tbuckley/cabot-search huggingface dataset:
Outcomes of Allogeneic Hematopoietic Cell Transplantation (allo-HCT) for Adults with Primary Mediastinal B Cells Lymphoma (PMBCL): A Retrospective Study on Behalf of the Société Francophone De Greffe De Moelle Et De Thérapie Cellulaire (SFGM-TC) and the Lymphoma Study Association (LYSA) Group
Authors: Baptiste Le Calvez, Benoit Tessoulin, Loic Renaud, Carmen Botella-Garcia, Micha Srour, Steven Le Gouill, Gaelle Guillerm, Rémy Gressin, Stephanie Nguyen, Sabine Furst, Adrien Chauchet, David Sibon, Philippe Lewalle, Xavier Poire, Natacha Maillard, Alban Villate, Michael Loschi, Mathilde Hunault, Yves Beguin, Remy Dulery, Jean Jacques Tudesq, Vincent Camus, Patrice Chevallier, Amandine Le Bourgeois, Amandine Fayard
Journal: Blood (2021)
NIMG-18. [18F]FLUCICLOVINE PET TO DISTINGUISH PSEUDOPROGRESSION FROM TUMOR PROGRESSION IN POST-TREATMENT GLIOBLASTOMA
Authors: S Ali Nabavizadeh, Robert K Doot, Anthony J Young, Stephen J Bagley, Jeffrey B Ware, Erin Schubert, Fraser Henderson Jr, Austin Pantel, H Isaac Chen, John Y K Lee, Arati Desai, Donald M O’Rourke, MacLean Nasrallah, Steven Brem
Journal: Neuro-Oncology (2021)

Abstract Differentiation of true tumor progression (TP) from pseudoprogression (PsP) is a major unmet need in patients with glioblastoma. [18F]Fluciclovine is a synthetic amino acid PET radiotracer that is FDA-approved in biochemical recurrence in prostate cancer. The study aim was to assess the value of [18F]Fluciclovine PET in differentiation of histologically confirmed (“true”) TP and PsP in post-treatment of glioblastoma. METHODS: 23 patients with glioblastoma with new contrast-enhancing lesions or lesions showing increased enhancement ( &amp;gt; 25% increase) on standard MRI after completion of radiation underwent 60-minutes dynamic [18F]Fluciclovine PET imaging. Patients subsequently underwent resection of enhancing lesion and tumor percentage vs. treatment-related changes were quantified on histopathology. Patients were considered "true” TP if tumor represented ≥ 50% of the resected specimen, mixed TP-PsP if &amp;lt; 50% and &amp;gt; 10%, and PsP if tumor represented ≤ 10%. Summed 30- to 40-minute post-injection PET images were used to measure SUVpeak and SUVmax (g/mL units). RESULTS: 15 patients with “true” TP, 3 with mixed TP-PsP, and 5 with PsP were included. There was a positive correlation between SUVpeak by PET and tumor percentage by histology (Rho= 0.56, p= 0.006). Patients who demonstrated “true” TP had significantly higher SUVpeak compared to patients with histological PsP (4.8±1.6 vs 2.9± 1.0, p= 0.02, AUC= 0.91, n=20). SUVpeak cut-off of 3.3 provided 93% sensitivity, 80% specificity, and 90% accuracy for differentiation of “true” TP from PsP. Patients with “true” TP/mixed TP-PsP also had significantly higher SUVpeak than patients with PsP (4.6±1.5 vs 2.9± 1.0, p= 0.03, AUC= 0.88, n=23). SUVmax and partial volume-corrected SUVpeak and SUVmax exhibited similar performance. CONCLUSION: Our results indicated that [18F]Fluciclovine PET imaging can accurately differentiate “true” TP from PsP. Further studies are required to confirm these promising early results and determine optimal criteria for interpreting [18F]Fluciclovine PET to distinguish PsP from TP.
Abstract 10071: Improved Accuracy of 4D Flow with Ferumoxytol in Comparison to Gadolinium Contrast for Small Children with Congenital Heart Disease
Authors: Sarah E Kollar, Jason Mandell, Yue-hin Loke, Laura Olivieri
Journal: Circulation (2021)

