tbuckley/cabot-search huggingface dataset:
Abstract 14187: Differential Neutralization of Unfractionated and Low Molecular Weight Heparin by Andexanet Alfa
Authors: Joseph Lewis, Omer Iqbal, Walter Jeske, Debra Hoppensteadt, Fakiha Siddiqui, Jawed Fareed
Journal: Circulation (2021)

Introduction: Andexanet Alfa is an antidote for the neutralization of the bleeding effects of Direct Oral Anticoagulant (Direct Xa) agents such as Rivaroxaban and Apixaban. It represents a molecularly modified factor Xa decoy protein with high specificity for factor Xa inhibitors. Unfractionated heparin (UFH) and low molecular weight heparins (LMWHs) exhibit both anti-Xa and anti-IIa activities. The purpose of this study is to investigate the relative neutralization of the anti-coagulant effects UFH and enoxaparin by andexanet alfa in whole blood assays such as activated clotting time (ACT) and thromelastography (TEG). Methods: The neutralization profiles of UFH and enoxaparin were studied by Andexanet at various concentrations. The final concentration of UFH used for activated clotting time (ACT) was 10 μg/ml, and for enoxaparin was 25 μg/ml. Andexanet was used in a concentration range of 12.5 ug/ml. For the thromboelastographic (TEG) analysis the concentration of all drugs were proportionately reduced. The results were analyzed using R open source statistical software. In order to compare the means of the groups, analysis of variance (ANOVA) tests were performed. If the ANOVA test yielded a significant result, a Tukey post-hoc analysis was performed. A pearson correlation was run for each parameter with respect to the dose of the drug. Results: Andexanet at 200 ug/ml moderately neutralized UFH (302 s vs 198). Andexanet minimally neutralized enoxaparin (200 s vs 190 s). There was no concentration dependent change in the neutralization profiles of UFH and enoxaparin at a concentration range of 12.5 ug/ml - 200 ug/ml. In the TEG assays, Andexanet alfa at 10 ug/ml partially neutralized the anticoagulant effects of UFH at 1 ug/ml as measured by various TEG parameters. At 20 ug/ml, stronger inhibition of all parameters were noted. Discussion: These studies suggest that Andexanet Alfa may be an effective neutralizing agent for UFH, however, it is ineffective in neutralizing LMWH at the concentrations studied. It is interesting to note that LMWHs have a higher anti-Xa to IIa ratio in comparison to heparin, however, their neutralization is lesser with Andexanet. These studies suggest that andexanet can be used in combination with protamine sulfate to neutralize UFH.
A First-in-Human Study of YTB323, a Novel, Autologous CD19-Directed CAR-T Cell Therapy Manufactured Using the Novel T-Charge TM platform, for the Treatment of Patients (Pts) with Relapsed/Refractory (r/r) Diffuse Large B-Cell Lymphoma (DLBCL)
Authors: Ian W. Flinn, Ulrich Jaeger, Nirav N. Shah, Didier Blaise, Javier Briones, Leyla Shune, Nicolas Boissel, Attilio Bondanza, Darlene Lu, Xu Zhu, Boris Engels, Jennifer L Brogdon, Jennifer Mataraza, Jaclyn Davis, Anne Laure Marchal, Luisa Mariconti, Michele Moschetta, Laure Moutouh-de Parseval, Pere Barba, Michael Dickinson
Journal: Blood (2021)
Association between plasma plasminogen activator inhibitor-1 and survival in colorectal cancer
Authors: N. Sattar, D. C McMillan, H. J. Nielsen, I. J. Christensen, N. Brunner, S. Sorensen
Journal: BMJ (1998)

Measuring C reactive protein concentrations may be more useful

EDITOR—Nielsen et al reported an association between circulating concentrations of plasminogen activator inhibitor-1 and survival in patients with colorectal cancer.1 They suggest that this reflects the specific role of plasminogen activator inhibitor-1 in tumour progression.

