tbuckley/cabot-search huggingface dataset:
EXTH-33. RETROVIRAL REPLICATING VECTORS PSEUDOTYPED WITH GIBBON APE LEUKEMIA VIRUS ENVELOPE FOR PRODRUG ACTIVATOR GENE THERAPY IN PRECLINICAL GLIOMA MODELS
Authors: Akihito Inagaki, Sara Collins, Alicia Freedman, Megan Montoya, Alexander Haddad, Maria Barcova, Noriyuki Kasahara
Journal: Neuro-Oncology (2021)

Abstract Amphotropic retroviral replicating vector (RRV) Toca 511, expressing the yeast cytosine deaminase (CD) prodrug activator gene, showed promising evidence of therapeutic benefit and increased survival in early-phase trials for recurrent high-grade glioma. While a multi-center Phase 3 trial did not meet its overall endpoints, highly statistically significant survival was observed within predetermined patient subgroups compared to matched randomized control patients, and clinical investigation is on-going. Hence it is worthwhile to consider strategies aimed at enhancing therapeutic efficacy, such as delivering combinations of multiple transgenes. However, RRVs encoated with the same envelope compete for the same cancer cell surface receptors. We have now developed novel RRV encoated (‘pseudotyped’) with a heterologous envelope derived from Gibbon ape leukemia virus (GALV), which utilizes a different cell surface receptor from the native amphotropic retrovirus envelope for cellular entry. RRV(GALV) vectors expressing either GFP or HSV thymidine kinase (TK) were constructed, and efficient replication and transgene expression was observed in &amp;gt; 90% of both established and primary human glioblastoma cells within 14 days after initial infection at 0.01 (1%) multiplicity of infection (MOI). Genomic stability of RRV(GALV) vectors was also confirmed over prolonged propagation. Established and primary human glioblastoma cells infected with RRV(GALV)-TK vector showed ≥ 50%-90% reduction in cell viability after exposure to Ganciclovir prodrug in the range of 1µM-100µM for 5 days, as compared to uninfected control cells or cells infected with RRV(GALV)-GFP control vector. Furthermore, dual infection with RRV(GALV)-TK and amphotropic RRV-CD (Toca 511) resulted in synergistic cytotoxicity upon simultaneous exposure to their respective prodrugs. Further data will be presented from on-going studies evaluating these vectors in intracerebral glioblastoma models. These results indicate that GALV envelope-pseudotyped RRV can efficiently deliver prodrug activator gene therapy in experimental glioma models, and open the door to combinatorial gene therapy regimens with this vector platform.
Outcomes with Chimeric Antigen Receptor T-Cell Therapy in Relapsed/Refractory Chronic Lymphocytic Leukemia: A Systematic Review and Meta-Analysis
Authors: Moazzam Shahzad, Raheel S Siddiqui, Sakina Abbas, Sibgha Gull Chaudhary, Mamoon Ahmed, Amna Y Shah, Muhammad Arslan, Iqra Anwar, Ramesh Balusu, Rajat Bansal, Nausheen Ahmed, Leyla Shune, Peiman Hematti, Joseph P. McGuirk, Muhammad Umair Mushtaq
Journal: Blood (2021)
BNT162b2 mRNA COVID-19 Vaccination (BNTCV) in Patients (Pts) Having Hematological Malignancies (HM): Early tolerance with telemedicine application connecting and antibody anti-Spike IgG response (AcAS)
Authors: Jean-Francois Rossi, Emmanuel Bonnet, Marion Velensek, Emma Wisniewski, Sophie Heraud, Rania Boustany, Celeste David, Jerome Dinet, Roland Sicard, Jean Pierre Daures, Marion Bonifacy, Lysiane Mousset, Emmanuel Goffard
Journal: Blood (2021)
Abstract 14341: Older Patients Do Well Following Surgical Treatment of Infective Endocarditis
Authors: Priyanka Boettger, Michael Buerke
Journal: Circulation (2021)

