tbuckley/cabot-search huggingface dataset:
Abstract 12366: Intracoronary Delivery of E06 Antibody Directed to Oxidized Phospholipids Decreases Infarct Size in a Porcine Model of Ischemia/Reperfusion Injury
Authors: Aleksandra Stamenkovic, Grant N. N Pierce, Joseph L Witztum, Sotirios Tsimikas, Amir Ravandi
Journal: Circulation (2021)

Introduction: Myocardial ischemia/reperfusion injury (IRI) results in additional myocardial cell loss post reperfusion. Oxidized phosphocholine(PC)-containing phospholipids (OxPL) have been shown to result in cardiomyocyte cell death during IRI. E06 is a natural murine monoclonal IgM antibody which binds to the PC headgroup of OxPL. Transgenic mice expressing a single-chain Fv E06 fragment have recently been shown to have smaller infarct sizes post myocardial IRI. The objective of this study was to determine if directly infused E06 IgM reduced IRI in a porcine model of reperfusion injury that more closely reflects human physiology. Methods: Male pigs, 45 to 50 kg, were randomized equally to IRI in two groups: 1) control with saline coronary infusion (n=7). 2) IgM E06 coronary infusion over 1 hour (n=7). The left anterior descending (LAD) artery was occluded distal to the second diagonal branch for 60 minutes using an angioplasty balloon. Following balloon deflation, saline or IgM E06 was infused over 60 min through a microcatheter. Following 120 min of total reperfusion, the area at risk (AAR) and infarct size (IS) were determined by triphenyltetrazolium chloride staining technique (TTC), and myocardial salvage index determined. Results: All animals survived post reperfusion and no differences were present in hemodynamics at the baseline and 2 h post reperfusion between groups. A 51.3% reduction in infarct size was noted in animals receiving intracoronary E06 compared to controls (IS/AAR 21.7% ± 3.4 vs 42.3% ± 3.7 p&lt;0.0005). IS/LV size (7.7 ± 3.2 vs 11.9 ± 1.2 p&lt;0.004) and myocardial salvage index (82.6% vs 57.6% in controls) were significantly improved in animals receiving E06 compared to controls. Conclusion: Intracoronary delivery of E06 antibody at the time of reperfusion leads to a significant reduction in infarct size, suggesting that generation of OxPL during reperfusion leads to cardiomyocyte cell death. Translation of this approach using humanized anti-OxPL antibodies may allow a novel approach to treat myocardial IRI in humans.
IMMU-50. GLIOBLASTOMA MANIPULATES HEMATOPOIETIC STEM CELL DIFFERENTIATION OUTCOMES AND DRIVES ALTERED IMMUNE RECONSTITUTION
Authors: Bayli DiVita Dean, Tyler Wildes, Joseph Dean, David Shin, Connor Francis, Laura Falceto Font, Ginger Moore, Catherine Flores
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Bone marrow-derived hematopoietic stem and progenitor cells (HSPCs) give rise to the cellular components of the immune system. Unfortunately, immune reconstitution from HSPCs are negatively impacted by solid cancers, including high-grade gliomas. For example, an expansion of myeloid progenitor cells has been previously described across several cancers that originate outside the CNS. A similar expansion of MDSCs coupled with diminished T cell function has also been described in the peripheral blood of patients with newly-diagnosed GBM. Alterations in both lymphoid and myeloid compartments due to CNS malignancy led us to determine how intracranial gliomas impact HSPCs in both their capacity to reconstitute the immune compartment and in their cell fate determination. This is important to better understand the impact of gliomas on immunity and how we can leverage these findings to better develop cellular immunotherapeutics. METHODS HSPCs were isolated from bone marrow of C57BL/6 mice with orthotopic KR158B glioma, or age-matched naïve mice. Experiments were conducted to compare relative changes in: gene expression (RNA-sequencing), precursor frequencies, cell fate determination, and cellular function of cells derived from HSPCs of glioma-bearing mice. RESULTS RNA-sequencing revealed 700+ genes whose expression was significantly up- or downregulated in HSPCs from glioma-bearing mice, particularly those involved with stemness and metabolic activity. Importantly, HSPCs from glioma-bearing mice expressed upregulation of genes involved in myelopoiesis relative to naïve mice. This was coupled with an expansion of granulocyte macrophage precursors (GMPs), the progenitors to gMDSCs. Next, differentiation assays revealed that HSPCs from glioma-bearing mice had higher propensity of differentiating into MDSC under homeostatic conditions relative to controls both in vitro and in vivo. Furthermore, mice bearing intracranial gliomas possess an expansion of MDSCs which are more suppressive on T cell proliferation and hinders T cell-mediated tumor cell killing relative to MDSCs derived from naïve control mice.
Efficacy and safety of SARS-CoV-2 revaccination in non-responders with immune-mediated inflammatory disease
Authors: David Simon, Koray Tascilar, Filippo Fagni, Katja Schmidt, Gerhard Krönke, Arnd Kleyer, Andreas Ramming, Verena Schoenau, Daniela Bohr, Johannes Knitza, Thomas Harrer, Karin Manger, Bernhard Manger, Georg Schett
Journal: Annals of the Rheumatic Diseases (2021)