It has been known for some time that disease progression in colorectal cancer is associated with an increase in the acute phase response as evidenced by the prototypical acute phase protein (C reactive protein).2 We have reported that an increase in circulating C reactive protein concentrations is associated with increased recurrence of tumour in patients who have undergone curative surgery for colorectal cancer.3 There is also evidence that an increased C reactive protein concentration is an independent predictive factor of survival in patients with gastrointestinal cancer.4 Therefore the association between increased plasminogen …
Association between Sociodemographic, Clinical and Immunophenotypic Variables with Disease Relapse and Survival at 12 Months, in Patients with B-Cell Acute Lymphoblastic Leukemia Treated at a Colombian University Hospital
Authors: Luis Antonio Salazar, Sandra Vanesa Rios, Angela María Peña, Maria Luna-Gonzalez, Mario Andrés Arenas, Zayda Muentes, Jonathan Javier Diaz-Jurado, Manuel Rosales, Carlos Alberto Orozco Oviedo, Sara Ines Jimenez, Luisa Sanchez-Sossa, Katherinee Morales-Chacon, Carlos Andrés Pérez, Jose Sandoval-Sus, Claudia Lucia Sossa
Journal: Blood (2021)
Abstract 10719: Deep Learning to Estimate COVID-19 Mortality Risk from Chest Radiographs
Authors: Vineet Raghu, Alexander Cheng, Sanjana Singh, Matthew D Li, Aniket Zinzuwadia, Jayashree Kalpathy-Cramer, Michael T Lu
Journal: Circulation (2021)

Introduction: Management of coronavirus disease 2019 (COVID-19) requires accurate assessment of risk of future cardiopulmonary complications. Deep learning can extract complex relationships between medical imaging and clinical outcomes. Hypothesis: A deep learning model can predict 30-day mortality from COVID-19 based on a chest radiograph image. Methods: A deep learning model (CXR-CovRisk) was developed to estimate 30-day mortality risk using a single chest radiograph image (chest x-ray or CXR). The model was developed using 1,738 patients with PCR-confirmed coronavirus disease 2019 (COVID-19) from four Boston-area hospitals between March 1, 2020 and April 24, 2020. CXR-CovRisk was tested on 903 consecutive patients with confirmed COVID-19 between April 25, 2020 and June 15, 2020. CXR-CovRisk was compared to two published deep learning models (PXS and COVID-GMIC) and a clinical risk factor-based severity score for discrimination of 30-day mortality. The continuous risk score was converted to three risk groups: Low, Medium, and High based on development dataset probability quantiles. Results are provided for the independent testing set only Results: CXR-CovRisk had high discrimination for 30-day mortality (AUC = 0.839, 95% CI [0.79,0.89]), which was higher than when using a deep learning lung disease severity score (PXS AUC 0.750 [0.70,0.80], p &lt; 0.001) or the output of a model trained for 96-hour mortality prediction (COVID-GMIC 0.755 [0.70,0.81], p = 0.003). CXR-CovRisk had added value to the clinical risk-factor based severity score (Clinical Severity Score AUC 0.799 [0.76,0.84] vs. Combined AUC 0.872 [0.84,0.90], p &lt; 0.001). Among outpatients not admitted to the hospital, the CXR-CovRisk High-risk group had a high rate of subsequent hospital admission and 30-day mortality (composite event rate 11/26, 42.3%), higher than the medium-risk (30/179, 16.8%, p=0.005) and low-risk groups (17/172, 9.9%, p &lt; 0.001). Conclusion: A deep learning model, CXR-CovRisk, can estimate 30-day mortality risk from a chest radiograph image.
