tbuckley/cabot-search huggingface dataset:
Abstract 9221: Long-Term Risk of New-Onset Arrhythmia in Patients With ST-Segment Elevation Myocardial Infarction According to Revascularization Status
Authors: Anna Foged Thomsen, Christian Jons, Reza Jabbari, Mia R Ravn Jacobsen, Niels K Stampe, Jawad H Butt, Niels T Olsen, Henning Kelbæk, Christian Torp-Pedersen, Emil Fosbol, Frants Pedersen, Lars Kober, Thomas Engstrom, Peter Karl K Jacobsen
Journal: Circulation (2021)

Introduction: Emerging data show that complete revascularization reduces cardiovascular death and recurrent myocardial infarction in ST-segment elevation myocardial infarction (STEMI). The influence of revascularization status on development of arrhythmia in the chronic post-STEMI phase is poorly described. Hypothesis: We hypothesized that incomplete compared with complete revascularization in STEMI is associated with an increased long-term risk of new-onset arrhythmia. Methods: Using unique Danish registries, the risk of new-onset arrhythmia was assessed in STEMI with complete or incomplete revascularization after primary percutaneous coronary intervention (PPCI) at Rigshospitalet University Hospital, Denmark, from 2009-2016. The primary outcome was new-onset arrhythmia defined as a composite of atrial fibrillation/flutter, sinoatrial dysfunction, advanced 2nd- or 3rd-degree atrioventricular block, ventricular tachycardia/fibrillation, cardiac arrest, or pacemaker/ICD implantation, with presentation &gt;7 days post-PPCI. Secondary outcome was all-cause mortality. Results: A total of 5,062 patients (median age: 62.0 years; 76% men) were included, of which 3,985 and 1,077 patients underwent complete and incomplete revascularization, respectively. During a median follow-up of 4.9 years, 580 (15%) patients in the complete and 217 (20%) patients in the incomplete revascularization group were diagnosed with new-onset arrhythmia (Figure 1). Compared with complete revascularization, incomplete revascularization was associated with a higher risk of new-onset arrhythmia (adjusted hazard ratio [HR] 1.3; 95% CI, 1.1-1.5; P=0.004) and higher all-cause mortality (adjusted HR 1.3; 95% CI, 1.0-1.5; P=0.02). Conclusions: Incomplete revascularization in STEMI was associated with an increased long-term risk of new-onset arrhythmia and all-cause mortality compared with complete revascularization.
Trial in Progress: Phase 1b Study of Lisaftoclax (APG-2575) As a Single Agent or Combined with Other Therapeutic Agents in Patients with Relapsed and/or Refractory Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (R/R CLL/SLL)
Authors: Matthew S. Davids, Tanya Siddiqi, Asher Chanan-Khan, Alan Skarbnik, Allison M. Winter, John M. Pagel, Carrie Smith, Nashat Gabrail, Tetiana Perekhrestenko, Halyna Pylypenko, Olena Kyselova, Olena Karpenko, Tetiana Popovska, Iryna Kriachok, Hanna Usenko, Andrew Proidakov, Vladimir Ivanov, Tamila Lysa, Elena Borisenkova, Bulat Bakirov, Les Lukavetsky, Olga Uspenskaya, Tatiana S. Konstantinova, Olga S. Samoylova, Zi Chen, Bo Huang, Mingyu Li, Mohammad Ahmad, Boyd Mudenda, Dajun Yang, Yifan Zhai
Journal: Blood (2021)
Abstract PO-088: Classification based on efficiency of mRNA translation reveals a metabolically-dependent subtype of pancreatic cancer
Authors: Sauyeun Shin, Remy Nicolle, Mehdi Liauzun, Jacobo Solorzano, Alexia Brunel, Christine Jean, Remi Samain, Jerôme Raffenne, Cindy Neuzillet, Carine Joffre, Stephane Rocci, Juan Iovanna, Nelson Dusetti, Ola Larsson, Stephane Pyronnet, Corinne Bousquet, Yvan Martineau
Journal: Cancer Research (2021)

