tbuckley/cabot-search huggingface dataset:
Abstract 10482: Renin-Angiotensin-Aldosterone System Inhibition is Associated with Reduced In-Hospital Mortality in Critically Ill Covid-19 Patients with Pre-Existing Hypertension
Authors: Kei Sato, Nicole White, Jonathon P Fanning, Nchafatso Obonyo, Vinesh Appadurai, Anna Ciullo, Meryta May, Elliott Worku, Leticia Helms, Shinichiro Ohshimo, Michael Yamashita, Jacky Y Suen, Gianluigi Li Bassi, John F Fraser, Rakesh C ARORA
Journal: Circulation (2021)

Background: The virus responsible for COVID-19 enters human cells by binding angiotensin-converting enzyme 2. The influence of renin-angiotensin-aldosterone system (RAAS) inhibitors, including angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs), remains uncertain. Aim: To examine the role of ACEi / ARB exposure on outcomes in COVID-19 patients with pre-existing hypertension (HTN) admitted to intensive care units (ICU). Methods: The COVID-19 Critical Care Consortium is a prospective, observational cohort study of patients requiring ICU admission for active COVID-19 spanning 354 participating sites in 54 countries. Patients &gt;18 years old with pre-existing HTN requiring antihypertensive therapy were analysed. Length of stay and in-hospital mortality to 90 days post ICU admission were analysed as time-to-event outcomes by multistate survival analysis, and the influence of ACEi / ARB use on the hazards of death and discharge by multi-state Cox proportional hazard modelling and sensitivity analysis. Results: From December 1, 2019 through December 30, 2020, 663 eligible patients were registered. Of these, 480 patients had received ACEi and / or ARB therapy (median age 65 years, 67% male) in the 2 weeks before ICU admission, while 183 had not (66 years, 61% male). Average lengths of ICU and general ward stays were longer in the ACEi / ARB than non-ACEi / ARB group (20.8 days and 6.5 days vs. 15.5 and 6.0 days, respectively). ACEi / ARB use was associated with a decreased hazard of death (HR, 0.69, 95% CI, 0.54 — 0.88) that persisted after adjusting for propensity scores (0.67, 0.53 — 0.86). Cumulative probabilities (unadjusted for baseline characteristics) for death and discharge post ICU admission are depicted in the figure for ACEi/ARB (red) and non-ACEi / ARB (blue) patients. Conclusions: In 663 critically ill COVID-19 patients with pre-existing HTN, RAAS inhibition pre-ICU admission was linked to reduced in-hospital mortality.
RADT-29. CHARACTERISTICS OF PATIENTS WITH MENINGIOMA WHO DEVELOPED SIGNIFICANT EDEMA REQUIRING STEROIDS AFTER GAMMA KNIFE RADIOSURGERY
Authors: Daniel Ma, Michael Schulder, Anuj Goenka
Journal: Neuro-Oncology (2021)

Abstract Gamma Knife stereotactic radiosurgery (GK-SRS) is an effective treatment of meningioma in the definitive and adjuvant setting. While SRS is generally safe, some patients develop significant post-treatment edema leading to seizures and neurological deficits requiring medical intervention. This study identifies risk factors associated with the development of significant edema after SRS. Between 2014 and 2020, 126 patients with 182 WHO grade I-III meningiomas were treated with GK-SRS at our institution. We retrospectively identified a subset of patients with clinically significant post-treatment edema on MRI and documented steroid use. Clinical and treatment parameters such as treatment intent, dose, tumor location, and tumor volume were collected. The median follow-up was 34 months. A total of 6 patients (4 females and 2 males, median age 60.5) developed symptomatic edema, including 4 of 71 patients treated in the definitive setting, 1 of 16 patient in the postoperative adjuvant setting, and 1 of 39 patient in the salvage setting. 2 patients had convexity meningioma, 3 patients had parasagittal meningioma, and 2 patients had skull base meningioma. The median onset of symptomatic edema after SRS was 5 months (range: 2-5months); the median duration of steroid use was 1.5 months (range: 0.5-3months). Mild headache and vision changes were reported in 2 patients. 4 patients developed seizures and required hospital admission. 1 patient died of cardiac arrest during admission. The remainder of patients were symptom-free following discontinuation of steroids and required no surgical intervention. The median tumor volume was 3.625cc (range: 2.74-12.15cc). All patients received single-fraction SRS with a median dose of 16Gy (range: 16-20Gy). 2 patients had received prior fractionated cranial radiation. A subset of meningioma patients treated with SRS can develop significant post-treatment edema requiring intervention. This small series showed that the risk of symptomatic edema with SRS is low, and most symptoms are transient.