Abstract 11028: Gender Inequality in Enrollment in Late-Breaking Cardiovascular Clinical Trials
Authors: Gurleen Kaur, Jessica Holtzman, Juliette Power, Daniel Ambinder, Amit Goyal, Martha Gulati
Journal: Circulation (2021)

Introduction: Cardiovascular disease is the leading cause of mortality in both men and women. Prior studies have demonstrated the underrepresentation of women in published clinical trials, but to date no study has assessed inclusion of women in late-breaking clinical trials (LBCT) presented at national meetings. Methods: Using the American College of Cardiology’s 2021 Scientific Sessions’ LBCT, the inclusion of women was assessed. The inclusion to prevalence ratio (IPR) was calculated by dividing the percentage women participants in the trial by the percentage women in each disease population. IPRs less than 1 indicate under-enrollment of women. Of the 26 LBCT, 1 trial was excluded, as it exclusively enrolled women. Results: Inclusion of women ranged from 16.8% to 53.1%. The average IPR was 0.71 for all trials and did not vary based on single vs. multi-center, size, or funding source. The average IPR varied based on sub-specialty, with statistical differences noted between electrophysiology (EP) and heart failure (0.53 vs 0.86, p=0.02), as well as between EP and general/preventive (0.53 vs 0.72, p=0.04). The average IPR was significantly lower for procedural studies compared with medication trials (0.51 vs 0.73, p=0.02). There was no difference in IPR based on female authorship (Figure 1). Conclusions: LBCT can impact novel drug/device approval, indications, and patient management. Nonetheless, most LBCT under-enroll women. In particular, EP, interventional cardiology, and procedural LBCT have the lowest inclusion of women. These findings warrant further investigation into ways to increase enrollment of women, including potential requirements for consideration as LBCT by meeting organizers.
Abstract 14383: Medical Therapy Before, During, and After Hospitalization in Medicare Beneficiaries With Heart Failure and Diabetes: The Get With the Guidelines - Heart Failure Registry
Authors: Ankeet S Bhatt, Gregg C Fonarow, Stephen J Greene, DaJuanicia N Holmes, Brooke Alhanti, Adam D Devore, Javed Butler, Paul A Heidenreich, Joanna Huang, Michelle M Kittleson, Karen E Joynt Maddox, James J McDermott, Anjali T Owens, Pamela Peterson, Scott Solomon, Orly Vardeny, Clyde W Yancy, Muthiah Vaduganathan
Journal: Circulation (2021)

Introduction: Patients with heart failure with reduced ejection fraction (HFrEF) and diabetes mellitus (DM) are at risk for worsening HF events, yet little is known about therapeutic changes surrounding hospitalization. We aimed to characterize use of medical therapies before, during, and after hospitalization for HF. Methods: We identified Medicare beneficiaries in the GWTG-HF registry with HFrEF and DM who were hospitalized between July 2016 and September 2017 and had Part D prescription coverage for ≥6 months before and ≥3 months after hospital discharge. Medication fills for evidence-based HFrEF and antihyperglycemic therapies were assessed at 6 and 3 months before hospitalization, at hospital discharge, and 3 months post-discharge. Results: Among 3,272 Medicare beneficiaries with HFrEF and DM, mean age was 77±7y, 41% were women, and 15% were Black. Overall, 92%, 56%, 28%, and 6% were prescribed β-blocker, ACEi/ARB, MRA, and ARNI at discharge. Rates of all therapies were higher at discharge than immediately prior to hospitalization, though rates of β-blocker and ACEi/ARB use declined 3-months post-discharge. ‘Triple therapy’ (ACEI/ARB/ARNI+β-blocker+MRA) was prescribed in 9% prior to hospitalization and 20-21% at discharge and early-post-discharge. After hospitalization, insulin was prescribed most frequently (35%), followed by metformin (21%), sulfonylureas (19%), and DPP4i (11%), while GLP-1RA (2%) and SGLT2i (0.5%) use was infrequent. Modest changes in antihyperglycemic therapies were observed pre- vs. post-hospitalization, including an increase in insulin from 32% to 35% and decrease in metformin from 26% to 21% and SGLT2i from 0.8% to 0.5%. Conclusions: Despite modest improvements in use of evidence-based therapies for HFrEF during and shortly after hospitalization for HF, only 1 out of 5 patients are treated with comprehensive medical therapy. Early adoption in 2016-2017 of SGLT2i was low in a high-risk population with comorbid HFrEF and DM.