Objectives To test whether patients with immune-mediated inflammatory disease (IMIDs), who did not respond to two doses of the SARS-CoV-2 vaccine, develop protective immunity, if a third vaccine dose is administered. Methods Patients with IMID who failed to seroconvert after two doses of SARS-CoV-2 vaccine were subjected to a third vaccination with either mRNA or vector-based vaccines. Anti-SARS-CoV-2 IgG, neutralising activity and T cell responses were assessed at baseline and 3 weeks after revaccination and also evaluated seprarately in rituximab (RTX) and non-RTX exposed patients. Results 66 non-responders were recruited, 33 treated with RTX, and 33 non-exposed to RTX. Overall, 49.2% patients seroconverted and 50.0% developed neutralising antibody activity. Seroconversion (78.8% vs 18.2%) and neutralising activity (80.0% vs 21.9%) was higher in non-RTX than RTX-treated patients with IMID, respectively. Humoral vaccination responses were not different among patients showing positive (59.3%) or negative (49.7%) T cell responses at baseline. Patients remaining on mRNA-based vaccines showed similar vaccination responses compared with those switching to vector-based vaccines. Conclusions Overall, these data strongly argue in favor of a third vaccination in patients with IMID lacking response to standard vaccination irrespective of their B cell status.
Abstract 10957: Inflammation: A Window into the Pathobiology of Impaired Vascular Regeneration in Patients with Coronary Artery Disease
Authors: Zakaria Almuwaqqat, Jeong Hwan Kim, Mariana Garcia, Jamil Alkhalaf, Anurag Mehta, Amit J Shah, Brad Pearce, Doug Bremner, Edmund Waller, Viola Vaccarino, Arshed A Quyyumi
Journal: Circulation (2021)

Introduction: The mechanisms by which cardiovascular regenerative capacity, estimated as circulating levels of progenitor cell (CPC) counts, protect against adverse cardiovascular events remain unclear. Hypothesis: Circulating progenitor cells possess immune-modulatory properties and are hypothesized to mitigate inflammation that is characteristic of patients with CAD. We hypothesized that patients with fewer CPC will have higher inflammatory markers and worse outcomes. Methods: Patients with stable CAD were enrolled in a prospective study enumerating CPCs as CD34-expressing mononuclear cells (CD34+), and inflammation as levels of interleukin-6 (IL-6). Patients were followed for 5 years for the endpoints of death and myocardial infarction (primary) with repeat inflammatory biomarkers measured after a median of 2 years. The association between CPCs and change in IL-6 levels over time was determined using linear regression after adjustment demographic and clinical risk factors. Cox hazard models were used for time-to-event analyses after adjustment. Results: In the entire cohort of 392 patients, IL-6 remained unchanged (0.3 ± 2.4 pg/mL, p=0.45) after 2 years. CPC counts (log-transformed) were inversely correlated with the change in IL-6 levels (r=- 0.17, P &lt;0.001). Thus, IL-6 declined by - 0.59 ((95%CI), -0.90, -0.20) pg/mL per 1 log higher CPC counts after adjustment for the demographic and clinical variables as well as medications. Using Cox hazard models adjusted for these risk factors, a rise in 1 pg/mL of IL-6 was associated with a 11% (95%CI, 9, 13) greater risk of death/MI. Low CPC counts were associated with a higher risk of death/MI (HR=1.7 (95%CI, 1.1-2.6). Using mediation analysis, we found that the change in IL6 level partly (by 40%) mediated the higher risk of adverse events among those with low CPC counts. Conclusions: Reduced cardiovascular regenerative capacity, measured as low circulating CPC levels, is independently associated with progressive inflammation in patients with CAD, which in turn is associated with poor outcomes. These findings support the role of endogenous regenerative capacity in passivating systemic inflammation and is a potential mechanism underlying its protective effects.
Abstract 10974: Durable Reductions in Circulating Angiotensinogen and Blood Pressure Six Months After Single Doses of ALN-AGT, an RNA Interference Therapeutic Targeting Hepatic Angiotensinogen Synthesis, in Hypertensive Patients
Authors: Stephen Huang, Jorg Taubel, Sarah Casey, Pui Man Leung, David J Webb, Akshay S Desai, Yansong Cheng, Sean Rhyee, Jamie Harrop, Bahru Habtemariam, George L Bakris
Journal: Circulation (2021)

