3.52] (Figure panel B). No significant heterogeneity or publication bias was found. Conclusions: Based on this NMA, WM appears to provide no benefit in prevention of thromboembolism/stroke compared to DOAC in patients with AF. However, a reduction in the risk of major bleeding with WM cannot be ruled out. Future RCTs are necessary to better quantify the risk and benefit of WM compared to DOAC for patients with AF.
Abstract 10742: Implication of the Importins KPNA2 and KPNB1 in Pulmonary Arterial Hypertension
Authors: Sarah-eve Lemay, Charifa Awada, Victoria Toro, Charlotte Romanet, Mark Orcholski, Roxane Paulin, Steeve Provencher, Sebastien Bonnet, Olivier BOUCHERAT, François Potus
Journal: Circulation (2021)

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by the elevation of mean pulmonary arterial pressure and resistance, culminating in right ventricular failure and premature death. Pulmonary artery smooth muscle cells (PASMCs) isolated from PAH patients exhibit cancer-like phenotypes such as exaggerated proliferation and resistance to apoptosis, key elements contributing to pulmonary arteries (PA) remodeling. Taking benefits of our previously published proteomic study realized on PASMCs isolated from PAH and control patients, we identified the upregulation of importins proteins, namely KPNA2 and KPNB1. The importins contribute to the nucleocytoplasmic shuttling of macromolecules and transcription factors. Cancer studies highlighted the contribution of the KPNA2 and KPNB1 complex in the pro-proliferative and anti-apoptotic phenotypes of cancer cells. Given the cancer-like phenotype of PAH cells, we hypothesized that increased KPNA2-KPNB1 expression promotes PASMCs survival and adverse PA remodeling.We confirmed that KPNA2 and KPNB1 expression is increased in PASMCs and distal PAs isolated from PAH patients compared to controls (western-blot, n=8-9, p&lt;0.05). Similarly, we reported an increased expression of KPNA2-KPNB1 in 3 preclinical models of PH: hypoxic mice, monocrotaline rats and Sugen-hypoxia (Su-Hx) rats (n=8-12, p&lt;0.05). In vitro , molecular (siRNA) and pharmacological (Ivermectin) inhibition of KPNA2-KPNB1 complex decreases PAH-PASMCs proliferation (WB: PCNA; IF: Ki67 and EdU incorporation labeling) and resistance to apoptosis (WB: Survivin; IF: Annexin V labeling) (n=5, p&lt;0.5). Those results are associated with decreased expression of NFAT, NF-kB and STAT3. In vivo , Ivermectin improved PA remodeling (EVG staining) and hemodynamic parameters as assessed by echocardiography (PAAT, TAPSE) and right heart catheterization (RVSP, SV, CO) in Su-Hx rats (n=20, p&lt;0.05). We demonstrated 1) an increased expression of the importins KPNA2 and KPNB1 in PAH, 2) targeting KPNA2-KPNB1 reverses adverse PA remodeling and PH development. Thus, the repurposing of Ivermectin could represent a novel therapeutic strategy from the laboratory bench to patients’ bedside to reverse PAH development.
Abstract MP205: Human Induced Pluripotent Stem Cell Derived Cardiomyocyte And Fibroblast Patch To Treat Heart Failure
Authors: Jordan J Lancaster, Jennifer Koevary, Ryan Avery, Sherry L Daugherty, Kenneth Fox, Grace Gorman, Laryenth LANCASTER, Alice McArthur, Jacob Ref, Adrian Grijalva, Steven Goldman
Journal: Circulation Research (2021)

Background: We tested a tissue engineered (TE) patch composed of a biodegradable mesh embedded with human neonatal fibroblasts and seeded with human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) to treat heart failure in Yucatan mini swine receiving no immune suppression. Methods: Swine (N=12) underwent a 90-minute balloon occlusion/reperfusion of the left anterior descending coronary artery to create a myocardial infarction (MI). Following a 4-week recovery, the TE patch was implanted via a mini median sternotomy. The following were obtained: Cardiac Magnetic Resonance (CMR) imaging, cardiac catheterization, activity monitoring with FitBark collars, treadmill testing, 24/7 ECGs with implanted loop recorders. Results: At 4 weeks after MI, swine had increased left ventricular (LV) volumes, decreased end-systolic elastance (Ees), a shift of the diastolic pressure/volume (P/V) to the right of baseline and an increase in the LV mass/volume. After 6 months of treatment, the TE treated swine (N=7) compared to inert tissue treated swine (N=5): End-systolic volume (2% decrease vs 18% increase); End-diastolic volume (7% decrease vs 26% increase): Ees (1.0±0.2 vs 1.9±0.2 mmHg/mL, P=0.006); the diastolic P/V loops shifted back toward baseline with no change in slope, and LV mass decreased. There was no mortality related to treatment; the TE patch was well tolerated as assessed by CMR and histology. The loop recorders showed TE treated animals remained in sinus rhythm throughout with no ventricular arrhythmias, no change in heart rate and a 20% increase in daily activity levels and a 20% increase in exercise tolerance. Conclusions: This TE patch with human neonatal fibroblasts and hiPSC-CMs improves LV function, partially reverses LV remodeling and improves exercise in non-immune suppressed swine with heart failure after 6 months of treatment.
Abstract 12627: Effects Of Lipid Control On Coronary Calcification
Authors: Mustafa Alam, Olga V Savinova
Journal: Circulation (2021)