Introduction: Cardiac magnetic resonance (CMR) now allows for time-resolved three-dimensional phase-contrast (4D flow) analysis of congenital heart disease (CHD). In infants with small vessels, the influence of contrast agent type (ferumoxytol vs. gadolinium) on 4D flow has not been investigated. Thus, we investigated the accuracy of 4D flow measurements in ferumoxytol vs. gadolinium-enhanced CMR of small CHD patients. Methods: This was a retrospective study consisting of CMR studies from CHD patients less than 20 kg who had ferumoxytol or gadolinium-enhanced 4D flow and standard phase contrast (2D-PC) flow collected. 4D flow clinical software (Arterys) was used to measure flow in great vessels, systemic veins and pulmonary veins. 4D flow accuracy was defined as % difference or correlation against conventional measurements from (2D-PC) of the same vessels. Subgroup analysis was performed on two-ventricular (2V) vs. single ventricular (1V) CHD, as well as low flows (defined as &lt; 1.5 L/min) in 1V CHD. Results: Twenty-one ferumoxytol-enhanced and 23 gadolinium-enhanced CMR studies were included, with no difference in age (2.1 ± 1.5 vs. 2.3 ± 1.8 years, p = 0.7), patient size (0.49 ± 0.18 vs. 0.51 ± 0.16 m 2 , p = 0.67), or vessel diameter (11.4 ± 5.2 vs. 12.4 ± 5.6, p = 0.22). 10 CMR studies with 1V CHD were included. Overall, ferumoxytol-enhanced 4D flow measurements demonstrated less % difference to 2D-PC when compared to gadolinium-enhanced studies (Figure 1A). In subgroup analysis of low flows in 1V CHD, ferumoxytol-enhanced 4D flow measurements had stronger correlation to 2D-PC (Figure 1B). Conclusions: In infants, ferumoxytol-enhanced 4D flow has improved accuracy when compared to gadolinium, particularly for small vessels in 1V CHD.
Immune dysregulation and immunopathology induced by SARS-CoV-2 and related coronaviruses — are we our own worst enemy?
Authors: Lok-Yin Roy Wong, Stanley Perlman
Journal: Nature reviews. Immunology (2021)

Human coronaviruses cause a wide spectrum of disease, ranging from mild common colds to acute respiratory distress syndrome and death. Three highly pathogenic human coronaviruses — severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus and SARS-CoV-2 — have illustrated the epidemic and pandemic potential of human coronaviruses, and a better understanding of their disease-causing mechanisms is urgently needed for the rational design of therapeutics. Analyses of patients have revealed marked dysregulation of the immune system in severe cases of human coronavirus infection, and there is ample evidence that aberrant immune responses to human coronaviruses are typified by impaired induction of interferons, exuberant inflammatory responses and delayed adaptive immune responses. In addition, various viral proteins have been shown to impair interferon induction and signalling and to induce inflammasome activation. This suggests that severe disease associated with human coronaviruses is mediated by both dysregulated host immune responses and active viral interference. Here we discuss our current understanding of the mechanisms involved in each of these scenarios. In this Perspective, Lok-Yin Roy Wong and Stanley Perlman consider how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and related coronaviruses are able to drive immune dysregulation and immunopathology. They provide an overview of the coronavirus-derived molecules that interfere with key innate immune responses, including interferon pathways and complement, NF-κB signalling and inflammasome activation, as well as with the activation of host adaptive immunity.
Abstract P443: Loss Of Pkm2 Alters Myocardial Metabolism And Increases Oxidative Stress After Infarction
Authors: Katie C Lee, Allison L Williams, Ralph V Shohet
Journal: Circulation Research (2021)