EXTH-28. NLGN4X TCR TRANSGENIC T CELLS TARGETING EXPERIMENTAL GLIOMAS
Authors: Christopher Krämer, Michael Kilian, Rainer Will, Khwab Sanghvi, Edward Green, Mirco Friedrich, Wolfgang Wick, Michael Platten, Lukas Bunse
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND The application of personalized vaccines has shown to be effective in patients with newly diagnosed glioblastoma in phase 1 clinical trials. Responses of CD8 T cells directed against the glioma-associated antigen Neuroligin-4, X-linked (NLGN4X) were reported in multipeptide vaccine trials in patients with glioblastoma. Here, we characterized the functional status of NLGN4X TCR transgenic T cells in vitro and assessed their therapeutic capacity in vivo. METHODS TCR encoding sequences were delivered by lentiviral transduction to activated T cells from healthy donors. After confirmation of TCR surface expression T cells were used for a functional in vitro characterization. For in vivo assessment of NLGN4X-specific TCR transgenic T cells, NLGN4X-expressing U87 glioma cells were injected into the flank of NSG MHCI/MHC II knockout mice, which do not develop graft versus host disease. TCR transgenic T cells were injected intravenously on day 11 and day 18 and tumor size was monitored. RESULTS TCR transgenic T cells depicted stable surface expression for at least 11 days in vitro after transduction. Thereby, murine TCR beta constant region positive T cells featured a polyfunctional phenotype demonstrated by a significant increase of Interferon-γ and TNF-α and remained reactive to the NLGN4X epitope for at least 7 days. Additionally, NLGN4X TCR transgenic T cells showed significantly increased antigen-specific production of the cytolytic protein granzyme B and elevated levels of perforin. In a novel xenograft mouse model NLGN4X TCR transgenic T cells slowed the tumor growth compared to the initial tumor size until day 25 after tumor inoculation. DISCUSSION We demonstrate that NLGN4X TCR transgenic T cells specifically and consistently recognize their corresponding immunogenic sequence and target antigen-overexpressing glioma cells. We present first evidence of in vivo reactivity, while further experiments are required to assess the full therapeutic potential of NLGN4X-TCR-transgenic T cell therapy for glioma patients.
Comprehensive Analysis of TP53 Mutation Characteristics and Identification of Patients with Inferior Prognosis and Enhanced Immune Escape in Diffuse Large B Cell Lymphoma
Authors: Tingting Zhang, Yue Fei, Bin Meng, Qiongli Zhai, Xiubao Ren, Kai Fu, Xianhuo Wang, Huilai Zhang
Journal: Blood (2021)
Abstract 14190: Cardiac Damage in COVID-19: An Undertreated Threat to Survival
Authors: Francesco Moretti, Enrico Baldi, Ilaria Costantino, Cosimo Marangi, Elisabetta Stagnitto, Sergio Leonardi, Rita Camporotondo, Luigi Oltrona Visconti, Massimiliano Gnecchi
Journal: Circulation (2021)

Introduction: Cardiac injury occurs in about 20-30% of patients hospitalized for COVID-19 and influence the prognosis but many aspects like the role of age and magnitude of cardiac damage in determining the prognosis, remains vague. Hypothesis: Age and magnitude of cardiac damage may influence the mortality of patients hospitalized for COVID-19. Methods: We considered all patients consecutively admitted at a third-level European Hospital for COVID-19 between February and June 2020. Cardiac injury was defined as a high-sensitivity cardiac Troponin I (hs-cTnI) value greater than the upper reference limit (URL) of 47 ng/dL. Firstly, we analyzed the data by hs-cTnI across age tertiles (&lt;62 years, 62-73 years and &gt;73 years). Then, we compared patients with no-damage, mid-damage (hs-cTnI up to 10-fold URL) and high-damage (more than 10-fold URL). The primary endpoint was in-hospital mortality. Results: We enrolled 543 patients (median age 69, 67% males); hs-cTnI was available in 509. The survival was lower in elderly patients and high levels of hs-cTnI worsened the prognosis across all age tertiles (Fig. 1A). Surprisingly, the magnitude of cardiac damage did not influence the overall in-hospital mortality (Fig. 1B), but patients with high-damage died earlier (survival at 15 days: 86% no-damage vs 61% mid-damage vs 49% high-damage; p&lt;0.001). Of note, among patients with high-damage, only 7 received coronary angiography, cardiac magnetic resonance or heart biopsy. Conclusions: Cardiac injury dramatically increased the mortality across all ages in patients hospitalized for COVID-19. The magnitude of cardiac damage did not influence overall in-hospital mortality but almost all patients with high-damage died within 15 days from admission. A second-level diagnostic test was performed seldomly in high-damage patients, suggesting that the unexpected high burden of the first COVID-19 wave negatively influenced the health system and our clinical daily practice.