CAR-T Therapy Followed By Unrelated Cord Blood Transplantation for the Treatment of Children and Young Adults Relapsed/Refractory B-Cell ALL: Superior Survival but Relatively High Post-Transplant Relapse
Authors: Guangyu Sun, Baolin Tang, Xiang Wan, Wen Yao, Kaidi Song, Liangquan Geng, Ping Qiang, Yue Wu, Lijun Zhu, Dongyao Wang, Yun Wu, Huilan Liu, Zimin Sun, Xiaoyu Zhu
Journal: Blood (2021)
Abstract 10928: Chlorogenic Acid Ameliorates Pressure Overload-Induced Cardiac Hypertrophy in Mouse Models
Authors: Atsushi Morio, shiho satomi, Hirotsugu Miyoshi, Yukari Toyota, Yasuo M Tsustumi
Journal: Circulation (2021)

Introduction: Cardiac hypertrophy leading to heart failure is one of the critical causes of morbidity and mortality. Although social interest in treatment and prevention of cardiovascular disease is high, sufficient outcome has not been obtained yet. Chlorogenic acid (CGA) is one of the most abundant phenolics in plants, and is called caffeic acid. Recently, the cardioprotective effects of CGA which ameliorate isoproterenol-induced hypertrophy in vitro research have been reported. However, it has not been elucidated whether CGA affects cardiac hypertrophy in vivo models with TAC. Hypothesis: We assessed the hypothesis that the administration of CGA has protective effect on TAC-induced cardiac hypertrophy. Methods: We used mouse models of cardiac hypertrophy induced by TAC for four weeks. Mice were randomly assigned to sham, TAC, and TAC+CGA groups. CGA was administered at dose of 40mg/kg intraperitoneally once a day for four weeks after the TAC operation. cardioprotective effect was investigated by echocardiography and histological analysises. In addition, immunoblot and metabolome analysises and biomedical assays were conducted in excised hearts. Statistical analysis was performed by one-way ANOVA. All data are expressed as mean ± SD. Statistical significance was defined as P &lt; 0.05. Results: We evaluated sham group (n=8), TAC group (n=7), TAC+CGA group (n=7) four weeks after TAC operation. TAC group showed an increase of heart weight, which was attenuated by CGA (120.3±9.3mg, 148.8±9.0mg, 126.6±6.2mg, p&lt;0.05). Consistently, echocardiography revealed that the change of myocardial diastolic wall thickness (0.79±0.1mm, 1.13±0.1mm, 0.93±0.1mm, p&lt;0.05). Histological analysis indicated that fibrosis induced by TAC was alleviated by CGA. According to immunoblot analysis, TAC group showed overexpression of TGF-β, IL-6, and TNF-α. In addition, the enhancements of glycolysis and TCA cycle were indicated in metabolome analysis. These changes were modulated by CGA administration. Conclusion: In conclusion, the present study revealed that CGA administration ameliorates pressure overload-induced cardiac hypertrophy in rodent model. As a key factor, expression of inflammatory cytokines and modulation of glucose metabolism were observed.
Romidepsin Plus CHOP Versus CHOP in Patients With Previously Untreated Peripheral T-Cell Lymphoma: Results of the Ro-CHOP Phase III Study (Conducted by LYSA)
Authors: Emmanuel Bachy, Vincent Camus, Catherine Thieblemont, David Sibon, René-Olivier Casasnovas, Loïc Ysebaert, Gandhi Damaj, Stéphanie Guidez, Gian Matteo Pica, Won Seog Kim, Soon Thye Lim, Marc André, Alejandro Martín García-Sancho, Maria Jesus Penarrubia, Philipp B. Staber, Judith Trotman, Andreas Hüttmann, Vittorio Stefoni, Alessandro Re, Philippe Gaulard, Marie-Helene Delfau-Larue, Laurence de Leval, Michel Meignan, Ju Li, Franck Morschhauser, Richard Delarue
Journal: Journal of Clinical Oncology (2021)

Romidepsin, a histone deacetylase inhibitor, has demonstrated activity in relapsed or refractory peripheral T-cell lymphoma (PTCL) as a single agent. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy is widely used as first-line treatment of PTCL; however, it has limited efficacy. Results from a phase Ib and II study showed the feasibility of combining romidepsin with CHOP (Ro-CHOP).This study is a randomized phase III study of Ro-CHOP versus CHOP in adult patients with previously untreated PTCL. All patients received CHOP in 3-week cycles for six cycles. Romidepsin, 12 mg/m2, was administered intravenously over a 4-hour period on days 1 and 8 of each 3-week cycle for six cycles. The primary end point was progression-free survival (PFS) according to International Working Group 1999 criteria.Between January 2013 and December 2017, 421 patients were enrolled (Ro-CHOP, n = 211; CHOP, n = 210). The median PFS for Ro-CHOP versus CHOP was 12.0 months (95% CI, 9.0 to 25.8) versus 10.2 months (95% CI, 7.4 to 13.2) with a hazard ratio of 0.81 (P = .096). In the Ro-CHOP versus CHOP arms, the median overall survival was 51.8 versus 42.9 months and the objective response rate was 63% versus 60% with complete response plus unconfirmed complete response rates of 41% versus 37% (P > .1 in all comparisons), respectively. Grade 3 or 4 treatment-emergent adverse events occurring in ≥ 30% of patients in the Ro-CHOP arm included thrombocytopenia (50% v 10% in the Ro-CHOP v CHOP arms, respectively), neutropenia (49% v 33%), anemia (47% v 17%), and leukopenia (32% v 20%).The addition of romidepsin to CHOP did not improve PFS, response rates, nor overall survival and increased the frequency for grade ≥ 3 treatment-emergent adverse events. Ro-CHOP does not represent a significant advance in the standard of care for patients with previously untreated PTCL.