Introduction: Pyruvate kinase (Pkm1) directs pyruvate to the TCA cycle for oxidative metabolism in the healthy heart. Our lab described a hypoxia-mediated switch to the alternatively spliced isoform Pkm2, enhancing pyruvate to lactate conversion. Recently, we have also found that Pkm2 knockout (KO) mice had profound depletion of basal glucose in the heart compared to control mice. Pkm2 has also been shown to reduce oxidative damage and promote cardiomyocyte cell proliferation after myocardial infarction (MI). We hypothesize that the upregulation of Pkm2 alters metabolic pathways after injury to promote glycolysis and preserve ATP production in hypoxia, which protects the heart from the stresses of hypoxia and injury. Methods: Global Pkm2 KO mice were subjected to permanent ligation of the left anterior descending coronary artery to mimic an MI. RNA-seq analysis of left ventricles from control (n=8) and Pkm2 KO mice (n=8) before and 3 days after sham or MI surgery was performed. Semiquantitative real-time PCR (qPCR) was used to confirm changes in selected genes of interest. Results: Loss of Pkm2 did not alter gene expression substantially at baseline. 68 genes were differentially expressed in Pkm2 KO hearts after MI (q&lt;0.05, FDR&lt;0.05) not observed in control MI hearts. MI in Pkm2 KO hearts resulted in considerable reduction of transcripts of enzymes in the insulin signaling pathway, mitochondrial oxidative phosphorylation, fatty acid metabolism, and increase in transcripts encoding enzymes in the pentose phosphate pathway, response to oxidative stress, and apoptotic signaling. qPCR of selected genes involved in glucose metabolism confirmed RNA-seq results. Conclusions: RNA-seq analysis of Pkm2 KO hearts demonstrated that loss of Pkm2 altered gene expression of metabolic and mitochondrial enzymes. Conversely, Pkm2 KO hearts showed increased abundance of pro-apoptotic markers which may be a result of increased oxidative stress.
Abstract 13841: Transcriptomic Signatures of Atrial- And Ventricular-like Human Induced Pluripotent Stem Cell Derived Cardiomyocytes
Authors: Jared Churko, Barbara Treutlein, Priyanka Garg, Meenakshi Venkatasubramanian, Haodi Wu, Shih-Yu Chen, Wen-Yi Chen, Jaecheol Lee, Vittavat Termglinchan, Gary Mantalas, Norma Neff, Eric Jabart, Garry Nolan, Nathan Salomonis, Joseph Wu
Journal: Circulation (2016)

Differentiation of cardiomyocytes from human induced pluripotent stem cells (hiPSC-CMs) can be used to gain insight into the signaling pathways that regulate human heart development. The resulting hiPSC-CMs formed have been reported to possess either atrial- or ventricular-like characteristics and uncovering the molecular mechanisms which regulate the development of these cardiomyocyte subtypes will be instrumental in drug screening and disease modelling research efforts. To investigate the molecular signatures of atrial- and/or ventricular-like hiPSC-CMs formed after differentiation, we profiled the transcriptomic signatures of day 30 hiPSC-CMs using single-cell RNA-seq. Using unsupervised and supervised clustering approaches, we defined distinct subpopulations of hiPSC-CMs representing different stages of maturity as well as expressing atrial or ventricular markers. Expression of NR2F2 was found to be specifically enriched within the atrial defined subpopulation while HEY2 expression was enriched within the ventricular defined subpopulation. To further investigate the role that these transcription factors play in defining each cardiomyocyte subpopulation, we created cell lines deficient in either HEY2 or NR2F2 using CRISPR technology. Patch-clamp analysis revealed an increase in atrial-like action potentials within HEY2 gene-edited cardiomyocytes and single cell Westerns revealed a decrease in the expression of the ventricular marker MYL2 within these cells. Finally, by assessing the temporal expression of transcription factors during differentiation by RNA-seq (along with CyTOF analysis), we observed that the expression of atrial markers preceded the expression of ventricular markers. By defining the transcriptomic signatures of cardiomyocyte subpopulations using single-cell RNA-seq and additional novel supporting methods, we provide a platform for understanding human heart developmental pathways in vitro, hiPSC-CM heterogeneity, and cardiomyocyte subtype specificity.
EPCO-16. ONCOHISTONE INTERACTOME PROFILING UNCOVERS MECHANISMS OF CHROMATIN DISRUPTION AND IDENTIFIES POTENTIAL THERAPEUTIC TARGETS IN PEDIATRIC HIGH-GRADE GLIOMA
Authors: Robert Siddaway, Laura Canty, Sanja Pajovic, Etienne Coyaud, Scott Milos, Stefanie-Grace Sbergio, Evan Lubanszky, Haley Yun, Sheyenne Carette, Alessia Portante, Brian Raught, Eric Campos, Cynthia Hawkins
Journal: Neuro-Oncology (2021)