Efficacy and Safety of CD19-Targeted CAR-T Cell Therapy for Refractory/Relapsed B-Cell Lymphoma: A Single Center of Real World Data
Authors: Jing Huang, Jia Fei, Ruiming Ou, Zhi Liu, Liling Zheng, Yangmin Zhu, Huijuan Shen, Yuanyuan Du, Qinjun Zhou, Jiali Chen, Changhua Zhou, Rongrong Yan, Jiale Wang, Shuang Liu, Qing Zhang
Journal: Blood (2021)
Lesion Characteristics and Patterns of Failure in Diffuse Large B Cell Lymphoma Patients Treated with Bridging Radiotherapy Prior to Chimeric Antigen Receptor T Cell Therapy
Authors: Harper Hubbeling, Emily A. Silverman, Neil Ari Wijetunga, M. Lia Palomba, Kathryn Tringale, Emily Lebow, Ana Alarcon Tomas, Roni Shouval, Connie Lee Batlevi, Renier J Brentjens, Parastoo B. Dahi, Sergio A Giralt, Richard J Lin, Jae H Park, Michael Scordo, Craig S. Sauter, Gunjan L Shah, Miguel-Angel Perales, Carla Hajj, Joachim Yahalom, Brandon S. Imber
Journal: Blood (2021)
EXTH-45. MICROGLIA-SPECIFIC DISRUPTION OF SIALIC ACID-SIGLEC-9/E INTERACTIONS: A NOVEL IMMUNOTHERAPY AGAINST GLIOBLASTOMA?
Authors: Philip Schmassmann, Tomás A Martins, Michal Stanczak, Marie-Françoise Ritz, Tala Shekarian, Marta McDaid, Heinz Läubli, Gregor Hutter
Journal: Neuro-Oncology (2021)

Abstract Recently, ‘don’t eat me’-signals like CD47 have emerged as novel innate immune checkpoints, enabling cancer cells to evade clearance by phagocytes such as monocyte-derived macrophages (MDM) or microglia (MG). Here, we aim at defining the role of inhibitory Siglec-9 in human and its mouse homologue Siglec-E in MG-centered immunotherapy against GBM. TCGA RNA-sequencing data revealed a significant correlation between high expression of immunoinhibitory SIGLEC9 and poor survival in GBM patients (log-rank p = 0.02). Siglec-E blockade increased murine MG mediated GBM cell in vitro phagocytosis (normalized phagocytosis of 1.00 in isotype vs. 1.76 in anti-Siglec-E antibody, p &amp;lt; 0.001). By employing a CT-2A orthotopic GBM mouse model with MG-specific spatio-temporal deletion of Siglece (Sall1 CreERT2 x Siglece flox ), we observed high MG-proliferation upon Siglec-E knockdown (Ki-67+ MG 14.8% in Cre- vs. 34.9% in Cre+, p &amp;lt; 0.0001) accompanied by an enhanced microglial GBM-cell uptake (5.6% in Cre- vs. 12.3% in Cre+, p &amp;lt; 0.001). This beneficial response was counteracted by an accentuated influx of pro-tumorigenic MDM in the Cre+ group (CD163high CD86low MDM of total MDM 47.1% in Cre- vs. 65.3% in Cre+, p = 0.002), which prevented an efficient adaptive anti-tumor immune response and survival benefit. Currently, we are investigating the cross-talk between GBM-associated MG and MDM upon Siglec-E knockdown by scRNAseq of the tumor-infiltrating immune compartment, including TCR-clonotype tracking. By genetically targeting sialic acids, the ligand for Siglec receptors, on CT-2A cells (GNE-KO), we observed a strong innate and adaptive immune response with less exhausted tumor-infiltrating CD8+ T-cells (14.8% in WT vs. 5.9% in GNE-KO, p = 0.003), which resulted in a prolonged survival (30d in WT vs. 41d post-tumor-injection in GNE-KO, p = 0.03). These data identify the sialic-acid-Siglec-E pathway as an anti-phagocytic signal in a pre-clinical GBM model, and demonstrate its therapeutic potential in GBM immunotherapy.