Introduction: Evidence for the role of surgery in the management of infectious endocarditis (I.E.) is conflicting and there is no data relating specifically to the elderly subgroup. We hypothesised that for I.E., the elderly have different presentation, treatment profile and outcomes compared to the remainder of the adult population. Methods: We collected registry data on consecutive cases of IE treated in our tertiary centre over 10 years. Data for symptoms and signs, treatment, response, the development of complications (graded into four groups of severity) and outcome, were gathered. We identified characteristics particular to the elderly I.E. population compared to those of a younger age. Results: Of 107 patients, 50 were over 59 and 19 over 69 years of age. Risk factors for adverse outcome did not include age. Those over 69 more commonly had non-specific symptoms (e.g. weight loss and dyspnoea). Only of 37% the over 69 age group were treated surgically compared to 72% of those under 69. Across age groups the complication profile in surgically managed patients was higher than conservatively managed patients (since this is a higher risk subset). However, most strikingly, amongst the surgically managed patients, the outcomes in patients over 69 years compares well with all other age groups (Fig 1). Conclusion: The proportion of elderly patients treated surgically is lower than other age groups, reflecting understandable caution in surgical management of older patients. However, since the outcome in these patients compares favourably with all other age groups, we conclude that the surgical treatment of I.E. is an attractive option in carefully selected elderly patients.
NIMG-75. ANALYZING THE INTERFACE BETWEEN MRI AND DRUG DISTRIBUTION USING ORTHOTOPIC GBM-DERIVED XENOGRAFT (PDX) MODELS
Authors: Sameer Channar, Sara Ranjbar, Pamela Jackson, Leland Hu, Michael Regan, Walid Abdelmoula, Begona Lopez, Slobodan Macura, Jefferey Agar, Jann Sarkaria, Nathalie Agar, Kristin Swanson
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Glioblastoma (GBM) is a diffusely invasive primary brain tumor with significant spread of tumor cells to the periphery of visible image abnormality. Enhancement of Gadolinium (Gd) contrast agent on magnetic resonance imaging (MRI) has historically been considered a confirmation of local breakdown of the blood brain barrier (BBB) and sufficient drug delivery to the bulk of tumors. In this work, we used GBM-derived xenograft (PDX) models to compare drug delivery in GBM brain for high and low BBB-permeable drugs. MATERIALS AND METHODS Five patient-derived orthotopic xenograft models from two GBM cell lines (GBM39 and GBM12) were co-dosed with erlotinib and osimertinib, two drugs with low and high BBB-permeability, respectively. T1Gd and T2-weighted MRIs were acquired from all animals prior to model sacrifice. Tumors were manually segmented on denoised and standardized MRIs and intensity patterns were captured using first and second order statistical features in the moving 3x3 kernel. We compared drug levels found in Matrix Assisted Laser Desorption Ionization (MALDI) in T1Gd enhancement, T2 enhancement, and normal brain. We also performed linear regression modeling to predict drug levels using MRI features. Model performance was measured using root mean squared error (RMSE). RESULTS Our analysis showed correlations between imaging features and MALDI drug levels. Osimertinib had a uniform distribution across the brain for all animals and all cell lines, consistent with our expectation for a high BBB-penetrant drug. Erlotinib showed the highest drug levels in T2 for GBM39 and in T1Gd for GBM12. Regression models showed promising results for predicting Erlotinib with a low RMSE of 0.037. CONCLUSION Our preliminary results suggest MRI can be predictive of drug levels for low-BBB penetrant drugs. Understanding the relationship between MRIs and drug distribution in diffuse tumors can be beneficial to developing effective treatment.