Abstract Mutations in histone H3 at amino acids 27 (H3K27M) and 34 (H3G34R) occur with high-frequency in pediatric high-grade glioma. H3K27M mutations have been shown to lead to global disruption of H3K27me3 through dominant negative PRC2 inhibition with accompanying gains in H3K36me3, while H3G34R mutations lead to local losses of H3K36me3 through inhibition of SETD2. However, the mechanism of action of these mutants on the broader landscape of chromatin-associated proteins remains unknown. Importantly, proteins with differential associations with oncohistones could be targeted therapeutically. Here we profiled the interactomes of the H3.1K27M, H3.3K27M and H3.3G34R oncohistones using BioID to gain an unbiased measure of their interaction landscapes. Among the differential interactors all 3 mutants lost interaction with H3K9 methyltransferases, while H3G34R also had reduced interaction with DNA methyltransferases accompanied by genome-wide DNA hypomethylation. In contrast, H3K27M mutants had increased association with transcription factors, consistent with the activation of transcription induced by the global loss of H3K27me3. H3K9me3 was reduced in H3K27M-containing nucleosomes, and cis-H3K9 methylation was required for H3K27M to exert its effect on global H3K27me3. Depletion of H3K9 methyltransferases with shRNA or treatment with H3K9 methyltransferase inhibitors was lethal to H3.1K27M, H3.3K27M and H3.3G34R mutant pHGG cell lines, underscoring the importance of H3K9 methylation for oncohistone-mutant gliomas and suggesting it could make an attractive therapeutic target.
Comparing Video-Based, Telehealth-Delivered Exercise and Weight Loss Programs With Online Education on Outcomes of Knee Osteoarthritis
Authors: Kim L. Bennell, Belinda J. Lawford, Catherine Keating, Courtney Brown, Jessica Kasza, Dave Mackenzie, Ben Metcalf, Alexander J. Kimp, Thorlene Egerton, Libby Spiers, Joseph Proietto, Priya Sumithran, Anthony Harris, Jonathan G. Quicke, Rana S. Hinman
Journal: Annals of Internal Medicine (2021)