Abstract Molecular profiling of Pancreatic Ductal Adenocarcinoma (PDA), based on transcriptomic analyses, identifies two main prognostic subtypes (basal-like and classical), but does not allow personalized first-line treatment. To date, tumors have not been profiled based on protein synthesis rates, yet the step of mRNA translation is highly dysregulated in both PDA cancer cells and their microenvironment. We aim at assessing whether quantification of mRNA translation could provide a distinct perspective on PDA and identify novel tumor subtypes. Using a collection of twenty-seven pancreatic Patient-Derived Xenografts (PDX), we performed transcriptome-wide analysis of translated mRNA (translatome). Unsupervised bioinformatics analysis allowed PDA tumors classification according to mRNA translation rate. PDX-derived cancer cells as well as common PDA cell lines were used to functionally characterize newly identified subtype. Independent component analysis revealed a new tumor subtype harboring a low protein synthesis rate, but associated with a robust translation of mRNAs encoding effectors of the integrated stress response (ISR), including the transcription factor ATF4. Functional characterization of the “ISR-activated” human cancer cells revealed a high resistance to drugs, low autophagic capacities, and importantly, metabolic impairments in the serine synthesis and transsulfuration pathways. Therefore, the drug-resistant cancer cell phenotype showing auxotrophy to both serine and cysteine may be amenable to targeted therapy. Overall, our study highlights profiling of mRNA translation in cancer as an underexplored avenue for identification of previously unrecognized subtypes together with potential treatments. Citation Format: Sauyeun Shin, Remy Nicolle, Mehdi Liauzun, Jacobo Solorzano, Alexia Brunel, Christine Jean, Remi Samain, Jerôme Raffenne, Cindy Neuzillet, Carine Joffre, Stephane Rocci, Juan Iovanna, Nelson Dusetti, Ola Larsson, Stephane Pyronnet, Corinne Bousquet, Yvan Martineau. Classification based on efficiency of mRNA translation reveals a metabolically-dependent subtype of pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-088.
Vaccine targeting ANGPTL3 ameliorates dyslipidemia and associated diseases in mouse models of obese dyslipidemia and familial hypercholesterolemia
Authors: Hirotaka Fukami, Jun Morinaga, Hironori Nakagami, Hiroki Hayashi, Yusuke Okadome, Eiji Matsunaga, Tsuyoshi Kadomatsu, Haruki Horiguchi, Michio Sato, Taichi Sugizaki, Takashige Kuwabara, Keishi Miyata, Masashi Mukoyama, Ryuichi Morishita, Yuichi Oike
Journal: Cell Reports Medicine (2021)

Dyslipidemia is a risk factor for cardiovascular disease (CVD), a major cause of death worldwide. Angiopoietin-like protein 3 (ANGPTL3), recognized as a new therapeutic target for dyslipidemia, regulates the metabolism of low-density lipoprotein-cholesterol (LDL-C) and triglycerides. Here, we design 3 epitopes (E1-E3) for use in development of a peptide vaccine targeting ANGPTL3 and estimate effects of each on obesity-associated dyslipidemia in B6.Cg-Lepob/J (ob/ob) mice. Vaccination with the E3 (32EPKSRFAMLD41) peptide significantly reduces circulating levels of triglycerides, LDL-C, and small dense (sd)-LDL-C in ob/ob mice and decreases obese-induced fatty liver. Moreover, E3 vaccination does not induce cytotoxicity in ob/ob mice. Interestingly, the effect of E3 vaccination on dyslipidemia attenuates development of atherosclerosis in B6.KOR/StmSlc-Apoeshl mice fed a high-cholesterol diet, which represent a model of severe familial hypercholesterolemia (FH) caused by ApoE loss of function. Taken together, ANGPTL3 vaccination could be an effective therapeutic strategy against dyslipidemia and associated diseases.