Kinetics of Anti-Sars-Cov-2 Antibody Responses 3 Months Post Complete Vaccination with BNT162b2; A Prospective Study in 283 Health Workers
Authors: Evangelos Terpos, Ioannis P. Trougakos, Vangelis Karalis, Ioannis Ntanasis-Stathopoulos, Filia Apostolakou, Sentiljana Gumeni, Aimilia D. Sklirou, Stamatia Skourti, Maria Gavriatopoulou, Efstathios Kastritis, Eleni Korompoki, Ioannis Papassotiriou, Meletios A. Dimopoulos
Journal: Blood (2021)
Epidemiology of Hospitalizations Due to Autoimmune Hemolytic Anemia in the United States
Authors: Sanjana Mullangi, Preeti Yadav, Ekim Kilinc, Silpa Gudivada, Javaria Khan, Prathyusha Anumolu, Shushmita Khadka, Ruchir Goswami, Achint Patel, Karim Welaya, Manidhar Reddy Lekkala
Journal: Blood (2021)
Retrospective Study Evaluating Effect of Voxelotor Treatment on Acute Care Utilization during the Peak of COVID-19
Authors: Shivani Rao, Nicole K. Yun, James L. Coggan, Peter Wu, Teresa O'Brien, Katherine Barnett, Sean O'Mahony, Ramandeep Kaur, Christopher Bruti, Celine Goetz, Jerome J Martin, Sefer Gezer, Parameswaran Venugopal, Shivi Jain
Journal: Blood (2021)
Asthma, COPD and their overlap: coexistence or something more?
Authors: David M. Mannino
Journal: European Respiratory Journal (2021)

The overlap of multiple chronic lower respiratory diseases, including asthma, COPD, emphysema and chronic bronchitis, has been described for many years [1]. Recently, this list of overlapping diseases has expanded to include bronchiectasis, pulmonary fibrosis and obstructive sleep apnoea [2]. The relationship between asthma and COPD was the focus of Professor N.G.M Orie's 1960 symposium and subsequent publication Bronchitis [3]. He suggested that "asthma and chronic obstructive pulmonary disease (COPD; at that time labelled bronchitis) had common origins and clinical expressions and were determined both by endogenous (heredity, age, and sex) and exogenous (environment: allergens, smoking, viruses, and air pollution) factors" [3, 4]. This became known in later years as the "Dutch Hypothesis", postulating that asthma and COPD share a common pathway with bronchial hyperresponsiveness being important in both. This could be differentiated from the "British Hypothesis" that thought the role of respiratory infections to be central to COPD development [5]. Asthma–COPD overlap syndrome has been around for a while and will continue to be! <https://bit.ly/3fmpCUz>
Circulating Cell-Free DNA (ccfDNA) Isolation from Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Comparative Analysis of Commercial Kits
Authors: Karolliny Silva de Oliveira, Hebert Fabricio Culler, Débora Levy, José Roberto Assis Filho, Daniel Silva Nogueira, Lis Vilela de Almeida, Luiz Henrique da Silva, Fernando Luiz Affonso Fonseca, Sarah Isabel Pinto Monteiro do Nascimento Alves, Luis Alberto de Padua Covas Lage, Juliana Pereira
Journal: Blood (2021)
Abstract 12913: Under Pressure: An Unusual Case of Pulmonary Hypertension and Pericardial Effusion
Authors: Megan McLaughlin, Peter Ganz, Matthew Durstenfeld, Priscilla Hsue
Journal: Circulation (2021)

A 50-year-old male smoker with hypertension presented with subacute bilateral leg swelling, weight gain, and dyspnea. Exam revealed tachycardia, jugular venous distention, peripheral edema, diminished breath sounds, and pulsus paradoxus. Labs were notable for elevated creatinine and leukocytosis. ECG showed sinus tachycardia and low voltages. CXR showed left hemithorax opacification. TTE revealed normal LV function, septal flattening, severely dilated RV with reduced function, RVSP 81 mmHg, and a large pericardial effusion with exaggerated respirophasic variation in mitral inflow but no chamber collapse. The elevated RVSP with RV failure raised concern for acute pulmonary embolism (PE). CT chest excluded PE but revealed a large mediastinal mass compressing both pulmonary arteries (PA) and large left pleural effusion. Pulmonary angiogram demonstrated a totally occluded left PA and severe stenosis of the right PA. Right heart catheterization showed RAP 24, RV 83/21, PA 84/29 (mean 53), intrapericardial pressure 15 mmHg, and low cardiac index (1.6 L/min/m2). Pericardiocentesis was performed with close monitoring by PA catheter. Removal of 500cc fluid was well tolerated with stable hemodynamics, cardiac output, and intracardiac pressures. Pericardial fluid cytology and lymph node biopsy demonstrated small cell lung cancer. Cautious diuresis was initiated. After one cycle of chemotherapy, repeat CT chest showed reduced extrinsic compression of the right PA with improved lung perfusion. Repeat TTE showed dramatic improvement with normal RV size and function, RVSP 22 mmHg, and trivial pericardial effusion. Pericardial effusion in the setting of severe PH is associated with poor outcomes and presents both diagnostic and therapeutic challenges. Classic findings of tamponade (e.g. right sided chamber collapse) may be masked by elevated right heart pressures. Compression of the PA by a mediastinal mass is an unusual cause of PH and right heart failure that can mimic acute PE. This rare clinical scenario presents the following challenges: (1) diuresis may precipitate tamponade, (2) pericardiocentesis may enable an already enlarged RV to acutely dilate and thus worsen RV failure, and (3) there is uncertainty regarding the role for PA stenting.