Introduction: Lipid lowering drugs are some of the most prescribed medications to control coronary artery disease (CAD). The long-term lipid lowering effects on coronary artery calcium (CAC) progression remain a subject of controversy with inconclusive results from multiple literature reviews. The purpose of this meta-analysis is to elucidate the relationship between lipid control and CAC progression. Methods: A computerized search of MEDLINE was conducted using the search terms “coronary”, “calcification”, “statin”, and “lipid lowering.” Studies were included if they measured mean value changes from baseline in coronary calcium using cardiac computed tomography. Data were extracted from the articles using the Cochrane method. RevMan 5.4 was used to aggregate the studies and report statistics. Results: A total of 13 studies were included with a total of 6671 patients. LDL reduction amongst the studies was significant as compared to placebo or lower dose lipid lowering therapy (standardized mean difference [SMD]: -0.71; 95% CI: -0.79, -0.64; p&lt;0.00001). A small increase in CAC was not statistically significant (standardized mean difference [SMD]: 0.10; 95% CI: 0.02, 0.17; p=0.19). Conclusions: Lipid lowering therapy shows efficacy in LDL reduction however, it does not lead to coronary calcium reduction. Further studies are needed to elucidate the long-term effects of lipid powering on CAC and the prognostic value of CAC in CAD parents receiving optimal therapy.
IMMU-18. GLIOBLASTOMA-DERIVED EXTRACELLULAR VESICLES INDUCE DRAMATIC CHANGES IN THE TRANSCRIPTOMIC LANDSCAPE OF MONOCYTES
Authors: Benjamin Himes, Cody Nesvick, Helen Li, Mi-Yeon Jung, Ian Parney
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) is the most common and deadly primary brain tumor. Novel therapeutic strategies are urgently needed to improve outcomes, but a number of disease-specific barriers pose challenges to innovation. Tumor-mediated immunosuppression is one such hurdle, and a growing body of evidence suggests that GBM-derived extracellular vesicles (EVs) play an important role in host immunosuppression. GBM-derived EVs have been shown to induce the formation of immunosuppressive monocytes, including myeloid-derived suppressor cells. Work by our group and others has increasingly shown that these immunosuppressive monocytes are a heterogenous group, and that many constellations of surface markers are inadequate to capture the changes wrought by EVs. In order to better understand the effects of GBM-EVs on monocytes, we conducted RNA-seq analysis on monocytes collected from four healthy donors treated with GBM-derived EVs harvested by ultracentrifugation from the patient-derived BT116 cell line. Following 72h of EV conditioning, total RNA was harvested from treated monocytes and untreated controls. RNA-seq was performed using the Illumina HiSeq4000 platform with paired end index reads. Analysis was performed using RNA STAR and the hg19 ENCODE reference sequence. Differential expression analysis was performed using DESeq2. Genes with a false-discovery rate (FDR)-corrected P value &amp;lt; 0.05 and a log2 fold-change value of &amp;gt;|1| were considered significantly different between groups. Pathway analysis was performed using ClueGO in Cytoscape (GO term fusion on, p&amp;lt; 0.05). Unsupervised clustering analysis of the top 500 most differentially-expressed genes demonstrated grouping of BT116 EV-treated monocytes together versus untreated monocytes. Pathway analysis upregulated genes in pathways important for heparan sulfate proteoglycan synthesis and cholesterol synthesis, which could potentially point to positive regulation of EV uptake. Downregulated pathways included regulation of T cell differentiation and chemoattractant activity, underscoring the induction of a potentially immunosuppressive phenotype by GBM-derived EVs.
Abstract 1885: Decreasing Hemoglobin Oxygen Affinity With Inositol Tripyrophosphate (itpp) Increases Maximal Exercise Capacity In Mice With Severe Heart Failure
Authors: Andreia Biolo, Ruth Greferath, Deborah Siwik, Richard Schwarz, Jean-Marie Lehn, Claude Nicolau, Wilson S Colucci
Journal: Circulation (2007)

Background: A major determinant of maximal exercise capacity is the delivery of oxygen to exercising muscles, which in turn is a function of cardiac output and the amount of oxygen released from he...
The 2021 WHO Classification of Lung Tumors: Impact of Advances Since 2015
Authors: Andrew G. Nicholson, Ming S. Tsao, Mary Beth Beasley, Alain C. Borczuk, Elisabeth Brambilla, Wendy A. Cooper, Sanja Dacic, Deepali Jain, Keith M. Kerr, Sylvie Lantuejoul, Masayuki Noguchi, Mauro Papotti, Natasha Rekhtman, Giorgio Scagliotti, Paul van Schil, Lynette Sholl, Yasushi Yatabe, Akihiko Yoshida, William D. Travis
Journal: Journal of Thoracic Oncology (2021)