Single Cell Characterization of Myeloma and Its Precursor Conditions Reveals Transcriptional Signatures of Early Tumorigenesis
Authors: Rebecca Boiarsky, Nicholas Haradhvala, Romanos Sklavenitis-Pistofidis, Tarek H Mouhieddine, Jean-Baptiste Alberge, Oksana Zavidij, Danielle Firer, Shankara Anand, Habib El-Khoury, François Aguet, David Sontag, Irene M. Ghobrial, Gad Getz
Journal: Blood (2021)
Mismatch in Sirpα, a Regulatory Protein in Innate Immunity, Is Associated with Outcomes of Allogeneic Stem Cell Transplantation for Lymphoid Malignancies
Authors: Rima M. Saliba, Uri Greenbaum, Qing Ma, Samer A. Srour, Gabriela Rondon, Elizabeth J. Shpall, Kai Cao, Richard E. Champlin, Jun Zou
Journal: Blood (2021)
Abstract 8916: Frequency Analysis of the QRS Differentiates Left Bundle Branch Pacing from RV Septal Pacing
Authors: Mark J Niebauer, Roy Chung, Mina K Chung, Niraj Varma
Journal: Circulation (2021)

Introduction: Left bundle branch pacing (LBBP) is an increasingly common procedure. The pacing lead is advanced via the RV septum into the myocardium with the goal of directly stimulating the LBB for more effective left ventricular (LV) activation. We have previously found that QRS frequency is useful for assessing successful LV activation in cardiac resynchronization therapy. Hypothesis: We surmised that the QRS complex of patients who underwent LBBP would exhibit significantly different frequency characteristics than simple RV septal pacing. Methods: We analyzed the QRS frequency of 36 patients with normal LV ejection fraction (≥50%) who have undergone LBBP for comparison to 33 patients who underwent RV septal pacing. Time frequency analysis was performed which yields a weighted average frequency (AKA: “center of energy” frequency or Cf) of the QRS. Chest lead V2 yielded the best frequency discrimination. We performed ROC analysis for all significant variables in multivariate analysis to obtain the area under the curve (AUC) predictive value. Results: See table: QRS duration, LVAT: paced LV activation time, AUC: area under the curve. Conclusions: Our data show that the QRS in LBB paced patients is significantly shorter and has a much higher Cf in lead V2 with high predictive value by ROC analysis compared to RV septal pacing. Baseline LVEF and paced LVAT exhibited lower AUC values. Such measurements may be of use during implantation of the pacing lead to ensure capture of the LBB when LV activation times and/or morphologic changes are equivocal.
Ischemic Heart-Derived Small Extracellular Vesicles Impair Adipocyte Function
Authors: Lu Gan, Demin Liu, Dina Xie, Wayne Bond Lau, Jing Liu, Theodore A. Christopher, Bernard Lopez, Lian Liu, Hang Hu, Peng Yao, Yarong He, Erhe Gao, Walter J. Koch, Jianli Zhao, Xin-Liang Ma, Yu Cao, Yajing Wang
Journal: Circulation Research (2021)

Patients with acute myocardial infarction suffer systemic metabolic dysfunction via incompletely understood mechanisms. Adipocytes play critical role in metabolic homeostasis. The impact of acute myocardial infarction upon adipocyte function is unclear. Small extracellular vesicles (sEVs) critically contribute to organ-organ communication. Whether and how small extracellular vesicle mediate post-MI cardiomyocyte/adipocyte communication remain unknown. Plasma sEVs were isolated from sham control (Pla-sEVSham) or 3 hours after myocardial ischemia/reperfusion (Pla-sEVMI/R) and incubated with adipocytes for 24 hours. Compared with Pla-sEVSham, Pla-sEVMI/R significantly altered expression of genes known to be important in adipocyte function, including a well-known metabolic regulatory/cardioprotective adipokine, APN (adiponectin). Pla-sEVMI/R activated 2 (PERK-CHOP and ATF6 [transcription factor 6]-EDEM [ER degradation enhancing alpha-mannosidase like protein 1] pathways) of the 3 endoplasmic reticulum (ER) stress pathways in adipocytes. These pathological alterations were also observed in adipocytes treated with sEVs isolated from adult cardiomyocytes subjected to in vivo myocardial ischemia/reperfusion (MI/R) (Myo-sEVMI/R). Bioinformatic/RT-qPCR analysis demonstrates that the members of miR-23-27-24 cluster are significantly increased in Pla-sEVMI/R, Myo-sEVMI/R, and adipose tissue of MI/R