Abstract 10720: Outcomes of Ultrasound Assisted Catheter Directed Thrombolysis Compared to Anticoagulation Alone in Patients with Intermediate Risk Pulmonary Embolism: A Meta-Analysis
Authors: Mishita Goel, Mansj Oberoi, Nishit Choksi, sarwan kumar
Journal: Circulation (2021)

Purpose: USCDT is evolving as a popular treatment for PE. Studies have shown that USCDT causes significant reduction in RV strain and pulmonary hypertension risk. However, impact of these treatment modalities on clinical outcomes remains unclear. We conducted meta-analysis of observational studies to assess safety and mortality outcomes of USCDT compared with systemic anticoagulation alone in patients with submassive PE. Methods: Systematic literature search was performed using PUBMED database. Studies published from January 2008-December 2020 were identified using search terms “catheter thrombolysis” and “pulmonary embolism”. Outcomes included mortality and bleeding. Meta-analysis was performed using Review-Manager version-5.4. Effect size was measured using random effects with 95%-confidence interval. Results: 5 retrospective observational studies with 985 patients were included. Meta-analysis was performed for both mortality and major bleeding outcomes. Mortality rate was significantly greater in the anticoagulation group as compared to the USCDT group (odds ratio=3.08, 95%CI 1.62-5.87). There was no statistically significant difference in major bleeding rates between anticoagulation and USCDT groups (Risk-ratio=0.68, 95%CI 0.25-1.83). Heterogeneity was not significant among the five studies for mortality or bleeding outcome (I 2 =0%, p=0.82; I 2 =18%, p=0.30, respectively). Conclusions: USCDT, in addition to its known therapeutic efficacy, is associated with better mortality outcomes and no significant difference in major bleeding risk when compared to systemic anticoagulation. Clinical Implications: USCDT can be utilized over systemic anticoagulation alone in patients presenting with submassive PE for better outcomes.