IMMU-43. IMMUNE CONTEXTURE OF ISOCITRATE DEHYDROGENASE STRATIFIED HUMAN GLIOMAS REVEALED BY SINGLE-CELL TRANSCRIPTOMICS AND ACCESSIBLE CHROMATIN
Authors: Pravesh Gupta, Minghao Dang, Dapeng Hao Hao, Krishna Bojja, Tuan M Tran, Huma Shehwana, Carlos Kamiya-Matsuoka, Jianzhuo Li, Alessandra Audia, Cynthia Kassab, Martina Ott, Joy Gumin, Sanaalarab Al-enazy, Veerakumar Balasubramaniyan, John DeGroot, Frederick Lang, Antonio Iavarone, Nicholas E Navin, Amy B Heimberger, Linghua Wang, Krishna Bhat
Journal: Neuro-Oncology (2021)

Abstract The immune cell composition of isocitrate dehydrogenase wild type (IDH-wt) glioma patients significantly differs compared to IDH-mutant (IDH-mut) yet a detailed and unbiased understanding of their transcriptomic and epigenetic landscapes remains elusive. To this end, we performed single-cell RNA-sequencing (scRNA-seq) and single-cell Assay for Transposase-Accessible Chromatin using sequencing (sc-ATAC-seq) on ~100,000 tumor-associated immune cells from seventeen IDH mutation classified primary and recurrent human gliomas and non-glioma brains (NGBs). Our analyses revealed sixty-two transcriptionally distinct myeloid and lymphoid cell states within and across glioma subtypes and we noted microglial attrition with increasing disease severity concomitant with invading monocyte-derived cells (MDCs) and lymphocytes. Specifically, certain microglial and monocyte-derived subpopulations were associated with antigen presentation gene modules, akin to cross-presenting dendritic cells. As tissue macrophages exhibit multifaceted polarization in response to microenvironmental cues, we clarify the existence of microglia/macrophage functional states beyond M1/M2 paradigms exemplified by the presence of palmitic-, oleic- acid, and glucocorticoid responsive polarized states. We identified cytotoxic T cells with poly-functional cytolytic states mostly in recurrent IDH-wt gliomas. Furthermore, ligand-receptor interactome analyses showed a preponderance of antigen presentation/phagocytosis over the checkpoint axis in IDH-wt compared to IDH-mut gliomas. Additionally, our sc-ATAC-seq analyses revealed differences in regulatory networks in NGBs, IDH-mut, and IDH-wt glioma-associated immune cells. In particular, we noted reduced microglial usage of an iron recycling SPIC transcription factor and Interferon Regulatory Factors (IRFs); IRF1 and IRF2 in IDH-wt relative to IDH-mut and NGBs. Unique features such as amplification of 11-Zinc Finger Protein accessibility were restricted to MDCs. Finally, sc-ATAC-seq profiles of CD8+ exhausted T cells from IDH-wt showed strong enhancer accessibility on CTLA-4, Layilin, and TIM-3 but no enrichment on PD1 was seen. In summary, our study provides unprecedented granular detail of transcriptionally and epigenomically defined glioma-specific immune contexture that can be exploited for immunotherapy applications.