animals. Administration of cardiomyocyte-specific miR-23-27-24 sponges abolished adipocyte miR-23-27-24 elevation in MI/R animals, supporting the cardiomyocyte origin of adipocyte miR-23-27-24 cluster. In similar fashion to Myo-sEVMI/R, a miR-27a mimic activated PERK-CHOP and ATF6-EDEM-mediated ER stress. Conversely, a miR-27a inhibitor significantly attenuated Myo-sEVMI/R-induced ER stress and restored APN production. An unbiased approach identified EDEM3 (ER degradation enhancing alpha-mannosidase like protein 3) as a novel downstream target of miR-27a. Adipocyte EDEM3 deficiency phenocopied multiple pathological alterations caused by Myo-sEVMI/R, whereas EDEM3 overexpression attenuated Myo-sEVMI/R-resulted ER stress. Finally, administration of GW4869 or cardiomyocyte-specific miR-23-27-24 cluster sponges attenuated adipocyte ER stress, improved adipocyte endocrine function, and restored plasma APN levels in MI/R animals. We demonstrate for the first time that MI/R causes significant adipocyte ER stress and endocrine dysfunction by releasing miR-23-27-24 cluster-enriched small extracellular vesicle. Targeting small extracellular vesicle-mediated cardiomyocyte-adipocyte pathological communication may be of therapeutic potential to prevent metabolic dysfunction after MI/R.
The epidemiology, impact, and diagnosis of micronutrient nutritional dermatoses part 1: Zinc, selenium, copper, vitamin A, and vitamin C
Authors: Jacob Nosewicz, Natalie Spaccarelli, Kristen M. Roberts, Phil A. Hart, Jessica A. Kaffenberger, John C. Trinidad, Benjamin H. Kaffenberger
Journal: Journal of the American Academy of Dermatology (2021)
Management of Severe and Moderate Hypercholesterolemia in Young Women and Men
Authors: Shauna L. Newton, Alexander P. Hoffmann, Zhi Yu, Sara Haidermota, Pradeep Natarajan, Michael C. Honigberg
Journal: JAMA Cardiology (2021)

This study uses clinical registry data to assess achievement of low-density lipoprotein cholesterol reduction and lipid-lowering therapy prescribing patterns among adults aged 20 to 39 years with moderate to severe hypercholesterolemia.
Do MYC Alterations Matter in HIV-Associated Large B Cell Lymphomas? the "Euromyc" Study (a European retrospective study)
Authors: Chiara Pagani, Chiara Rusconi, Alessia Dalla Pria, Emanuele Ravano, Philipp Schommers, Mariana Bastos-Oreiro, Luisa Verga, Guido Gini, Michele Spina, Luca Arcaini, Sara Steffanoni, Davide Dalu, Chiara Cattaneo, Fabio Facchetti, Giuseppe Rossi, Alessandra Tucci, Alessandro Re
Journal: Blood (2021)
Abstract 14408: An Angiotensin Receptor Blocker in the Presence of SARS CoV2 Pseudovirus Does Not Change Protein Expression of ACE2 in Human Heart Cell Models
Authors: Mitali Das, Taylor Schilling, Beth Lovano, Laurie Castel, Dokyun Kim, Sadashiva S Karnik, John Barnard, David R Van Wagoner, Jae Jung, Mina K Chung
Journal: Circulation (2021)

Introduction: ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) use in COVID-19 raised concern due to reported increases in ACE2, the cell receptor for SARS-CoV2. We tested the hypothesis that ARB (Losartan) and ACEI (Captopril) do not impact SARS-CoV2 associated ACE2 expression in cardiomyocytes (CMs). Methods: Beating monolayer ventricular CMs were generated from human iPSCs and grown as engineered heart tissue constructs (EHTs), which mimic a more mature phenotype than monolayer CMs. Drug treatments (24hrs) without pseudovirus were applied to EHTs: (A) Vehicle, 1μM Losartan (ARB), 1μM Angiotensin II (AngII), 1μM Losartan+1μM Ang II; (B) Vehicle, 1μM Captopril, 1μM Ang I, or 1μM AngI+1μM Captopril with 2-3 replicates for each combination and RNAseq as outcome. Drug treatment A only was repeated in monolayer CMs with a 5-6 day to rVSV-SARS-Cov2Spike-Luciferase-FLAG tagged pseudovirus (2-4 replicates) with immunoblotting for ACE2, Cathepsin B (CTSB) and Furin proteins. Results: Immunoblot densitometry showed abundant ACE2 protein in untreated CMs and EHTs. A focused mRNA analysis of 12 genes associated with SARS-Cov2 entry and processing (EHTs) revealed no significant changes in expression of ACE2, NRP1, CTSB, CTSL and FURIN due to Losartan or Captopril treatment. There was a nonsignificant trend towards Losartan-induced