Scalable knee osteoarthritis programs are needed to deliver recommended education, exercise, and weight loss interventions.To evaluate two 6-month, telehealth-delivered exercise programs, 1 with and 1 without dietary intervention.3-group, parallel randomized (5:5:2) trial. (Australian New Zealand Clinical Trials Registry: ACTRN12618000930280).Australian private health insurance members.415 persons with symptomatic knee osteoarthritis and a body mass index between 28 and 40 kg/m2 who were aged 45 to 80 years.All groups received access to electronic osteoarthritis information (control). The exercise program comprised 6 physiotherapist consultations via videoconference for exercise, self-management advice, and behavioral counseling, plus exercise equipment and resources. The diet and exercise program included an additional 6 dietitian consultations for a ketogenic very-low-calorie diet (2 formulated meal replacements and a low-carbohydrate meal daily) followed by a transition to healthy eating, as well as nutrition and behavioral resources.Primary outcomes were changes in knee pain (numerical rating scale [NRS] of 0 to 10, higher indicating worse) and physical function (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]; scale, 0 to 68, higher indicating worse) at 6 months (primary time point) and 12 months. Secondary outcomes were weight, physical activity, quality of life, mental health, global change, satisfaction, willingness to have surgery, orthopedic appointments, and knee surgery.A total of 379 participants (91%) provided 6-month primary outcomes, and 372 (90%) provided 12-month primary outcomes. At 6 months, both programs were superior to control for pain (between-group mean difference in change on NRS: diet and exercise, -1.5 [95% CI, -2.1 to -0.8]; exercise, -0.8 [CI, -1.5 to -0.2]) and function (between-group mean difference in change on WOMAC: diet and exercise, -9.8 [CI, -12.5 to -7.0]; exercise, -7.0 [CI, -9.7 to -4.2]). The diet and exercise program was superior to exercise (pain, -0.6 [CI, -1.1 to -0.2]; function, -2.8 [CI, -4.7 to -0.8]). Findings were similar at 12 months.Participants and clinicians were unblinded.Telehealth-delivered exercise and diet programs improved pain and function in people with knee osteoarthritis and overweight or obesity. A dietary intervention conferred modest additional pain and function benefits over exercise.Medibank, the Medibank Better Health Foundation Research Fund, and a National Health and Medical Research Council Centre of Research Excellence.
Covid-19: UK approves monoclonal antibody sotrovimab for over 12s at high risk
Authors: Elisabeth Mahase
Journal: BMJ (2021)

Covid-19: UK approves monoclonal antibody sotrovimab for over 12s at high risk Elisabeth MahaseThe UK's medicines regulator has approved a second monoclonal antibody, sotrovimab, for the treatment of people over 12 years with mild to moderate covid-19 who are at high risk of developing severe disease. 1 1
Contemporary medicinal chemistry strategies for the discovery and optimization of influenza inhibitors targeting vRNP constituent proteins
Authors: Lingxin Hou, Ying Zhang, Han Ju, Srinivasulu Cherukupalli, Ruifang Jia, Jian Zhang, Bing Huang, Arianna Loregian, Xinyong Liu, Peng Zhan
Journal: Acta Pharmaceutica Sinica B (2021)

Influenza is an acute respiratory infectious disease caused by the influenza virus, affecting people globally and causing significant social and economic losses. Due to the inevitable limitations of vaccines and approved drugs, there is an urgent need to discover new anti-influenza drugs with different mechanisms. The viral ribonucleoprotein complex (vRNP) plays an essential role in the life cycle of influenza viruses, representing an attractive target for drug design. In recent years, the functional area of constituent proteins in vRNP are widely used as targets for drug discovery, especially the PA endonuclease active site, the RNA-binding site of PB1, the cap-binding site of PB2 and the nuclear export signal of NP protein. Encouragingly, the PA inhibitor baloxavir has been marketed in Japan and the United States, and several drug candidates have also entered clinical trials, such as favipiravir. This article reviews the compositions and functions of the influenza virus vRNP and the research progress on vRNP inhibitors, and discusses the representative drug discovery and optimization strategies pursued.
Abstract 10087: Variable Exposure to Infarct and Ischemia in Stress Echocardiography Among Cardiology Fellows-in-Training
Authors: Patrick J Bergquist, Matthew J Bierowski, Umer Qureshi, Madeline Matzelle-Zywicki, Jacob R Staub, Brandon R Peterson
Journal: Circulation (2021)