Abstract 13286: Ryanodine Receptor Inhibition Prevents Sudden Cardiac Death by Preserving Cardiac Repolarization Reserve in Stressed Arrhythmogenic Hearts
Authors: Pooja Joshi, BABUNAGESWARARAO KANURI, Jeffrey S Crocker, Sonia Y Byon, Deeptankar DeMazumder, Bjorn C Knollmann, Swati Dey
Journal: Circulation (2021)

Introduction: Current therapies for preventing sudden cardiac death (SCD) are limited. Prior studies have shown that cardiac stress-induced ryanodine receptor (RyR2) hyperactivity increases sarcoplasmic calcium leak, leading to ventricular tachyarrythmias (VT) and SCD. We hypothesized that inhibition of RyR2 with dantrolene sodium (DS) reduces Ca 2+ leak and mitigates VT and SCD risk in pressure-overloaded arrhythmogenic hearts. Methods: We used an established guinea pig model that uniquely recapitulates key features of human SCD, including a high incidence of spontaneous VT in freely ambulating animals, randomized to placebo vs. DS treatment. We performed in vivo (e.g., VT/SCD incidence, ECG heart rate and QT variability, echocardiographic measures of cardiac function) and ex vivo (e.g., pressure-volume, electrophysiology) studies. We performed intention to treat analysis for 4-week VT-free survival. Results: About half the animals receiving placebo had SCD by 4 weeks. By contrast, dantrolene treatment reduced SCD incidence by 50%. Compared to placebo, dantrolene treatment preserved chronotropic competency during transient β-adrenergic challenge, and improved heart rate variability (SDNN: 11±1.1 vs 17±2.8 ms, p&lt;0.05), reduced QT variability (0.52±0.13 vs 0.19±0.08 (log, ms, p&lt;0.05), and improved cardiac function (fractional shortening: 26±1.9 vs 45±4.5 %, p&lt;0.05). In perfused excised hearts, dantrolene treatment mitigated VT (induced by isoproterenol or burst pacing). Conclusion: Inhibition of RyR2 hyperactivity by dantrolene treatment prevents VT and SCD by increasing cardiac repolarization reserve. Dantrolene also improved overall cardiac electromechanical function in stressed arrhythmogenic hearts. Targeted inhibition of RyR2 hyperactivity may be an effective therapeutic strategy for preventing VT and SCD.
Abstract P359: Electroconductive Scaffolds To Mature Induced Pluripotent Stem Cell-derived Cardiomyocytes For Cardiac Tissue Engineering
Authors: Suh Hee T Cook, Jessica Gluck
Journal: Circulation Research (2021)

Heart disease is the leading cause of death worldwide. Cardiac tissue engineering (CTE) aims to repair and replace heart tissue, offering a solution. Induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) could revolutionize CTE due to their theoretical ability to supply limitless patient-specific CMs. However, iPSC-CMs are electrophysiologically immature compared to functional adult CMs, and therefore incapable of sustaining a heartbeat. Thus, a scaffold capable of electrophysiologically maturing iPSC-CMs is needed. My research increases the electroconductivity of electrospun (ES) scaffolds by incorporating carbon nanotubes (CNTs), which I hypothesize will mature iPSC-CMs seeded onto them due to their excellent electroconductive properties. Morphological, biocompatibility, and electrical analyses have been performed on ES polycaprolactone (PCL) and gelatin scaffolds with CNTs incorporated via a ‘sandwich’ and dual deposition method in order to increase electroconductivity. Morphological analyses were performed via ImageJ on SEM images. Fiber diameter and pore size quantification confirmed the ability to exert morphological control by modifying solution properties and ES parameters, which is crucial to achieve biomimicry of the cardiac extracellular matrix. Live/dead assays and immunofluorescence revealed the CNT scaffolds offer high biocompatibility for NIH 3T3 fibroblasts, which attach, proliferate, and migrate well. Electrical analysis performed with a multimeter and two-probe resistance measurement confirms that inclusion of CNTs significantly increases scaffold conductivity, moreso for dual deposition scaffolds than ‘sandwich’ ones, and moreso parallel to the CNT arrays than orthogonally. These results prove the feasibility of using such scaffolds as a method for in vitro electrophysiological iPSC-CM maturation. Next steps include optimization of scaffolds, analysis of iPSC-CM biocompatibility and response, and recapitulation and manipulation of the electrophysiology of cardiac tissue, including quantification of markers for cardiac function and maturity, and assessment of iPSC-CM + scaffold response to electrical pacing.