Introduction: ALN-AGT, a subcutaneous (SC) investigational RNA interference therapeutic targeting hepatic angiotensinogen (AGT) synthesis, is being evaluated as a novel treatment for hypertension in a multicenter, randomized, placebo-controlled single ascending dose study. Here we present new data on the long-term pharmacodynamic and antihypertensive effects of ALN-AGT six months after single-dose administration. Methods: As part of a Phase 1 program to assess the safety and tolerability of ALN-AGT, hypertensive patients (mean seated systolic blood pressure [SBP] of &gt;130 and ≤165 mmHg after a washout of antihypertensive medications) were randomized 2:1 to ascending single doses of ALN-AGT (10-800 mg) or placebo. Change from baseline BP was measured by ambulatory BP monitoring (ABPM) at Week 8, Week 12, and Month 6. Interim results as of May 28, 2021 are reported. Results: 84 hypertensive patients (mean age 53 years, 61% male, 26% black, mean (SD) baseline 24-h SBP 140 (9) mm Hg) were enrolled in ascending single dose cohorts of ALN-AGT up to 800 mg SC. Dose-dependent and durable reductions in serum AGT levels were observed, with single doses ≥100 mg achieving serum AGT reductions &gt;90% and 24-h SBP reductions &gt;10 mm Hg (17 mm Hg in the 800 mg cohort) through Week 12. The 24-hour ABPM profile of ALN-AGT-treated patients showed sustained reductions of daytime BP with equally marked nighttime BP reduction. Notably, new data from follow-up visits show that all patients who received a single dose of 800 mg maintained serum AGT reductions &gt;90% from Week 3 to Month 6, with a mean (SD) 24-h SBP reduction of 22 (15) mm Hg at Month 6 (5 of 8 patients without add-on antihypertensive treatment). There were no treatment-related serious adverse events or clinically significant elevations in blood creatinine or potassium. No patient required intervention for hypotension. Conclusions: Single dose administration of ALN-AGT to hypertensive patients was generally well tolerated and resulted in profound reductions in serum AGT and BP through Month 6. The durable reduction of serum AGT &gt;90% with sustained 24-hour BP reduction over a period of 6 months after single dose SC administration of ALN-AGT 800 mg supports further evaluation of both quarterly and biannual dose administration.
EXTH-77. POLIO VIROTHERAPY OF MURINE BRAIN TUMORS INDUCES MICROGLIA PROLIFERATION AND INFLAMMATION THAT IS POTENTIATED BY IMMUNE CHECKPOINT BLOCKADE
Authors: Yuanfan Yang, Michael Brown, Kevin Stevenson, Giselle lopez, Reb Kornahrens, Gao Zhang, Matthias Gromeier
Journal: Neuro-Oncology (2021)

Abstract Immunotherapy with polio:rhinovirus recombinant (PVSRIPO) has shown evidence of efficacy in a phase I clinical trial for recurrent GBM, resulting in durable radiographic responses and 21% long-term survival at 36 months. Ongoing research aims to enhance the clinical response rate by resolving the mechanisms of action and therapy resistance in vivo, thereby devising more effective therapies. Mouse glioma (CT2A) cells were intracranially implanted (day 0) in transgenic mice carrying poliovirus receptor CD155, and treated with intratumor PVSRIPO (5×105 pfu; day 6) to dissect early and late events following therapy. A blinded pathological review of 45 post-treatment tumors was performed. On day 8, a histological response, featured by tumor dissociation and shrinkage, with inflammation and microglia enrichment in the treated hemisphere, was common in PVSRIPO group (6/7) compared to controls (0/4). However, the response rate fell over time (7/12 on day 12; 1/7 on day 15) and the therapy was overcome by aggressive tumor regrowth. RNAseq was performed and Gene Set Enrichment Analysis of the tumor microenvironment revealed an acute type-I interferon (IFN)-related inflammation, correlating with the histological findings of profound proinflammatory engagement of microglia (Iba1+) widespread in the treated hemisphere. Microglia proliferation (Ki67+) was observed in the treated hemisphere, likely resulting from PVSRIPO infection, in CT2A and B16 intracranial models. This suggests an association of adaptive antitumor immunity—elicited by immediate intratumor type-I IFN-dominant inflammation—with tumor regression. Thus, buttressing type-I IFN directed antitumor CD8+T cell immunity, e.g. with blockade of the PD1:PD-L1 immune checkpoint, might contribute to tumor remission. Indeed, combination therapy with αPD-L1 antibody in the CT2A model showed longer median survival and higher long-term remission rate compared to monotherapy alone; CD8 T cell depletion can completely abrogate this efficacy with this therapy combination, confirming the role of anti-tumor immunity in this approach.
Abstract P456: High Glucose Suppresses Cardiomyocyte Progenitor Cell Regenerative Capacity And The Role Of Mir-195/ezh2 Crosstalk In Gestational Diabetes Mellitus
Authors: Pranav Mellacheruvu, Progyaparamita Saha, Rachana Mishra, Sudhish Sharma, Sunjay Kaushal
Journal: Circulation Research (2021)