Introduction: COCATS guidelines recommend that fellows interpret a minimum of 100 stress echocardiograms to achieve proficiency for independent practice. Whether this recommended number is sufficient to gain adequate exposure to varied patterns of infarct and ischemia on stress echocardiography is unclear. We investigated whether cardiology fellows who interpreted the recommend number by COCATS lacked exposure to pathologies of infarct or ischemia on stress echocardiography. Methods: We reviewed reports from the first 100 stress echocardiograms interpreted by our fellows who completed training from 2017 through 2021 for findings of infarct or ischemia in the left anterior descending coronary artery (LAD), right coronary artery (RCA), and circumflex coronary artery (CX) territories. Paired T-test was used to compare the mean incidence of studies with and without infarct and ischemia. Results: 2,400 stress echocardiography reports were reviewed from 24 fellows. Normal stress echocardiograms (mean 81 per fellow) were significantly more common than those with infarct (mean 5 per fellow, p&lt;0.001) or with ischemia (mean 6 per fellow, p&lt;0.001, see figure below). Among the first 100 stress echocardiograms interpreted, 10/24 fellows had no cases with CX infarct, 4/24 had no cases with RCA infarct, 3/24 had no cases with LAD infarct, 3/24 had no cases with CX ischemia, 4/24 had no cases with RCA ischemia, and 4/24 had no cases with multivessel ischemia. Conclusion: The recommended number of stress echocardiograms to interpret in COCATS does not ensure adequate exposure to varied patterns of infarct and ischemia due to the relative infrequency of these findings compared with normal studies. To ensure competency-based learning, fellowship programs should identify deficiencies and supplement learning as needed in stress echocardiography beyond what fellows achieve by interpreting the minimum recommended number from COCATS.
Impact of p53 Disruption on Mantle Cell Lymphoma (MCL) Treatment out-Come, Multi-Centre Retrospective Study
Authors: Ezzat Elhassadi, Brian Hennessy, Senthil Kumar, Louise Sutton, Michelle Griffin, Osasere Osarhieme, Rehman Faryal, Christine Schilling, Mutaz Nur, Eimear Lee, Ramadan Shatwan, Anne Marie Quinn, Mark Catherwood, Amjad Hayat
Journal: Blood (2021)
Abstract 13778: Disease Modelling and Gene Therapy of Hereditary Hemorrhagic Telangiectasia Combined With Pulmonary Artery Hypertension
Authors: Jian Shi, Xingqiang Lai, Guifu Wu, jianwen Liang, Wenbin Wei
Journal: Circulation (2021)

Introduction: Hereditary hemorrhagic telangiectasia combined with pulmonary arterial hypertension(HHT-PAH) caused by pathogenic variants of ACVRL1 gene progresses with poor prognosis. However, there is few treatments, thus developing novel models and innovative therapy is crucial. Combination of iPSCs with gene editing technologies may be a promising applications to illuminate the disease. Hypothesis: Gene editing is a promising therapy for HHT-PAH with ACVRL1 gene mutations. Methods: Patients with HHT-PAH who carrying ACVRL1 heterozygous c.1270C&gt;G mutation were recruited. The reprogramming factors (Oct3/4, Sox2, c-Myc, and Klf4) were transferred into the PBMCs by using non-integrating Sendai virus. The obtained hiPSCs were passaged, individually isolated and expanded 3 weeks after reprogramming factors transduction. The mutated ACVRL1 gene was repaired by CRISPR Base Editing tools to generate ACVRL1 corrected -iPSCs line. Both the patient-specific iPSCs and ACVRL1 corrected -iPSCs were differentiated into induced endothelium. EC adhesion and survival were tested in the endothelial lines. Results: The patient-specific iPSCs showed typical morphology with high alkaline phosphatase activity and normal karyotype (46, XX). Pluripotency markers OCT4, NANOG, SOX2, and TRA-1-60 were confirmed by Immunofluorescence staining and qRT-PCR. Markers of three germ layers, TUBB3+ , αSMA+ and SOX17+ cells were found in the differentiated cell population as revealed by immunostaining in vitro . These two iPSCs cell lines formed teratomas composed of tissues derived from three germ layers in immunodeficient mice. Fluorescence-activated cell sorting analysis showed that most of patient-specific iPSCs and ACVRL1 corrected -iPSCs population expressed the mature EC surface marker CD144 or CD31, and none of cells expressed the early mesoderm marker KDR during the differentiation process. Cell adhesion and survival capacity were preserved in ACVRL1 corrected iPSC-ECs, which were similar to the control, whereas these functions were significantly impaired in patient-specific iPSC-ECs. Conclusions: This study presented an in vitro cell model for exploring the pathogenesis of HHT-PAH and gene editing therapy might be a novel strategy.