Abstract 10206: First <i>in-vivo</i> Evidence of Aureolysin ( <i>aur</i> ) Up-Regulation by <i>Staphylococcus Aureus</i> Causing Invasive Prosthetic Valve Endocarditis
Authors: Haytham Elgharably, Muhammad Etiwy, Marion Tuohy, James Witten, Gary W Procop, Naseer Sangwan, Nabin Shrestha, Jan Claesen, Paul Cremer, Jose L Navia, Lars G Svensson, Gosta B Pettersson
Journal: Circulation (2021)

Background: Staphylococcus aureus prosthetic valve endocarditis (PVE) is resistant to antimicrobial therapy and commonly associated with tissue invasion, which necessitates complex high risk surgical intervention for cure. Hypothesis: S. aureus virulence in infective endocarditis (IE) is dynamic and changes upon colonizing cardiac valves from blood stream. Methods: Six patients undergoing cardiac surgery for left-sided S. aureus IE, 3 native (NVE) and 3 PVE, were included in this study. Vegetation samples were collected during surgery as well as corresponding blood culture isolates during S. aureus bacteremia. Total RNA was extracted from all samples and underwent mRNA sequencing for transcriptomic analysis of S. aureus . Data was pooled into STAR aligner and gene expression related to virulence factors was compared between different groups (Deseq2; p-value &lt; 0.05 for statistical significance). Results: In NVE vegetations, S. aureus showed an increased expression of genes associated with biofilm formation, cell division, and metabolic activity, when compared to blood culture isolates (e.g. rsmA , agrB , dnaK , clpB , ezrA , fusA , ftsZ , adh , pstS , qoxA ). S. aureus isolated from blood cultures had significantly higher expression of clfA (encoding for clumping factor A) compared to cardiac vegetations. Interestingly, in PVE vegetations, S. aureus had a significant higher expression of aur (encoding for metalloprotease aureolysin) compared to corresponding blood culture isolates or NVE vegetations. Aureolysin is an important virulence factor responsible for immune evasion and toxin production. Conclusions: In clinical IE, S. aureus up-regulates genes responsible for biofilm formation when attached to cardiac valves. Planktonic S. aureus cells in the blood stream express clfA , which could bind to fibrinogen to clump within platelet network to form vegetations. On prosthetic valves, S. aureus expresses aureolysin, which could function to evade the host immune response and promote destruction of cardiac tissues. These novel in-vivo findings provide explanations for S. aureus IE pathophysiology that warrant further investigation.
TAMI-27. METABOLIC MANIPULATION OF T CELLS TO TREAT BRAIN TUMORS
Authors: Guimei Tian, Linchun Jin, Devshri Doshi, Aida Karachi, Mariana Dajac, Fernanda Pohl-Guimaraes, Ginger Moore, Maryam Rahman, Catherine Flores, Matthew Sarkisian, Jianping Huang, Duane Mitchell, Loic Deleyrolle
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Glioblastoma are a challenge for neuro-oncologists and current therapies are minimally effective. Standard-of- care treatment is almost inevitably followed by disease recurrence. Adoptive T cell transfer has emerged as a viable therapeutic for brain malignancies. While promising, the efficacy of this approach is often limited by a complex immunosuppressive tumor microenvironment. These complexities mean that more sophisticated T cell products are required. OBJECTIVES The brain tumor microenvironment provides local restraints via metabolic competition suppressing antitumor immunity, specifically inhibiting infiltration and tumoricidal functions of host and adoptively transferred tumor-reactive T cells. The overall goal of this project is to test new treatments to reverse immune dysfunction in cancer through the regulation of T cell metabolic signaling. We propose that modulating glucose pathway in T cells can potentiate their anti-tumor activity once adoptively transferred. METHODS T cells glucose metabolic pathway was modulated via glucose transporters overexpression. The functionality of metabolically modified T cells was investigated in murine and human models. RESULTS We demonstrated the existence of a competition for glucose between T cells and tumor cells, with tumor cells imposing glucose restriction mediating T cell hyporesponsiveness. Overexpression of glucose transporters such as Glut1 and Glut3 increased T cell glucose utilization and provide survival/growth advantage and enhanced T cell activation in glucose-restricted conditions. We also established that glucose transporter overexpression improves intratumoral infiltration of adoptively transferred T cells. CONCLUSION This project integrates fundamental concepts of tumor and immune metabolism in the design of immunotherapy and confirms that immunometabolism represents a viable target for new cancer therapy to treat brain tumors.