Introduction: Gestational diabetes mellitus (GDM) is associated with a five-fold increase in congenital heart defects. It is critical to determine the biological effects of diabetes mellitus (DM) in vivo and high glucose in vitro on neonatal cardiomyocyte progenitor cells (nCPCs) to maximize their regenerative potential. In the present study we seek to investigate the roles of Mir-195 and its hypothesized target gene, enhancer of zeste homolog 2 (Ezh2), in GDM. Hypothesis: We predict that high glucose is associated with decreased cellular proliferation, viability and increased senescence through oxidative stress. We also hypothesize that expression of Mir-195 will be higher in DM-nCPCs and inhibit cell proliferation via Ezh2 silencing. Methods: We subjected nCPCs in vitro to increasing glucose concentrations; cellular proliferation, migration, reactive oxygen species generation, and apoptosis were assessed using cell counting kit-8, wound healing, dihydroethidium, and annexin assays respectively. Our in vivo experiments involved injecting four-week old female mice with streptozocin. After pairing diabetic mice with non-diabetic male mice, timed embryos at E14.5 were evaluated for viability, proliferation and characterization. mRNA expression levels of Mir-195 and Ezh2 protein levels were detected using RT-qPCR and western blot analysis respectively. Lipofectamine transfection, with siRNA inhibiting Mir-195, was performed on c-kit+ cardiac stem cells obtained from diabetic mothers. Results: We found that subjecting nCPCs in vitro to increased glucose concentration led to increased % cell death, decreased proliferation and expression of paracrine factors indicating poorer secretome quality from these cells. Our in vivo models showed that maternal diabetes impedes prenatal development as decreased expression of c-kit+/Lin- cells and ISL1+ cells and increased DHE positivity were seen in DM-nCPCs at E14.5. Expression of Mir-195 was higher in DM-nCPCs but Ezh2 mRNA and protein expression levels were significantly decreased. siRNA inhibition of Mir-195 revealed higher EZH2 expression in c-kit+ cells and concomitant increase in regenerative capacity. Conclusion: In conclusion, the viability of DM-nCPCs both in vivo and in vitro is decreased compared to NDM-nCPCs suggesting decreased postnatal regenerative capacity. Mir-195 is associated with increased apoptosis and decreased proliferation of nCPCs via abrogation of the protective effects of EZH2.
Alcaligenes faecalis metallo-β-lactamase in extensively drug-resistant Pseudomonas aeruginosa isolates
Authors: Yue Li, Yiwei Zhu, Wanqing Zhou, Zhongju Chen, Robert A. Moran, Huanhuan Ke, Yu Feng, Willem van Schaik, Han Shen, Jingshu Ji, Zhi Ruan, Xiaoting Hua, Yunsong Yu
Journal: Clinical Microbiology and Infection (2021)
Perspectives of General Surgery Program Directors on Paternity Leave During Surgical Training
Authors: Manuel Castillo-Angeles, Douglas S. Smink, Erika L. Rangel
Journal: JAMA Surgery (2021)

Although men are increasingly involved in childrearing, little is known about paternity leave in surgical residency. Conflict between professional and family duties contribute to burnout and decreased career satisfaction for surgeons of both sexes. With men more likely than women to have children during their clinical years of surgical training, understanding the issues surrounding paternity leave is imperative to ensuring the longevity of our workforce.
Abstract 13731: Randomized Trial of CMR Guidance for Cardiac Resynchronization Therapy: Findings in Nonischemic Cardiomyopathy From an Interim Analysis
Authors: Kenneth C Bilchick, Xu Gao, Mohamad Abdi, Pim Oomen, Derek Bivona, Srikar Tallavajhala, Sula Mazimba, Pamela K Mason, Rohit Malhotra, Christopher M Kramer, Frederick Epstein
Journal: Circulation (2021)