Abstract 12145: N <sup>6</sup> -methyladenosine and Adenosine-to-Inosine Modifications as Biomarkers for Ischemic Heart Disease
Authors: Vilbert T Sikorski, Antti E Vento, Esko M Kankuri, IHD-EPITRAN Consortium
Journal: Circulation (2021)

Introduction: Chemical modifications in RNA have unveiled as a layer of molecular regulation with notable effects to the flow of genetic information from DNA through RNA to proteins. These epitranscriptomic modifications guide and contribute to normal and pathological cellular responses. To date, more than 170 epitranscriptomic modifications have been identified. Most interest has been attracted by RNA adenosines, which are also the ones most often modified. Especially N-6-methylation or deamination resulting in N 6 -methyladenosine (m 6 A) and inosine (A-to-I), respectively, have been associated with cardiovascular diseases, including atherosclerosis and myocardial ischemia, the lead causes of mortality. Remarkably, m 6 A and A-to-I modifications have emerged as early drivers of atherosclerosis and promising druggable targets. Hypothesis: The I schemic H eart D isease Epitran scriptomics and Biomarkers (IHD-EPITRAN) study aims to determine those features of IHD that are mirrored in the circulating blood epitranscriptome. In particular, the study focuses on changes in m 6 A and A-to-I in blood RNA. Methods: Patients (initial subgoal n=200) are recruited from four cohorts: (1) patients with myocardial infarction undergoing angioplasty and revascularization; (2) patients with stable IHD undergoing coronary artery bypass surgery; (3) controls without coronary obstructions undergoing valve replacement surgery due to aortic stenosis and (4) controls with healthy coronaries verified by computed tomography. The profiles of m 6 A and A-to-I in blood RNA will be charted using a combinatory approach including mass spectrometry and DNA/RNA sequencing and referenced to other modified nucleosides and candidate biomarkers for IHD and heart failure. The study is registered (ClinicalTrials.gov NCT04533282), is seeking collaborators (www.ihd-epitran.com), and has recruited 40 patients at the time of abstract submission. Conclusion: Comparison of blood m 6 A and A-to-I profiles combined with meticulous clinical evaluations can be expected to unveil epitranscriptomic biomarker candidates and drug targets for IHD.
CTNI-42. PHASE I STUDY OF RUXOLITINIB WITH RADIATION AND TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GRADE III GLIOMAS AND GLIOBLASTOMA
Authors: Yasmeen Rauf, Rachel Hufsey, Kathy robinson, John Suh, Samuel Chao, Erin Murphy, Jennifer Yu, David Peereboom, Manmeet Ahluwalia
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Ruxolitinib is a novel, potent, selective inhibitor of JAK1 (Janus kinase 1) and JAK2 with modest to marked selectivity against TYK2 (tyrosine kinase 2) and JAK3. Ruxolitinib interferes with the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression. METHODS Newly diagnosed patients with MGMT not hypermethylated, Glioblastoma or grade III glioma were recruited to Arm 1. Every patient received ruxolitinib and 60 Gy radiation for 6 weeks (2Gy x 30). The dose of Ruxolitinib was administered given the 3 + 3 design. Level 1 or starting dose was 10 mg twice daily, level 2 was 15 mg twice daily, level 3 was 20 mg twice daily. Patients with MGMT hypermethylated glioblastoma or grade III glioma were eligible for Arm 2. Every patient received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks. RESULTS 45 patients had survival data, 25 patients were in Arm I and 20 arm in II. The median OS and PFS were 18.2 (95% CI: 3.6-NA) months for Arm 1 and were not reached for Arm 2. OS and PFS Rate at 1 year was 61% (95% CI: 43-85%) and 51% (35-76%) for Arm 1, and 95% (85-100%) for Arm 2 (p=0.01 and p= 0.002), respectively. 9 patients had partial response, 16 patients were stable, and 28 patients had progression. CONCLUSION Patients that received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks (Arm 2) had significantly better PFS and OS than those that received ruxolitinib + radiation x 60 Gy alone..
Comparative Effectiveness of Venetoclax Combinations Vs Other Therapies Among Patients with Newly Diagnosed Acute Myeloid Leukemia: Results from the AML Real World Evidence (ARC) Initiative
Authors: Jacqueline S. Garcia, Ofir Wolach, Pankit Vachhani, Joshua F. Zeidner, Chetasi Talati, Daniel A. Pollyea, Catherine Lai, Yakir Moshe, Sameem Abedin, David Lavie, Tsila Zuckerman, Marin Xavier, Sangmin Lee, Wesleigh Edwards, Evan Chen, Cat N. Bui, Anders Svensson, Rebecca Burne, Steve Kye, Jessica Maitland, Esprit Ma, Melissa Montez, Moshe Grunspan, Aaron D Goldberg
Journal: Blood (2021)