increase in AGTR1 with attenuation when AngII was administered, while ITGA5 trended upwards with Losartan+AngII. AGTRI also trended upwards with Captopril and AngI+Captopril. Upon pseudoviral challenge, CMs demonstrated increased ACE2 (55%) and slightly decreased Furin (24%) protein, with unchanged CTSB, although results were not statistically significant. Losartan addition, regardless of AngII, did not alter SARS-CoV2Spike pseudovirus mediated changes of ACE2, Furin or CTSB proteins. Conclusions: Losartan or Captopril did not substantially alter gene expression of ACE2, CTSB, CTSL, FURIN and NRP1 in EHTs without pseudovirus. Losartan did not show convincing evidence for pseudoviral mediated changes of proteins important for viral entry and processing in CM cell models.
Daratumumab As a Treatment for Adult Immune Thrombocytopenia: A Phase II Study with Safety Run-in (the DART Study)
Authors: Galina Tsykunova, Pal André Holme, Hoa Thi Tuyet Tran, Tor Henrik Anderson Tvedt, Ludvig Andre Munthe, Marc Michel, Henrik Frederiksen, James B Bussel, David J. Kuter, Waleed Ghanima
Journal: Blood (2021)
83 Spatially resolved transcriptomic and proteomic investigation of breast cancer and its immune microenvironment
Authors: Jennifer Chew, Cedric Uytingco, Rapolas Spalinskas, Yifeng Yin, Joe Shuga, Benton Veire, Naishitha Anaparthy, Ryo Hatori, Anna-Maria Katsor, Layla Katiraee, Alexander Hermes, Jun Ding Chiang, Patrick Roelli, Stephen Williams, William Nitsch, Neil Weisenfeld, Dan Walkser, Jason Koth, Subham Basu, Will Howat, Karthik Ganapathy, Marlon Stoeckius
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background The tumor microenvironment (TME) is composed of highly heterogeneous extracellular structures and cell types such as endothelial cells, immune cells, and fibroblasts that dynamically influence and communicate with each other. The constant interaction between a tumor and its microenvironment plays a critical role in cancer development and progression and can significantly affect a tumor’s response to therapy and capacity for multi-drug resistance. High resolution analyses of gene and protein expression with spatial context can provide deeper insights into the interactions between tumor cells and surrounding cells within the TME, where a better understanding of the underlying biology can improve treatment efficacy and patient outcomes. Here, we demonstrated the ability to perform streamlined multi-omic tumor analyses by utilizing the 10X Genomics Visium Spatial Gene Expression Solution for FFPE with multiplex protein enablement. This technique simultaneously assesses gene and protein expression to elucidate the immunological profile and microenvironment of different breast cancer samples in conjunction with standard pathological methods. Methods Serial (5 µm) sections of FFPE human breast cancer samples were placed on Visium Gene Expression (GEX) slides. The Visium GEX slides incorporate ~5,000 molecularly barcoded, spatially encoded capture spots onto which tissue sections are placed, stained, and imaged. Following incubation with a human whole transcriptome, probe-based RNA panel and an immuno-oncology oligo-tagged antibody panel, developed with Abcam conjugated antibodies, the tissues are permeabilized and the representative probes are captured. Paired GEX and protein libraries are generated for each section and then sequenced on an Illumina NovaSeq at a depth of ~50,000 reads per spot. Resulting reads from both libraries are aligned and overlaid with H&amp;E-stained tissue images, enabling analysis of both mRNA and protein expression. Additional analyses and data visualizations were performed on the Loupe Browser v4.1 desktop software. Conclusions Spatial transcriptomics technology complements pathological examination by combining histological assessment with the throughput and deep biological insight of highly-multiplexed protein detection and RNA-seq. Taken together, our work demonstrated that Visium Spatial technology provides a spatially-resolved, multi-analyte view of the tumor microenvironment, where a greater understanding of cellular behavior in and around tumors can help drive discovery of new biomarkers and therapeutic targets.