Introduction: Cardiac resynchronization therapy (CRT) response rates in unselected cohorts are suboptimal. Cardiac magnetic resonance (CMR) provides high-quality imaging of strain and scar, and post-CRT CMR offers reliable assessment of left ventricular (LV) reverse remodeling. Hypothesis: Cardiac magnetic resonance (CMR) guidance for CRT will increase CRT response rates, particularly in nonischemic cardiomyopathy (NICM). Methods: Patients were randomized 1:1 to standard CRT or CMR guidance for CRT using circumferential strain from Displacement Encoding with Stimulated Echoes (DENSE) and scar (late gadolinium enhancement [LGE]) by CMR. The primary endpoint is the percent change in LV end-systolic volume (LVESV) calculated from CMRs before CRT and 6 months after CRT. A pre-specified interim analysis by cardiomyopathy type was performed after completion of enrollment of 45 of the projected 90 patients needed for adequate power. Results: Of 45 patients enrolled (age 65.9 +/- 10.3 years, 29% female), two patients did not undergo a CRT procedure, and the LV lead could not be placed in one patient. Of the remaining 42 patients, 26/42 had NICM and 21/42 were randomized to CMR guidance. In a linear regression model for the primary endpoint adjusted for baseline QRS duration (p=0.04) and cardiomyopathy type (p=0.01), a favorable trend for the intervention on response was noted (p=0.06). Box plots demonstrate a significant difference in the primary endpoint among NICM patients (p=0.03) and a favorable trend for QRS shortening (0.07) in NICM patients (Figure). In all patients (including ICM patients), the overall p-value for the intervention relative to the primary endpoint was 0.08. Conclusion: An interim analysis in CRT patients with NICM demonstrated a favorable effect of CMR guidance on LV reverse remodeling after CRT, as assessed with post-CRT CMRs. Enrollment is continuing to evaluate the effect of the intervention on the entire cohort and other endpoints.
Abstract 11208: Usefulness of Remapping with a Multi-Electrode Catheter in Post-Myocardial Infarction Patients Undergoing Substrate-Based Catheter Ablation for Ventricular Tachycardia
Authors: Sanghamitra Mohanty, CHINTAN G TRIVEDI, Domenico G Della Rocca, William Zagrodzky, Jorge Romero, John Burkhardt, Rodney Horton, Mohamed Bassiouny, Luigi Di Biase, Amin Al-ahmad, Andrea Natale
Journal: Circulation (2021)

Introduction: Scar-related VT is common in post-MI patients. We evaluated the benefits of remapping with the multi-electrode catheter after acute success was achieved with the single-point ablation catheter in post-MI VT patients undergoing catheter ablation. Methods: Consecutive post-MI patients undergoing VT ablation were included. 3-D electroanatomic maps were obtained in sinus rhythm and/or during hemodynamically-stable VT with the multi-electrode PentaRay catheter. All underwent substrate mapping with standard scar settings (≤ 1.5 mV). Ablation was performed with the single-point ablation catheter and acute success was defined as non-inducibility of all VT at the end of the procedure. After acute success was achieved, some operators remapped with the PentaRay catheter to identify residual abnormal potentials. Results: A total of 121 patients (table) undergoing VT ablation were prospectively analyzed. Acute success was achieved in 117 (96.6%) cases. Remapping with the PentaRay catheter was performed in 102 (84.3%) cases. Few sites with delayed potentials were detected in 66/102 (61%) cases. These sites were targeted for further ablation. At 1 year follow-up, 76/102 (74.5%) of the remap population and 14/19 (73.6%) patients from the no-remap group remained arrhythmia-free off-AAD (p=NS). Conclusion: In our series, detection of few sites with late potentials by remapping with the multi-electrode catheter, after achieving acute success with single-point ablation did not improve the success rate at 1 year. Thus, the clinical benefits of remapping with multi-electrode catheters is not clear in VT patients undergoing substrate-based catheter ablation.
Next-Generation Sequencing to Assess the Impact of Low Dose Melphalan on Residual Disease before High-Dose Melphalan and Stem Cell Transplant in Multiple Myeloma
Authors: Ehsan Malek, Mary Hislop, Leland Metheny, Molly Gallogly, Marcos J.G. de Lima, Farhad Sanati, Hannah Elizabeth Schmikla, Brett Glotzbecker, James Driscoll
Journal: Blood (2021)