Abstract 12205: A New Mouse Model of Myocardial Lipids, Fibrosis, Arrhythmia and Diastolic Dysfunction Induced by Hyperlipidemia and Cardiac LDLR
Authors: Monique Williams, Camila Iansen Irion, Jose Manuel Condor Capcha, Guerline Lambert, Grace Seo, Jeffrey J Goldberger, Lina A Shehadeh
Journal: Circulation (2021)

Background: Hyperlipidemia is a major risk factor for CVD. Patients with HF with preserved ejection fraction (HFpEF) have more myocardial lipid accumulation than patients with reduced EF (HFrEF). RNASeq data from cardiac biopsies showed downregulation of the gene for lipoprotein lipase (LPL) that degrades triglycerides, in HFpEF patients compared to healthy and HFrEF controls. Poloxamer-407 (p407) induces hyperlipidemia by blocking LPL and subsequent increase in plasma triglycerides and low-density lipoprotein (LDL) cholesterol. We hypothesized that mice treated with p407 and cardiac LDL-Receptor (LDLR) over-expression (OE) develop hyperlipidemia, myocardial lipid accumulation, and diastolic dysfunction resulting in HFpEF and arrhythmias. Methods: Baseline cardiac function was assessed by echo for male and female C57Bl6 mice (n=9) for 2 groups: 4wk biweekly i.p. p407-injections with (n=4) or without (n=3) single i.v. injection with AAV9-cTnT-LDLR. Cardiac function was assessed by echocardiography at 3 and 4 wks. Blood Pressure (BP) and Whole Body Plethysmography (WBP) were assessed during wk4. Ttest was used for statistics. PR and ORO staining and telemetry were performed at wk4. Results: At wk3, P407 and LDLR OE led to alterations in diastolic function (increased IVCT, IVRT, MV E/E’, MPI, and NFT) and increased LV wall thickness, p&lt;0.05. At wk4, there was pulmonary hypertension (increased mean pulmonary arterial pressure, decreased pulmonary acceleration time p &lt;.05).Histology showed excessive myocardial lipids and fibrosis, and telemetry showed incidents of second-degree and higher-degree AV block. The group injected solely with p407 show e d alterations in diastolic function (increased IVCT, IVRT, NFT, LVMPI, LVMPI NFT p&lt;.05 ) and decreased EDV, ESV, EDLVM, ESLVM, p&lt;.05 at wk4. All groups had preserved %EF and no abnormalities in BP or WBP. Conclusions: P407 and cardiac LDLR OE induce a drastic decline in cardiac diastolic function over a shorter period of time compared to p407 alone. Diastolic dysfunction was observed in wk3 followed by pulmonary hypertension, arrhythmia, myocardial lipid accumulation and fibrosis in wk4. This new model may allow for more rapid investigations of cardiac abnormalities seen in HFpEF patients.