Abstract 9321: Cardiac Work and End-Organ Perfusion During Biventricular Compared to Left Ventricular Impella and Norepinephrine Support in a Porcine Model of Severe Cardiogenic Shock
Authors: Nanna L Junker Udesen, Jakob Josiassen, Ole K Helgestad, Ann B Banke, Peter H Frederiksen, Lisette O Jensen, Henrik Schmidt, Hanne B Ravn, Jacob E Moller
Journal: Circulation (2021)

Background: Vasopressors are often combined with left ventricular (LV) mechanical support in severe cardiogenic shock to increase end-organ perfusion. Biventricular mechanical support might improve end-organ perfusion at lower cardiac workload compared to LV mechanical support and vasopressor infusion in severe cardiogenic shock. Aim: To compare LV and right ventricular (RV) total cardiac work (pressure-volume area x heart rate x 10 3 ) and organ-specific venous oxygen saturations from the pulmonary artery (SvO 2 ), kidney- and cerebral- veins in pigs with cardiogenic shock treated with biventricular (Bipella) versus ImpellaCP + norepinephrine 0.10 μg/kg/min (Imp+NE). Methods: Cardiogenic shock was induced by injections of microspheres into the left main coronary artery in eight pigs (approx. 70 kg). From conductance catheters in both ventricles, cardiac workload was calculated, and oxygen saturations were attained from the pulmonary artery, internal jugular- and kidney vein. Pigs were allocated in a crossover model to Bipella for 60 minutes (n=4) or Imp+NE for 30 minutes (n=4) and after completion shifted to the opposite treatment. Results are presented as median(Q1;Q3). Results: Bipella effectively unloaded the LV with reduction in LV work compared to Imp+NE (569[410-685] vs 357[206-509] 10 3 ml x mmHg/min, p=0.0078) while RV work was comparable (p=0.74). A significant increase in SvO 2 (66[63-73] vs 49[44-58]%, p=0.01) and cerebral venous oxygen saturations (71[63-77] vs 62[48-66]%, p=0.016) was observed during Imp+NE compared to Bipella, whereas no difference in kidney oxygen saturations was demonstrated (p=0.31). Conclusion: In this porcine study of cardiogenic shock due to left main coronary ischemia, Bipella decreased LV workload, but systemic oxygen delivery was not optimal (Figure). Imp+NE provided a higher LV workload balanced by an improvement in cerebral- and mixed venous oxygen saturation.
Post-Transplant Cyclophosphamide, Abatacept, and Short Course of Tacrolimus Combination (CAST) Is Safe and Seems Highly Effective in Preventing Graft-Versus-Host Disease Following Haploidentical Peripheral Blood Stem Cell Transplantation
Authors: A Samer Samer Al-Homsi, Frank Cirrone, Kelli Cole, Kelsey Stocker, Benedetto Bruno, J Andres Suarez-Londono, Judith Goldberg, Maher Abdul-Hay
Journal: Blood (2021)
Tolerability and Single Agent Anti-Neoplastic Activity of the CD3xCD123 Bispecific Antibody APVO436 in Patients with Relapsed/Refractory AML or MDS
Authors: Justin M Watts, Tara L. Lin, Alice S. Mims, Prapti Patel, Paul J Shami, Elizabeth H. Cull, Christopher R. Cogle, Cynthia Lee, Fatih Uckun
Journal: Blood (2021)