Abstract 14048: Torsades De Pointes Risk Drugs and Out-of-Hospital Cardiac Arrest: A Nationwide Study
Authors: Johanna Kroell, Camilla Jespersen, Emil Fosbøl, Gunnar Gislason, Fredrik Folke, Freddy Lippert, Kristian Kragholm, Christian Jons, Steen Hansen, Mads Wissenberg, Christian Torp-Pedersen, Lars Koeber, Peter Karl Jacobsen, Jacob Tfelt-hansen, Peter E Weeke
Journal: Circulation (2021)

Introduction: Pharmacotherapy with proarrhythmic or QT prolonging properties are known to augment the risk of malignant arrhythmias (e.g. TdP). We examined TdP risk drug usage prior to OHCA and how it may be associated with shockable rhythm and survival. Methods: Patients ≥18 years with an OHCA of cardiac origin were identified from the Danish Cardiac Arrest Registry (2001-2014). From nationwide registries TdP risk drug usage before OHCA according to CredibleMeds was assessed. We performed multivariable logistic regression to determine factors associated with TdP risk drug usage among OHCA patients and how usage may affect OHCA related factors (e.g. shockable rhythm or survival). Age and sex controls were identified (matching 1:5). Results: Overall, 10139 OHCA patients were identified, of which 43% were in treatment with a TdP risk drug 0-30 days before OHCA compared with 15% from the control population. Furthermore, this was significantly more than 61-90 days before OHCA (37%). Most common prescribed drugs with known risk of TdP were citalopram (31.1%), methadone (16.4%), and fluconazole (8.2%). OHCA patients in treatment with a TdP risk drug at the time of event had a significantly higher burden of comorbidities compared with OHCA patients not in treatment (e.g. cancer [19.3% and 8.7%], COPD [20.0% and 6.6%], psychiatric disease [21.9% and 13.5%], p&lt;0.001). TdP risk drug usage was not associated with increased likelihood of the presenting rhythm being shockable (OR=0.9, CI: 0.7-1.1). Moreover, OHCA patients in TdP risk drug treatment had less likelihood of ROSC (OR=0.8, CI: 0.7-0.9). Conclusion: Almost half of OHCA patients were in treatment with TdP risk drugs before OHCA. Subsequently, TdP risk drug usage did not modify the likelihood of presenting with a shockable rhythm as first recorded rhythm. However, this could partly be due to the large burden of comorbidities. Figure: Factors associated with TdP risk drug usage (adjusted for below mentioned factors).
EXTH-66. ENHANCEMENT OF ANTI-PD-1 THERAPY WITH EXTENDED HALF-LIFE IL-2 IS INDEPENDENT OF MHC CLASS I RESTRICTED ANTIGEN RECOGNITION FOR TREATMENT OF EXPERIMENTAL GLIOMA
Authors: Zachariah Tritz, Katayoun Ayasoufi, Courtney Malo, Benjamin Himes, Roman Khadka, Cori Fain, Emma Goddery, Lila Yokanovich, Fang Jin, Michael Hansen, Ian Parney, Chensu Wang, Kelly Moynihan, Darrell Irvine, Dane Wittrup, Aaron Johnson
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) is the most common malignant brain tumor in adults, responsible for approximately 225,000 deaths per year. Despite pre-clinical successes, therapeutic interventions have failed to extend patient survival by more than a few months. Anti-PD-1 checkpoint inhibition monotherapy has had efficacy against some tumor types but not GBM. The aim of this study was to determine whether supplementing anti-PD-1 checkpoint blockade with an engineered extended half-life IL-2 could improve outcomes in a preclinical model of disease. Our enhanced checkpoint blockade (ECB) strategy reliably cures approximately50% of C57BL/6 mice bearing orthotopic GL261 gliomas and extended median survival even in the mice that eventually succumbed. This therapy generates robust immunologic responses, features of which include secondary lymphoid organ enlargement and increased activation status of both CD4 and CD8 T cells. Further, many of the characteristics of brain-tumor mediated peripheral immunosuppression, including MHC class II downregulation on APCs, are prevented by ECB combination therapy. This immunity is durable, with long-term ECB survivors able to resist GL261 rechallenge. Notably, ECB’s efficacy is independent of host MHC class I restricted antigen presentation, being equally efficacious in MHC class I and CD8 T cell deficient mice. Conversely, ECB combination therapy is reliant on CD4 T cells and their depletion abrogates the therapy’s survival benefit. Our data shows ECB combination immunotherapy to be efficacious against the GL261 glioma model through an MHC class I independent mechanism, enhancing its off-the-shelf translational appeal relative to strategies requiring extensive knowledge of tumor-specific antigens.